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Reproductive choices in women with poor ovarian reserve and recurrent miscarriages

Musters, A.M.

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Anna Musters

A.M

. Musters

Rep

roductive choices in w

omen w

ith poor ovarian reserve and

recurrent miscarriag

es


Anna M Musters


PhD Thesis, University of Amsterdam, The Netherlands

© 2011 Anna May Musters

The printing of this thesis was supported by: Stichting gynaecologische endocrinology

en kunstmatige voortplanting; Amsterdam

Cover Jasper Symons

Lay-out C.D. Bor, Medical Photography and Illustration, AMC, Amsterdam

Printed by Buijten & Schipperheijn, Amsterdam

ISBN 978-90-9026513-1


ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof.dr. D.C. van den Boom

ten overstaan van een door het college voor promoties ingestelde

commissie, in het openbaar te verdedigen in de Aula der Universiteit

op woensdag 11 januari 2012, te 15.00 uur

door

Anna May Musters

geboren te Bussum

Promotiecommisie

Promotores: Prof. dr. F van der Veen

Prof. dr. S Repping

Co-promotores: Dr. M Goddijn

Dr. MH Mochtar

Overige leden: Prof. dr. NS Macklon

Prof. dr. E Schadé

Prof. dr. CB Lambalk

Dr. W Verpoest

Prof. dr. MJ Heineman

Factulteit der Geneeskunde

Contents

Chapter 1 Introduction 9

Chapter 2 The effect of recombinant LH on embryo-quality: a randomized controlled trial in women with poor ovarian reserve.

Human Reproduction 2011; Epub: Nov 16

23

Chapter 3 Women’s perspectives on subcutaneous injections, costs en live birth rates during IVFHuman Reproduction 2011;26:873-7

39

Chapter 4 Pregnancy outcome after pre-implantation genetic screening (PGS) or natural conception in couples with unexplained recurrent miscarriage: a systematic review of the best available evidenceFertility Sterility 2011;95:2153-2157

59

Chapter 5 Reproductive outcome after preimplantation genetic diagnosis (PGD) in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic reviewHuman Reproduction Update 2011;17:467-75

75

Chapter 6 Supportive care for women with unexplained recurrent miscarriages: patients’ perspectives Human Reproduction 2011;26:873-7

93

Chapter 7 Supportive care for women with recurrent miscarriage: a survey to quantify women’s preferences Human Reproduction conditionally accepted August 2011

105

Chapter 8 General discussion 129

Chapter 9 Summary 145

Samenvatting 153

Dankwoord 161

List of other publications 167

About the author 171

1Introduction

Introduction

11

1Chapter

Worldwide, more and more women are having their first child later in life (Mathews

and Hamilton, 2009). This delayed child bearing has major repercussions, because - as

women get older- reproductive problems such as subfertility and miscarriages lay on

the lure (Wood, 1989, Brigham et al., 1999).

In the Netherlands, delayed childbearing is evident, as the mean age of women who

become mothers for the first time has increased over the last 17 years from 24.8 to 29.4

years. This makes Dutch women among the oldest mothers in the world (Mathews and

Hamilton, 2009). As older women have lower natural conception rates (te Velde and

Pearson, 2002), more women turn to assisted reproductive technology for conception.

As a consequence, the mean age of women undergoing IVF is increasing year after

year (de Mouzon et al., 2010).

IVF is not a guarantee for success in older women, considering that female age is

the most important predictive factor for chances of pregnancy after IVF (Hughes et

al., 1989; Lintsen et al. 2007; van Loendersloot et al., 2010; Broer et al., 2011). One

of the consequences of advanced female age in IVF is a poor response to ovarian

hyperstimulation which reflects a physiologic decline in ovarian reserve of primordial

follicles (ie poor ovarian reserve) (Pellicer et al., 1994; Beckers et al., 2002; de Boer

et al., 2002; Lawson et al., 2003). Also in young women a poor response to ovarian

hyperstimulation may occur, which then reflects a pathologic decline in number and

quality of primordial follicles (Jacobs et al., 1990; El-Toukhy et al., 2002).

The term poor response was introduced in 1983, as it became evident that ovarian

response after ovarian hyperstimulation in IVF differed between women (Garcia et al.,

1983). Poor response was defined as a peak estradiol level <300 pg/mL (1100pmol/L).

Since then poor ovarian response has become a collective term that is defined in

numerous ways based on different diagnostic tests or patient characteristics; i.e. ovarian

response to an IVF treatment cycle, female age, peak estradiol level, basal follicle

stimulating hormone (FSH) level, anti-müllerian hormone (AMH) level, basal antral follicle

count (AFC), number of mature follicles, number of oocytes at follicle aspiration, dose

of gonadotrophins used and/or embryo quality (Klinkert, thesis 2005). This definition is

probably so broad because the term poor response was coined before the introduction

of ovarian function tests such as AFC, FSH and AMH. Poor response actually describes

the clinical manifestation of a poor ovarian reserve. This is supported by the fact that

ovarian function tests are good predictors for ovarian response after IVF (van Rooij et

al., 2002; Broekmans et al., 2006; Kwee et al., 2007, Broer et al., 2009).

Poor ovarian reserve is a common clinical problem, with 26% of IVF cycles resulting

in poor response (Pellicer et al., 1987;Keay et al., 1997). Women with poor ovarian

reserve that do proceed to follicle aspiration produce low numbers of oocytes and

embryos and have low pregnancy rates and high miscarriage rates (Jenkins et al., 1991;

Chapter 1

12

Ulug et al., 2003; Haadsma et al., 2010). As this is an increasing problem, it is evident

that more research should be conducted on this subject.

When women finally conceive, either through IVF or through natural conception, the

next obstacle is the risk of a miscarriage. Miscarriages are a frequent complication

of pregnancy with one out of every nine pregnancies ending in a spontaneous first

trimester miscarriage (Nybo Andersen et al., 2000). Three percent of all women will

experience 2 or more miscarriages before 20 weeks pregnancy (Regan and Rai, 2000).

Current diagnostic procedures for recurrent miscarriage (RM) identify aetiological

factors as structural chromosome abnormalities, antiphospholipid syndrome,

endocrine disorders and uterine abnormalities in approximately 50% of these couples

(Christiansen et al., 2005, Jauniaux et al., 2006). The other 50% are diagnosed as

couples with unexplained RM (Rai and Regan, 2006). Even though a cause for RM can

be found in 50% of the women, only women with RM resulting from antiphospholipid

syndrome have a potentially effective treatment namely the use of anti-coagulants (Rai

et al., 1997; Empson et al., 2011).

RM is a distressing condition for the affected couple and a frustrating problem for the

clinician, because in most cases there is no effective therapy. Even so, clinicians often

propose non-evidence based diagnosis and treatment and find it difficult to adhere to

the guidelines that state that treatment for these couples should not be commenced

upon (Franssen et al., 2007). One of the most frequently mentioned barriers for good

adherence to the Dutch guideline on RM was that doctors find it difficult to refuse

demands of insistent patients (van den Boogaard et al., 2011). Thus, women with

unexplained RM are eager and willing to try any form of treatment and clinicians are

challenged to withhold from non evidence based treatment.

Supportive care is frequently offered to women with unexplained RM, reporting live

birth rates up to 85% (Javert, 1954; Stray-Pedersen and Stray-Pedersen, 1984; Liddell

et al., 1991; Clifford et al., 1997, Brigham et al., 1999). Current guidelines from the

European Society of Human Reproduction and Embryology (ESHRE) and the Royal

College of Obstetricians and Gynaecologists (RCOG) recommend supportive care

during the next pregnancy for women with unexplained RM (RCOG, 2003; Jauniaux et

al., 2006), suggesting it has a beneficial effect.

Nevertheless, there are several issues with implementing this recommendation. First,

supportive care for women with unexplained RM is an ill-defined concept (van den

Boogaard et al., 2011). Second, no uniform treatment protocol can be distilled from

studies on supportive care, because the care offered in these studies varied widely

from early ultra sound investigation during the next pregnancy, to relaxation tapes and

admittance to the hospital ward on the same gestational age as previous miscarriages.

Third, what the women themselves prefer as supportive care in their next pregnancy

has never been investigated.

Introduction

13

1Chapter

Background of the research described in this thesis

In 2007, when we started the studies that led to this thesis, the addition of recombinant

luteinizing hormone (rLH) to ovarian stimulation protocols in IVF was becoming more

and more a topic of research in women with poor ovarian reserve. There was evidence

that the addition of an injection rLH to recombinant follicle stimulating hormone (rFSH)

increased ongoing pregnancy rates in women with poor ovarian reserve. Studies

indicated that the addition of rLH resulted in higher implantation rates in women aged

35 years or older (Marrs et al., 2004; Humaidan et al., 2004).

A meta-analysis of randomized clinical trials comparing the addition of rLH to rFSH with

rFSH alone had just been completed and confirmed the beneficial effect on pregnancy

rates in these women. The pooled estimate of ongoing pregnancy per woman was a

significant 10% higher in women co-treated with rLH compared to the women treated

with rFSH alone (OR 1.85, 95% CI 1.10-3.11) (Mochtar et al., 2007). However, the exact

mechanism through which rLH increases ongoing pregnancy rates in this population

remained unclear.

We set out to explore the possible beneficial effect of rLH on embryo quality in women

with a poor ovarian reserve defined as all women aged 35 to 41 years old and women

younger than 35 years old with a FSH level >12 IU/ml and an AFC ≤ 5.

What women prefer when it comes to injections during IVF had not been investigated

at that time and the addition of rLH means an extra daily subcutaneous injection

in an already invasive and burdensome treatment (Eugster and Vingerhoets, 1999).

There is data that suggests that women prefer an IVF treatment with less injections

rather than more, but the studies generating this data, were designed to investigate

the reasons why women drop out of treatment and not how women receiving IVF

perceive treatment aspects (Fauser et al., 1999; Olivius et al., 2004; Heijnen et al.,

2007; Verberg et al., 2008; Verberg et al., 2009; Domar et al., 2010). To elucidate how

women precieve injections, we investigated patients’ perspectives on an extra daily

injection during an IVF treatment.

An intervention approaching the issue of low pregnancy rates in women of increased

age from a completely different angle is pre-implantation genetic screening (PGS). In

PGS embryos are selected for transfer based on the ploidy status of a single blastomere

biopsied from that embryo (Gianaroli et al., 1997; Munné et al., 1999). However, in

2007, a trial revealed that in women of advanced maternal age PGS in fact decreased

pregnancy rates (Mastenbroek et al., 2007). The results showed an ongoing pregnancy

rate of 25% in the PGS group compared to 37% in the control group (rate ratio: 0.69:

95% CI: 0.51-0.93).

Chapter 1

14

Besides women of advanced age, couples with unexplained RM have also been

suggested as candidates for PGS. The rationale behind the use of PGS in case of

unexplained RM was that aneuploidy of the embryo may be the cause of the RM

(Gianaroli et al., 2002; Werlin et al., 2003; Rubio et al., 2005; Munné et al., 2005,

Mantzouratou et al., 2007). Similarly, Pre-implantation Genetic Diagnosis (PGD) was

proposed to improve live birth rates and decrease miscarriage rates in couples with

RM who carry a structural chromosome abnormality (Munné et al., 2000; Otani et al.,

2006). The rationale behind the use of PGD for this purpose was that relatively more live

births are achieved and that the number of miscarriages can be reduced by eliminating

the transfer of unbalanced embryos. Since PGS and PGD are invasive and require IVF,

the claim that PGS and PGD increases live birth rates should be substantiated beyond

any reasonable doubt before this technique is introduced into daily clinical practice.

Apart from these medical-technical options, supportive care for women with RM is

recommended by guidelines, but what these women actually perceive and prefer

as supportive care has never been investigated (RCOG, 2003; Jauniaux et al., 2006).

Therefore an important goal of our research was to qualify and quantify supportive

care options for women with RM.

Introduction

15

1Chapter

Outline of the thesis

Chapter 2 evaluates the effect of adding rLH to rFSH for controlled ovarian

hyperstimulation in IVF on embryo quality in women with poor ovarian reserve defined

as women aged 35 to 41 years and women younger than 35 years with a FSH level

>12 IU/ml and an AFC ≤ 5. By means of a randomized controlled trial we included 224

women awaiting their first IVF/ICSI cycle between August 2008 and April 2010. The

primary outcome was the rate of top-quality embryos, defined as the percentage of

embryos per woman that develop into a top-quality embryo on the day of transfer,

i.e. three days after follicle aspiration. Secondary outcomes were the number of

stimulation days until hCG administration, the number of follicles ≥ 17 mm on the

day of hCG administration, the number of oocytes, the fertilization rate, the number of

embryos, the number of women with ≥1 top-quality embryo, the biochemical, clinical

and ongoing pregnancy rate and the miscarriage rate.

Chapter 3 investigates women’s perspectives on an additional injection of rLH with

respect to live birth rates and ‘out of pocket’ costs in a discrete choice experiment.

Two-hundred-twenty-three of 234 women eligible for IVF returned the questionnaire

(response rate 95%) and finally 206 questionnaires were analysed. Women were asked

to choose between IVF treatments that differed in live birth rate after one IVF cycle,

the amount of self administered subcutaneous injections and ‘out of pocket’ costs or

reimbursement. A model was developed to estimate the relative weights that women

place on these attributes and to distinguish which patient characteristics (age, parity,

duration of subfertility, income, previous treatment with subcutaneous injections and

diagnosis of the subfertility) influence decision making.

Chapter 4 reviews systematically the literature on the effect of PGS on the live birth

rate and miscarriage rate in couples with unexplained RM. Results of four studies

reporting on the reproductive outcome of couples with unexplained RM receiving PGS

and four studies reporting on the reproductive outcome of these couples after natural

conception are presented.

Chapter 5 reviews systematically the literature on the effect of PGD on the live birth rate

and miscarriage rate in couples with RM carrying a structural chromosome abnormality.

Results of 21 studies reporting on reproductive outcomes of carrier couples with RM

receiving PGD and four studies reporting on the reproductive outcomes of couples

after natural conception are presented.

Chapter 1

16

Chapter 6 provides qualitative data on what women with unexplained RM prefer

as supportive care during their next pregnancy. Fifteen explorative, semi-structured,

in-depth interviews were performed among women with unexplained RM.

Chapter 7 identifies the main preferred and non-preferred supportive care options

for women with recurrent miscarriages in their next pregnancy. By means of a

questionnaire returned by 174 of 266 women (response rate 65%) preferences were

elucidated and a multivariable model was estimated including patient characteristics

(ethnicity, education level, parity, pregnancy during questionnaire and timeline of

previous miscarriage) to further quantify the preferred and non-preferred supportive

care options.

Chapter 8 provides a general discussion of the results presented in this thesis and

outlines their clinical implications. Finally suggestions for future research for women

with poor ovarian reserve and in couples with unexplained RM are given.

Chapter 9 summarizes the data presented in this thesis.

Introduction

17

1Chapter

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Introduction

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1Chapter

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Introduction

21

1Chapter

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Wood JW. Fecundity and natural fertility in humans. Oxf Rev Reprod Biol, 1989;11:61-109.

2The effect of recombinant LH on embryo-quality: a randomized controlled trial in women with poor ovarian reserve

Anna M. MustersMadelon van WelySebastiaan MastenbroekEugenie M. KaaijkSjoerd ReppingFulco van der VeenMonique H. Mochtar

Human Reproduction 2011; Epub: Nov 16

Chapter 2

24

Abstract

BACKGROUND Poor ovarian response is a common clinical problem, affecting up to

26% of IVF cycles. For these women, addition of recombinant luteinizing hormone (rLH)

to ovarian hyperstimulation with recombinant FSH has a beneficial effect on ongoing

pregnancy rates, but its effect on the yield of top-quality embryos is unknown.

METHODS We conducted a randomized controlled trial in women expected to respond

poorly under ovarian hyperstimulation during their first IVF cycle (all women aged

35–41 and women with FSH > 12 IU/ml and antral follicle count (AFC) ≤ 5). Women

were randomly allocated to rFSH and rLH (2:1 ratio) or rFSH alone (control group) after

down-regulation with a GnRH agonist. The primary outcome was the proportion of

top-quality embryos per woman on the day of transfer. Secondary outcomes were

the number of stimulation days, the number of follicles ≥17 mm, the number of

oocytes, the fertilization rate, the number of embryos, the number of women with

≥1 top-quality embryo, the biochemical, clinical and ongoing pregnancy rates and the

miscarriage rate.

RESULTS There were 116 women allocated to the rLH group and 128 allocated to the

control group. The proportion of top-quality embryos per woman was 17% in the rLH

group and 11% in the control group (mean difference 0.06; 95% confidence interval

(CI) -0.01–0.14). In the rLH and control groups respectively, 47 (41%) and 41 (32%)

women had at least one top-quality embryo on the day of transfer (relative risk: 1.3,

95% CI 0.91–1.77). The ongoing pregnancy rate was 13 versus 12% (relative risk: 1.1;

95% CI 0.57–2.16) for the rLH group compared with the control group.

CONCLUSIONS This study found no significant difference in embryo quality after the

addition of rLH to rFSH for ovarian stimulation in women with poor ovarian reserve.

The effect of recombinant LH on embryo-quality

25

2Chapter

Introduction

After the introduction of ovarian hyperstimulation in IVF, it soon became evident

that ovarian response differs between women. Already in 1983, the first study that

described women with poor response was published (Garcia et al., 1983). Poor

response is often related to women with advanced age, in whom the low response to

gonadotrophins reflects a physiologic decline in ovarian reserve of primordial follicles

(Pellicer et al., 1994; Beckers et al., 2002; De Boer et al., 2002; Lawson et al., 2003).

Hence, poor ovarian response is the clinical manifestation of a poor ovarian reserve. A

pathologic decline in number and quality of primordial follicles may also occur in young

women (Jacobs et al., 1990; El-Toukhy et al., 2002). Poor reserve is a common clinical

problem, with up to 26% of IVF cycles resulting in poor response (Pellicer et al., 1987;

Keay et al., 1997). In the future this percentage is likely to increase as women continue

to postpone childbearing (Mathews and Hamilton, 2009).

To date, the diagnosis of poor ovarian reserve is based upon the ovarian response in an

IVF treatment cycle and/or patient characteristics such as age, basal FSH, anti-Müllerian

hormone (AMH) and/or basal antral follicle count (AFC) (Toner et al., 1991; Scott and

Hofmann, 1995; Frattarelli et al., 2000, 2004; Tarlatzis et al., 2003; Hellberg et al.,

2004; Muttukrishna et al., 2004; Sallam et al., 2005). In women with poor ovarian

reserve, the number of mature follicles that develop during stimulation is frequently

considered to be insufficient for a successful treatment, leading to cancellation of the

cycle. Women with poor ovarian reserve who do proceed to ovum pick up produce low

numbers of oocytes and embryos and have low pregnancy rates (Jenkins et al., 1991;

Ulug et al., 2003).

The effect of the addition of recombinant lutenizing hormone (rLH) to IVF stimulation

has been debated in the past decade, but increasing evidence on the beneficial effect

of rLH in women with poor ovarian reserve has been published. A Cochrane review

suggested that the addition of rLH to controlled ovarian hyperstimulation (COH) with

rFSH increases ongoing pregnancy rates in women with poor ovarian reserve [odd ratio

(OR) 1.85, 95% confidence interval (CI) 1.10–3.11] (Mochtar et al., 2007). A recent large

randomized trial in women with poor ovarian reserve reported ongoing pregnancy

rates of 34% for women treated with rFSH and rLH compared with 25% for women

treated with rFSH (OR 1.49, 95% CI 0.93–2.38) (Bosch et al., 2011).

How exactly rLH increases ongoing pregnancy rates in this population remains unclear.

An explanation could be the effect of rLH on oocyte and embryo quality. LH is known

to be important in oocyte growth and maturation (Filicori et al., 1999, 2002; Sullivan

et al., 1999; Filicori and Cognigni, 2003). Exogenous LH has been suggested to have an

intrinsic effect on embryo competence (Tesarik and Mendoza, 2002).

Chapter 2

26

To obtain better data on the relation between rLH and embryo quality, we evaluated the

yield of top-quality embryos in women with poor ovarian reserve after IVF stimulation

with rLH and rFSH compared with rFSH alone.

Materials and Methods

Study populationBetween August 2008 and April 2010, all women 35–41 years old or women younger

than 35 years old with an FSH level > 12 IU/ml accompanied with an AFC ≤ 5 and who

were scheduled for their first IVF or ICSI in the Academic Medical Center or the Onze Lieve

Vrouwe Gasthuis in Amsterdam, were asked to participate in a randomized controlled

trial. Women were excluded from the trial if they had any endocrinopathological

disease: Cushing’s syndrome, adrenal hyperplasia, hyperprolactinaemia, acromegaly,

hypothalamic amenorrhea, hypothyroidism and diabetes mellitus type I or polycystic

ovary syndrome.

After providing written informed consent, the women were randomly assigned to

undergo one cycle of IVF or ICSI, with COH with rFSH and rLH (rLH group) or with

rFSH alone (control group). Randomization took place during cycle scheduling (base

line visit); this was usually 3 months before the treatment cycle started. During this

consultation, an appointment was made for a transvaginal sonography for a basal AFC

and blood sampling for AMH and basal FSH. Women who had an AFC and/or FSH

sampling before randomization were asked to repeat these tests to make sure the

values were from 1 to 3 months before the start of stimulation. Blood sampling (basal

FSH and AMH) was only performed in women receiving treatment in the Academic

Medical Centre (n= 196).

Central web-based randomization was performed prior to the start of ovarian

stimulation using a computer program minimization procedure with stratification

according to study centre. The study was not blinded for patients and doctors, but the

embryologists and IVF technicians who evaluated the primary outcome of the study,

i.e. embryo quality, were unaware of treatment allocation.

The study protocol was approved by the institutional review boards of the two

participating hospitals and by the Central Committee on Research Involving Human

Subjects in the Netherlands. The study was registered with EudraCT (EudraCT number

2007-007487-22) and the Dutch National Trial Register (Trial ID: NTR1457).

Treatment protocolWomen underwent COH after down-regulation with the GnRH agonist triptorelin

(Decapeptyl®) in a long protocol with a midluteal start. COH was started on cycle


27

2Chapter

day 5 with rFSH (GONAL-f®, MerckSerono) or rFSH with addition of rLH (Luveris®,

MerckSerono) depending on the allocation.

Depending on the AFC, women started with different doses of gonadotrophins.

If the AFC was three or lower on cycle day 5, women started with a maximal stimulation

of 450 IU rFSH and 225 IU rLH or 450 IU rFSH alone. If the AFC was between 4 and

14 follicles on cycle day 5, women started with 300 IU rFSH and 150 IU rLH or 300 IU

rFSH alone. If the AFC was 15 or higher on cycle day 5, women started with 150 IU

rFSH and 75 IU rLH or 150 IU rFSH alone.

After 7 days of stimulation, the dosage was kept the same or was adjusted according

to ovarian response to a maximum of 450 IU rFSH and 225 IU rLH or 450 IU rFSH

alone, always keeping the ratio of rFSH to rLH at 2:1.

Follicular maturation was induced by 6500 IU hCG hormone (Ovitrelle®, MerckSerono)

when at least three follicles ≥17 mm had developed. Cumulus–oocyte complexes were

recovered by transvaginal ultrasound-guided follicle aspiration 36 h thereafter.

If there were only one or two follicles in the first cycle and the maximum rFSH dose of

450 IU/l had not been administered, the cycle was converted to IUI. These IUI cycles

were analysed separately. If these women did not conceive after IUI another IVF or

ICSI cycle was started, but this time with the maximum rFSH dosage of 450 IU/l and

if appropriate 225 IU/l rLH. Follicle aspiration was performed when at least one follicle

of 17 mm or more was seen on transvaginal sonography and this cycle was included in

the final analysis.

When women started their cycle with the maximum doses, rFSH 450 IU/l with/without

225 IU/l rLH, and there was no development of follicles, the cycle was cancelled. These

women did not proceed to another IVF or ICSI cycle. These cancelled cycles were

included in the final analysis.

Embryo transfer policy, 3 days after follicle aspiration was according to a standard

protocol; women younger than 35 years with a top-quality embryo received one

embryo; women younger than 35 years, but without a top-quality embryo received

two embryos; women between 35 and 39 years received two embryos and women

older than 39 years received three embryos. When less than the required number of

embryos was obtained, all available embryos were transferred into the uterine cavity.

Morphological scoringEmbryos were morphologically assessed daily from fertilization (pronuclear morphology)

until time of transfer (Puissant et al., 1987; Veeck, 1990; Steer et al., 1992). Embryos

were assessed using an Olympus IX71 inverted microscope equipped with Relief

Contrast optics at a magnification of ×320. On Day 3, one or more embryos were

selected for transfer. Top-quality embryos were defined as embryos with a cumulative

embryo score of ≥24 on Day 3 after follicle aspiration. In the cumulative embryo score,

Chapter 2

28

the number of cells is amplified with the morphological score that ranges from scores

1 (excellent, 4 points) to 4 (poor, 1 point); for example: a score 2, good quality 8-cell—

embryo, received 8 × 3 = 24 points. Morulae were considered top-quality if <20%

fragments were present and at least 50% of the cells were part of the compacting

process. Embryo assessment was performed blinded for the allocation of the woman.

Study end-pointsThe primary outcome measure was the proportion of top-quality embryos per woman

on the day of transfer, i.e. 3 days after follicle aspiration. The proportion of top-quality

embryos per woman was calculated by dividing the number of top-quality embryos

over the total number of embryos within that cycle per woman (e.g. if one of the five

embryos developed into a top embryo, the embryo rate was 0.2). Secondary outcomes

were the number of stimulation days until hCG administration, the number of follicles

≥17 mm on the day of hCG administration, the number of oocytes, the fertilization

rate, the number of women with ≥1 top-quality embryos, the biochemical pregnancy

rate (defined as an increase in serum HCG ≥ 3, 14 days after follicle aspiration), the

clinical pregnancy rate (defined as positive heartbeat on transvaginal sonography in

week 8 of pregnancy), the miscarriage rate and the ongoing pregnancy rate (defined

as a positive heartbeat at ≥12 weeks gestational age).

Power calculationBased on a historical analysis of the data from our centre, ∼20% of the total numbers

of embryos are expected to develop into a top-quality embryo after COH with rFSH

alone. A mean number of eight oocytes, five embryos and one top-quality embryo are

available per woman with advanced age in our population (Mastenbroek et al., 2007).

We expected the same proportion of top-quality embryos in women 35 years old or

with an FSH level > 12 IU/ml accompanied by an AFC ≤ 5.

To prove that the addition of rLH yields an increase of 10% in the proportion of top-

quality embryos compared with a standard proportion of 20%, with a power of 80%

and an alpha of 5% and a correlation coefficient (rho) between embryos and women

of 0.2, we required 520 embryos per treatment arm. Assuming a mean number of

five embryos are available per woman this means that 104 women would have to be

included per arm. To be able to account for 15% drop-out during the trial, we aimed at

including a total of 242 women.

Statistical analysis

Data were analysed using the SPSS 18.0 software. All analyses were performed on an

intention-to-treat basis. The effectiveness of rFSH and rLH compared with rFSH alone

was expressed as mean differences with corresponding 95% CIs for continuous data

such as the proportion of top-quality embryos per woman, fertilization rate, number of


29

2Chapter

oocytes and number of embryos. Formal comparisons were done using independent

t-tests.

Differences in dichotomous data such as pregnancy outcomes were expressed as rate

ratios with 95% CIs. We used chi-square statistics to test for significance.

We expected the primary outcome to have a skewed distribution as many women will

not produce a top-quality embryo. We therefore used non-parametric bootstrapping,

to calculate mean and CIs for the proportion of top-quality embryos per woman.

To identify if there was an association between AFC, age and BMI and the proportion of

top-quality embryos per woman corrected for treatment allocation, a linear regression

with bias-corrected and accelerated bootstrapping was calculated (Efron, 1987) (Stata

SE 11.1).These calculations were performed by an epidemiologist (M.v.W.).

Results

There were 270 women who met the inclusion criteria and were eligible for inclusion,

26 women declined participation. The remaining 244 women were randomized; 116

women were allocated to rLH and rFSH (rLH group) and 128 women were allocated

to rFSH alone (control group). In total, six women (three in each group) were younger

than 35 years and had a basal FSH > 12 IU/ml accompanied by an AFC ≤ 5. All other

women were between 35 and 41 years of age.

There were 107 women in the rLH group and 117 in the control group who actually

underwent the assigned intervention (Fig. 1). Completion of treatment was reached in

January 2011. The baseline characteristics were similar in the two study groups (Table I).

There were 10 cycles in the rLH group and 15 cycles in the control group cancelled

because of low response. Of these, three women in the rLH group and seven women

in the control group had no response at all, despite maximal ovarian stimulation (450

IU rFSH with/without 225 IU rLH).

There were seven women in the rLH group and eight women in the control group

who had their first IVF attempt converted to IUI. No pregnancies resulted from these

IUI cycles. These women continued with the maximal stimulation in the subsequent

stimulation cycle. The seven women in the rLH group all proceeded to a follicle

aspiration. Of the eight women in the control group, six women went on for follicle

aspiration and two women had no response.

In total 109 women in each group underwent a follicle aspiration. In the rLH group, 4

women had a follicle aspiration in which no oocytes were found and 14 women had

a cycle where no oocytes were fertilized. In the control group, three women had a

follicle aspiration in which no oocytes were found, 17 women had a cycle where no

Chapter 2

30

* no pregnancies after IUI, **1 woman still had cryo-embryos at end of follow-up, ̂ no pregnancies after IUI, ^^2 women still had cryo-embryos at end of follow-up

Figure 1. CONSORT Flow Diagram Assignment, Treatment, and Analysis of women

244 women were randomly assigned to treatment

47 women with 1 ≥ top embryo(s) (n= 95 top embryos)

41 women with 1 ≥ top embryo(s) (n= 87 top embryos)

4 never received IVF/ICSI - 3 conceived spontaneously - 1 second opinion 5 did not use LH - 3 women rFSH only - 1 woman used HMG - 1 found 3 injections too many

10 first cycles were cancelled* - 3 no further cycles: no response after

max.stim first cycle - 7 went on with next cycle, after failed

IUI

10 never received IVF/ICSI - 3 conceived spontaneously - 4 second opinion elsewhere - 3 had an illness (DMII, DVT(2)) 1 Did not use rFSH (received HMG)

15 first cycles were cancelled^ - 7 no further cycles: no response after

max.stim first cycle - 8 went on with next cycle, after failed

IUI (2 cycles were cancelled: no response after max. stim)

3 OPU cycles no oocytes found 17 cycles with a TFF 2 vitrified oocytes

87 women with 1 ≥ embryo(s)^ ̂(n= 458 embryos)

4 OPU cycles no oocytes found 14 cycles with a TFF

270 women were eligible 26 declined to participate: - wanted standard IVF (8) - did not understand the trial (7) - found 3 injection s too many (5) - did not want extra hormones (4) - no reason (2)

116 + rLH

112 women started stimulation 109 women with a follicle

aspiration cycle 91 women with 1 ≥ embryo(s)** (n= 445 embryos)

128 control group

118 women started stimulation

109 women with a follicle

aspiration cycle

Table I. Characteristics of the women

Women assigned rLH + rFSH* (n=116)

Controls(n=128)

Age years (mean ± sd) 38.3 ± 5.7 38.6 ± 2.4

BMI kg/m2 (mean ± sd) 24.0 ± 4.2 25.1 ± 4.2

Primary infertile n (%) 61 (53) 58 (45)

Duration of infertility years (mean ± sd) 3.6 ± 6.2 3.7 ± 3.0

AFC (mean ± sd) 9.2 ± 5.7 9.1 ± 4.9

FSH^ (mean ± sd) 10,4 ± 11.9 9.4 ± 6.3

AMH^ (mean ± sd) 1,7 ± 1,4 1.5 ± 1.2

Cause of infertility n (%)

Unexplained 51 (44) 63 (49)

Poor semen quality 44 (38) 43 (34)

Tubal 10 (9) 14 (11)

Imminent ovarian failure 7 (6) 8 (6)

Ovarian failure* 3 (3) 0 (0)

cervix 1 (1) 0 (0)

* Donated oocytes from women of advanced maternal age were used in these cases.^ basal FSH and AMH were only performed in women receiving treatment in the Academic Medical Centre (n=196).


31

2Chapter

oocytes were fertilized and the oocytes of 2 women were vitrified because no viable

spermatozoa were found on the day of follicle aspiration. Therefore, 91 women in the

rLH group and 87 women in the control group had embryos available for transfer.

OutcomesThe primary outcome, the proportion of top-quality embryos per woman, was 17%

in the rLH group and 11% in the control group (mean difference 0.06; 95% CI -0.01–

0.14). In the rLH group, 91 women had one or more embryo(s) and of these 47 (41%)

women had one or more top-quality embryo(s), while in the control group, 87 women

had one of more embryo(s) and of these 41 (32%) women had one or more top-quality

embryo(s) on the day of transfer (relative risk: 1.3; 95% CI 0.91–1.77).

The ongoing pregnancy rate per woman was 13 versus 12% (relative risk: 1.1; 95% CI

0.57–2.16) for the rLH group compared with the control group. All other secondary

outcomes are listed in Table II.

We found no association between AFC, age or BMI and the proportion of top-quality

embryos per woman (AFC coefficient = 0.004, age coefficient = −0.002 and BMI

coefficient = −0.006).

Discussion

We found no evidence of a statistically significant difference in embryo quality or

any other outcome in women with poor ovarian reserve after addition of rLH to rFSH

compared with FSH alone for COH.

Our randomized trial aimed at finding a biological explanation for the apparent

beneficial effect of rLH in women with poor ovarian reserve. Although there was a

higher proportion of top-quality embryos per woman and more women had at least

one top-quality embryo in the rLH group, the difference was not statistically significant.

One other study has investigated the number of embryos after the addition of rLH in

women with poor ovarian reserve and reported no difference in number of embryos

between the rLH group and control group (Barrenetxea et al., 2008). This study

unfortunately did not report on embryo quality.

A strength of our study is that rLH was given throughout the stimulation phase, in

analogy to the trials that compared rFSH versus highly purified hMG, a gonadotrophin

that also has LH activity and which has been demonstrated to result in a 3% higher

ongoing pregnancy rate compared with rFSH alone (Coomarasamy et al., 2008; van

Wely et al., 2011). Only the most recently published RCT used the same approach,

by giving 225 rFSH and 75 IU/day rLH from the beginning of the stimulation to the

women assigned to rLH (Bosch et al., 2011). Other trials studying the addition of rLH

Chapter 2

32

to rFSH administered rLH before rFSH stimulation as a pretreatment (Durnerin et al.,

2008; Kovacs et al., 2010) or as a late follicular phase treatment (Ferraretti et al., 2004;

Marrs et al., 2004; De Placido et al., 2005; Fabregues et al., 2006; Barrenetxea et

al., 2008; Nyboe Andersen et al., 2008; Gutman et al., 2009; Matorras et al., 2009;

Pezzuto et al., 2009).

Also, the dose of rLH should be considered. In our study, we used a two rFSH: one

rLH ratio throughout the stimulation, to guarantee high levels of rLH throughout the

stimulation regime. In the earlier used stimulation protocols with hMG, the amount of

rLH was automatically adjusted in concordance with rFSH, because hMG contains a 1:1

ratio of LH and FSH. Consequently, when the amount of FSH was increased according

to the ovarian response, the amount of LH was automatically increased too. In most

rLH studies, the commonly used doses were 75 or 150 IU. The rLH dosage in previous

studies was not adjusted according to the ovarian response, but remained equal during

Table II. Outcomes in women who received IVF with rFSH +rLH or rFSH

Outcome Women assigned rFSH + rLH (n=116)

Women assigned rFSH (Controls) (n=128)

Mean difference (95% CI)

Relative risk (95% CI)

Primary outcome

Proportion of top quality embryos per woman * mean (95%CI) 0.17 (0.06 - 0.28) 0.11 (0.04 - 0.19) 0.06 (-0.01 - 0.14)

Stimulation phase

No. of stimulation days mean (95%CI) 11.6 (11.0 - 12.2) 11.3 (10.6 - 12.0) 0.28(-0.66 - 1.23)

Woman started stim: 450 rFSH ± 225 rLH 38 35 1.2 (0.82 – 1.76)


Total amount of rFSH administrated (95% CI) 3998.2 (2206.7 – 5789.7) 3984.4 (2173.5 – 5795.3) 13.8 (-459.9 – 487.1)

Total amount of rLH administrated (95% CI) 1841.8 (845 – 2843.6) - -

Women with no response after max stim n (%) 3 (3) 9 (7) 0.4 (0.10 - 1.33)

Number of follicles ≥ 17 mm on hCG day 6.3 (5.5 - 7.1) 6.1 (5.3 - 6.9) 0.22 (-0.89 - 1.33)

Oocyte collection phase

No. of oocytes per woman mean (95%CI) 8.6 (7.4 - 9.8) 7.4 (6.4 - 8.5) 1,19 (-0.39 - 2.77)

Women with total fertilization failure n (%) 14 (12) 17 (13) 0.9 (0.47 - 1.76)

Fertilization rate per woman mean (95%CI) 0.40 (0.35 - 0.46) 0.39 (0.33 - 0.45) 0.01 (-0.07 - 0.09)

No. of embryos per woman mean (95%CI) 3.8 (3.1 - 4.6) 3.6 (2.9 - 4.3) 0.26 (-0.76 - 1.27)

No. of top quality embryos per woman mean (95%CI) 0.82 (0.53 - 1.1) 0.68 (0.44 - 0.92) 0.14 (-0.23 - 0.51)

Women with 1 ≥ top embryos n (%) 47 (41) 41 (32) 1.3 (0.91 - 1.77)

Clinical outcomes

Women with 1 ≥ ongoing pregnancies n (%) 15 (13) 15 (12) 1.1 (0.57 - 2.16)

Women with 1 ≥ biochemical pregnancies 33 (28) 30 (23) 1.2 (0.79 - 1.86)

Women with 1 ≥ clinical pregnancies 18 (16) 20 (16) 1.0 (0.55 - 1.78)

Women with 1 ≥ miscarriages 3 (3) 5 (4) 0.7 (0.16 - 2.71)

* total number of top quality embryos per woman/ total number of embryos per woman


33

2Chapter

the entire stimulation phase, while the rFSH dosage was often increased, especially in

case of a poor ovarian response. (Ferraretti et al., 2004; Marrs et al., 2004; De Placido

et al., 2005; Fabregues et al., 2006; Barrenetxea et al., 2008; Durnerin et al., 2008;

Nyboe Andersen et al., 2008; Gutman et al., 2009; Matorras et al., 2009; Pezzuto et

al., 2009; Kovacs et al., 2010; Bosch et al., 2011).

Contrary to what was expected, we found 445 embryos in the rLH group and 458

embryos in the control group, instead of the anticipated 522 embryos per arm. This was

due to cycle cancellations, lack of oocytes after follicle aspiration and total fertilization

failure in both study groups (in total 18% in the rLH group and in total 23% in the

control group). It was also due to the fact that there was no association between

AFC and the proportion of top-quality embryos per woman and that the women who

did have embryos had an average of four instead of the estimated five embryos per

Table II. Outcomes in women who received IVF with rFSH +rLH or rFSH

Outcome Women assigned rFSH + rLH (n=116)

Women assigned rFSH (Controls) (n=128)

Mean difference (95% CI)

Relative risk (95% CI)

Primary outcome

Proportion of top quality embryos per woman * mean (95%CI) 0.17 (0.06 - 0.28) 0.11 (0.04 - 0.19) 0.06 (-0.01 - 0.14)

Stimulation phase

No. of stimulation days mean (95%CI) 11.6 (11.0 - 12.2) 11.3 (10.6 - 12.0) 0.28(-0.66 - 1.23)



Total amount of rFSH administrated (95% CI) 3998.2 (2206.7 – 5789.7) 3984.4 (2173.5 – 5795.3) 13.8 (-459.9 – 487.1)

Total amount of rLH administrated (95% CI) 1841.8 (845 – 2843.6) - -

Women with no response after max stim n (%) 3 (3) 9 (7) 0.4 (0.10 - 1.33)

Number of follicles ≥ 17 mm on hCG day 6.3 (5.5 - 7.1) 6.1 (5.3 - 6.9) 0.22 (-0.89 - 1.33)

Oocyte collection phase

No. of oocytes per woman mean (95%CI) 8.6 (7.4 - 9.8) 7.4 (6.4 - 8.5) 1,19 (-0.39 - 2.77)

Women with total fertilization failure n (%) 14 (12) 17 (13) 0.9 (0.47 - 1.76)

Fertilization rate per woman mean (95%CI) 0.40 (0.35 - 0.46) 0.39 (0.33 - 0.45) 0.01 (-0.07 - 0.09)

No. of embryos per woman mean (95%CI) 3.8 (3.1 - 4.6) 3.6 (2.9 - 4.3) 0.26 (-0.76 - 1.27)

No. of top quality embryos per woman mean (95%CI) 0.82 (0.53 - 1.1) 0.68 (0.44 - 0.92) 0.14 (-0.23 - 0.51)

Women with 1 ≥ top embryos n (%) 47 (41) 41 (32) 1.3 (0.91 - 1.77)

Clinical outcomes

Women with 1 ≥ ongoing pregnancies n (%) 15 (13) 15 (12) 1.1 (0.57 - 2.16)

Women with 1 ≥ biochemical pregnancies 33 (28) 30 (23) 1.2 (0.79 - 1.86)

Women with 1 ≥ clinical pregnancies 18 (16) 20 (16) 1.0 (0.55 - 1.78)

Women with 1 ≥ miscarriages 3 (3) 5 (4) 0.7 (0.16 - 2.71)

* total number of top quality embryos per woman/ total number of embryos per woman

Chapter 2

34

women. This all indicates that the women in this study had an even poorer ovarian

function than expected and really did represent women with a poor prognosis.

Worldwide there is no consensus on the definition of women with poor ovarian reserve

or for that matter poor ovarian response. As we found it important to include all

women with poor ovarian reserve, we included women of advanced age, i.e. women

35–41 years old, and women younger than 35 years old with an FSH level > 12 IU/

ml accompanied by an AFC ≤5). In both groups, a poor response during COS has

been described (Croucher et al., 1998; Hsieh et al., 2001; Bancsi et al., 2002). The

observed response to ovarian hyperstimulation in our study confirm the extremely poor

prognosis of these women.

A Cochrane review suggested that the addition of rLH to COH has a beneficial effect

on ongoing pregnancy rates in women with poor ovarian response (OR 1.85, 95% CI

1.10–3.11) (Mochtar et al., 2007). When adding the pregnancy results of our trial and

those of a recently published randomized study in women with poor ovarian response

(Bosch et al., 2011) to the available data in the Cochrane review, the summarized OR is

1.39 (95% CI 1.01–1.92). This substantiates the evidence that there is indeed an effect,

on ongoing pregnancy rates, of the addition of rLH to FSH in women with poor ovarian

response. The present trial was not powered to identify a difference in pregnancy rates

between the two groups. To prove that the addition of rLH yields an increase of 10% in

the pregnancy rate compared with a standard rate of 25%, with a power of 80% and

an alpha of 5%, would require 700 women per treatment arm.

How would the addition of exogenous LH activity lead to higher implantation and

pregnancy rates in women of increased age? Next to the biological explanation of

embryo quality investigated in this trial, another possible explanation could be an

intrinsic effect of LH activity on the endometrium. In an oocyte donation program,

women treated with a combination of rFSH and rLH, yielded more mature oocytes

and good-quality embryos and achieved higher implantation rates within the oocyte

recipients compared with oocyte donor women treated with rFSH alone (Tesarik and

Mendoza, 2002; Acevedo et al., 2004).

Before considering the addition of rLH to IVF stimulation for women with poor ovarian

reserve, its costs should be balanced against its potential benefits with proper cost-

effectiveness studies and also patient preference studies should be implored upon.

In conclusion, the present study investigated in a randomized setting if embryo quality

increased with the addition of rLH to ovarian stimulation for women with poor ovarian

reserve. The addition of LH favoured an increase from 11 to 17% in the proportion

of top-quality embryos per woman and the proportion of women with at least one

top-quality embryo increased from 32 to 41%. However the differences were not

significant.


35

2Chapter

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Bancsi LF, Broekmans FJ, Eijkemans MJ, de Jong FH, Habbema JD, and te Velde ER. Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve. Fertil Steril, 2002;77:328-336.

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Coomarasamy A, Afnan M, Cheema D, van der Veen F, Bossuyt PM, and van Wely M. Urinary hMG versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in IVF or ICSI treatment: a systematic review and meta-analysis. Hum Reprod, 2008;23:310-315.

Croucher CA, Lass A, Margara R, and Winston RM. Predictive value of the results of a first in-vitro fertilization cycle on the outcome of subsequent cycles. Hum Reprod, 1998;13:403-408.

de Boer EJ, den Tonkelaar I, te Velde ER, Burger CW, Klip H, vanLeeuwen FE; OMEGA-project group. A low number of retrieved

oocytes at in vitro fertilization treatment is predictive of early menopause. Fertil Steril 2002;77:978–985.

De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, De PR, Ranieri A, Colacurci N, and Mollo A. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod, 2005;20:390-396.

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Fabregues F, Creus M, Penarrubia J, Manau D, Vanrell JA, and Balasch J. Effects of recombinant human luteinizing hormone supplementation on ovarian stimulation and the implantation rate in down-regulated women of advanced reproductive age. Fertil Steril, 2006;85:925-931.

Ferraretti AP, Gianaroli L, Magli MC, D’angelo A, Farfalli V, and Montanaro N. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril, 2004;82:1521-1526.

Filicori M and Cognigni GE. Efficiency and efficacy of exogenous gonadotrophins containing LH activity. Reprod Biomed Online, 2003;7:254-255.

Filicori M, Cognigni GE, Tabarelli C, Pocognoli P, Taraborrelli S, Spettoli D, and Ciampaglia W Stimulation and growth of antral ovarian follicles by selective LH activity administration in women. J Clin Endocrinol Metab, 2002;87:1156-1161.

Filicori M, Cognigni GE, Taraborrelli S, Spettoli D, Ciampaglia W, and de Fatis CT. Low-dose human chorionic gonadotropin therapy can improve sensitivity to exogenous follicle-stimulating hormone in patients with secondary amenorrhea. Fertil Steril, 1999;72:1118-1120.

Frattarelli JL, Bergh PA, Drews MR, Sharara FI, and Scott RT. Evaluation of basal estradiol levels in assisted reproductive technology cycles. Fertil Steril, 2000;74:518-524.

Frattarelli JL, Levi AJ, Miller BT, and Segars JH. Prognostic use of mean ovarian volume in in vitro fertilization cycles: a prospective assessment. Fertil Steril, 2004;82:811-815.

Garcia JE, Jones GS, Acosta AA, and Wright G, Jr. Human menopausal gonadotropin/human chorionic gonadotropin follicular maturation for oocyte aspiration: phase II, 1981. Fertil Steril, 1983;39:174-179.

Gutman G, Barak V, Maslovitz S, Amit A, Lessing JB, and Geva E. Recombinant luteinizing hormone induces increased production of ovarian follicular adiponectin in vivo: implications for enhanced insulin sensitivity. Fertil Steril, 2009;91:1837-1841.

Hellberg D, Waldenstrom U, and Nilsson S. Defining a poor responder in in vitro fertilization. Fertil Steril, 2004;82:488-490.

Hsieh YY, Chang CC, and Tsai HD. Antral follicle counting in predicting the retrieved oocyte number after ovarian hyperstimulation. J Assist Reprod Genet, 2001;18:320-324.

Jacobs SL, Metzger DA, Dodson WC, and Haney AF. Effect of age on response to human menopausal gonadotropin stimulation. J Clin Endocrinol Metab, 1990;71: 1525-1530.


Keay SD, Liversedge NH, Mathur RS, and Jenkins JM. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol, 1997;104:521-527.

Kovacs P, Kovats T, and Kaali SG. Results with early follicular phase recombinant luteinizing hormone supplementation during stimulation for in vitro fertilization. Fertil Steril, 2010;93:475-479.


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Marrs R, Meldrum D, Muasher S, Schoolcraft W, Werlin L, and Kelly E. Randomized trial to compare the effect of recombinant human FSH (follitropin alfa) with or without recombinant human LH in women undergoing assisted reproduction treatment. Reprod Biomed Online, 2004;8:175-182.

Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, Vogel NE, Arts EG, de Vries JW, Bossuyt PM et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med, 2007;357:9-17.


Matorras R, Prieto B, Exposito A, Mendoza R, Crisol L, Herranz P, and Burgues S. Mid-follicular LH supplementation in women aged 35-39 years undergoing ICSI cycles: a randomized controlled study. Reprod Biomed Online, 2009;19:879-887.

Mochtar MH, van der Veen F, Ziech M, and van Wely M. Recombinant Luteinizing Hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles. Cochrane Database Syst Rev, 2007 CD005070.

Muttukrishna S, Suharjono H, McGarrigle H, and Sathanandan M. Inhibin B and anti-Mullerian hormone: markers of ovarian response in IVF/ICSI patients? BJOG, 2004: 111: 1248-1253.

Nyboe Andersen A, Humaidan P, Fried G, Hausken J, Antila L, Bangsboll S, Rasmussen PE, Lindenberg S, Bredkjaer HE, and Meinertz H. Recombinant LH supplementation to recombinant FSH during the final days of controlled ovarian stimulation for in vitro fertilization. A multicentre, prospective, randomized, controlled trial. Hum Reprod, 2008;23:427-434.

Pellicer A, Lightman A, Diamond MP, Russell JB, and DeCherney AH. Outcome of in vitro fertilization in women with low response to ovarian stimulation. Fertil Steril, 1987;47:812-815.


Pezzuto A, Ferrari B, Coppola F, and Nardelli GB LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels. Gynecol Endocrinol, 2009 1-7.

Puissant, F., Van Rysselberge, M., Barlow, P., Deweze, J., and Leroy, F. Embryo scoring as a prognostic tool in IVF treatment. Hum. Reprod.,1987;2:705-708.

Sallam HN, Ezzeldin F, Agameya AF, Rahman AF, and El-Garem Y Defining poor responders in assisted reproduction. Int J Fertil Womens Med, 2005;50:115-120.

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Steer, C. V., Mills, C. L., Tan, S. L., Campbell, S., and Edwards, R. G. The cumulative embryo score: a predictive embryo scoring technique to select the optimal number of embryos to transfer in an in-vitro fertilization and embryo transfer programme. Hum. Reprod. 1992;7:117-119.

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Sullivan MW, Stewart-Akers A, Krasnow JS, Berga SL, and Zeleznik AJ Ovarian responses in women to recombinant follicle-stimulating hormone and luteinizing hormone (LH): a role for LH in the final stages of follicular maturation. J Clin Endocrinol Metab, 1999;84:228-232.

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Tarlatzis BC, Zepiridis L, Grimbizis G, and Bontis J Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update, 2003;9:61-76.

Tesarik J and Mendoza C Effects of exogenous LH administration during ovarian stimulation of pituitary down-regulated young oocyte donors on oocyte yield and developmental competence. Hum Reprod, 2002;17:3129-3137.

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Veeck, LL. The morphological assessment of human oocytes and early conception. In Keel, B. A. and Webster, B. W. Handbook of the laboratory diagnosis and treatment of infertility. CRC Press, 1990 Boston, 353-369.

3Women’s perspectives regarding subcutaneous injections, costs and live birth rates in IVF

Anna M. MustersEsther W. de Bekker-GrobMonique H. MochtarFulco van der VeenNorah M. van Mello

Human Reproduction 2011;26:873-7

Chapter 3

40

Abstract

BACKGROUND The addition of recombinant LH (rLH) to controlled ovarian

hyperstimulation (COH) shows a beneficial effect on ongoing pregnancy rates in poor

responder women, with an increase of ongoing pregnancy rate. Next to this possible

beneficial effect, there are two potential drawbacks of adding rLH to COH; women

have to administer extra injections, and daily rLH injections generate additional costs.

We therefore investigated women’s perspectives on an additional injection of rLH with

respect to live birth rates (LBR) and out-of-pocket costs in a discrete choice experiment.

METHODS Women eligible for IVF were asked to choose between treatments that

differed in LBR after one IVF cycle, the amount of self-administered injections and out-

of-pocket costs or reimbursement. The relative weights that women place on these

attributes were estimated with a logistic regression model. To test for heterogeneity of

preferences among women, patient characteristics were included in the model.

RESULTS Two-hundred and thirty-four women were asked to participate in the

study. In total, 223 women responded (response rate 95%) and 206 questionnaires

were analysed. An increase of one daily injection did not alter women’s treatment

preference. LBR and costs did have a significant (P < 0.001) impact on women’s choice

of IVF treatment. Patient characteristics significantly influenced the effect of costs on

women’s preferences.

CONCLUSIONS One extra daily injection will not cause a woman to refrain from a

certain IVF treatment. However, to compensate for the out-of-pocket costs of this extra

daily injection, the expected LBR should at least be 6%.

Women’s perspectives regarding subcutaneous injections, costs and live birth rates in IVF

41

3Chapter

Introduction

The aim of women embarking on IVF is to have a child, and patient preference studies

in reproductive medicine have clearly demonstrated that live birth rates (LBR) are the

pivotal factors for women in their decision-making (Nieuwkerk et al., 1998; Bayram et

al., 2005; Steures et al., 2005; Twisk et al., 2007; Van Mello et al., 2010). On the other

hand, monetary resources in society are not unlimited. As such, healthcare workers are

to provide the most cost-effective treatment.

An important part of IVF treatment is ovarian hyperstimulation, and many regimens

have been tried and studied in an attempt to optimize IVF results. Recently, it has

been suggested that the addition of recombinant LH (rLH) to controlled ovarian

hyperstimulation (COH) shows a beneficial effect on ongoing pregnancy rates in poor

responder women, with an increase of ongoing pregnancy rate from 20 to 32% with

the addition of rLH (Mochtar et al., 2007). Next to this possible beneficial effect, there

are two potential drawbacks of adding rLH to COH; women have to administer extra

subcutaneous injections and these daily rLH injections generate additional costs.

What women prefer when it comes to injections during IVF has not been substantiated.

We do know that IVF is perceived as an invasive and burdensome treatment (Eugster

and Vingerhoets, 1999). The mental and psychological distress that accompanies an IVF

treatment has been described since the early 1990s (Kopitzke et al., 1991; Edelmann

et al., 1994). This burden and distress even causes women to drop out of treatment

for the following reasons: psychological burden, poor prognosis, relationship problems

and physical burden (Olivius et al., 2004; Verberg et al., 2008; Domar et al., 2010).

This physical burden encompasses infection, ovarian hyperstimulation syndrome and

administration of subcutaneous injections (Olivius et al., 2004). The cumulative dropout

rate after three reimbursed IVF cycles can be as high as 62% (Land et al., 1997).

Studies that compared drop out rates in women during conventional IVF and mild

stimulation IVF (i.e. fewer daily injections and shorter duration of the stimulation) state

that mild stimulation IVF has a lower drop out rate (Heijnen et al., 2007; Verberg et al.,

2008) and suggest that a mild treatment protocol is related to a reduction of anxiety

and treatment-related stress (Verberg et al., 2008). Other research goes on to suggest

that mild stimulation protocols will be better tolerated by patients (Fauser et al., 1999).

These data suggest that women prefer an IVF treatment with fewer injections rather

than more, but the studies generating these data were designed to investigate the

reasons why women drop out of treatment and not how women receiving IVF perceive

treatment aspects—for example, injections.

One study that investigated patient preferences in conventional IVF versus mild

stimulation IVF showed that 60% of the women undergoing conventional IVF find

side effects of hormone treatment unacceptable or severe, compared with 5% of the

Chapter 3

42

women treated with mild IVF (Højgaard et al., 2001). The side effects of the hormone

treatment were not mentioned, and only 49% of respondents had commented on this

section of the questionnaire.

Public financing of assisted reproduction treatments (ARTs) ranges from virtually no

subsidy in the USA to funding of a limited number of cycles in most European countries

and to unrestricted reimbursement with co-payments in Australia (Hughes and

Giacomini, 2001; Nachtigall, 2006; Chambers et al., 2009; Connolly et al., 2010). In the

Netherlands, where state funding is available for up to three IVF attempts, the costs of

an additional rLH injection are, as yet, not reimbursed. A recent study demonstrated that

a price increase in ART associated with the introduction of co-payment for ART reduced

the utilization of IVF (Connolly et al., 2009). This suggests that when treatment access

is dependent on user fees, costs are restrictive for many patients (Connolly et al., 2010).

So, in view of the existing data, it would seem that both the addition of daily injections

of rLH and the costs may affect patients’ preferences for an IVF treatment. We therefore

investigated patients’ perspectives by performing a discrete choice experiment (DCE),

in which we examined the relative weight women place on an additional subcutaneous

injection of rLH with respect to LBRs and out-of-pocket costs.


SettingThis patient preference study was conducted alongside an RCT (the L-AGE trial),

comparing the effect of COH with rFSH and rLH versus rFSH alone in 244 women with

poor ovarian response undergoing their first IVF cycle, in the Academic Medical Centre

or the Onze Lieve Vrouwe Gasthuis in Amsterdam, the Netherlands. Women with

poor ovarian response were defined as all women aged 35–41 years or women aged

less than 35 years with poor ovarian reserve, defined as FSH > 12 IU/ml accompanied

with an antral follicle count ≤ 5. Women in the trial were randomly allocated to rLH

plus rFSH (1:2 ratio) or rFSH alone after down-regulation with a GnRH agonist in a

long protocol with a mid-luteal start. The study was registered with EudraCT (EudraCT

number 2007–007487–22) and the Dutch National Trial Register (Trial ID: NTR1457).

ParticipantsAll women who attended an IVF information session in the period from July 2009 to

May 2010 before commencing their first IVF cycle were asked to participate in the DCE.

In total, 234 women were asked to participate. The IVF information sessions were held

every 3 months in the period from July 2009 to May 2010 in the Academic Medical

Centre in Amsterdam, the Netherlands. After these sessions, a questionnaire was


43

3Chapter

handed out and women were asked to fill it in and hand it back when they returned to

the out-patient clinic 1 month later for cycle scheduling. All women started treatment

within 3 months after the cycle scheduling appointment. The women who forgot to

bring their questionnaire were given a new one upon arrival at the clinic. They were

asked to complete the questionnaire on the spot before their scheduling appointment

to ensure that all questionnaires were filled in before the start of the treatment. In

the L-AGE trial, women were included if they were poor responders; in the DCE, we

decided to include women of all subfertility indications to get a broad view of the

women’s preferences.

QuestionnaireThe questionnaire included a letter explaining the purpose of the study and information

on COH and rLH, focusing on the extra subcutaneous injection, costs of rLH and LBRs

(The Supplementary Data contain a translated version of the information provided).

The questionnaire consisted of two parts. In the first part, general data on the women

were collected. This included their age, education, income, duration of subfertility,

cause of subfertility, prior fertility treatment and obstetric history. In the second part of

the questionnaire, preferences for LBR, an additional injection and costs were studied

by means of a DCE. Institutional review board approval was not needed because a

questionnaire study is not subject to the Dutch ‘Medical Research Involving Human

Subjects Act’.

Discrete choice experimentThe DCE assumes that a given healthcare treatment can be described by its

characteristics. These characteristics are called ‘attributes’. The patients’ preference for

a treatment is determined by the variants of these attributes, called ‘levels’. In this

case, the treatment was an IVF cycle, and its attributes were LBR, daily subcutaneous

injections and out-of-pocket costs. The relative importance of the attributes and trade-

offs that patients make between them can be assessed by offering a series of choices

between two or more (hypothetical) treatment alternatives with different combinations

of attribute levels (Louviere et al., 2007).

In comparison with other preference techniques (e.g. visual analogue scale and

the time-trade-off method), a DCE presents a reasonably straightforward task and

resembles more closely a real-world decision, i.e. trading-off health and non-health

outcomes (Bijlenga et al., 2009).

Attributes and attribute levelsThe selection of the most relevant attributes of an IVF cycle and their levels was based

on the data from the literature on LBR per cycle (Templeton et al., 1996; Lintsen et

Chapter 3

44

al., 2007; HFEA, 2008; SART, 2008; Nyboe Andersen et al., 2009), and monetary

information was acquired from a pharmaceutical company that produces the rLH

injections (Merck Serono). After consensus (by A.M.M. and N.M.M.) on the attributes

and levels and development of the choice sets, the questionnaire was presented to an

expert panel (consisting of two gynaecologists, one resident and one PhD student,

all specialized in reproductive medicine) that offered the final adjustments. The final

decisions were made by A.M.M and N.V.M.

The attributes and their levels are presented in Table I. The attribute levels of LBR per

cycle ranged from 5 to 30%. These percentages are based on literature (Templeton

et al., 1996), a large Dutch study (Lintsen et al., 2007) and LBRs per fresh cycle from

national databases; the USA (SART, 2008), the UK (HFEA, 2008) and the European

Society of Human Reproduction and Embryology (ESHRE) consortium (Nyboe Andersen

et al., 2009). Women aged below 35 years have a higher average LBR fresh per cycle

than women aged 40 year, therefore, we used a LBR ranging from 30 to 5%. The

attribute levels of daily injections were two or three daily subcutaneous injections. In

our IVF stimulation protocol, women receive a daily GnRH agonist injection and a daily

Table I. Attributes with corresponding levels per IVF cycle

Attributes Levels

Live birth rate (%) 5

10

15

20

25

30

Daily injections 2

3

Costs (€) 0*

1.000

* Insurance company reimbursement

rFSH injection (in total, two injections); therefore, if we were to add rLH, this would

result in three daily injections.

In the Netherlands, where state funding is available for up to three IVF attempts, the

costs of an additional rLH injection are not reimbursed. The out-of-pocket cost of rLH

injections for one IVF treatment cycle is roughly €1000 (Merck Serono). The attribute

levels of costs were reimbursement (zero cost) or out-of-pocket costs of €1000.


45

3Chapter

Development of the choice setsThe combination of the three IVF attributes, with two attributes at two levels and

one attribute at six levels, provided 24 (22× 61) hypothetical alternatives for an IVF

treatment. We used a fractional factorial design to generate a functional sample of 14

alternatives. The fractional factorial method systematically selects this sample according

to an orthogonal design. Orthogonality guarantees an optimal balance of the levels and

attributes with a minimal correlation (Louviere et al., 2007). The orthogonal design was

generated by Orthoplan [Statical Package for Social Sciences (SPSS) version 14.0 SPSS

Inc., USA) and a set of 14 alternatives were selected and formed treatment option A.

To ensure minimal overlap of attribute levels, we created a set of alternatives to form

treatment option B by means of a syntactical fold over technique, based on the profiles

of treatment option A (Ryan et al., 2001). As a result, each choice set consisted of two

options representing hypothetical alternatives for an IVF treatment. An example of a

choice set is shown in Fig. 1. The 14 choice sets for treatment options A and B were

considered sufficient to estimate all main effects representing the relative importance

of each attribute.

Women had to choose their most preferable option in each choice set, without an opt

out alternative (e.g. ‘no treatment’ option) as these women would all be undergoing

IVF treatment in the future and ‘no treatment’ would not have been a realistic option.

Figure I. An example of a choice set, representing hypothetical alternatives for an IVF treatment, as presented in the questionnaire.

Chance for a child

Daily hormone injections

Costs

Choice A or B(circle your choice)

A B

Chapter 3

46

To assess the understanding of the attributes (LBR, number of injections and out-of-

pocket costs), the questionnaire contained two dominant choices (rationality tests).

In these sets, one of the two IVF alternatives was characterized by equal or logically

preferable levels on all attributes. Statistical significance was set at P < 0.05

Pilot studyThe questionnaire was tested for interpretation and face validity among 14 fertility

doctors and nurses at the Academic Medical Centre in Amsterdam, the Netherlands,

and 10 subfertile women without previous IVF experience. The information letter was

clear, and the DCE itself was well understood by all participants in the pilot study and

therefore only minor modifications were made to the final version of the questionnaire.

AnalysesThe DCE was analysed by taking each choice between the two treatment alternatives

as an observation and then analysed by a logistic regression model. Assuming that all

attributes have an independent effect on a women’s preference, the following model

was estimated (Hahn and Shapiro, 1966; Ryan et al., 2001; Louviere et al., 2007):

V = β0+ β1 ´ livebirthrate + β2 ´ numberofinjections + β3 ´ costs

i. V is the observable relative utility (i.e. satisfaction or happiness) that is composed of

the preference scores for the individual β-coefficients of the model.

ii. β0 is the constant term reflecting the preference option A relative to option B.

iii. β1 to β3 are the coefficients of the attributes indicating the relative weight individuals

place on a certain attribute.

The absolute value of V has no direct interpretation, but an alternative with a higher

V is preferred over an alternative with a lower V (Louviere et al., 2007). The sign of

a coefficient reflects whether the attribute has a positive or negative effect on the

overall utility. The value of each coefficient represents the importance that respondents

assign to an attribute.

To take heterogeneity of preferences into account among women, we included age,

parity, duration of subfertility, income, previous treatment with subcutaneous injections

and diagnosis of the subfertility as interaction terms in the model. The statistically

insignificant variables were excluded from the model by backward stepwise elimination.

Results are presented for the final reduced model, which includes the main effects and

significant interactions effects only.

To investigate the willingness of women to trade-off €1000 to achieve a certain LBR,

we calculated the ratio between the coefficient of the cost attribute and the attribute

LBR. Thus, β3/–β1 represents an estimate of what the minimum preferred LBR for

women is in order to be willing to pay €1000 of out-of-pocket costs.


47

3Chapter

Table II. Baseline characteristics of subfertile women awaiting IVF treatment. (N= 206)

Age women n (%) < 35 years old 99 (48)

≥ 35 years old 107 (52)

Women with ≥ 1 pregnancies n (%) 74 (36)

≥ 1 children 38 (18)

≥ 1 miscarriages 37 (18)

≥ 1 TOP 13 (6)

≥ 1 ectopic pregnancy 3 (1)

≥ 1 preterm delivery 3 (1)

≥ 1 neonatal death 1 (0.5)

Duration of subfertility (months ± SD) 37.7 ± 26.5

Previous fertility treatment n (%)~

≥ 1 Clomiphene Citrate cycles 4 (2)

≥ 1 IUI cycles 57 (28)

≥ 1 IVF cycles 33 (16)

Primary diagnosis of subfertility n (%)

Male factor 90 (44)

Unexplained subfertility 62 (30)

Imminent ovarian failure 25 (12)

Tubal factor 18 (9)

Oocyte Vitrification 4 (2)

Anovulation (PCOS) 2 (1)

Endometriosis 2 (1)

Not reported 3 (1)

Education Level n(%)

Low* 19 (9)

Moderate** 63 (31)

High*** 121 (59)

Not reported 3 (1)

Household Income per year n (%)

Very Low ^ 26 (13)

Low ^^ 60 (29)

Moderate ^^^ 47 (23)

High^^^^ 57 (28)

Not reported 16 (8)

TOP: terminantion of pregnancy IUI: Intra uterine insemination PCOS: polycystic ovary syndrome~Some women had received both IUI and IVF; * primary school / intermediate vocational education ** higher general secondary education / pre-university secondary education; ***higher vocational education / university; ^ €10,000 - €25,000; ^^ €25,000 - €50,000; ^^^ €50,000 - €75,000; ^^^^ > €75,000

Chapter 3

48

Results

Two-hundred and twenty-three women completed the questionnaire. The response

rate was 95% (223/234), which is comparable with other DCE studies (Bijlenga et al.,

2009; Bekker-Grob de et al., 2010). Sixteen questionnaires were excluded because the

women did not complete all the 14 choice sets. Of the 207 women, 206 passed the

rationality test, which indicates that the women understood the DCE task well.

Baseline characteristicsIn total, 206 data sets were analysed. Baseline characteristics of the women are shown

in Table II.

Discrete choice experimentThe results of the reduced logistic regression model, which contains the main effects

of the attributes and the significant interaction effects, are shown in Table III. Both LBR

(β1) and costs (β3) had a significant impact on women’s preference for IVF treatment (P

< 0.001). The positive sign on LBR indicates that womens’ preference for IVF treatment

increased with the increase of LBR. The negative sign on costs indicates that women’s

preference decreased in case of ‘out-of-pocket’ cost of €1000. An increase of one

daily subcutaneous injection, from two to three injections, did not affect women’s

preference for IVF treatment (P= 0.54).

As for the interaction terms, the costs attribute was found to be significantly more

important for women: (i) 35 years or younger, (ii) with one or more children, (iii) with

subfertility for 2.5 years or longer and (iv) with a very low and low/moderate household

Table III. Logistic regression model including significant interaction effects. N=206

Regression coefficient (β) P value

Main effects

β1 live birth rate per 10% 2.3 <0.001

β2 number of daily subcutaneous injections 0.04 0.54

β3 costs of rLH injections - 1.3 <0.001

Interaction effects

costs* Very low income - 1.3 <0.001

costs* Low/Moderate income - 0.5 <0.001

costs* ≤ 35 years old - 0.3 0.03

costs* desire for a child ≥ 2,5 years - 0.2 0.05

costs* 1≥ children - 0.4 0.01

Constant

β0 Constant term - 1.3 <0.001


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3Chapter

income. The negative signs on these interaction terms indicate that women with these

characteristics have additional negative attitudes towards out-of-pocket cost of €1000.

The minimum preferred LBRs for the specific patient profiles are shown in Table IV. The

LBRs were calculated from the beta coefficients of the attributes and the interaction

effects. In general, women participating in this study were willing to pay €1000 when

the LBR is 6% or more. Women found that a LBR of <6% is not worth €1000 of out-

of-pocket costs. Depending on age, parity, duration of subfertility and income, women

Table IV. Trade-off; Minimum desired live birth rate as a compensation for costs of an extra injection (rLH). (N=206)

Reimbursement (costs= €0) Desired live birth rate

All women 6%

No reimbursement (costs= €1,000)

Age Parity Duration subfertility

Income levels

≥ 36 years old 1≥ children ≥ 2,5 yrs Very low 13%

Low / Moderate 10%

High 7%

< 2,5 yrs Very low 12%

Low / Moderate 9%

High 6%

No child ≥ 2,5 yrs Very low 11%

Low / Moderate 8%

High 6%


Low / Moderate 7%

High 5%

≤ 35 years old 1≥ children ≥ 2,5 yrs Very low 14%

Low / Moderate 11%

High 8%


Low / Moderate 10%

High 7%

No child ≥ 2,5 yrs Very low 10%

Low / Moderate 7%


Low / Moderate 8%

High 6%

Income levels; Very low €10,000 - €25,000; Low / Moderate €25,000 - €50,000 / €50,000 - €75,000; High > €75,000

Chapter 3

50

were willing to pay €1000 of out-of-pocket costs if compensated by at least a LBR

ranging from 5 to 14% per IVF cycle. For example, a secondary subfertile 35-year-old

woman with a very low income who has been trying to conceive for less than 2.5 years

is willing to pay out-of-pocket costs of €1000 if it coincides with at least a LBR of 13%

per IVF cycle. On the other hand, a primary subfertile 40-year-old woman with a high

income who has been trying to conceive for more than 2.5 years is willing to pay out-

of-pocket costs of €1000 if it coincides with at least a LBR of 6% per IVF cycle.

Discussion

The basic concept investigated in this study was: does the addition of an extra daily

subcutaneous injection change women’s preferences for an IVF treatment? Mild

stimulation IVF protocols, for example, have been called patient-friendly IVF in the

literature without any studies to determine what ‘patient-friendliness’ really means

(Verberg et al., 2009). If we indeed want to offer IVF that is patient-friendly, we

should start by inquiring what patients prefer during IVF. In this study, we addressed

a part of this issue, and further research should investigate patient preferences in IVF

in more detail.

Here, we assessed the preferences of women regarding the addition of an injection of

rLH to rFSH relative to LBRs and out-of-pocket costs. LBR and costs did have a significant

impact on women’s preference. An increase of the daily subcutaneous injections, from

two to three injections, did not affect women’s preference. The costs attribute was more

important for women 35 years or younger, with one or more children, with subfertility

for 2.5 years or longer and with a very low and low/moderate household income. All

the earlier-mentioned patient characteristics that give an additional negative attitude

towards out-of- pocket cost are easily understood except for women with subfertility

of 2.5 years or longer. Before an attempt is made to explain this finding, the variable

outcome should be put in context. This variable was marginally significant (P-value

0.05) and had a low β-coefficient (−0.2). We hypothesize the following explanations:

women with a longer subfertility have lost hope of achieving a live birth after all these

years and feel that investing €1000 is throwing their money away. However, if they

have lost hope of a live birth, it is counterintuitive that they would continue with their

treatment. Another explanation could be that women who have a longer subfertility

have already invested in previous fertility treatments and have a better insight into what

the costs are; therefore they make a more informed decision, resulting in a negative

attitude towards paying 1000 euro.

The strength of this study is that it has high external validity. The population is a good

representation of women eligible for IVF, owing to the large number of participants,


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various indications of subfertility and large range of duration of subfertility. This study

also includes women in all walks of life, and considers the differences of income and

education level between the women. When comparing the demographic characteristics

of our participants to the demographic characteristics of Dutch women undergoing

IVF; the indications for IVF are similar to data from a large Dutch cohort study

comprising almost 5000 patients undergoing IVF, representing 11 of the 13 IVF clinics

in the Netherlands (Lintsen et al., 2010). The only difference is that the participants

of our study are older (52% ≥ 35 years old) than the IVF population in the Lintsen et

al. (2010) study (38% ≥ 35 years old). This may well be explained by the fact that the

Dutch cohort study was performed on data from 2002 to 2004, and our study was

from 2009 to 2010. Over those years, the average maternal age for undergoing a first

IVF has increased (de Mouzon et al., 2010).

Still, a DCE has its limitations. Attributes and attribute levels were designed with the

help of an expert panel and data from literature, but this careful procedure does not

guarantee that other attributes are irrelevant. An example of other attributes that are

also a part of an IVF treatment are time on a waiting list, continuity of staff and

attitudes of staff. We refrained from including these attributes because we wanted to

make clean cut, easy to follow trade-offs for women comparing the preference for two

or three injections and we did not want to dilute this effect by adding more attributes.

Another limitation is that 44% of the women participating in this study had previous

intrauterine insemination (28%) and/ or IVF (16%) treatment elsewhere and thus had

used subcutaneous injections before, which could have influenced their preference. On

the other hand, this does mimic real life and therefore increases the generalizability of

the data. To check for this confounder, we included previous treatment as an interaction

term into the model and it did not influence women’s preferences.

Economic evaluations of IVF have implicitly assumed that leaving the facility with a

child is the most important factor for women (Bartels, 1987; Batman, 1988; Page,

1989; Wagner and St Clair, 1989; Webb and Holman, 1990; Haan, 1991; Neumann

et al., 1994). Our findings confirm this but also indicate that out-of-pocket costs do

start to matter when the LBR falls <5–14% per IVF cycle, depending on specific patient

characteristics. The only DCE published to date on patient preferences in IVF did not

investigate the effect of an additional daily injection on the preferences of women but

focused on more general aspects of an IVF treatment (Ryan, 1999). Ryan (1999) found

that good staff attitudes were more important than a 6% increase in the chances of

taking home a baby and concluded that women care about more issues than purely

leaving the service with a child.

As patient preference studies in IVF and other fertility treatments are overdue, the

DCE model presented in this study could be used to answer more patient preference

questions.

Chapter 3

52

In summary, daily subcutaneous injections do not influence the preferences for an

IVF treatment, in contrast to LBR and costs. Therefore, it is important for doctors to

know that an extra daily injection will not cause a woman to refrain from a certain

IVF treatment. Also, the results of this study have important implications for future

economic evaluations of IVF, as the willingness to pay of out-of-pocket costs is strongly

related to LBR and specific patient characteristics.


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3Chapter

Supplementary Data

ADDENDUM I. A translation of the information provided on luteinizing hormone and the aim of the questionnaire.

Dear Madame,In the Academical Medical center in Amsterdam we are performing a study that investigates improvement of embryo quality (the L-AGE study). Through the addition of luteinizing hormone (LH) during an IVF/ICSI treatment we hope to increase embryo quality. We want to know what women’s views are on this topic, because the preference of a patient is very important when choosing a treatment. Therefore we would like to ask you to complete this questionnaire that measures your preference.

If you are to receive IVF/ICSI we would like to ask you to fill in this questionnaire. We would appreciate it. It takes roughly15 minutes to complete the questionnaire.

The questionnaire is comprised of the following parts:l Information about LH administration and the

influence of LH on the pregnancy rate.l Explanation of the study.l General questions about your age, education level and previous pregnanciesl 14 preference choice questions

Your participation in this questionnaire study is voluntary. Your answers will be anonymous and have no consequences for you personally or your treatment.

How does LH work during the IVF/ICSI stimulation?During the IVF/ICSI treatment the ovaries are stimulated with help of FSH (follicle stimulating hormone) in the form of a subcutaneous injection, with as aim the growth of multiple follicles. This process has been done for many years. In the natural cycle the growth of follicles is not only done with the help of FSH, but also with LH. Although it is not strictly necessary to add LH to the stimulation, there are indications that LH increases embryo quality for women above 36 years old and for younger women that have a reduced number of egg cells (imminent ovarian failure). The aim of the L-AGE study, is to investigate if the addition of LH will increase the quality of the embryo’s and therefore lead to more pregnancies.

Do I have more chance for a child if I administer LH during an IVF/ICSI cycle?At this moment we do not know yet. The results of the L-Age trial are expected and will help us answer this question.

What are the costs of LH?We calculated that the total costs of LH injections during an IVF/ICSI treatment are thousand euro’s. At the moment it is not assured that the stimulation of LH increases the number of live births, therefore insurance companies do not reimburse the costs.

Chapter 3

54

What is the aim of this study?We want to investigate how important the following factors are for you:l The chance of a child after an IVF/ICSI treatmentl An extra daily injection of LH during an IVF/ICSI treatmentl The payment of 1000,- euro’s during an IVF/ICSI treatment

Acquiring insight in what factors you find important will help us to give a higher quality of patient care in the future.

Explanation of the questionnaireThe questionnaire comprises of 14 similar questions.During the questionnaire you will be confronted with two treatment possibilities (A and B). The treatment possibilities represent two different IVF/ICSI cycles. However they differ in:l The chance for a child after a IVF/ICSI cyclel Number of daily injections; 2 (standard treatment) or 3 (an extra injection)l The costs; 1000,- payment of the reimbursement by the insurance companies.

Participation is voluntaryYour participation in this study is completely voluntary. Participation will in no means have consequences for your treatment of relationship with your doctor.

Confidentiality of your informationThe information that is acquired during this study is all anonymous. The results of this study can be used for scientific publication. The information will be used during the study and will be destroyed afterwards.

Sincerely,

A.M.MustersM.D. and PHD studentAMC, AmsterdamFor information please contact me at [email protected]


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HFEA, Human Fertilisation Embryo Authority. http://guide.hfea.gov.uk/guide/CloserLook.aspx?code=19&s=l&nav=1&rate=i&rate_sub=FSO&bdy=2008&bda=40-42&bds=FSO&bdt=ivf_icsi#cyclesTreatments

Højgaard A, Ingerslev HJ, Dinesen J. Friendly IVF: patient opinions. Hum Reprod, 2001:16:1391-6.

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Lintsen AM, Eijkemans MJ, Hunault CC, Bouwmans CA, Hakkaart L, Habbema JD, Braat DD. Predicting ongoing pregnancy chances after IVF and ICSI: a national prospective study. Hum Reprod, 2007: 22: 2455-62.

Lintsen AM, Braat DD, Habbema JD, Kremer JA, Eijkemans MJ. Can differences in IVF success rates between centres be explained by patient characteristics and sample size? Hum Reprod, 2010: 25:110-7.

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4Pregnancy outcome after pre-implantation genetic screening (PGS) or natural conception in couples with unexplained recurrent miscarriage: a systematic review of the best available evidence

Anna M. MustersSjoerd Repping Johanna C. Korevaar Sebastiaan Mastenbroek Jacqueline Limpens Fulco van der Veen Mariëtte Goddijn

Fertility Sterility 2011;95:2153-2157

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Abstract

The objective of this systematic review was to assess live birth rates and miscarriage

rates after preimplantation genetic screening or natural conception for unexplained

recurrent miscarriage. There were no randomized controlled trials or comparative

studies found on this topic. Until data from randomized controlled trials become

available, this review summarizes the best available evidence of the efficacy of

preimplantation genetic screening vs. natural conception.

PGS in couples with unexplained recurrent miscarriage

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Recurrent miscarriage (RM), defined as two or more miscarriages, affects approximately

5% of all couples (Rai and Regan, 2006). Current diagnostic procedures can identify

etiologic factors in approximately 50% of these couples (Rai and Regan, 2006). Unexplained RM is a distressing condition for the affected couple and a frustrating

problem for the clinician, because there is no effective therapy for these couples as of

yet. Some authors have proposed preimplantation genetic screening (PGS) for couples

with unexplained RM. The rationale behind the use of PGS in cases of unexplained

RM is that aneuploidy of the embryo may be the cause of the RM (Gianaroli et al.,

2002; Werlin et al., 2003; Rubio et al., 2005a; Munné et al., 2005; Mantzouratou et

al., 2007).

Data from the European Society of Human Reproduction and Embryology

preimplantation genetic diagnosis consortium shows an increase of PGS cycles for

couples with RM, from 285 in 2003 to 990 in 2006 (Harper et al., 2006; Goossens et

al., 2008). The current guidelines from this consortium do not give a recommendation

in favor of or against PGS for couples with RM (Thornhill et al., 2005). On the other

hand, the American Society of Reproductive Medicine guideline states that the available

evidence does not support the use of PGS as currently performed to improve live birth

rates in patients with recurrent pregnancy loss (ASRM, 2008), because randomized

control trials are not available. Because PGS is still being performed for this indication

worldwide (Goossens et al., 2008), we systemically searched the literature for the

best available evidence on live birth rates and miscarriage rates after PGS and natural

conception (NC) in couples with unexplained RM.

The following electronic databases were searched: MEDLINE (1950 to December 2009),

EMBASE (1980 to December 2009), and the Cochrane Central Register of Controlled

Trials (CENTRAL) (December 2009). A search strategy was carried out based on the

following terms: recurrent miscarriage, preimplantation genetic screening, natural

conception, live birth rate, and miscarriage rate (Supplementary Fig. I, Supplementary

Tables I and II). The search was performed by a clinical librarian (J.L.).

Unexplained RM was defined as two or more preceding—not necessarily consecutive—

miscarriages (≤20 weeks’ gestational age) without an identified underlying cause (i.e.,

women with normal uterine cavities, negative for antiphospholipid syndrome, and

normal parental karyotypes) (Jauniaux et al., 2006).

We first searched for randomized control trials and/or comparative studies comparing

PGS with NC in couples with unexplained RM. Subsequently, if these could not be

found, a secondary search was performed in which we searched for cohort studies

or randomized studies in which PGS or NC were compared with an intervention other

than the one under investigation in this study. For NC, studies were only selected if

the study included nonpregnant patients, to allow for a fair comparison with data

from PGS studies. In addition, because PGS cycles are usually completed within as

Chapter 4

62

restricted a time frame as 1 year, we included NC studies with a follow-up duration of

1 year. Outcome measures were live birth rate per couple, defined as the percentage of

couples for whom the pregnancy resulted in live birth, and miscarriage rate per couple,

defined as the loss of a pregnancy before the 20th week of gestation.

As a first step, titles were screened. In addition, we hand-searched the reference lists

of selected studies, of recent reviews on the subject, and the abstract books of the

annual meetings of the American Society of Reproductive Medicine and the European

Society of Human Reproduction and Embryology. The abstracts of the included titles

were read. Next, full articles of the approved abstracts were read. The final selection of

the studies was reached by consensus of two separate reviewers (A.M. and M.G.) after

they had read the full articles. Any disagreement was settled by a third investigator

(S.R.). In case published data was incomplete, corresponding authors were contacted

for clarification.

Table I. Main results of included studies in fertile couples with unexplained recurrent miscarriages receiving PGS or conceiving naturally.

Study Couples Started cycles OPU cycles ET cycles TE per cycle Live birthsN (% per couple)

MiscarriagesN (% per couple)

PGS

Wilding et al.a (2004) 3 FISH probes13,18,21 16 - 26 - 2.9 (±1.3) 3 (19) -

Wilding et al.a (2004) 5 FISH probes 13,16,18, 21, 22 48 - 62 - 3.8 (±1.0) 22b (46) -

Platteau et al. (2005) FISH probes 13,16,18, 21, 22, X. Y 49 - 69 49 2 10 (20) 5 (10)

Munne et al. (2005) FISH probes 13,15,16, 17, 18, 21,22, X, Y 58 69 69 60 2.3 25 (43) 5 (9)

Mantzouratou et al. (2007) FISH probes 13,15,16, 18, 21,22 10 12 12 12 1.7c 4 (40) 0 (0)

Total 181 238 121 64 (35) 10 (9)

Natural Conception

Christiansen et al. (1994) 26 NA NA NA NA 10 (39) 11 (42)

Clifford et al. (1996) 31 NA NA NA NA 19 (61) 7 (23)

Stephenson et al. (1998) 30 NA NA NA NA 10 (33) 8 (27)

Ober et al. (1999) 85 NA NA NA NA 41 (48) 18 (21)

Ramhorst et al. (2000) 37 NA NA NA NA 12 (32) 5d (14)

Pandy et al. (2004) 19 NA NA NA NA 2 (11) 6 (32)

Scarpellini et al. (2009) 33 NA NA NA NA 16 (48) 17 (52%)

Total 261 110 (42) 72 (28)

Note: PGS= preimplantation genetic screening, OPU= ovum pick-up cycles TE=transferred embryos per cyclea same article different probes were usedb clinical pregnancies, not “live-birth events”, resulting in 54 children, due to multiple pregnancies.

c information kindly provided by the author, after email correspondenced not clearly stated: unsuccessful pregnancies- = Not mentioned, NA = Not applicable


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4Chapter

We found no randomized controlled trials, nor did we find nonrandomized comparative

studies in which PGS was directly compared with NC (primary search, Supplementary

Fig. I).

Because the aim of our review was to find the best available evidence, we performed

a secondary search in which we searched for cohort studies or randomized studies in

which PGS was compared with an intervention other than the one under investigation

in this study. This search resulted in 196 publications on women with unexplained

RM receiving PGS (secondary search, Supplementary Fig. I (Levine, 1964; Burton and

Wachtel, 1967; Svigos, 1982; Harrison, 1985; Mowbray et al., 1985; Cauchi et al.,

1991; Ho et al., 1991; Gilchirst et al, 1991; Christiansen et al., 1992; Harrison, 1992;

Gatenby et al., 1993; Tulppala et al., 1993; Collins and Roberts, 1994; Coulam, 1994a;

Coulam, 1994b; Illeni et al., 1994; Quenby and Farquharson, 1994; Carp et al., 1995;

Christiansen et al., 1995; Coulam et al., 1995; Clifford et al., 1997; Simon et al., 1998;

Vidal et al., 1998; Pellicer et al., 1999; Jablonowska et al., 1999; Carp et al., 2001;

2002; 2003; Christiansen et al., 2002; Rai et al., 2002; Diejomaoh et al., 2003; Rubio

Table I. Main results of included studies in fertile couples with unexplained recurrent miscarriages receiving PGS or conceiving naturally.

Study Couples Started cycles OPU cycles ET cycles TE per cycle Live birthsN (% per couple)

MiscarriagesN (% per couple)

PGS

Wilding et al.a (2004) 3 FISH probes13,18,21 16 - 26 - 2.9 (±1.3) 3 (19) -

Wilding et al.a (2004) 5 FISH probes 13,16,18, 21, 22 48 - 62 - 3.8 (±1.0) 22b (46) -

Platteau et al. (2005) FISH probes 13,16,18, 21, 22, X. Y 49 - 69 49 2 10 (20) 5 (10)

Munne et al. (2005) FISH probes 13,15,16, 17, 18, 21,22, X, Y 58 69 69 60 2.3 25 (43) 5 (9)

Mantzouratou et al. (2007) FISH probes 13,15,16, 18, 21,22 10 12 12 12 1.7c 4 (40) 0 (0)

Total 181 238 121 64 (35) 10 (9)

Natural Conception

Christiansen et al. (1994) 26 NA NA NA NA 10 (39) 11 (42)

Clifford et al. (1996) 31 NA NA NA NA 19 (61) 7 (23)

Stephenson et al. (1998) 30 NA NA NA NA 10 (33) 8 (27)

Ober et al. (1999) 85 NA NA NA NA 41 (48) 18 (21)

Ramhorst et al. (2000) 37 NA NA NA NA 12 (32) 5d (14)

Pandy et al. (2004) 19 NA NA NA NA 2 (11) 6 (32)

Scarpellini et al. (2009) 33 NA NA NA NA 16 (48) 17 (52%)

Total 261 110 (42) 72 (28)

Note: PGS= preimplantation genetic screening, OPU= ovum pick-up cycles TE=transferred embryos per cyclea same article different probes were usedb clinical pregnancies, not “live-birth events”, resulting in 54 children, due to multiple pregnancies.

c information kindly provided by the author, after email correspondenced not clearly stated: unsuccessful pregnancies- = Not mentioned, NA = Not applicable

Chapter 4

64

et al., 2003; Carp et al., 2004; Kahraman et al., 2004; Lashen et al., 2004; Pehlivan et

al., 2004; Dendrinos et al., 2005; El-Zibdeh, 2005; Rubio et al., 2005b; Dolotzky et al.,

2006; Garrisis et al., 2007; Nonaka et al., 2007; Amin et al., 2008; Badawy et al., 2008;

Fawzy et al., 2008; Harper et al., 2008; Twisk et al., 2008; Garrisi et al., 2009; Rubio et

al., 2009) (192 from electronic searchers, 3 from abstract books searched manually, 1

from reference lists of relevant publications). Of these, 157 were excluded because it

was clear from the title that they did not fulfill the selection criteria. From the remaining

39 articles, 20 were excluded on the basis of the abstract. For the remaining 19 articles

we obtained the full manuscripts; 15 were excluded (Supplementary Fig. I). The total

number of studies included in the review was therefore four (Munné et al., 2005;

Mantzouratou et al., 2007; Wilding et al., 2004; Platteau et al., 2005) (Table I).

The secondary search, in which we searched for cohort studies or randomized studies

in which NC was compared with an intervention other than the one under investigation

in this study, resulted in 2,272 publications (Supplementary Fig. I) (2,272 from

electronic searchers, 0 from reference lists of relevant publications). Of these, 2,187

publications were excluded because it was clear from the title that they did not fulfill

the selection criteria. From the remaining 85 articles, 39 were excluded on the basis of

the abstract. We obtained the full manuscripts of the remaining 46 articles; 39 articles

were excluded. Therefore, a total of seven studies on NC were included (Christansen

et al., 1994; Clifford et al., 1996; Stephenson et al., 1998; Ober et al., 1999; Ramhorst

et al., 2000; Padey and Agrawal et al., 2004; Scarpellini and Sbracia, 2009) (Table I).The exact reasons for exclusion of the titles, abstracts, and full manuscripts are shown

in Supplementary Fig. I.

In the four observational studies concerning unexplained RM and PGS, the number

of included couples was 181 and varied from 10 to 58 per study. The mean number

of previous miscarriage varied between 2.8 and 4.7, and the mean maternal age

varied from 35.4 to 37.6 years. In all studies the embryos were biopsied at day 3

of development, and one or two blastomeres were aspirated and analyzed. The

fluorescence in situ hybridization (FISH) probes used for aneuploidy screening differed

in each study (minimum of three and maximum of nine probes). Additionally, the

number of embryos transferred varied per study; from single-embryo transfer to five

embryos per transfer. There was an average of 1.3 cycles (range, 1.2–1.6 cycles) per

couple in the four studies.

Live birth rate per couple varied between 19% and 46% (mean 35%; median 40%),

and miscarriage rate ranged from none to 10% (mean 9%; median 9%).

In the seven studies found for NC in RM couples the control arms of randomized

controlled trials (comparing NC with any intervention other than PGS) and prospective

cohorts were included. The patients in six of the seven studies received placebo

treatment (Christansen et al., 1994; Clifford et al., 1996; Stephenson et al., 1998;


65

4Chapter

Ober et al., 1999; Ramhorst et al., 2000; Padey and Agrawal et al., 2004; Scarpellini

and Sbracia, 2009). This varied from autologous blood injections to vaginal placebo

pessaries to saline injections. In one study, patients used expectant management

(Ramhorst et al., 2000). The number of included couples was 261 and varied from 19

to 85. The mean number of previous miscarriages varied between 3.0 and 5.6, and the

mean maternal age varied from 25.1 to 34.6 years. The live birth rate ranged from 11%

to 61% (mean 41%; median 36%), and the miscarriage rate ranged from 14% to 52%

per couple (mean 28%; median 25%).

Our systematic search of the literature revealed no randomized controlled trials or

nonrandomized comparative studies directly comparing the efficacy of PGS with NC for

couples with unexplained RM. The need for randomized controlled trials on this topic

is evident, considering the increasing numbers of PGS performed for this indication

worldwide (Harper et al., 2006; Goossens et al., 2008).

A secondary search strategy, for the best available evidence, allowing other study

comparisons or cohort studies on PGS and NC, provided data on a total of 442 couples

(181 PGS and 261 NC).

The studies that were finally included have a number of limitations. The quality of the

available data was low, owing to the limited number of observational studies, small

sample sizes, and heterogeneity between studies. The heterogeneity among the PGS

studies was considerable; the mean RM rate varied between 2.8 and 4.7; chromosomes

tested per blastomere varied from three to nine, and the number of embryos transferred

per cycle varied between one and five. There was also heterogeneity among the NC

studies. The mean maternal age varied from 25.1 to 34.6 years, and in six of the seven

included studies placebo treatment was administered to the patients because of the

randomized controlled design of these studies. The heterogeneity between the two

study groups, apart from receiving PGS or expectant management, was also apparent.

The mean maternal age within studies varied almost 10 years; in the PGS studies

maternal age varied between 35.4 and 37.6 years, whereas in the NC studies mean

maternal age varied between 25.1 and 34.6 years.

Because of the above-mentioned heterogeneity between the PGS and NC studies, no

meta-analysis could be performed, and as a result we can only summarize the data by

tabulation and listing of ranges. When focusing on the data at hand, keeping in mind

their low quality, a similar live birth rate is reported for PGS and NC (35% and 42%,

respectively). The miscarriage rate for the PGS group (9%) seems to be lower than in

the NC group (28%).

This review summarizes the best available evidence of the efficacy of PGS vs. NC. Live

birth rates for PGS and NC groups are not very far apart, and the miscarriage rate after

PGS may be lower. The need for comparative studies of high quality is urgent.

Chapter 4

66

Supplementary Table I Searches: MEDLINE

1. habitual abortion/

2. ((habitual* or recurr* or multiple or repeat* or repetit$ or consecutive or unexplained) adj4 (Abortion* or miscarriage*)).tw.

3. ((habitual* or recurr* or multiple or repeat* or repetit* or consecutive or unexplained) adj4 ((pregnanc* or fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 loss*)).tw.

4. ((habitual* or recurr* or multiple or repeat* or repetit* or consecutive or unexplained) adj4 ((fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 death*)).tw.

5. ((three or “3” or two or “2” or frequent or previous or more) adj2 (Abortion* or miscarriage* or ((pregnanc* or fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 loss*) or ((fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 death*))).tw.

6. ((IRM or RSA or RM or RPL) and (pregnan* or abortion*)).tw.

7. or/1-6

8. exp animals/ not (exp animals/ and exp humans/)

9. 7 not 8

10. preimplantation diagnosis/

11. ((preimplant* or pre-implant*) and (diagn* or screen*)).tw.

12. ((Preimplant* or pre-implant*) adj10 (testing or tests or test)).tw.

13. (pgd* or (pgs and screen*)).tw.

14. ((preimplant* or pre-implant*) and genetic*).tw.

15. (aneuploid* adj10 (diagn* or screen*)).tw.

16. or/10-15

17. double-blind method/ or random allocation/ or single-blind method/ or Placebos/

18. ((singl* or doubl* or treb* or tripl*) adj (blind*3 or mask*3)).tw.

19. (randomi?ed or placebo* or randomly or groups or trial or (clinic* adj trial*1) or (allocated adj2 random)).tw.

20. exp clinical trial/ or exp Clinical Trials as Topic/

21. or/17-20

22. 9 and 16 and 21

23. 9 and 16

24. 9 and 21

25. exp cohort studies/ or cohort*.tw.

26. (consecutive adj2 wom#n).tw.

27. or/25-26

28. Birth Rate/ or live birth/ or stillbirth/ or pregnancy outcome/ or pregnancy rate/

29. ((birth*1 adj2 (rate*1 or live or child*)) or livebirth*).ti,ab.

30. ((newborn*1 or child*) adj2 (live or born)).ti,ab.

31. ((viable adj2 pregnanc*) or (ongoing adj pregnanc*)).ti,ab.

32. (Success* adj (rate* or outcome*)).ti,ab.

33. ((pregnanc* or gestation or reproducti*2) adj2 (achiev*2 or succes* or outcome*1)).ti,ab.

34. or/28-33

35. 9 and 27 and 34


67

4Chapter

Supplementary Figure I Flow chart

Supplementary Table II Search: EMBASE

1. recurrent abortion/ or ((Spontaneous Abortion/ or fetal wastage/) and Recurrent Disease/)

2. ((habitual* or recurr* or multiple or repeat* or repetit$ or consecutive or unexplained) adj4 (Abortion* or miscarriage*)).tw.

3. ((habitual* or recurr* or multiple or repeat* or repetit* or consecutive or unexplained) adj4 ((pregnanc* or fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 loss*)).tw.

4. ((habitual* or recurr* or multiple or repeat* or repetit* or consecutive or unexplained) adj4 ((fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 death*)).tw.

5. ((three or “3” or two or “2” or frequent or previous or more) adj2 (Abortion* or miscarriage* or ((pregnanc* or fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 loss*) or ((fetal or foetal or foetus* or fetus* or embryo* or intrauterine or intra-uterine or in-utero) adj2 death*))).tw.


7. or/1-6

Chapter 4

68

8. limit 7 to humans

9. ((preimplant* or pre-implant*) and (diagn* or screen*)).tw.


11. (pgd* or (pgs and screen*)).tw.


13. (aneuploid* adj10 (diagn* or screen*)).tw.

14. or/9-13

15. 8 and 14

16. prenatal diagnosis/ or genetic screening/ or prenatal screening/

17. exp autosome/ or exp sex chromosome/

18. fluorescence in situ hybridization/ or FISH.tw.

19. chromosome aberration/ or aneuploidy/

20. embryo.mp.

21. or/17-20

22. exp controlled study/ or cohort.mp.

23. birth rate/ or fetus outcome/ or pregnancy outcome/ or pregnancy rate/ or childbirth/ or progeny/

24. or/22-23

25. 8 and 16 and 21 and 24

26. 15 or 25

27. exp controlled clinical trial/ or double blind procedure/ or single blind procedure/ or randomization/ or placebo/

28. (randomized and controlled and trial).ti,ab.

29. ((controlled adj (trial or study)) or (controlled adj clinical adj (trial or study))).ti,ab.

30. or/27-29

31. 8 and 26 and 30

32. 8 and 30

33. “parameters concerning the fetus, newborn and pregnancy”/ or birth rate/ or fetus heart rate/ or fetus mortality/ or fetus outcome/ or live birth/ or pregnancy outcome/ or pregnancy rate/ or child birth/ or progeny/

34. ((birth*1 adj2 (rate*1 or live or child*)) or livebirth*).ti,ab.

35. ((newborn*1 or child*) adj2 (live or born)).ti,ab.

36. ((viable adj2 pregnanc*) or (ongoing adj pregnanc*)).ti,ab.

37. (Success* adj (rate* or outcome*)).ti,ab.

38. ((pregnanc* or gestation or reproducti*2) adj2 (achiev*2 or succes* or outcome*1)).ti,ab.

39. or/33-38

40. cohort analysis/ or cohort.tw.

41. (consecutive wom#n or consecutive nonpregnant wom#n).tw.

42. longitudinal study/ or prospective study/

43. or/40-42

44. 8 and 39 and 43

45. 8 and (14 or (16 and 21 and 24))


69

4Chapter

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5Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review

Maureen T.M. Franssen Anna M. MustersFulco van der Veen Sjoerd Repping Nico J. LeschotPatrick .M.M. BossuytMariëtte Goddijn Johanna C. Korevaar

Human Reproduction Update 2011;17:467-75

Chapter 5

76

Abstract

BACKGROUND Preimplantation genetic diagnosis (PGD) has been stated to improve

live birth rates compared with natural conception in couples with recurrent miscarriage

(RM) carrying a structural chromosome abnormality. It is unclear to what extent this

claim can be substantiated by evidence. A systematic review of the literature was

performed on the reproductive outcome of these couples after natural conception or

after PGD.

METHODS MEDLINE, EMBASE and the Cochrane database were searched until April

2009. Trials, patient series and case reports describing reproductive outcome in couples

with RM carrying a structural chromosome abnormality after natural conception and/

or after PGD were included. Since no randomized controlled trials or non-randomized

comparative studies were found, separate searches for both groups were conducted.

Primary outcome measure was live birth rate per couple. Secondary outcome measure

was miscarriage rate per couple.

RESULTS Four observational studies reporting on the reproductive outcome of

469 couples after natural conception and 21 studies reporting on the reproductive

outcome of 126 couples after PGD were found. After natural conception, live birth rate

per couple varied between 33 and 60% (median 55.5%) after parental chromosome

analysis; miscarriage rate ranged from 21 to 40% (median 34%). After PGD, live birth

rate per couple varied between 0 and 100% (median 31%) after parental chromosome

analysis; miscarriage rate ranged from 0 to 50% (median 0%).

CONCLUSIONS Currently, there are insufficient data indicating that PGD improves the

live birth rate in couples with RM carrying a structural chromosome abnormality.

PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality

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5Chapter

Introduction

Couples with two or more miscarriages are at increased risk of either of the partners

carrying a structural chromosome abnormality (Tharapel et al., 1985; de Braekeleer et

al., 1990). In couples with recurrent miscarriage (RM), the incidence of either of the

partners being a carrier of a structural chromosome abnormality is ∼3–4%, mainly

consisting of reciprocal translocations (61%) and Robertsonian translocations (16%)

(Clifford et al., 1994; Franssen et al., 2005). Other abnormalities include pericentric

inversions and paracentric inversions. The karyotype of the products of conception

in these carrier couples can be normal, balanced or unbalanced, the latter leading

to miscarriage, stillbirth or a child born with major congenital defects and severe

mental handicaps. In view of these consequences, most guidelines advise prenatal

chromosome analysis in future pregnancies to make termination of pregnancy possible

in case of an unbalanced fetal karyotype (ACOG, 2002; RCOG, 2003; Jauniaux et al.,

2006; NVOG, 2007).

Nowadays, preimplantation genetic diagnosis (PGD) is an established alternative to

invasive prenatal diagnosis and as such may avoid termination of pregnancy in couples

with a high risk of transmitting genetic disorders such as X-linked diseases, various

monogenic diseases and also for structural chromosome abnormalities (Handyside et

al., 1990; Geraedts et al., 2001; Sermon et al., 2004). PGD has also been proposed

to improve live birth rates in couples with RM who carry a structural chromosome

abnormality (Munne et al., 2000; Otani et al., 2006). The rationale behind the use

of PGD for this purpose is that relatively more live births will be achieved and that

the number of miscarriages will be reduced by eliminating the transfer of unbalanced

embryos. Since PGD is invasive and requires IVF-ICSI, the claim that PDG increases

live birth rates should be substantiated before this technique is introduced into daily

clinical practice. To improve informed decision-making, we systematically searched the

literature on live birth rates and miscarriage rates after natural conception and after

PGD, in couples with a history of two or more miscarriages and carrying a structural

chromosome abnormality.

Methods

Search strategyEMBASE (Ovid, 1980 to April 2009), MEDLINE (Ovid, 1950 to April 2009) and Cochrane

Central Register of Controlled Trials (Central, April 2009) were systematically searched

as well as the reference lists of the selected articles.

Chapter 5

78

Initially, a search was conducted for randomized controlled trials (RCTs) and/or non-

randomized comparative studies comparing natural conception with PGD in couples

with RM carrying a structural chromosome abnormality. Since no such RCTs or non-

randomized comparative studies were found, two separate searches were conducted;

one for all study designs reporting on the reproductive outcome after attempting natural

conception, using the keywords ‘recurrent miscarriage’ and ‘structural chromosome

abnormalities’, and one for the reproductive outcome after PGD, using the keywords

‘preimplantation genetic diagnosis’, ‘recurrent miscarriage’ and ‘structural chromosome

abnormalities’. The searches were performed by a clinical librarian (J.L.)

The appendix shows the search strategies in EMBASE, and adapted for MEDLINE,

which were used to investigate the reproductive outcome after natural conception and

after PGD in couples with RM and carrying a structural chromosome abnormality.

Study selection and data extraction

All cohort studies, patient series and case reports describing the reproductive

outcome after attempting natural conception or after PGD for structural chromosome

abnormalities and in which couples with a history of at least two miscarriages could

be identified were eligible for this review. Structural chromosome abnormalities

were classified according to the recommendations of The International Standing

Committee for Human Cytogenetic Nomenclature (ISCN, 2005). RM was defined as

the loss of two or more pregnancies before the 20th week of gestation regardless

of the outcome of intervening pregnancies. The intervention was PGD by polar body

biopsy or by blastomere biopsy. The primary outcome measure was live birth rate per

couple, defined as the percentage of couples achieving a live birth. Secondary outcome

measure was miscarriage rate per couple.

Data were extracted by four independent investigators (M.T.M.F., J.C.K., M.G. and

A.M.M.), and results were compared. Any disagreement was resolved by discussion.

Results

Results of the searchThe flow chart of study inclusion is presented in Fig. 1. There were no RCTs or non-

randomized comparative studies comparing reproductive outcome after attempting

natural conception to reproductive outcome after PGD. The search on studies

describing reproductive outcome after attempting natural conception resulted in 945

publications. After rejection of articles not addressing the research question, four

articles were included. The search for studies reporting on the reproductive outcome

in couples with RM carrying a structural chromosome abnormality after PGD resulted


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5Chapter

in 359 publications. After rejection of articles not addressing the research question, 21

articles were included.

Figure 1 Flowchart of trial inclusion—reproductive outcome after natural conception or after PGD in couples with RM carrying a structural chromosome abnormality.

Chapter 5

80

Reproductive outcome after natural conceptionThe main characteristics of the four studies on reproductive outcome after attempting

natural conception in couples with RM carrying a structural chromosome abnormality

are presented in Table I (Carp et al., 2004; Franssen et al., 2006; Stephenson and Sierra,

2006; Sugiura Ogasawara et al., 2008). These were two prospective cohort studies and

two retrospective cohort studies. The total number of couples included was 469. The

average number of miscarriages prior to parental chromosome analysis varied between

2.9 and 4.3 and the average maternal age varied from 29.8 to 32.8 years. In one of

these studies, 21 couples were mosaic for a numeric chromosome abnormality (Carp

et al., 2004). The reproductive outcome of these couples could not be distinguished

from couples with structural chromosome abnormalities. Data on live birth rate and

miscarriage rate per couple after parental chromosome analysis are summarized in

Table II. Studies are divided into those reporting on reproductive outcome of the

first pregnancy after parental chromosome analysis and studies reporting on the

cumulative reproductive outcome of pregnancies after parental chromosome analysis

(0–12 pregnancies). In total, 12% (range: 3–26%) of all couples failed to conceive.

Live birth rate per couple varied between 33 and 60% (median 55.5%) after parental

chromosome analysis; miscarriage rate ranged from 21 to 40% (median 34%). In none

of the first pregnancies after parental chromosome analysis were viable unbalanced

offspring reported.

In the two studies reporting on the cumulative reproductive outcome of all reported

pregnancies after parental chromosome analysis, at least one healthy child was

documented in 64% and in 83% of the couples, respectively and at least one

miscarriage was documented in 21% and in 49% of the couples in these two studies,

Table I. Characteristics of the four included studies on reproductive outcome after attempting natural conception in couples with RM carrying a structural chromosome abnormality.

Design No. of couples

Patient characteristics Follow-up

Average maternal age (years) ± SEM

Average no. of previous miscarriages

Average no. of previous live

births

Data on first pregnancy only or long-term follow-up

Mean follow-up (years)

Carp et al. (2004) Single centre retrospective cohort

99 32.8 ± 5.8 4.3 ± 1.6 First pregnancy 1.0 ± 1.1

Sugiura Ogasawara et al. (2008)

Single centre prospective cohort

71 31.4 (23–42) 2.9 (2–6) 0.2 (0–1) First pregnancy 0.8 ± 0.6

Stephenson and Sierra (2006)


52 29.8 ± 5.0 3.4 Long-term Duration not mentioned 0–3 pregnancies

Franssen et al. (2006) Multicentre retrospective cohort

247 32.1 ± 4.3 3 Long-term 5.9 (2.0–11.4) 0–12 pregnancies

Number of couples per study varied from 52 to 247.


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5Chapter

respectively (Franssen et al., 2006; Stephenson and Sierra, 2006). In one study, two

fetuses with an unbalanced karyotype were detected at prenatal diagnosis (0.4%) and

two children with an unbalanced karyotype were born (0.4%) (Franssen et al., 2006).

Reproductive outcome after PGD

Table I. Characteristics of the four included studies on reproductive outcome after attempting natural conception in couples with RM carrying a structural chromosome abnormality.

Design No. of couples

Patient characteristics Follow-up

Average maternal age (years) ± SEM


Average no. of previous live

births

Data on first pregnancy only or long-term follow-up

Mean follow-up (years)

Carp et al. (2004) Single centre retrospective cohort

99 32.8 ± 5.8 4.3 ± 1.6 First pregnancy 1.0 ± 1.1

Sugiura Ogasawara et al. (2008)


71 31.4 (23–42) 2.9 (2–6) 0.2 (0–1) First pregnancy 0.8 ± 0.6

Stephenson and Sierra (2006)


52 29.8 ± 5.0 3.4 Long-term Duration not mentioned 0–3 pregnancies

Franssen et al. (2006) Multicentre retrospective cohort

247 32.1 ± 4.3 3 Long-term 5.9 (2.0–11.4) 0–12 pregnancies

Number of couples per study varied from 52 to 247.

Table II. Live birth rate and miscarriage rate per couple after natural conception in couples with RM carrying a structural chromosome abnormality.

Study No. of couples Live births after parental chromosome analysis n (%)

Miscarriages after parental chromosome analysis n (%)

No. of (potential)

viable unbalanced offspring

(a) Reproductive outcome in the first pregnancy after parental chromosome analysis (including couples with failure to conceive)

Carp et al. (2004) 99 33 (33%) 40 (40%) None reported

Franssen et al. (2006) 247 148 (60%) 91 (37%) 0

Stephenson and Sierra (2006) 52 29 (56%) 11 (21%) 0

Sugiura Ogasawara et al. (2008) 71 39 (55%) 22 (31%) 0

(b) Reproductive outcome of all pregnancies after parental chromosome analysis

Franssen et al. (2006) 247 205 (83%)a 120 (49%)b 4

2 at PND

2 live births

Stephenson and Sierra (2006) 52 33 (64%)a 11 (21%)b 0

Studies are categorized by (a) the first pregnancy after parental chromosome analysis and (b) all pregnancies reported after parental chromosome analysis. PND, invasive prenatal diagnosis.aCouples with at least one live birth after parental chromosome analysis. bCouples with at least one miscarriage after parental chromosome analysis.

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82

The main characteristics of the 21 studies presenting results after PGD are listed in

Table III (Conn et al., 1998; Munne et al., 1998a, b, c; Conn et al., 1999; Van Assche et

al., 1999; Willadsen et al., 1999; Coonen et al., 2000; Escudero et al., 2000; Lee and

Munne, 2000; Munne et al., 2000; Durban et al., 2001; Escudero et al., 2001; Fridstrom

et al., 2001; Scriven et al., 2001; Emiliani et al., 2002; Pujol et al., 2003; Simopoulou et

al., 2003; Kyu Lim et al., 2004; Sampson et al., 2004; Otani et al., 2006). In total, these

studies included 164 couples receiving PGD for structural chromosome abnormalities,

among whom 126 couples with a history of two or more miscarriages prior to PGD

were identified. Baseline characteristics of these 126 couples are listed in Table III. The

average number of miscarriages prior to PGD varied between 2.0 and 7.7, and the

average maternal age varied between 29.0 and 37.5 years. In 104 couples, one of the

Table III. Characteristics of the 21 included studies reporting on reproductive outcome after PGD in couples carrying a structural chromosome abnormality in which couples with RM could be identified.

Design No. of couples with RM

Average maternal age (years)


Average no. of previous live births

1 Van Assche et al. (1999) Descriptive 1 29 5 0

2 Conn et al. (1998) Descriptive 1 37 2 0


4 Coonen et al. (2000) Descriptive 2 – 6.5 (6–7) 0

5 Durban et al. (2001) Descriptive 5 35.2 (32–37) 3.2 (5–5) 0

6 Emiliani et al. (2002) Descriptive 1 37 6 0

7 Escudero et al. (2000) Descriptive 2 30 2.5 (2–3) 0.5 (0–1)

8 Escudero et al. (2001) Descriptive 1 33 3 0

9 Fridstrom et al. (2001) Descriptive 8 – 2.8 (2–4) 1 (1–2)

10 Kyu Lim et al. (2004)a Cohort study 49 31.4 ± 3.9 2.9 (0–8) 0.2 (0–1)

11 Lee and Munne (2000) Descriptive 1 31 2 1

12 Munne et al. (1998a) Descriptive 1 32 5 0

13 Munne et al. (1998b) Descriptive 3 33.7 (28–37) 4.7 (4–5) 0.3 (0–1)

14 Munne et al. (1998c) Descriptive 2 35 (33–37) ≥6 0

15 Munne et al. (2000) Descriptive 3 – 7.7 (2–15) 0

16 Otani et al. (2006)b Descriptive 33 32.7 (26–41) 3.5 ± 1.9 0

17 Pujol et al. (2003) Descriptive 2 37.5 (36–39) 4 (3–5) 0

18 Sampson et al. (2004) Descriptive 4 29.8 (25–33) 2.3 (2–3) 0.5 (0–2)

19 Scriven et al. (2001) Descriptive 1 34 4 0

20 Simopoulou et al. (2003) Descriptive 3 33.7 (32–36) 3.7 (2–5) 0

21 Willadsen et al. (1999) Descriptive 2 34 (31–37) ≥2 –

Number of couples per study varied from 1 to 49 couples. aIncluding seven couples without two or more miscarriages prior to PGD, which could not be separated. bOngoing pregnancies, no live births reported.


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partners carried a reciprocal translocation, in 20 couples a Robertsonian translocation

and in two couples a pericentric inversion. The results after PGD in these 126 couples

are presented in Table IV. One of the studies (Otani et al., 2006) only reported ongoing

pregnancies and miscarriages after PGD, and did not detail the number of live births:

since this study presents one of the largest series of couples with RM carrying a

structural chromosome abnormality who had undergone PGD, it was decided not to

exclude these data but to consider these ongoing pregnancies as live births. Live birth

rate per couple varied between 0 and 100% (median 31%) after parental chromosome

analysis; miscarriage rate ranged from 0 to 50% (median 0%). Live birth rate per

started cycle varied between 0 and 100% (median 17%) after parental chromosome

analysis; miscarriage rate per started cycle ranged from 0 to 50% (median 0%). No

studies reported that viable unbalanced offspring occurred after PGD.

Table III. Characteristics of the 21 included studies reporting on reproductive outcome after PGD in couples carrying a structural chromosome abnormality in which couples with RM could be identified.

Design No. of couples with RM

Average maternal age (years)


Average no. of previous live births

1 Van Assche et al. (1999) Descriptive 1 29 5 0



4 Coonen et al. (2000) Descriptive 2 – 6.5 (6–7) 0

5 Durban et al. (2001) Descriptive 5 35.2 (32–37) 3.2 (5–5) 0

6 Emiliani et al. (2002) Descriptive 1 37 6 0

7 Escudero et al. (2000) Descriptive 2 30 2.5 (2–3) 0.5 (0–1)

8 Escudero et al. (2001) Descriptive 1 33 3 0

9 Fridstrom et al. (2001) Descriptive 8 – 2.8 (2–4) 1 (1–2)

10 Kyu Lim et al. (2004)a Cohort study 49 31.4 ± 3.9 2.9 (0–8) 0.2 (0–1)

11 Lee and Munne (2000) Descriptive 1 31 2 1

12 Munne et al. (1998a) Descriptive 1 32 5 0

13 Munne et al. (1998b) Descriptive 3 33.7 (28–37) 4.7 (4–5) 0.3 (0–1)

14 Munne et al. (1998c) Descriptive 2 35 (33–37) ≥6 0

15 Munne et al. (2000) Descriptive 3 – 7.7 (2–15) 0

16 Otani et al. (2006)b Descriptive 33 32.7 (26–41) 3.5 ± 1.9 0

17 Pujol et al. (2003) Descriptive 2 37.5 (36–39) 4 (3–5) 0

18 Sampson et al. (2004) Descriptive 4 29.8 (25–33) 2.3 (2–3) 0.5 (0–2)

19 Scriven et al. (2001) Descriptive 1 34 4 0

20 Simopoulou et al. (2003) Descriptive 3 33.7 (32–36) 3.7 (2–5) 0

21 Willadsen et al. (1999) Descriptive 2 34 (31–37) ≥2 –

Number of couples per study varied from 1 to 49 couples. aIncluding seven couples without two or more miscarriages prior to PGD, which could not be separated. bOngoing pregnancies, no live births reported.

Chapter 5

84

Discussion

In couples trying to conceive, RM causes tremendous grief, feelings of insecurity

and ambivalence about each subsequent pregnancy. Once a structural chromosome

abnormality is detected in one of the partners, couples are confronted with difficult

choices, such as whether or not to try to conceive again, to undergo prenatal diagnosis

in future pregnancies and to terminate a pregnancy once an unbalanced fetal

karyotype is found. Although PGD might seem an attractive alternative for couples

desperately seeking help to carry a pregnancy to term, its benefits should be clear

before introducing this technique into daily clinical practice.

Table IV. Results of PGD in couples with at least two miscarriages, prior to current PGD, carrying a structural chromosome abnormality.

No. of couples

Started cycles

Embryo transfer cycles

Transferred embryos

TE per embryo transfer cycle

Pregnancies resulting in live birth n (%)

No. of healthy children

Miscarriages Other pregnancy outcome

1 Van Assche et al. (1999) 1 3 2 7 3.5 (3–4) 0 (0%) 0 0 0

2 Conn et al. (1998) 1 3 2 2 1 0 (0%) 0 0 1 biochemical

3 Conn et al. (1999) 1 2 1 1 1 (1) 0 (0%) 0 0 1 ongoing

4 Coonen et al. (2000) 2 4 2 3 1.5 (1–2) 1 (50%) 1 0 0

5 Durban et al. (2001) 5 5 2 3 1.5 (1–2) 0 (0%) 0 1 0

6 Emiliani et al. (2002) 1 2 2 3 1.5 (1–2) 1 (100%) 2 0 0

7 Escudero et al. (2001) 1 2 2 6 3 (3) 1 (100%) 1 0 1 ongoing

8 Escudero et al. (2000) 2 2 2 2 1 (1) 1 (50%) 2 0 0

9 Fridstrom et al. (2001) 8 16 9 14 1.6 (1–2) 2 (25%) 3 0 0

10 Kyu Lim (2004)a 49 70 64 169 2.6 (1–4) 15 (31%) 16 3 2 ectopic

11 Lee and Munne (2000) 1 1 2 4 2 1 (100%) 1 0 1 biochemical

12 Munne et al. (1998a) 1 2 0 0 0 (0) 0 (0%) 0 0 0

13 Munne et al. (1998b) 3 3 2 3 1.5 (1–2) 1 (33%) 2 0 1 ongoing

14 Munne et al. (1998c) 2 2 2 4 2 (2) 1 (50%) 2 1 0

15 Munne et al. (2000) 3 3 3 6 2 (1–3) 0 (0%) 0 0 0

16 Otani et al. (2006) 33 – 41 – Max 3 18b (55%) – 1 18 ongoing

17 Pujol et al. (2003) 2 2 2 2 1 (1) 0 (0%) 0 0 0

18 Sampson et al. (2004) 4 5 1 1 1 (1) 0 (0%) 0 0 0

19 Scriven et al. (2001) 1 1 1 3 3 (3) 1 (100%) 3 0 0

20 Simopoulou et al. (2003) 3 3 3 5 1.7 (1–3) 1 (33%) 1 0 1 biochemical

21 Willadsen et al. (1999) 2 2 1 1 1 0 (0%) 0 0 1 affected childc

ET, embryo transfer; TE, transferred embryos.aIncluding seven couples without two or more miscarriages prior to PGD, which could not be separated. bOnly ongoing pregnancies, no live births reported. cChild with 46,XX karyotype and severe ventricular septal defect with complications.


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5Chapter

We found that little information was available addressing our specific research

question. This review deals with the specific subgroup of couples with RM carrying a

structural chromosome abnormality and not with couples with RM in general or with

couples carrying a structural chromosome abnormality without RM in their obstetric

history. Unfortunately, in larger series describing the reproductive outcome after PGD

in carriers of structural chromosome abnormalities in general, such as the data from

the European Society of Human Reproduction and Embryology PGD Consortium,

details on obstetric history are not presented or not provided by case (Goossens et al.,

2009). The obstetric history, including the previous number of miscarriages, cannot be

extracted from these data.

Table IV. Results of PGD in couples with at least two miscarriages, prior to current PGD, carrying a structural chromosome abnormality.

No. of couples

Started cycles

Embryo transfer cycles

Transferred embryos

TE per embryo transfer cycle

Pregnancies resulting in live birth n (%)

No. of healthy children

Miscarriages Other pregnancy outcome

1 Van Assche et al. (1999) 1 3 2 7 3.5 (3–4) 0 (0%) 0 0 0

2 Conn et al. (1998) 1 3 2 2 1 0 (0%) 0 0 1 biochemical

3 Conn et al. (1999) 1 2 1 1 1 (1) 0 (0%) 0 0 1 ongoing

4 Coonen et al. (2000) 2 4 2 3 1.5 (1–2) 1 (50%) 1 0 0

5 Durban et al. (2001) 5 5 2 3 1.5 (1–2) 0 (0%) 0 1 0

6 Emiliani et al. (2002) 1 2 2 3 1.5 (1–2) 1 (100%) 2 0 0

7 Escudero et al. (2001) 1 2 2 6 3 (3) 1 (100%) 1 0 1 ongoing

8 Escudero et al. (2000) 2 2 2 2 1 (1) 1 (50%) 2 0 0

9 Fridstrom et al. (2001) 8 16 9 14 1.6 (1–2) 2 (25%) 3 0 0

10 Kyu Lim (2004)a 49 70 64 169 2.6 (1–4) 15 (31%) 16 3 2 ectopic

11 Lee and Munne (2000) 1 1 2 4 2 1 (100%) 1 0 1 biochemical

12 Munne et al. (1998a) 1 2 0 0 0 (0) 0 (0%) 0 0 0

13 Munne et al. (1998b) 3 3 2 3 1.5 (1–2) 1 (33%) 2 0 1 ongoing

14 Munne et al. (1998c) 2 2 2 4 2 (2) 1 (50%) 2 1 0

15 Munne et al. (2000) 3 3 3 6 2 (1–3) 0 (0%) 0 0 0

16 Otani et al. (2006) 33 – 41 – Max 3 18b (55%) – 1 18 ongoing

17 Pujol et al. (2003) 2 2 2 2 1 (1) 0 (0%) 0 0 0

18 Sampson et al. (2004) 4 5 1 1 1 (1) 0 (0%) 0 0 0

19 Scriven et al. (2001) 1 1 1 3 3 (3) 1 (100%) 3 0 0

20 Simopoulou et al. (2003) 3 3 3 5 1.7 (1–3) 1 (33%) 1 0 1 biochemical

21 Willadsen et al. (1999) 2 2 1 1 1 0 (0%) 0 0 1 affected childc

ET, embryo transfer; TE, transferred embryos.aIncluding seven couples without two or more miscarriages prior to PGD, which could not be separated. bOnly ongoing pregnancies, no live births reported. cChild with 46,XX karyotype and severe ventricular septal defect with complications.

Chapter 5

86

The absence of RCTs and non-randomized comparative studies makes a direct

comparison between PGD and natural conception in couples with RM carrying a

structural chromosome abnormality impossible. The best outcome measures to directly

compare the reproductive outcome of these groups would be the time required to

obtain a healthy live birth or the live birth rate in a fixed time period. None of the

studies carried out thus far have included these details. Data can only be derived

from observational studies or even from case reports. Considering the poor quality

and the heterogeneity of these studies, performing a meta-analysis was considered

inappropriate. Describing the results of two separately performed systematic reviews,

as presented in this paper, is therefore the best alternative for investigating the potential

benefits of PGD over natural conception. Other weaknesses of the individual studies

reporting on the reproductive outcome after PGD were that none of them reported on

the costs of PGD, or complications related to the IVF-ICSI procedure, such as ovarian

hyperstimulation syndrome.

The results after PGD might be inflated as these data are based upon small series

and case reports that are notorious for being prone to publication bias. Also, one

of the studies included in this review (Otani et al., 2006) only reported on ongoing

pregnancies, not number of live births: in this study subsequent miscarriage or stillbirth

might have occurred, leading to a lower live birth rate.

Little is known on the karyotype of miscarried conceptuses in couples with RM carrying

a structural chromosome abnormality, since karyotyping miscarriage tissue in these

couples is not routine practice. It has been described that after natural conception

in carrier couples with RM, ∼25% of the miscarried conceptuses has an unbalanced

karyotype (Carp et al., 2006; Stephenson and Sierra, 2006). In addition, it has been

reported that after PGD in carrier couples, only 25% of the embryos with a diagnostic

Table V. Summary of live birth rate and miscarriage rate per couple after natural conception and after PGD in couples with RM carrying a structural chromosome abnormality.

No. of studies

No. of couples

Started cycles

No. of live births (%)

No. of miscarriages (%)

Natural conception

First pregnancy after natural conception

4 469 NA 249 (range: 33–60%, median: 55.5%)

164 (range: 21–40%, median: 34%)

All pregnancies after natural conceptiona

2 299 NA 238b (range: 64–83%, median: 73.5%)

131c (range: 21–49%, median: 35%)

PGD 21 126 133 44 (range: 0–100%, median 31%)d

6 (range: 0–50%, median: 0%)

NA, not applicable.a0–12 pregnancies.bCouples with at least one live birth. cCouples with at least one miscarriage. dIncluding 18 ongoing pregnancies.


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5Chapter

result were transferable, confirming the high level of chromosomally abnormal embryos

in these patients (Goossens et al., 2009). This might explain why the results of PGD

in these couples are rather poor. For unbalanced products of conception, miscarriage

serves as a natural selection mechanism which, to date, cannot be improved by clinical

interventions.

In theory, offering PGD to couples with RM and carrying a structural chromosome

abnormality might be beneficial to prevent the birth of children with an unbalanced

karyotype and to reduce the number of miscarriages. We know, however, that the risk

of viable unbalanced offspring in these couples is very low after natural conception

(Franssen et al., 2006). The finding of a low miscarriage rate after PGD was to be

expected since PGD selects for the replacement of unbalanced embryos. It has been

reported that couples with RM and carrying a structural chromosome abnormality are

at a higher risk of repeat miscarriages compared with non-carrier couples (Carp et al.,

2004; Franssen et al., 2006; Stephenson and Sierra, 2006; Sugiura Ogasawara et al.,

2008). In unbalanced products of conception, miscarriage serves as a natural selection

mechanism.

In some of the studies included in this review, preimplantation genetic screening

(PGS) for aneuploidies (or PGD-S) had been conducted as well as PGD for structural

chromosome abnormalities, which might contribute to a lower miscarriage rate.

However, PGD for aneuploidies in couples of advanced maternal age has been shown

to be not beneficial (Mastenbroek et al., 2007). The low miscarriage rate found in this

review could also be the result of publication bias.

Conclusion

In conclusion, at present there are insufficient data indicating that PGD improves the

live birth rate in couples with RM carrying a structural chromosome abnormality. More

research on this topic is urgently required. We would welcome future attempts to

perform RCTs and to present details on obstetric history so that it might become clear

whether subgroups of carrier couples exist that might benefit from PGD. To date,

it remains a matter of debate whether a lower miscarriage rate after PGD in these

couples would justify its use in light of the limited change in live birth rate, the high

costs and procedure-related complications, given the scarce data. It is our opinion that,

currently, there are insufficient arguments to introduce PGD, with its high costs and

potential complications related to the IVF procedure, into the daily clinical practice for

couples with RM carrying a structural chromosome abnormality.

Chapter 5

88

Supplementary data

Search strategies used in systematic review of literature:

Natural conception: 1. recurrent abortion/or Spontaneous Abortion/((habitual* or recurr* or multiple

or repeat* or repetit* or consecutive or unexplained or spontaneous*) adj4

(Abortion* or miscarriage*)).tw.

2. ((habitual* or recurr* or multiple or repeat* or repetit* or consecutive or

unexplained or spontaneous*) adj4 ((pregnanc* or fetal or fetal or fetus* or fetus*

or embryo* or intrauterine or intrauterine or in-utero) adj2 loss*)).tw.

3. ((habitual* or recurr* or multiple or repeat* or repetit* or consecutive or

unexplained) adj4 ((fetal or fetal or fetus* or fetus* or embryo* or intrauterine or

intrauterine or in utero) adj2 death*)).tw.

4. ((three or “3” or two or “2” or frequent or previous or more) adj2 (Abortion* or

miscarriage* or ((pregnanc* or fetal or fetal or fetus* or fetus* or embryo* or

intrauterine or intrauterine or in-utero) adj2 loss*) or ((fetal or fetal or fetus* or

fetus* or embryo$ or intrauterine or intrauterine or in-utero) adj2 death*))).tw.


6. or/1–6

7. exp human/

8. 7 and 8

9. structural chromosome aberration/or chromosome duplication/or chromosome

insertion/or double minute chromosome/or partial monosomy/or ring chromosome/

or exp chromosome deletion/or chromosome inversion/or exp chromosome

translocation/

10. genetic recombination/

11. (Structural adj2 chromosom* adj2 (abnormal* or aberra* or anomal* or defect*

or error*)).tw.

12. translocation*.tw.

13. (chromosom* and (deletion* or inversion*)).tw.

14. (chromosom* adj2 rearrangement*).tw.

15. robertson*.tw. and (chromosom* or transloc*).mp.

16. or/10–16

17. 9 and 17

18. ((preimplant* or pre-implant*) and (diagn* or screen*)).mp.


20. (pgd* or (pgs and screen*)).mp.



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5Chapter

22. (aneuploid$ adj10 (diagn$ or screen$)).mp.

23. or/19–23

24. 18 and 24

25. exp controlled clinical trial/or double blind procedure/or single blind procedure/or

randomization/or placebo/

26. (randomized and controlled and trial).ti,ab.

27. ((controlled adj (trial or study)) or (controlled adj clinical adj (trial or study))).ti,ab.

28. or/26–28

29. 18 and 24 and 29

30. from 30 keep 1

31. from 18 keep 1–568

32. from 32 keep 1–10

PGD: 1. ((preimplant$ or pre-implant$) adj4 (diagnos$ or testing or tests)).mp.

2. ((prenatal$ or antenatal$) adj2 genetic adj2 (diagnos$ or testing or tests)).mp.

3. pgd.mp.

4. or/1–3

5. ((habitual$ or recurr$ or multiple or repeat$ or repetit$ or three or “3” or two

or “2”) adj4 (((pregnanc$ or fetal or fetal or fetus) adj2 loss$) or (Abortion$ or

miscarriage$))).ti,ab.

6. ((IRM or RSA or RM or RPL) and (pregnan$ or abortion$)).ti,ab.

7. recurrent Abortion/

8. or/5–7

9. structural chromosome aberration/or chromosome duplication/or chromosome

insertion/or double minute chromosome/or partial monosomy/or ring

chromosome/or exp chromosome deletion/or chromosome inversion/or exp

chromosome translocation/

10. (structural adj2 chromosom$ adj2 (abnormal$ or aberra$ or anomal$ or defect$

or error$)).tw.

11. exp chromosome translocation/or translocation$.mp.

12. chromosom$ and (deletion$ or inversion$)).mp.

13. or/9–12

14. 4 and (8 or 13)

Chapter 5

90

References

American College of Obstetricians and Gynecologists, Practice Bulletin. Management of recurrent early pregnancy loss. Int J Gynaecol Obstet,. 2002;78:179-90.

Braekeleer de M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod, 1990;5:519-28.

Carp H, Feldman B, Oelsner G, Schiff E. Parental karyotype and subsequent live births in recurrent miscarriage. Fertil Steril, 2004;81:1296-301.

Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod, 1994;9:1328-32.

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Coonen E, Martini E, Dumoulin JC, Hollanders-Crombach HT, de Die-Smulders C, Geraedts JP, Hopman AH, Evers JL. Preimplantation genetic diagnosis of a reciprocal translocation t(3;11)(q27.3;q24.3) in siblings. Mol Hum Reprod, 2000;6:199-206.

Durban M, Benet J, Boada M, Fernandez E, Calafell JM, Lailla JM, Sanchez-Garcia JF, Pujol A, Egozcue J, Navarro J. PGD in female carriers of balanced Robertsonian translocations by first polar body analysis. Hum Reprod Update, 2001;7:591-602.

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Munne S, Scott R, Sable D, Cohen J. First pregnancies after preconception diagnosis of translocations of maternal origin. Fertil Steril, 1998;69:675-81.

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Munne S, Morrison L, Fung J, Marquez C, Weier U, Bahce M, Sable D, Grundfeld L, Schoolcraft B, Scott R et al. Spontaneous abortions are reduced after preconception diagnosis of translocations. J Assist Reprod Genet, 1998;15:290-6.

Munne S, Sandalinas M, Escudero T, Fung J, Gianaroli L, Cohen J. Outcome of preimplantation genetic diagnosis of translocations. Fertil Steril, 2000;73;1209-18.


Pujol A, Durban M, Benet J, Boiso I, Calafell JM, Egozcue J, Navarro J. Multiple aneuploidies in the oocytes of balanced translocation carriers: a preimplantation genetic diagnosis study using first polar body. Reproduction, 2003;126:701-11.

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Royal College of Obstetricians and Gynaecologists (2003) The investigation and treatment of couples with recurrent miscarriage. Guideline No. 17.

Sampson JE, Ouhibi N, Lawce H, Patton PE, Battaglia DE, Burry KA, Olson SB. The role for preimplantation genetic diagnosis in balanced translocation carriers. Am J Obstet Gynecol, 2004;190:1707-11.

Scriven PN, Flinter FA, Braude PR, Ogilvie CM. Robertsonian translocations--reproductive risks and indications for preimplantation genetic diagnosis. Hum Reprod. 2001;16: 67-2273.

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Simopoulou M, Harper JC, Fragouli E, Mantzouratou A, Speyer BE, Serhal P, Ranieri DM, Doshi A, Henderson J, Rodeck CH, Delhanty JD. Preimplantation genetic diagnosis of chromosome abnormalities: implications from the outcome for couples with chromosomal rearrangements. Prenat Diagn, 2003;23:652-62.

Stephenson MD, Sierra S. Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod, 2006;21:1076-82.

Sugiura Ogasawara M, Aoki K, Fujii T, Fujita T, Kawaguchi R, Maruyama T, Ozawa N, Sugi T, Takeshita T, Saito S. Subsequent pregnancy outcomes in recurrent miscarriage patients with a paternal or maternal carrier of a structural chromosome rearrangement. J Hum Genet, 2008;53:622-28.

Tharapel AT, Tharapel SA, Bannerman RM. Recurrent pregnancy losses and parental chromosome abnormalities: a review. Br J Obstet Gynaecol 1985;92:899-914.

Van Assche E, Staessen C, Vegetti W, Bonduelle M, Vandervorst M, Van Steirteghem A, Liebaers I. Preimplantation genetic diagnosis and sperm analysis by fluorescence in-situ hybridization for the most common reciprocal translocation t(11;22). Mol Hum Reprod, 1999;5:682-90.

Willadsen S, Levron J, Munné S, Schimmel T, Márquez C, Scott R, Cohen J. Rapid visualization of metaphase chromosomes in single human blastomeres after fusion with in-vitro matured bovine eggs. Hum Reprod, 1999;14:470-5.

6Supportive care for women with unexplained recurrent miscarriages; patients’ perspectives

Anna M. MustersElsbeth F. Taminiau-Bloem Emmy van den BoogaardFulco van der Veen Mariëtte Goddijn

Human Reproduction 2011;26::873-7

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Abstract

BACKGROUND Supportive care is currently the only ‘therapy’ that can be offered to

women with unexplained recurrent miscarriage (RM). What these women themselves

prefer as supportive care in their next pregnancy has never been substantiated.

Therefore the aim of this study was to explore what women with unexplained RM

prefer as supportive care during their next pregnancy.

METHODS We performed explorative, semi-structured, in-depth interviews. The

interviews were performed with 15 women with unexplained RM who were actively

seeking conception. All interviews were conducted by telephone. The interviews were

fully transcribed and two researchers independently identified text segments from the

transcribed interviews and categorized them in the appropriate domain.

RESULTS Women identified 20 different supportive care options; 16 of these options

were preferred for their next pregnancy. Examples of the preferred supportive care

were early and frequently repeated ultrasounds, βHCG monitoring, practical advice

concerning life style and diet, emotional support in the form of counselling, a clear

policy for the upcoming 12 weeks and medication. The four supportive care options

that were not preferred by the women were admittance to a hospital ward at the

same gestational age as previous miscarriages, Complementary Alternative Medicine,

ultrasound every other day and receiving supportive care from their general practitioner.

CONCLUSIONS Our study identified several relevant preferences for supportive care in

women with unexplained RM. Many of these can be offered by the gynaecologist and

will help in guaranteeing high-quality patient-centred care.

Supportive care for women with unexplained recurrent miscarriages: Qualitative research

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Introduction

Recurrent miscarriage (RM), defined as two or more miscarriages before 20

weeks pregnancy, affects approximately 3% of all couples (Regan and Rai, 2000).

Current diagnostic procedures identify aetiological factors, such as translocations,

antiphospholipid syndrome, endocrine disorders and uterine abnormalities in

approximately 50% of these couples. The other 50% are diagnosed as couples with

unexplained RM (Rai and Regan, 2006). Unexplained RM is a distressing condition for

the affected couple and a frustrating problem for the clinician, as there is no effective

therapy for these couples. In addition to the grief that accompanies a miscarriage,

anxiety is a common response during a next pregnancy (Cordell and Thomas, 1997;

Cote-Arsenault, 2001; Brier, 2004; O’Leary, 2004; Bennett et al., 2005; Fertl et al.,

2009).

Supportive care is frequently offered to women with unexplained RM, reporting live

birth rates up to 85% (Javert, 1954; Stray-Pedersen and Stray-Pedersen, 1984; Liddell

et al., 1991; Clifford et al., 1997; Brigham et al., 1999). Current guidelines from the

European Society of Human Reproduction and Embryology (ESHRE) and the Royal

College of Obstetricians and Gynaecologists (RCOG) recommend supportive care

during the next pregnancy for women with unexplained RM (RCOG, 2003; Jauniaux et

al., 2006), suggesting it has a beneficial effect.

Nevertheless, there are several problems with implementing this recommendation.

First, supportive care for women with unexplained RM is an ill-defined concept (van

den Boogaard et al., 2011). Second, no uniform treatment protocol can be distilled

from studies on supportive care, because the care offered in these studies varied widely

from early ultrasound investigation during the next pregnancy, to relaxation tapes and

admittance to the hospital ward on the same gestational age as previous miscarriages

(Javert, 1954; Stray-Pedersen and Stray-Pedersen, 1984; Liddell et al., 1991; Clifford et

al., 1997, Brigham et al., 1999). Third, what the women themselves prefer as supportive

care in their next pregnancy has never been substantiated.

Therefore, the objective of this study was to explore what women with unexplained

RM would prefer as supportive care during their next pregnancy.


Women were invited to participate at the Centre for Reproductive Medicine of the

Academic Medical Centre in Amsterdam after the diagnostic work-up for RM had been

performed.

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Women were eligible if they had two or more first trimester miscarriages (≤20 weeks

pregnancy), were actively seeking conception and if no aetiology could be found for the

miscarriages. The eligible women were contacted by the first author. To obtain a group

of women with unexplained RM that was representative for the whole unexplained RM

population, we employed purposive sampling based on demographic characteristics,

number of preceding miscarriages and having children.

The semi-structured in-depth interviews, which consisted of both a topic list and

open questions, were designed by an expert panel consisting of a gynaecologist, a

resident, two PhD students, all specializing in RM and a medical psychologist with

experience in the development of in-depth interviews (Taminiau-Bloem et al., 2010;

van den Boogaard et al., 2011). The topic list and the open questions were based on

information acquired at expert panel meetings and supplemented with ideas from the

sparse literature on this topic (Javert, 1954; Stray-Pedersen and Stray-Pedersen, 1984;

Liddell et al., 1991; Clifford et al., 1997; Brigham et al., 1999). The content of the

interview was then presented to the expert panel that offered their final adjustments.

The translated semi-structured in-depth interview with the open questions and topic

list can be found in the Supplementary data. To test the interview procedure, the final

set of interview questions were pilot-tested on two women with unexplained RM.

The interview started with an open question asking the women what they preferred

as supportive care during their next pregnancy, followed by a structured topic list of

supportive care options on which the women could comment on (see Supplementary

data for full topic list and all open questions). During the interview, women were asked

if there were any other items they wanted to add to the topic list. Each new possible

option of supportive care was subsequently added to this list.

When the interview was concluded, the interviewer summarized the responses to

assure accuracy. When the interviews of three consecutive women did not provide

new insights, i.e. when saturation was achieved, data collection was stopped (Pope et

al., 2000).

Interviews took place over a 6-month period from November 2009 till June 2010. All

interviews were done by telephone and took 30–60 min. The interviewer was not

involved in the RM work-up or treatment to ensure objectivity. The interviews were

audio-recorded and transcribed verbatim.

Study design and analysis were performed according to the established criteria for

conducting qualitative research (Britten, 1995; Mays and Pope, 2000; Pope et al.,

2000). Two researchers (A.M.M. and E.F.T.B.) independently identified text segments

from the transcribed interviews and categorized them in the appropriate domain. After

an interview had been coded by the two researchers, they discussed their findings. Any

discrepancies were mutually discussed until consensus was achieved.


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Ethical approvalSubjects did not undergo additional investigations nor treatment. As assessed by the

Institutional Review Board (IRB), Academic Medical Center Amsterdam, the study was

not subject to the Dutch ‘Medical Research Involving Human Subjects Act’ (meaning

that no formal IRB approval was needed).

Results

Twenty women were asked to participate. Three women declined the invitation.

Seventeen women were interviewed. The two pilot interviews were not used in the

data analysis. Five main options were added during the interview process: to make

a plan with their gynaecologist for the first 12 weeks, βHCG monitoring before

ultrasound, receiving medication during pregnancy only if it is safe, miscarriage after-

care and waiting in the waiting room with visibly pregnant women (see Supplementary

data for the five additions the women made to the topic list). Data saturation was

achieved after 15 interviews. Quotes were taken verbatim from the transcripts of the

interviews and are presented in separate sections in italic.

The median age of the women was 32 years (ranging from 26 to 39 years old). The

median number of preceding miscarriages per woman was three (ranging from two to

seven miscarriages) and the median gestational age of the miscarriages was 7 weeks

(ranging from 5 to 17 weeks). Fourteen women had had their last miscarriage a median

5.5 months prior to the interview (ranging from 3 to 16 months); one woman was 8

weeks pregnant during the interview. Four women had one living child, all conceived

prior to the miscarriages. One woman had undergone IVF due to male subfertility.

Preferred supportive careThe women identified 20 different supportive care options for their next pregnancy, in

all three domains of the theoretical model. In this section, we summarize in more detail

the 16 factors that were preferred by the women (Table I).

All women had the need to inform their gynaecologist that they were pregnant.

The women indicated they would like to make a plan with their gynaecologist for

consultations and ultrasound appointments during the first 12 weeks of pregnancy.

When I go to the doctor in the beginning (of my pregnancy) I would like to discuss

what we are going to do during the next couple of weeks. Patient 14 Additionally,

women would like to ask for the gynaecologist’s advice concerning life style and diet

to make sure that they were not harming their pregnancy in any way. The women also

found it helpful if the gynaecologist could advise certain internet sites, considering the

large amount of information that can be found on the internet. The women would

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appreciate a consultation and an ultrasound early on in their pregnancy, preferably

right after a positive pregnancy test or when they would be sure that a viable

pregnancy could be seen on ultrasound. After the first ultrasound they would like to

have repeated ultrasounds every week or every 2 weeks. If they develop symptoms

resembling a miscarriage all women indicated they would want to have an ultrasound.

Although the women described that the time before an ultrasound appointment is very

stressful, they still wanted an ultrasound for certainty and reassurance that the fetus

was (still) alive.

The women preferred treatment from one gynaecologist. If more than one gynaecologist

had to be involved in their care, women stated that all treating gynaecologists would

have to have full knowledge of their medical history to gain the women’s trust and

confidence. For most women, gender of the gynaecologist was not an issue.

“It is nice when you have one or two clinicians, it means you do not have to keep on

repeating your story and you can build a trusting relationship.” Patient 2

Women stated that they would feel supported if they had βHCG monitoring at least

two times before their first ultrasound to gain confidence for this first ultrasound.

“Before 7 weeks I would like βHCG monitoring to check if it is rising, (it) gives me

peace, a good or bad ultrasound is confrontational.” Patient 4

Table I. Preferred supportive care options for women with unexplained RM during next pregnancy (n=15)

Domain 1: Medical supportive care

Domain 2: Non-medical supportive care

Domain 3: Other types of supportive care

Make a plan for the first 12 weeks with their gynaecologist

From gynaecologist Women prefer an increase in partner involvement

Receive advice from their gynaecologist concerning life style, diet and internet sites

Enquire how the patient is doing and what her emotional needs are

The need for supportive care directly after a miscarriage

Preference of one or max two well informed gynaecologists

Take the women seriously Feel unhappy in the waiting room with visibly pregnant women

Give the women the feeling they are listened to and understood

Receive frequent ultrasounds in early pregnancy and during symptoms

Counselling from social worker

ßHCG blood monitoring before first ultrasound

Experiencing supportive care from family, friends and peer groups

Receive medication only if it is safe for the child

Relaxation tools to unwind

Bereavement therapy for patients and explanation of bereavement levels for gynaecologists


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In general, women had a reserved attitude towards medication during their pregnancy.

Their concerns were mostly related to uncertainty about the medication’s safety for

their unborn child. If a specific medicine was proven as safe, then the women would

want this medication during their pregnancy. Women would participate in a scientific

trial, emphasizing again the importance of the medication’s safety. Women’s reasons

for participating were 2-fold; first to contribute for the greater good and secondly for

themselves (i.e. a higher chance of a viable pregnancy that would result in a child).

“Yes, I will seize every opportunity to increase my chances. Even if the chance is

low (for a good outcome), if it will not harm (my unborn child) than I would do it.”

Patient 9

Domain 2: Non-medical supportive careWomen did appreciate non-medical support from their gynaecologist in the form of

asking about their emotional needs and how they were doing. Furthermore women

wanted their gynaecologist to take them seriously and give them the feeling they were

listened to and understood. Women emphasized that their next pregnancy would not

be their first and they would like to be treated by a gynaecologist who was aware of

the stress and anxiety caused by multiple miscarriages.

“That they take you seriously. You lose confidence in your body if you’re not taken

seriously.” Patient 7

Women reported that they would like counselling either during their next pregnancy or

after another miscarriage. Additionally, women stated the importance of being offered

counselling even if they felt they did not need it at the moment. Women preferred

counselling from a social worker instead of a psychologist as they perceived social

workers more approachable. The women stressed that the social worker should have

experience in counselling patients with RM.

“At this moment I talk with a social worker, it is pleasant. (Because of the social

worker) I look at certain things with a different perspective now.”Patient 12

Women also stated that next to supportive care from their gynaecologist and para-

medicals, they also experienced supportive care from peer groups, family and friends.

Women actively sought peer-group contact on the internet to receive understanding

and support. At home women talked with family and/or friends for support. Some

women stated they would appreciate structured peer-group meetings conducted by

either a psychologist or a social worker.

“You feel at ease and comfortable to tell your story because they (peers) understand

me.” Patient 3

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Women stated that a relaxation tape would be helpful to unwind during their next

pregnancy. When asked about other forms of relaxation tools (massage, yoga) women

stated they might try it when offered.

“I would use a relaxation tape if offered. I am pretty stressed and I like the feeling

that I can do something. However I do not know if I would do it very often.” Patient

10

Women reacted positively to the possibility of bereavement therapy, because it

would give them closure and would help them to move on. Again, women thought

that the therapist should have experience with RM. They also thought it would be

helpful for gynaecologists to understand the different levels of bereavement women

with unexplained RM experience suffer since this would increase the gynaecologists’

recognition and empathy.

“Yes, I would like that (bereavement therapy). It would have to be bereavement

therapy specifically for people with RM. It is hard to understand for other people,

therefore you feel less supported. It can be lonely. If you lose someone other people

know, people understand. A miscarriage and pregnancy that is very real for you, is

difficult to understand for others.” Patient 13

Domain 3: Other types of supportive care

Women would feel supported in their next pregnancy if their partner was more

involved. They suggested that the gynaecologist should involve the partners more

during the consultation by addressing the partner directly. It is nice when my husband

is involved; it (RM) is just as frustrating for him. The gynaecologist should direct his

questions not only to me but also to my husband.

“The gynaecologist can do this by asking more general questions while looking at

him.” Patient 8

Women stated that aftercare was a part of supportive care that they wanted should

their next pregnancy miscarry. Women wanted guidance from their gynaecologist in

the form of a consultation with the opportunity to ask questions. This would help them

to start with their mourning process and be able to pause before they start on their

next pregnancy.

“I have had almost no guidance after my miscarriages. I would like to have the

feeling that I can ask questions when I feel the need. It is a struggle to accept my

miscarriages, and there is nowhere I can go to get support.” Patient 11


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Sitting in the waiting room with visibly pregnant women was a major problem for

women with RM. They found it very confrontational and uncomfortable. During their

next pregnancy, women would prefer to avoid this situation.

“Sitting between pregnant women is a problem for me.” Patient 1

Non-preferred supportive careOf the 20 factors we identified, four factors were not preferred by women or women

found them not to be relevant.

The first supportive care options that was not preferred was admittance to a hospital

ward on the same gestational age as previous miscarriages because they felt that

staying in hospital would not give an extra reassurance and they would rather be at

home. The second option that was not preferred was the exploration of Complementary

Alternative Medicine (CAM). Women stated that they would not seek CAM in their

next pregnancy. Some women simply would not think of it and others stated that

they were not ‘desperate enough’. The women who were positive towards CAM said

they wanted to investigate anything that might help and would prefer acupuncture.

Third, women found that an ultrasound every other day would not be needed, every

week or 2 weeks would be sufficient. Fourth, women would not go to their general

practitioner (GP) to receive supportive care because the women stated that they did

not feel comfortable discussing their RM with him or her, as their relationship with

their GP was not close or they did not feel the GP had experience with women with

unexplained RM.

Discussion

To delineate the so far ill-defined concept of supportive care in couples with

unexplained RM, we collected data on what women with unexplained RM would prefer

as supportive care in the very early weeks of their next pregnancy. Women identified

20 different supportive care options, of which 16 were preferred during their next

pregnancy. The women sought these supportive care options in their next pregnancy

for reassurance, comfort, certainty, trust and to feel understood and supported. As

anxiety is a common response during pregnancy for women who have experienced

(recurrent) miscarriage because they fear that another pregnancy loss might occur,

these feelings of support and care are very important for these women and may help

them to decrease anxiety.

Of the 16 different preferred supportive care options mentioned, 10 can be offered by

gynaecologists. This has great implications for the gynaecologist who feels frustrated

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that he or she cannot help women with unexplained RM, but can now focus on early

investigations and consultations to provide practical medical advice and supportive

care.

Of the 20 identified supportive care options, four were not preferred by the women.

CAM and admittance to a hospital ward at the same gestational age as previous

miscarriages were two of the four non-preferred supportive care options. This is in

contrary to what we hypothesized during our expert panel meetings.

Because of a lack of research on the preferences of women with unexplained RM

concerning supportive care, this study employed a qualitative, phenomenological

approach as an initial systematic and explorative description and evaluation (Patton,

2002; Leedy and Ormond, 2005). However, the performance of qualitative research

has limitations. First, interpretation of interviews is vulnerable to bias. For this reason,

all transcriptions of all interviews were analysed independently by two researchers who

were not involved in the work-up or treatment of the women to ensure objectivity.

Second, it is impossible to estimate the impact of each factor upon the preference

for supportive care. This would require quantitative research and assessment of

the magnitude of the factors. Third, the scope of this research was limited to the

preferences of women with RM. Further research should involve the perceptions of

the care givers to help categorize and prioritize the preferred supportive care options

regarding feasibility and superfluity.

Nevertheless, this study supplies the clinician with information on women’s preferences

and the clinician can manage expectations accordingly. Despite these limitations, we

believe our work provides necessary insights into the preferred supportive care in

women with unexplained RM. Quantitative research would be the logical next step

to measure the supportive care options, always keeping in mind the feasibility of the

preferred care.

In conclusion, our study identified several relevant preferences for supportive care in

women with unexplained RM. These results can help us to make a start in guaranteeing

high-quality patient-centred care. To implement specific supportive care for women

with unexplained RM, a quantitative confirmation and assessment of the magnitude of

the preferences is necessary, combined with an investigation of caregivers’ perceptions.


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7Supportive care for women with recurrent miscarriage: a survey to quantify women’s preferences

Anna M. MustersYvonne E.M. Koot Noortje M. van den BoogaardEugenie KaaijkNick S. MacklonFulco van der Veen Pytia T. NieuwkerkMariëtte Goddijn

Submitted

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106

Abstract

BACKGROUND Supportive care is regularly offered to women with recurrent

miscarriages (RM), reporting live birth rates up to 85%. What these women prefer

as supportive care in their next pregnancy has identified by qualitative research. The

aim of this study was to quantify these supportive care options and identify women’s

characteristics that predict the need for supportive care in women with RM.

METHODS A questionnaire study was conducted in 266 women with recurrent

miscarriages (2 ≥ miscarriages) in three hospitals in the Netherlands. All women

that received diagnostic work-up for recurrent miscarriages from January 2010 until

December 2010 were sent a questionnaire. The questionnaire assessed characteristics

of the women, quantified supportive care options identified by a previous qualitative

study and analysed women’s characteristics (age, ethnicity, education level, parity,

pregnancy during questionnaire and time passed since last miscarriage) in order to

elucidate the preferences of the different groups.

RESULTS Women with RM preferred the following supportive care options for their

next pregnancy; women requested a plan for the first trimester (80%) with one doctor

(70%) preferably a gynaecologist or doctor specialized in RM that shows understanding

(88%), takes them seriously (87%), has knowledge of their obstetric history (86%),

listens to them (86%) gives information about RM (84%), shows empathy (76%),

informs on progress (74%) and enquires about emotional needs (60%). Access to

ultrasound examination during symptoms (88%), directly after a positive pregnancy

test (67%) and every two weeks a repeat ultrasound (66%) were preferred by the

majority of women with RM. Finally, 61% of women would prefer to talk to a medical

or psychological professional after their next miscarriage. The majority of women did

not prefer admittance to a hospital ward at the same gestational age as previous

miscarriages (65%) nor bereavement therapy (66%). The mean preference on a scale

from 1-10 for supportive care was 8.0 for women with RM. Ethnicity, education level,

parity, pregnancy at the time of the survey and time passed since the last miscarriage

proved to be predictors in the preference of different supportive care options, female

age did not.

CONCLUSIONS Women with RM preferred several types of medical supportive care

from a gynaecologist or doctor specialized in RM that takes them seriously. Women

from ethnic minorities and women who were not pregnant during the questionnaire

were the two patient groups that preferred the most supportive care options. Tailor-

made supportive care can now be offered to women with RM.

Supportive care for women with recurrent miscarriage: Quantitative research

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Introduction

Recurrent miscarriage (RM), defined as two or more miscarriages before 20 weeks

pregnancy, affects approximately 3% of all couples (Regan and Rai, 2000). Current

diagnostic procedures identify aetiological factors as structural chromosome

abnormalities, antiphospholipid syndrome, elevated homocysteine fasting level and

uterine abnormalities in approximately 50% of these couples. The other 50% are

diagnosed as couples with unexplained RM (Rai and Regan, 2006). Even though a

cause for the RM can be found in up to 50% of the women, only for women with

recurrent miscarriages resulting from antiphospholipid syndrome a potentially effective

treatment namely the use of anti-coagulants is available (Rai et al.,1997, Empson et

al., 2005). For all other women with recurrent miscarriages this is not the case, which

is one of the reasons that RM is a distressing condition for the affected couple and a

frustrating problem for the clinician.

Current guidelines from the European Society of Human Reproduction and Embryology

(ESHRE) and the Royal College of Obstetricians and Gynaecologists (RCOG) recommend

supportive care during the next pregnancy for women with unexplained RM (RCOG,

2003; Jauniaux E et al., 2006), suggesting it has a beneficial effect. The guidelines

of the association of early pregnancy units suggest that all staff members should be

trained in emotional aspects of early pregnancy loss and offer bereavement counselling

(www.earlypregnancy.org.uk).

Supportive care is regularly offered to these women, after which live birth rates up

to 85% are reported (Javert, 1954; Stray-Pedersen and Stray-Pedersen, 1984; Liddell

et al., 1991; Clifford et al., 1997, Brigham et al., 1999). What women with recurrent

miscarriages perceive as supportive care during their next pregnancy was not known

until a recent qualitative study (Musters et al., 2011). In this study women identified

20 different supportive care options; 16 of these options were preferred for their next

pregnancy. Among the preferred supportive care options were early and frequently

repeated ultrasounds, βHCG monitoring, practical advice concerning life style and diet,

emotional support in the form of counselling, a clear policy for the upcoming 12 weeks

and medication. The four supportive care options that were not preferred by the

women were admittance to a hospital ward at the same gestational age as previous

miscarriages, Complementary Alternative Medicine (CAM), an ultrasound every other

day and supportive care from their general practitioner.

In this study we investigate which supportive care options 125 are most frequently

preferred by women with RM in their next pregnancy and which patient characteristics

predict the need for supportive care.

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Methods

SettingThis patient preference study was conducted in women with recurrent miscarriages in

three hospitals in the Netherlands; the Academic Medical Centre in Amsterdam, the

Onze Lieve Vrouwe Gasthuis in Amsterdam and the University Medical Centre Utrecht in

Utrecht. Institutional review board (IRB) approval was not needed because a questionnaire

study is not subject to the Dutch “Medical Research Involving Human ubjects Act”.

ParticipantsAll women that received diagnostic work-up for recurrent miscarriages from January

010 until December 2010 in the three hospitals, were sent a questionnaire (n= 266).

The women were sent a questionnaire after the diagnostic work-up for RM had been

performed. Women were eligible if they had two or more first trimester miscarriages

(≤ 20 weeks pregnancy). There is consensus that two or more -not necessarily

consecutive- miscarriages constitute recurrent miscarriage (Jaslow et al., 2010; van den

Boogaard et al., 2010).

Survey designThe questionnaire included a letter explaining the purpose of the study and information

on supportive care and recurrent miscarriages (the appendix contains a translated

version of the information provided).

The questionnaire consisted of three parts. In the first part, general data on the women

was collected. This included age, education, ethnicity, diagnosis of their recurrent

miscarriages (translocations, antiphospholipid syndrome, endocrine disorders, uterine

abnormalities and unexplained), their obstetric history and if they still had a wish to

conceive.The second part of the questionnaire contained 41 Likert scale items based

on the 20 supportive care options that were identified in our previous qualitative study

(Musters et al., 2011). The five point Likert scale items ranged from total disagreement

to total agreement for a particular option that could be offered in their next pregnancy.

After each topic, where applicable, we asked the women to choose a caregiver they

preferred to receive supportive care from (for instance: gynaecologist, 159 doctor

specialized in RM or a psychologist). In the third part of the questionnaire, we asked

participants to state their need for supportive care on a one to ten scale. Ten reflected

the highest and one reflected the lowest need for supportive care.

All questionnaires were sent by post in January 2011. To ensure the highest possible response

rate we used a short questionnaire (max. 15 minutes fill in time), prepaid return envelopes,

preliminary notification where possible, and two reminder questionnaires (Edwards et al.,

2002). The reminders were sent to non-respondents in a period of 10 weeks.


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Pilot studyThe questionnaire was pilot tested for interpretation among five women with recurrent

miscarriages, two gynaecologists (one specialized in recurrent miscarriages), two

fertility doctors, two PhD students (one specialized in recurrent miscarriages) and one

medical psychologist at the Academic Medical Centre in Amsterdam, the Netherlands.

The three parts of the questionnaire were well understood by all participants of the

pilot study and therefore only minor modifications were made to the final version of

the survey.

Statistical analysisTo quantify which supportive care options women with recurrent miscarriages prefer

or do not prefer during their next pregnancy, the five point Likert scale responses

were recoded into 3 point classification as 1=no need, 2=neutral or 3=need and the

percentages per supportive care option were calculated. Supportive care options that

were preferred by 60% or more of the women with RM were considered as preferred

by the ‘majority’ of the women.

Women’s characteristics (age, ethnicity, education level, parity, pregnancy during

survey and time passed since last miscarriage) were analysed in order to elucidate the

preferences of the different groups and to identify the characteristics that predict the

need for supportive care. Ethnicity was based on the woman’s country of birth and

the country of birth of her parents (CBS, 2001; Alders 2001; Stronks et al., 2009). The

patient characteristics were all dichotomous and the preference for a supportive care

option was dichotomized (1=preference and 0= neutral or no preference).

First, we tested the different patient characteristics for a univariable 192 relationship

with the different supportive care options in order to select the items for the

multivariable analysis. Chi-squared test was used to determine a relationship for the

univariable analysis. Variables with p≤ 0.05 were found to be eligible for multivariable

regression analysis. In the univariable and multivariable analysis the supportive care

options were the dependent variables. A backward selection method was applied, and

factors with p< 0.05 were considered significant.

Results

Two-hundred and sixty-six women were asked to participate in the study. Of

these women, 174 returned the questionnaire. The response rate was 65%. Three

questionnaires were excluded as the women did not fill in any of the preferences

questions. In total 171 questionnaires were analysed. Baseline characteristics of the

women are shown in table I.

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The mean preference on a scale from 1-10 for supportive care was 8.0 for all women

with RM. The majority of the women with RM preferred 15 of the 41 supportive

care options and rejected two of the 41 supportive care options (Table II). These 17

supportive care options are summarised per domain.

Domain 1: Medical supportive careThe majority of the women requested a plan for the first trimester with one doctor

(preferably a gynaecologist or doctor specialized in RM) with knowledge of their

Table I. Baseline characteristics of women with recurrent miscarriages. (N= 171)

Mean age ± SD (range) 34.8 ± 4.7 (22-46)

Women pregnant during questionnaire^ n (%) 56 (33)

Mean gestation in ± SD (range) (n=56) 21.3 ± 10.4 (4-38)

Obstetric history mean ± SD (range)

No. of pregnancies per woman 4.7 ± 2.1 (2-18)

No. of miscarriages per woman 3.6 ± 2.2 (2-18)

No. of children per woman 0.6 ± 0.8 (0-5)

Diagnosis of recurrent miscarriages n (%)

Unexplained 148 (87)

Thrombophilia 10 (6)

Translocation 3 (2)

Endocrine 1 (0.5)

Hyperhomocysteinemia 1 (0.5)

Work-up not completed 2 (1)

Could not remember diagnosis 6 (4)

Ethnic background n (%)

Caucasian 144 (84)

Minorities

Arab 13 (8)

African 9 (5)

Hispanic 2 (1)

Not mentioned 3 (2)

Education Level n (%)

Low* 12 (7)

Moderate** 51 (30)

High*** 106 (62)

Not reported 2 (1)

^ 44 (79%) pregnant women had a pregnancy duration that was 12 weeks or longer* primary school / intermediate vocational education** higher general secondary education / pre-university secondary education***higher vocational education / university


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obstetric history. Access to ultrasound examination directly after a positive pregnancy

test, when symptoms occurred and every two weeks a repeat ultrasound was preferred

by the majority of women with RM. The majority of the women wished to receive

medical information from their doctor relating to all aspects (diagnosis, treatment, and

prognosis) of recurrent miscarriage. In general, admission to a hospital ward at the

same gestational age as previous miscarriages was not considered necessary by the

majority of participating women.

Domain 2: Non-Medical supportive careWomen preferred non-medical support from their doctor in the form of taking them

seriously, listening to them, showing understanding and empathy, informing on

progress and enquiring about emotional needs. Next to non-medical support from

their doctor, they also valued support from their friends.

Domain 3: Other types of 226 supportive careFinally, the majority of the women expressed a need to talk to a professional (i.e.

medical or psychological) after their next miscarriage but bereavement therapy was

not considered necessary by the majority of participating women.

Patient CharacteristicsWomen under 35 years old did not differ from those over 35 in their preferences

for supportive care. Ethnicity, education level, parity, the presence of pregnancy at

the time of the survey and time passed since last miscarriage did appear to influence

supportive care options. These patient characteristics were all found to be independent

predictors in the multivariable analysis, of which the results are summarized in table III.

Ethnic backgroundA higher percentage of the women from an ethnic minority preferred admittance to

a hospital ward at the same gestational age as previous miscarriages, bereavement

therapy, counselling from a specialized nurse, advice about food and life style,

medication when it is proven safe for pregnancy, counselling from a psychologist,

ultrasound directly after a positive pregnancy test, BHCG sampling once before their

first ultrasound, doctor’s knowledge of the home situation, support from peers and

medication in general. Support from friends during the next pregnancy was preferred

by a lower portion of the women from an ethnic minority.

Education levelA higher portion of women with a low or moderate education level preferred

admittance to a hospital ward at the same gestational age as previous miscarriages,

medication in general and more partner involvement compared to women with a high

education level.

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Table II. Preferred and non preferred supportive care in next pregnancy for women with recurrent miscarriages. (N= 171)*

Preference (scale 1-10) for supportive care in next pregnancy mean

8.0 ± 2.2

No Need Neutral Prefer p-value**

Domain 1: Medical supportive care n (%)

Plan for first trimester 17 (10) 11 (6) 137 (80) ≤0.000

No. of doctors: 1 8 (5) 23 (14) 119 (70) ≤0.000

2 28 (16) 41 (24) 76 (44) ≤0.000

>2 86 (50) 28 (16) 31 (18) ≤0.000

Doctor has knowledge of obstetric history 1 (1) 3 (2) 147 (86) ≤0.000

Ultrasound: directly after a positive pregnancy test 33 (19) 15 (9) 114 (67) ≤0.000

during symptoms 3 (2) 7 (4) 150 (88) ≤0.000

once a week 42 (25) 19 (11) 100 (59) ≤0.000

once every 2 weeks 16 (9) 23 (14) 112 (66) ≤0.000

Information: from doctor 14 (8) 10 (6) 143 (84) ≤0.000

from internet 61 (36) 37 (22) 64 (37) 0.86

from peers 93 (54) 23 (14) 46 (27) ≤0.000

Advice: food 70 (41) 20 (12) 75 (44) 0.74

lifestyle 54 (32) 21 (12) 89 (52) 0.004

βHCG: once before 1st ultrasound 58 (34) 26 (15) 73 (43) 0.22

more times before 1st ultrasound 60 (35) 39 (23) 53 (31) 0.57

Medication: in general 72 (42) 41 (24) 45 (26) 0.02

safe for pregnancy 44 (26) 31 (18) 86 (50) ≤0.000

Admittance to a hospital 111 (65) 22 (13) 29 (17) ≤0.000

Domain 2: ‘Soft-skills’ medical supportive care n (%)

Doctor: takes you seriously 1 (1) 2 (1) 148 (87) ≤0.000

listens to you 1 (1) 3 (2) 147 (86) ≤0.000

shows understanding 4 (2) 7 (4) 140 (81) ≤0.000

shows empathy 8 (5) 13 (8) 130 (76) ≤0.000

informs on progress 9 (5) 16 (9) 126 (74) ≤0.000

informs on emotional needs 17 (10) 31 (18) 103 (60) ≤0.000

knowledge of home situation 46 (27) 41 (24) 64 (37) 0.11

Counselling from: a specialized nurse 63 (37) 30 (18) 48 (28) 0.19

a psychologist 83 (49) 25 (15) 33 (19) ≤0.000

a social worker 95 (56) 20 (12) 24 (14) ≤0.000

Domain 3: Other types of supportive care n (%)

Support from: friends 22 (13) 16 (9) 106 (62) ≤0.000

family 22 (13) 27 (16) 98 (57) ≤0.000

peers 86 (50) 17 (10) 39 (23) ≤0.000

Relaxation tools: Relaxation exercises 59 (35) 30 (18) 55 (32) 0.78

Yoga 61 (36) 29 (17) 54 (32) 0.58

Relaxation tapes 78 (46) 31 (18) 34 (20) ≤0.000


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Table II. Preferred and non preferred supportive care in next pregnancy for women with recurrent miscarriages. (N= 171)*


8.0 ± 2.2


Domain 1: Medical supportive care n (%)

Plan for first trimester 17 (10) 11 (6) 137 (80) ≤0.000

No. of doctors: 1 8 (5) 23 (14) 119 (70) ≤0.000

2 28 (16) 41 (24) 76 (44) ≤0.000

>2 86 (50) 28 (16) 31 (18) ≤0.000

Doctor has knowledge of obstetric history 1 (1) 3 (2) 147 (86) ≤0.000

Ultrasound: directly after a positive pregnancy test 33 (19) 15 (9) 114 (67) ≤0.000

during symptoms 3 (2) 7 (4) 150 (88) ≤0.000

once a week 42 (25) 19 (11) 100 (59) ≤0.000

once every 2 weeks 16 (9) 23 (14) 112 (66) ≤0.000

Information: from doctor 14 (8) 10 (6) 143 (84) ≤0.000

from internet 61 (36) 37 (22) 64 (37) 0.86

from peers 93 (54) 23 (14) 46 (27) ≤0.000

Advice: food 70 (41) 20 (12) 75 (44) 0.74

lifestyle 54 (32) 21 (12) 89 (52) 0.004

βHCG: once before 1st ultrasound 58 (34) 26 (15) 73 (43) 0.22

more times before 1st ultrasound 60 (35) 39 (23) 53 (31) 0.57

Medication: in general 72 (42) 41 (24) 45 (26) 0.02

safe for pregnancy 44 (26) 31 (18) 86 (50) ≤0.000

Admittance to a hospital 111 (65) 22 (13) 29 (17) ≤0.000

Domain 2: ‘Soft-skills’ medical supportive care n (%)

Doctor: takes you seriously 1 (1) 2 (1) 148 (87) ≤0.000

listens to you 1 (1) 3 (2) 147 (86) ≤0.000

shows understanding 4 (2) 7 (4) 140 (81) ≤0.000

shows empathy 8 (5) 13 (8) 130 (76) ≤0.000

informs on progress 9 (5) 16 (9) 126 (74) ≤0.000

informs on emotional needs 17 (10) 31 (18) 103 (60) ≤0.000

knowledge of home situation 46 (27) 41 (24) 64 (37) 0.11

Counselling from: a specialized nurse 63 (37) 30 (18) 48 (28) 0.19

a psychologist 83 (49) 25 (15) 33 (19) ≤0.000

a social worker 95 (56) 20 (12) 24 (14) ≤0.000

Domain 3: Other types of supportive care n (%)

Support from: friends 22 (13) 16 (9) 106 (62) ≤0.000

family 22 (13) 27 (16) 98 (57) ≤0.000

peers 86 (50) 17 (10) 39 (23) ≤0.000

Relaxation tools: Relaxation exercises 59 (35) 30 (18) 55 (32) 0.78

Yoga 61 (36) 29 (17) 54 (32) 0.58

Relaxation tapes 78 (46) 31 (18) 34 (20) ≤0.000

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114

Table II. Cont.


8.0 ± 2.2


medication 79 (46) 37 (22) 46 (27) 0.004

Bereavement therapy 113 (66) 14 (8) 16 (9) ≤0.000

More partner involvement 58 (34) 51 (30) 56 (33) 0.93

Visible pregnant women in the waiting room 59 (35) 37 (22) 67 (39) 0.53

Talk to someone after miscarriage 36 (21) 24 (14) 105 (61) ≤0.000

* not all questions were answered by all 171 women** p-values compared “No Need” group to the “Prefer” group

Table III. MULTIVARIATE analysis: Supportive care options preferred by different patient groups (total N= 171). Data shown in Odd Ratio’s (OR)

Ethnic minority(n= 24)

Low/moderate education

(n=63)

No children(n=94)

Not pregnant(n=115)

Miscarriage ≥ 6 months ago

(n=66)

Domain 1: Medical supportive care OR (95%CI)

No. of doctors: One docter 0.4 (0.2 - 0.9)

Ultrasound: directly after a positive pregnancy test 4.7 (1.0 - 21.6) 3.3 (1.6 - 6.7)

once a week 2.3 (1.2 - 4.4)

Advice: Food 7.3 (2.4 – 22.7)

Lifestyle 6.7 (1.9 – 23.7)

βHCG: once before 1st ultrasound 4.7 (1.4 – 16.1) 4.8 (2.2 -10.6)

more times before 1st ultrasound 5.0 (2.1 – 12.3)

Medication: in general 3.1 (1.1 - 9.1) 2.5 (1.1 – 5.3) 2.5 (1.0 – 6.2)

safe for pregnancy 6.3 (1.7 – 22.8) 2.6 (1.3 – 5.2)

Admittance to a hospital 26.4 (7.3 – 94.8) 3.3 (1.2 – 9.3)

Domain 2: “Soft-skills’ medical supportive care OR (95%CI)

Doctor: knowledge of home situation 4.0 (1.3 - 12.1) 2.5 (1.2 -5.2)

Counselling from: a specialized nurse 7.5 (2.3 - 24.7)

a psychologist 5.5 (1.9 – 16.4)

a social worker 4.7 (1.3 – 16.6)

Domain 3: Other types of supportive care OR (95%CI)

Support from: Friends 0.3 (0.09 – 0.7)

Peers 3.7 (1.3 – 10.3)

Relaxation tools: Relaxation exercises 2.9 (1.4 - 5.3)

Yoga 3.4 (1.6 – 7.0)

Relaxation tapes 2.6 (1.0 – 6.5)

CAM: medication 3.0 (1.4 – 6.1) 2.4 (1.1 – 5.0)

Bereavement therapy 10.2 (3.0 -33.8)

More partner involvement 2.5 (1.3 – 5.0) 2.2 (1.1 – 4.5)

1> is a significantly higher preference for a supportive care option (p≤0.05), 1< is a significantly lower preference for a supportive care option (p≤0.05)


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Table II. Cont.


8.0 ± 2.2


medication 79 (46) 37 (22) 46 (27) 0.004

Bereavement therapy 113 (66) 14 (8) 16 (9) ≤0.000

More partner involvement 58 (34) 51 (30) 56 (33) 0.93

Visible pregnant women in the waiting room 59 (35) 37 (22) 67 (39) 0.53

Talk to someone after miscarriage 36 (21) 24 (14) 105 (61) ≤0.000

* not all questions were answered by all 171 women** p-values compared “No Need” group to the “Prefer” group

Table III. MULTIVARIATE analysis: Supportive care options preferred by different patient groups (total N= 171). Data shown in Odd Ratio’s (OR)

Ethnic minority(n= 24)

Low/moderate education

(n=63)

No children(n=94)

Not pregnant(n=115)

Miscarriage ≥ 6 months ago

(n=66)

Domain 1: Medical supportive care OR (95%CI)

No. of doctors: One docter 0.4 (0.2 - 0.9)

Ultrasound: directly after a positive pregnancy test 4.7 (1.0 - 21.6) 3.3 (1.6 - 6.7)

once a week 2.3 (1.2 - 4.4)

Advice: Food 7.3 (2.4 – 22.7)

Lifestyle 6.7 (1.9 – 23.7)

βHCG: once before 1st ultrasound 4.7 (1.4 – 16.1) 4.8 (2.2 -10.6)

more times before 1st ultrasound 5.0 (2.1 – 12.3)

Medication: in general 3.1 (1.1 - 9.1) 2.5 (1.1 – 5.3) 2.5 (1.0 – 6.2)

safe for pregnancy 6.3 (1.7 – 22.8) 2.6 (1.3 – 5.2)

Admittance to a hospital 26.4 (7.3 – 94.8) 3.3 (1.2 – 9.3)

Domain 2: “Soft-skills’ medical supportive care OR (95%CI)

Doctor: knowledge of home situation 4.0 (1.3 - 12.1) 2.5 (1.2 -5.2)

Counselling from: a specialized nurse 7.5 (2.3 - 24.7)

a psychologist 5.5 (1.9 – 16.4)

a social worker 4.7 (1.3 – 16.6)

Domain 3: Other types of supportive care OR (95%CI)

Support from: Friends 0.3 (0.09 – 0.7)

Peers 3.7 (1.3 – 10.3)

Relaxation tools: Relaxation exercises 2.9 (1.4 - 5.3)

Yoga 3.4 (1.6 – 7.0)

Relaxation tapes 2.6 (1.0 – 6.5)

CAM: medication 3.0 (1.4 – 6.1) 2.4 (1.1 – 5.0)

Bereavement therapy 10.2 (3.0 -33.8)

More partner involvement 2.5 (1.3 – 5.0) 2.2 (1.1 – 4.5)

1> is a significantly higher preference for a supportive care option (p≤0.05), 1< is a significantly lower preference for a supportive care option (p≤0.05)

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ParityA higher portion of women without children preferred CAM medication, relaxation

exercises, more partner involvement and yoga compared to women with one or more

children. A lower proportion of women without children preferred one consulting

doctor compared women with one or more children.

Pregnant during questionnaireThe mean preference for supportive care, on a scale of one to ten, was significantly

higher (p=0.008) for women who were not pregnant compared to women who were

pregnant when completing the questionnaire (8.3 vs 7.3). A higher 260 portion of

women that were not pregnant preferred counselling from a social worker, frequent

HCG sampling prior to the first ultrasound, HCG sampling once before their first

ultrasound, ultrasound assessment directly following a positive pregnancy test,

medication if it was safe for their pregnancy, relaxation tapes, medication in general,

the doctors’ knowledge of the home situation and ultrasound once a every week for

the first 12 weeks of pregnancy, compared to women that were pregnant.

Time passed since last miscarriageA higher portion of women who had a miscarriage within the last six months preferred

CAM medication in their next pregnancy compared to the women with their last

miscarriage longer than 6 months ago. In the other domains there were no differences.

Discussion

This questionnaire study investigated which supportive care options are mostfrequently

preferred by women with RM in their next pregnancy and identified characteristics that

predict the need for supportive care.

The majority of women with recurrent miscarriages wanted to make a plan with one

gynaecologist or doctor specialized in RM that gives them medical information, is well

informed about their obstetric history, takes them seriously and offers ultrasound

assessment during symptoms once every two weeks during the first trimester and

preferably directly following a positive pregnancy test. Finally, if a miscarriage were to

occur again, women preferred miscarriage after-care from a medical or psychological

professional. The majority of the women did not express a wish to be admitted to a

hospital ward at the same gestational age as previous miscarriages nor bereavement

therapy. While age did not appear to influence preferences, variations were observed

according to ethnicity, education level, parity, pregnancy during questionnaire and

time passed since last miscarriage.


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Ethnic minorities preferred 12 supportive care options that were not preferred by

the majority of the women with RM, such as admittance to a hospital ward at the

same gestational age as previous miscarriages and bereavement therapy. This is the

first study to reveal different preferences in supportive care options in this group of

women. We also show that pregnancy at the time of completing the questionnaire was

associated with different preferences, with eight of their supportive care preferences

for their next pregnancy differing from those 294 generally expressed.

Moreover, the need for supportive care was less evident in pregnant women than in

non-pregnant women (7.3 vs 8.3). Considering that 79% of the women that were

pregnant had a gestation of 12 weeks or longer, it can be concluded that supportive

care is most needed in the first trimester when the risks of pregnancy loss are

the largest and the fear for a pregnancy loss is the highest for these women. The

differences in preferences found in women with low/moderate education, no children,

and miscarriage six months or longer ago were minor.

The strength of this study lies in the fact that it is based on results of a qualitative study

that identified the preferred options for supportive care (Musters et al., 2011).

Secondly, we were able to quantify this results of the qualitative study without losing

information. This was achieved by using a broad questionnaire that covered all the

domains of supportive care that were previously identified. Also, we analysed each

supportive care option as a separate outcome, to find out which specific care was

preferred by which particular subgroup. Thirdly, we identified key specific patient

characteristics which significantly influence the kinds of supportive care sought in

a future pregnancy. Finally, this study assessed the views of women actively trying

to conceive and thereby presents a current view of what women with RM want

considering supportive care.

Next to the strengths, certain limitations should be recognized. Caution is required in

interpreting and generalising this data as it was likely that women in greater need for

supportive care participated in this study. In contrast, pregnant women who were well

past their first trimester and therefore at less risk of a miscarriage also participated,

reducing a possible selection bias effect. Secondly, despite employing all feasible

recommended strategies to increase the response rate the response rate was 65%.

Why 35% of the women did not respond could be due to the sensitive nature of

the topic as questions about recurrent miscarriages may be confrontational for these

women (Edwards et al., 2002). Thirdly, as all data collection was carried out in the

Netherlands, the reported findings may not be generalisable to other countries.

However, the supportive care options we quantified are not specifically related to the

Dutch setting. Finally, the scope of this research was limited to the preferences of

women with RM.

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Another point that should be noted is that 87% of the women participating in this

study had unexplained recurrent miscarriages, which is higher than other studies that

report about half (54%) of the women having unexplained 328 recurrent miscarriages

(Habayeb and Konje 2004; Jaslow et al., 2010). There are several explanations for

this. Firstly, the average age of the women in our study is 35 years compared to 32

years in the other studies. As women get older the chance of “unexplained” miscarriage

increases. Secondly, it could be that women with unexplained recurrent miscarriage

feel more compelled to return the survey than women with a known cause of their

recurrent miscarriage. Finally, this remains a self report questionnaire in which women

themselves report on the cause of their miscarriage and women with a known, but

untreatable cause may have interpreted their recurrent miscarriages as unexplained.

Provision of the supportive care options preferred by women with RM is not always

feasible in our current heath care system, for example ethnic minorities prefer

admittance to a hospital ward at the same gestational age of a previous miscarriage. To

be able to implement these supportive care options in to daily practice, further research

should involve the perceptions of the care givers to help categorize and prioritize the

preferred supportive care options regarding feasibility and superfluity. In this respect, it

is interesting to note that guidelines of the association of early pregnancy units suggest

bereavement counselling training for all staff members while these study results show

that women do not prefer this.

Recurrent miscarriage is a frustrating condition for both women and clinicians alike.

The results of this study can help lessen this frustration for both groups, because we

now know which supportive care options women with RM find the most important.

This will bring clinicians a step closer to effectively helping and understanding women

with RM.


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7Chapter

Appendix

Dear Madam,

We would like to invite you to fill in this questionnaire.

It will take about 15 minutes.

3-5% of couples that are trying to conceive will have two or more miscarriages. In most

of these cases, there is no effective treatment (ie for example there is no medicine that

can increase the chance of an ongoing pregnancy).

At the moment supportive care is being offered to these couples. Research shows

that supportive care can lead to a successful outcome of the pregnancy in 75% -85%.

However in these studies, the care preferences of patients themselves have not been

investigated. With this questionnaire, we hope to discover what you think is important

when it comes to supportive care.

It may be that you are currently pregnant. If so, we would also appreciate it if you

filled in the questionnaire. If you decide to participate in this survey, your data will

be handled with strict confidentiality. Participation is completely voluntary and your

decision whether or not to participate has no bearing on your treatment.

Your attention for the following points:

• Cross one answer to each question

• Try to answer every question

If you have any questions concerning the questionnaire you can always contact the

researcher: Anna Musters, e-mail: [email protected].

Would you return the completed questionnaire in the envelope that is provided,

preferably within 14 days? A stamp is not necessary.

Thank you for your cooperation!

Sincerely,

(the contact person at each hospital was mentioned here)

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Is their a proven cause for your recurrent miscarriages?

c Yes, the cause is: ………………………………….

c No

I do not know Ý the docter has not told me yet c

Ý I forgot c

Ý a different reason, namely …………………………………………

Do you wish to conceive a this moment in time? c Yes

c No

Are you pregnancy at this time?

c No

c Yes, The first day of my last menstruation was:…….-………..- 201……

I am due to expect on:…………..-……………..- 201………

General Information

The following questions are meant to acquire general background information

1. What is your date of birth (day-month-year)?

For example: 3 November 1967 fill it is as 03 11 1967

c c c c c c c c

2. What is the birth country of

yourself your father your mother

The Netherlands c c c

Morocco c c c

Turkey c c c

The Dutch Antilles c c c

Suriname c c c

other, namely ______ ______ _______

3. What is your highest educational degree?

c no degree

c primary school

c intermediate vocational education

c higher general secondary education

c pre-university secondary education

c university

c other, namely ……………………………………………………………..


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7Chapter

Your Pregnancies

4. How many times have you been pregnant? Times

5. How many children do you have? ___ Times

6. How many miscarriages have you had? ___ Times

7. How many ectopic pregnancies have you had? ___ Times

8. How many pregnancies have you terminated? ___ Times

Will you please fill in the table below? Your first pregnancy is number 1, your second

pregnancy is number 2, etc. If you have been pregnant more than 10 times, you can

write the pregnancies on the back of the questionnaire

For each pregnancy give an outcome and select this from the following: child birth /

miscarriage / ectopic pregnancy / pregnancy termination (= abortion) / fetal death.

Enter the end date for each pregnancy: for example: child birth / abortion date / date

on ectopic pregnancy / abortion date.

How many weeks (and possibly days) pregnancy, was the child is born, was the

miscarriage or ectopic pregnancy established or pregnancy terminated? Specify the

duration of the pregnancy if known the number of weeks and days, eg 14+ 2 means a

gestation of 14 weeks and 2 days, 13 + 0 means exactly 13 weeks.

Question 9Pregnancy Outcome pregnancy Date end of pregnancy Duration of pregnancy

Example Miscarriage 5-6-2000 12+4

1

2

3

4

5

6

7

8

9

10

For all pregnancy that ended in miscarriage, an ectopic pregnancy or an abortion,

please fill in the following table. Behind the pregnancies that ended in childbirth, you

do not have to fill anything in.

Was the pregnancy test positive? Enter positive/negative/I do not know

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122

Was an ultrasound preformed? Enter yes / no / I do not know

What was seen on the ultrasound? Enter: fetus with beating heart / fetus without

beating heart / amniotic sac was empty / nothing / I can not remember

Hoe did the miscarriage end? Enter: spontaneous / curettage / other, namely ... ....

Question 10Pregnancy Outcome

pregnancy testUltrasound? Result of

ultrasoundMiscarriage

For example Positive yes fetus without beating heart

spontaneous

1

2

3

4

5

6

7

8

9

10

The following questions are about:

Preferred supportive care in the next pregnancy

11. During my next pregnancy I would feel supported if I could make a plan with my

doctor for the first 12 weeks of pregnancy

No, I do not prefer this c c c c c Yes, I prefer this

12. During my next pregnancy I would feel supported if I would receive advice about

food


13. During my next pregnancy I would feel supported if I would receive advice about

what to do and not to do (lifestyle)



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7Chapter

14. During my next pregnancy I would feel supported if I would receive an ultrasound:

Directly after a positive pregnancy test


Once a week


Once every 2 weeks


During symptoms


15. During my next pregnancy I would feel supported if I would:

Receive pregnancy hormone (βHCG) monitoring once before 1st ultrasound


Receive pregnancy hormone (βHCG) monitoring more times before 1st ultrasound


Be admitted to a hospital ward at the same gestational age as previous miscarriages


Receive medication


Receive medication only if it has been proven safe for my pregnacy


16. During my next pregnancy I would feel supported if I would:

Have one doctor


Two doctors


More than 2 doctors


17. During my next pregnancy I would feel supported if my doctor(s):

has knowledge of obstetric history


knowledge of home situation


shows empathy


informs on emotional needs


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124

takes you seriously


listens to you


shows understanding


informs on how you are doing


18. During my next pregnancy I would feel supported if:

I would receive counselling from:

A specialized nurse


A socialworker


Psychologist


Someone else, namely…………………


19. During my next pregnancy I look for support from:

My family


My friends


My peers


20. During my next pregnancy I would be able to relax and feel supported if:

I would listen to relaxation tapes


I would do relaxation exercises


If I would do yoga excerises


I would participate in a bereavement therapy/course


21. During my next pregnancy I would feel supported if I would receive information

about my pregnancy:

From my doctor(s)


From the internet


From peers


22. During my next pregnancy I would feel supported if my partner was more involved


23. During my next pregnancy I would feel supported if I

Would receive complementary alternative medicine (homeopathy, Chinees medicine,

etc).


Would receive complementary alternative therapies (acupuncture, reflexology, etc).


24. During my next pregnancy I would feel supported if I could wait in a waiting

room WITHOUT visibly pregnant women.

Helemaal niet mee eens c c c c c Helemaal mee eens

25. If my next pregnancy was to end in a miscarriage I would feel supportive if I could

talk to someone.


26. What is your need for supportive care during your next pregnancy? (circle your response) (1 = very little need to 10 = very great need)

1 2 3 4 5 6 7 8 9 10

Do you have any comments or additions?

…………………………………………………………………………………………………………………………

…………………………………………………………………………………………………………………………

Thank you for filling in this questionnaire!

You can use the enclosed reply envelope to return the questionnaire.

No stamp required

Chapter 7

126

References

Alders, M., 2001. Classification of the population with a foreign background in the Netherlands. Paper presented at The measure and mismeasure of populations conference, December 2001,Paris.

Boogaard van den E, Kaandorp SP, Franssen MT, Mol BW, Leschot NJ, Wouters CH, van der Veen F, Korevaar JC, Goddijn M. Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status? Hum Reprod 2010;25:1411-4.

Brigham SA, Conlon C and Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod 1999;14: 2868- 2871.

CBS Central Bureau of Statistics, 2000. Standaarddefinitie van allochtonen.” Index 10,10_13. Dutch Central Statisics office; Standard definition of immigrants.

Clifford K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod1997;12: 387–389.

Edwards P, Roberts I, Clarke M, DiGuiseppi C, Pratap S, Wentz R, Kwan I Increasing response rates to postal questionnaires: systematic review. BMJ 2002;324:1183.

Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005;2:CD002859.

Early pregnancy association guidelines: URL http://www.earlypregnancy.org.uk/ guideline 2007

Habayeb OM, Konje JC. The one-stop recurrent miscarriage clinic: an evaluation of its effectiveness and outcome. Hum Reprod 2004;19:2952-8.

Jaslow CR, Carney JL., Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril 2010;93:1234-43.

Javert CT Results of treatment in 100 patients. Obstet Gynecol 1954;3:420-434.

Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 2006;21:2216-22.

Liddell HS, Pattison NS, Zanderigo A. Recurrent miscarriage-Outcome after supportive care in early pregnancy. Aust NZ J of Obstet Gyn 1991;31:320-322.

Musters AM, Taminiau-Bloem EF, van den Boogaard E, van der Veen F, Goddijn M. Supportive care for women with unexplained recurrent miscarriage: patients’ perspectives.nHum Reprod 2011;26:873-7.

Rai R, Regan L.Recurrent miscarriage. Lancet 487 2006;368:601-11.

Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314:253-7.


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Regan L, Rai R. Epidemiology and the medical causes of miscarriage. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:839-54.



Stronks K, Kulu-Glasgow I, Agyemang C.The utility of ‘country of birth’ for the classification of ethnic groups in health research: the Dutch experience. Ethn Health 2009;14:255-69.

8General Discussion

General Discussion

131

8Chapter

Solving reproductive problems such as age-related subfertility and miscarriages seems

simple enough: women should not postpone childbearing. Yet women continue to do

just this (Mathews and Hamilton, 2009). The reason women postpone childbearing has

its roots in a continuously changing society (CBS, 2009; SCP, 2011).

Postponing child bearing in the NetherlandsUntil the late nineteen-sixties conception of children was a self-evident part of life. Most

people decided to get married after a period of engagement and the desire to have

children was rarely discussed; the birth of children followed naturally (Beets, 2008).

After the introduction of birth control in the form of “the pill” in 1963, fertility patterns

changed dramatically. Oral contraception paved the way for the postponement or

annulment of having children (de Graaf, 1998).

In the Netherlands shortly after the Second World War in 1946, a record number of

284,000 babies were born. In the nineteen-sixties, this number was around 240,000

babies per year and in the nineteen-seventies, the number fell to about 175,000 babies

a year. This decrease in the nineteen-seventies was caused by social factors such as

secularization, emancipation, individualization and by the availability of contraception

(van Nimwegen and Beets, 1994).

At that time, a growing number of young couples found social welfare and a career

equally important or more important than a family life with children. A feeling

of impending overpopulation prevailed among many Dutch, considering that the

prediction in 1965 for the Dutch population was 21 million before the end of the

twentieth century (Beets and de Graaf, 1980). The introduction and acceptance of

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132

reliable contraception provided a reliable and safe method to postpone pregnancy for

the first time.

Starting from the beginning of the nineteen-nineties a slow increase of the number of

babies born per year was seen up to 185,000 babies per year in 2009. The reason for

this annual increase was the favourable economic climate (CBS, 2008; van Duin, 2009).

It is expected that in the coming years there will –again- be a declining number of

babies born, due to the declining number of women that are in their reproductive life

span, an obvious consequence of the reproductive behaviour in the previous decades.

In addition to this decline in number of women of reproductive age, structural and

cultural factors play a role in the declining number of babies born: parenthood is

postponed. This delay of parenthood is closely related to educational level (Beets, 2007).

Due to educational expansion far more women can and do seek higher education

before they enter the workforce. By the time women have a diploma, find a good job

and are well incorporated in the labour market, they are generally no longer so young

(Kravdal and Rindfuss 2008, Mills et al., 2011). Also, having children is not perceived

as a duty anymore (SCP, 2011). Values such as self-development and autonomy are in

addition to parenting considered important (van de Kaa, 2001).

A survey study performed in 2008 among 3997 Dutch women reported that the two

main reasons women postpone motherhood are because they want to enjoy their

freedom (20%) and they do not have a partner (18%). Ten percent of the respondents

postponed children because of their career. Other reasons women postponed

motherhood had to do with their current partner; 10% mentioned that their

relationship was not stable enough and in 4% of the women their partner was not

ready for children. Finally, 9% of the women had doubts about ever wanting a child

(CBS, 2009). The remaining 29% of the women had various reasons such as finishing

their degree (4%), health reasons (3%), financial problems (3%), problems conceiving

(2%), unsuitable living situation (1%), and other non-defined reasons (16%).

In the late nineteen-seventies, about 70% of women in the Netherlands had a child

when they were younger than 30 years. At this moment only one third of women

younger than 30 years do. The average age of women at the birth of their first child is

currently 29.4 years. Women with a higher education are on average 34 years at the

birth of their first child (SCP, 2009). The proportion of mothers aged 40 years or older

has quadrupled from 1% in 1980 to over 4% in 2009 and over one fourth of these

women are a first-time mother at age 40 or above. This development has to do with

postponement of children and with “repartnering” (Wobma and de Graaf, 2009).

We too experience the effect of postponement of childbearing in our Centre for

Reproductive Medicine as the average age of the women visiting our centre for the

first time was 35 in 2009.

General Discussion

133

8Chapter

Women with poor ovarian reserveMany women who have postponed child bearing will experience subfertility and will

ultimately turn to in vitro fertilization (IVF), but IVF is no panacea for age related

subfertililty. One of the major problems of IVF in older women is poor response to

controlled ovarian hyperstimulation (COS) which reflects a physiologic decline in ovarian

reserve of primordial follicles (ie poor ovarian reserve) (Pellicer et al., 1994; Beckers et

al., 2002; de Boer et al., 2002; Lawson et al., 2003). Women of advanced female age,

but also younger women with high FSH levels and a low antral follicle count (AFC),

have low pregnancy rates after IVF or intracytoplasmic sperm injection (ICSI) (Jenkins

et al., 1991;Ulug et al., 2003).

The addition of recombinant luteinizing hormone (rLH) to COS showed a beneficial effect

on pregnancy rates in these women (Mochtar et al., 2007). This led us to hypothesize

that rLH increases embryo quality thereby leading to higher pregnancy rates. Although

we indeed found an increase in the rate of top-quality embryos per woman and more

women had at least one top-quality embryo in the rLH group, the difference was not

statistically significant (Chapter 2).

This may be because there is no difference in embryo quality or because the power

needed to demonstrate a difference was not achieved; we included 244 women in our

trial and in total 893 embryos were found instead of the anticipated 1040 embryos.

This was due to cycle cancellations, lack of oocytes after follicle aspiration and total

fertilisation failure in both study groups (in total 18% in the rLH group and in total 23%

in the control group). This indicates that the women in this study had an even poorer

ovarian function than expected and really represent women with an extremely poor

prognosis. Because power was not reached, it still remains undecided if the biological

explanation for the higher ongoing pregnancy rate with the addition of rLH can be

attributed to an increase of top quality embryos. More studies are needed to investigate

this. Adding the pregnancy results of our trial and the results of a recently published

large prospective randomized study (Bosch et al., 2010) to the available data in the

Cochrane review, the significant beneficial effect of rLH addition on ongoing pregnancy

rates in women with poor ovarian reserve holds (OR 1.39 95% CI: 1.01-1.92).

Even though there is a positive effect of rLH on ongoing pregnancy rates there are also

two potential drawbacks of adding rLH to COS; women have to administer extra daily

subcutaneous injections and the rLH injections generate additional costs.

Patient preference studies in reproductive medicine have clearly demonstrated that

live birth rates are the pivotal factors for women in their decision making (Nieuwkerk

et al., 1998; Steures et al., 2005; Bayram et al., 2005; Twisk et al., 2006; van Mello et

al., 2010). On the other hand, monetary resources in society are not unlimited and

health care workers are to provide the most cost effective treatment. Public financing

of ART ranges from virtually no subsidization in the USA, to funding of a limited

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134

number of cycles in most European countries and to unrestricted reimbursement with

co-payments in Australia (Hughes and Giacomini 2001, Nachtigall 2006; Chambers et

al., 2009, Connolly et al., 2010). In the Netherlands, where state funding is currently

available for up to three attempts, the costs of an additional rLH injection are as of yet

not reimbursed. A recent study demonstrated that a price increase in ART treatment,

associated with the introduction of co-payment for ART, reduced utilization for IVF

(Connolly et al., 2009). This suggests that when treatment access is dependent on user

fees, costs are preventative for many patients (Connolly et al., 2010).

Next to the costs of an extra injection, what women prefer when it comes to injections

during IVF has not been studied. We do know that IVF is perceived as an invasive

and burdensome treatment (Kopitzke et al., 1991;Edelmann et al., 1994; Eugster

and Vingerhoets 1999). This burden and distress even causes women to drop out of

treatment for the following reasons; pychological burden, poor prognosis, relationship

problems and physical burden (Olivius et al., 2004; Verberg et al., 2008; Domar et al.,

2010). The physical burden encompasses infection, ovarian hyperstimulation syndrome

and administration of subcutaneous injections (Olivius et al., 2004; Verberg et al.,

2008; Domar et al., 2010). These data suggests that women prefer an IVF treatment

with less injections rather than more, but the studies generating these data, were

designed to investigate the reasons why women drop out of treatment and not how

women receiving IVF perceive treatment aspects like for instance injections.

We therefore started a patient preference study in the form of a discrete choice

experiment (DCE) to investigate women’s perspectives on an additional injection of

rLH with respect to live birth rates and ‘out of pocket’ costs. We found that an extra

daily injection will not cause a woman to refrain from a certain IVF treatment, but to

compensate for the out of pocket costs of this extra daily injection the expected live

birth rate should at least be 6% (Chapter 3).

The fact that women did not find an extra injection a reason to refrain from IVF

and costs only started to matter when live birth rates were under 6%, suggest that

IVF treatments with the least injections are not per se considered the most “patient

friendly” by patients themselves.

In summary, the addition of rLH to COS gives a higher ongoing pregnancy rate than

COS with rFSH alone, potentially by increasing embryo quality, and women do not find

an extra injection a reason to refrain from IVF, but before we recommend the addition

of rLH to all IVF treatments in women with poor ovarian reserve we should put our

findings into the context of other gondotrophins with an intrinsic LH activity, such as

highly purified hMG (hp hMG) which has been demonstrated to result in a higher live

birth rate compared to rFSH alone (OR 1.19 95% CI: 1.01-1.93) (Coomarasamy et al.,

2008; van Wely et al., 2011).

General Discussion

135

8Chapter

From a cost-effective point of view hp hMG is favourable compared to rFSH (Connolly

et al., 2008; Melo et al., 2010; Wex-Wechowski et al., 2010). Hp hMG is relatively

cheap, and is well available. There are major considerations to recommending COS

with hp HMG for women with poor ovarian reserve. First, the trials included in the

meta-analysis that compare hp hMG with rFSH were all performed in a standard IVF

population, and no subgroup analysis could be done on women with poor ovarian

reserve. Only one study, not included in the meta-analysis, compared rFSH (150 IU) and

hpHMG (150 IU) to rFSH (375 IU) stimulation in women non responsive to 300 IU rFSH

and reported significantly higher number of oocytes retrieved in the rFSH/hpHMG

group and (not-significant) more pregnancies (De Placido et al., 2001). Second, hMG

is a urinary product that next to FSH and LH can contain unwanted proteins such as

prions. Although menopausal urine donors are screened for symptomatic neurological

disease, incubation of Creutzfeldt-Jakob disease (CJD) is impossible to exclude by non-

invasive testing. Also, the purification processes for different urine-derived preparations

are unable to remove prion proteins from the source material (Van Dorsselaer et al.,

2011). Third, even though hp hMG is cheaper than rLH, Chapter 3 of this thesis shows

that women are willing to pay out of pocket costs for a live birth rate above 6%. Fourth,

there are no sufficiently powered randomized controlled trials that have investigated

ongoing pregnancy rates in women receiving IVF with HMG compared to rLH/rFSH

stimulation, let alone in women with poor ovarian reserve.

In view of this, as of yet there is no evidence to recommend COS with hp HMG for

women with poor ovarian reserve. COS with the addition of rLH to rFSH can be

recommended for these women, but it is important to note that before considering

the addition of rLH as standard treatment in women with poor ovarian reserve, its

costs should be balanced against its potential benefits with proper cost effectiveness

studies.

Further research should focus on the effect of hp hMG on women with poor ovarian

reserve. An Individual Patient Data meta-analysis could be used to uncover data on

these women from the studies already preformed comparing hp hMG with rFSH. If hp

hMG is proven superior in this group, the next step is to investigate effect of hp hMG

compared to rLH and rFSH in women with poor ovarian reserve. This can be investigated

with randomized controlled trials or an Individual Patient Data meta-analysis.

Women with recurrent miscarriage: the role of invasive techniquesNext to tailoring ovarian hyperstimulation regimens to enhance IVF success rates,

investigating embryos for aneuploidies by means of pre-implantation genetic screening

(PGS) is another intervention that has been proposed to increase pregnancy rates and

also to lower miscarriage rates.

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136

The rationale behind the use of PGS was that aneuploidy of the embryo leads to

embryonic death, implantation failure and/or miscarriages and that testing embryos

for aneuploidies helps to choose the “right” embryo for transfer thereby lowering

miscarriage rates and improving ongoing pregnancy rates in women with advanced

maternal age (Gianaroli et al., 1997; Munne et al., 1999).

The use of PGS rapidly expanded to other indications like unexplained recurrent

miscarriage (RM). The rationale was that aneuploidy of the embryo may be the cause

of the RM (Gianaroli et al., 2002; Werlin et al., 2003; Rubio et al., 2005; Munne et al.,

2005; Mantzouratou et al., 2007). Similarly, pre-implantation genetic diagnosis (PGD)

was proposed to improve live birth rates, decrease miscarriage rates and decrease the

chance of unbalanced offspring in couples with RM who carry a structural chromosome

abnormality (Munne et al., 2000; Otani et al., 2006). The idea behind the use of PGD

for this purpose was that an unbalanced embryo causes the miscarriage and that

embryo selection eliminates the chance of an unbalanced offspring.

Both women with unexplained RM and couples with RM who carry a structural

chromosome abnormality have a good prognosis for natural conception and live birth

(Brigham et al., 1999; Franssen et al., 2006). By reviewing the literature on PGS in

women with unexplained RM and the literature on PGD in carrier couples with RM,

we found that there is insufficient data indicating that PGS or PGD improves live birth

rates in women with unexplained RM or couples with RM who carry a structural

chromosome abnormality compared to natural conception. Furthermore, couples with

RM who carry a structural chromosome abnormality have a low risk of viable offspring

(~0.8%) with unbalanced chromosomal abnormalities and no studies reported that

viable unbalanced offspring occurred after PGD (Chapter 4; Chapter 5).

It is our opinion that, currently, there are insufficient arguments to introduce PGS and/

or PGD, with its high costs and potential complications related to the IVF procedure,

into the daily clinical practice for couples with unexplained RM and couples carrying a

structural chromosome abnormality. The need for comparative studies of high quality

is urgent.

Women with recurrent miscarriage: supportive careNext to these invasive techniques, other interventions to increase live birth rates have

been studied in women with RM. A Cochrane review reported the effects of various

forms of immunotherapy, such as paternal cell immunization and immunoglobulin

infusions, and found no significant beneficial effect on live birth rate of any of these

techniques (Porter et al., 2006).

During the time span of this thesis a large trial showed that neither aspirin combined

with low-molecular-weight heparin nor aspirin alone improved the live-birth rate, as

compared with placebo, among women with unexplained RM (Kaandorp et al., 2010).

General Discussion

137

8Chapter

So only for women with RM resulting from antiphospholipid syndrome a potentially

effective treatment namely the use of anti-coagulants is available (Rai et al., 1997,

Empson et al., 2011). This leaves the vast majority of women with recurrent miscarriages

without a treatment, which is one of the reasons why RM is a distressing condition for

the affected couple and a frustrating problem for the clinician.

Current guidelines from the European Society of Human Reproduction and Embryology

(ESHRE) and the Royal College of Obstetricians and Gynaecologists (RCOG) recommend

supportive care during the next pregnancy for women with unexplained RM (RCOG,

2003; Jauniaux E et al., 2006), suggesting it has a beneficial effect. Supportive care

is regularly offered to these women reporting live birth rates up to 85% (Javert,

1954; Stray-Pedersen and Stray-Pedersen, 1984; Liddell et al., 1991; Clifford et al.,

1997, Brigham et al., 1999) but what these women themselves perceive and prefer

as supportive care has never been investigated until this thesis. The results of our

qualitative and quantitative studies indicate that women with RM are in need of

supportive care during their next pregnancy. In the qualitative study women identified,

20 different supportive care options, of which 16 were preferred during their next

pregnancy (Chapter 6). The women sought these supportive care options in their

next pregnancy for reassurance, comfort, certainty, trust, and to feel understood

and supported. From these 20 different options identified in the qualitative study we

developed a survey study that investigated which supportive care options women with

RM find most important (Chapter 7). Women with RM preferred different types of

medical supportive care from a gynaecologist or doctor specialized in RM who takes

them seriously. We also identified characteristics that predict the need for supportive

care and found that especially women from ethnic minorities and women who were

not pregnant during the questionnaire were the two patient groups that preferred the

highest number of supportive care options.

The results of this study can help lessen frustration for both women with RM and

doctors, because we now know which supportive care options women with RM

find most important. This will bring clinicians a step closer to effectively helping and

understanding women with RM. Also, considering the differences in preferences of

the subgroups of women, tailor-made supportive care can now be offered to women

with RM.

However, although we now know what women with RM want when it comes to

supportive care, the kinds of supportive care that women want are not always feasible

in our current heath care system, for example ethnic minorities prefer admittance to a

hospital ward at the same gestational age of a previous miscarriage. To put our findings

into context the next step should be to investigate doctors’ views, on supportive care

for women with RM to ensure practicability and enhance shared decision making.

Chapter 8

138

The results of the focus group interviews and questionnaires presented in this thesis

can be incorporated in the guidelines for the management of couples with recurrent

miscarriages.

There are many more issues to be addressed in future studies for women with recurrent

miscarriages. First of all, we should investigate all potential aetiological factors for

the strength of association with recurrent miscarriages. Then examine if the current

diagnostic tests and treatments are adequate. Finally, update guidelines and make sure

they are implemented and adhered to (van den Boogaard et al., 2011a).

Just recently, results of studies on couples with RM who carry a structural chromosome

abnormalities indicate that these couples should be counselled for their good prognosis

of a successful conception and low chances of a child with an unbalanced structural

chromosome abnormality (Thesis Franssen 2010). Also more and more evidence is

accumulating on the association between thyroid autoimmunity and RM (van den

Boogaard et al., 2011b; Thangaratinam et al., 2011).

In light of our current knowledge, future topics for research should include treatment

with thyroxin in a randomised setting in this subgroup of women, treatment with low-

molecular-weight heparin in women with RM and trombophilia, metroplasty in women

with RM and a septate uterus (TRUST trial number: NTR1676), supplementation

of progesterone in women with unexplained RM (PROMISE trial number:

ISRCTN92644181).

Although these trials should be done, it is important to realize that the current paradigm

of RM and its management are firmly anchored in the conjecture that pre-existent

disease, often much more relevant to subfertility, also underpins RM. Yet, two studies

that analyze time to pregnancy in 811 recurrent miscarriage patients revealed that

35-40% could be considered as ‘superfertile’, here defined as a mean time to pregnancy

of 3 months or less (Salker et al., 2010, thesis Kaandorp 2011). An explanation of this

superfertility may be that there is a failure in decidualizing endometrial stromal cells

that serve as biosensors of embryo quality, which enables maternal recognition and

elimination of compromised pregnancies (Teklenburg et al., 2010a). In other words

due to a disfunctioning endometrium abnormal embryos implant and finally result in a

clinical miscarriage (Teklenburg et al., 2010b). If these findings are true, than there is

no treatment for this condition considering that a miscarriage is a delayed “clean-up”

mechanism for an abnormal embryo.

Nevertheless, currently, supportive care, pre-conceptional lifestyle counselling and

making women aware of their childbearing postponement attitudes can be given to all

women with RM independent of aetiological factors and a disfunctioning endometrium.

General Discussion

139

8Chapter

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9Summary

Summary

1479Chapter

Worldwide, more and more women are having their first child later in life. This delayed

child bearing has major repercussions, because - as women get older- reproductive

problems such as age-related subfertility and miscarriages lay on the lure.

As older women have lower natural conception rates, more women turn to assisted

reproductive technology for conception, but are then faced with the fact that also in

IVF female age is the most important predictive factor for chances of success. One

of the consequences of advanced female age in IVF is a poor response to ovarian

hyperstimulation which reflects a physiologic decline in ovarian reserve of primordial

follicles (ie poor ovarian reserve). Also in young women a poor response to ovarian

hyperstimulation may occur, which then reflects a pathologic decline in number and

quality of primordial follicles. There is evidence that the addition of rLH to recombinant

follicle stimulating hormone (rFSH) during controlled ovarian hyperstimulation (COS)

increases ongoing pregnancy rates in women with poor ovarian reserve.

When women finally conceive, either through IVF or through natural conception, the

next obstacle is the risk of a miscarriage and 3% of all women will experience 2 or more

miscarriages before 20 weeks pregnancy. Recurrent miscarriage (RM) is a distressing

condition for the affected couple and a frustrating problem for the clinician, because in

most cases there is no effective therapy. Pre-implantation genetic screening (PGS) and

pre-implantation genetic diagnosis (PGD) are interventions that have been proposed to

increase pregnancy rates and also to lower miscarriage rates in women with RM.

Apart from these medical-technical options, supportive care for women with RM is

recommended by guidelines, but what these women actually perceive and prefer as

supportive care has never been investigated.

In this thesis we hypothesized that the higher ongoing pregnancy rates described in

women with poor ovarian reserve after COS with the addition of rLH to rFSH compared

to COS with rFSH alone is due to an increase top quality embryos. We investigated the

effect of rLH-addition for COS on the quality of embryos in women with a poor ovarian

reserve defined as women aged 35 to 41 years old and women younger than 35 years

old with a FSH level >12 IU/ml and an AFC ≤ 5. As the addition of rLH requires an extra

subcutaneous injection and costs we asked women’s perspectives on an additional

injection of rLH with respect to live birth rates and ‘out of pocket’ costs.

Since PGS and PGD are invasive and require IVF, the claim that PGS and PGD

increases live birth rates in women with RM should be substantiated and therefore

we systematically collected the evidence as published in the literature. Finally, we

investigated what women with RM perceive and prefer as supportive care.

Chapter 1 gives an outline and describes the objectives of this thesis.

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148

Chapter 2 gives the results of a randomized controlled trial that investigates the

effect of rLH-addition to rFSH for COS on the quality of embryos in women with poor

ovarian reserve. There was evidence of a beneficial effect of the addition of rLH to

ovarian hyperstimulation with FSH in COS on ongoing pregnancy rates in women with

poor ovarian reserve. Given the role of rLH in the maturation of the oocyte and effect

on embryo quality, the benefit of rLH on pregnancy rates in these women may be

mediated through an increase in embryo quality. At the time we started research, there

were no randomised controlled trials of the effect of rLH on embryo quality in women

with poor ovarian reserve. Two-hundred-forty-four women with poor ovarian reserve,

defined as all women aged 35 to 41 years old and women younger than 35 years

old with a FSH level >12 IU/ml and an antral follicle count ≤ 5, awaiting their first IVF

were randomly allocated to rFSH and rLH (2:1 ratio) or rFSH alone (control group); 116

women were allocated to the rLH group and 128 women were allocated the control

group. The primary outcome was proportion of top-quality embryos per woman i.e.

three days after oocyte retrieval. Analysis was by intention to treat. Proportion of top-

quality embryos per woman was 17% in the rLH group and 11% in the control group

(Mean difference 0.06; 95%CI -0.01 to 0.14). From these data we conclude that there

was a non-significant increase in the proportion of top-quality embryos per woman

when rLH was added to rFSH during COS in women with poor ovarian reserve.

Chapter 3 investigates women’s perspectives on an additional injection of rLH with

respect to live birth rates and ‘out of pocket’ costs in a discrete choice experiment. Next

to this possible beneficial effect of adding rLH to COS there are two potential drawbacks

of adding rLH to COS; women have to administer extra subcutaneous injections and

daily rLH injections generate additional costs. Two-hundred-thirty-four women eligible

for IVF were asked to choose between IVF treatments that differed in live birth rate

after one IVF cycle, the amount of self administered subcutaneous injections and ‘out of

pocket’ costs or reimbursement. In total 206 questionnaires were analysed. An increase

of one daily subcutaneous injection did not alter women’s preference. Live birth rate

and costs did have a statistical significant (p<0.001) impact on women’s choice for an

IVF treatment. Patient characteristics such as age, parity, duration of subfertility and

income significantly influenced the effect of costs on women’s preferences. Depending

on these characteristics, women were willing to pay a thousand euros of out of pocket

costs if it is compensated with at least a live birth rate ranging from 5% to 14%. These

results show that an extra daily injection will not cause a woman to refrain from a

certain IVF treatment, but to compensate for the out of pocket costs of this extra daily

injection the expected live birth rate should at least be 6%.

Summary

1499Chapter

Chapter 4 presents a systematic review that assesses live birth rates and miscarriage

rates after PGS or natural conception for couples with unexplained RM. MEDLINE,

EMBASE and the Cochrane database were searched until December 2009. Randomized

trials and cohort studies describing reproductive outcome in couples with unexplained

RM after PGS and/ or after natural conception were included. Primary outcome measure

was live birth rate per couple. Secondary outcome measure was miscarriage rate per

couple. No randomized controlled trials or comparative studies comparing PGS with

natural conception in couples with unexplained RM were found. Four observational

studies reporting on the reproductive outcome of 181 couples after PGS conception

and 7 studies reporting on the reproductive outcome of 261 couples after natural

conception were found. Live birth rate per couple after PGS varied between 19% and

46% (mean 35%; median 40%), and miscarriage rate ranged from 0% to 10% (mean

9%; median 9%). Live birth rate per couple after natural conception varied between

11% and 61% (mean 41%; median 36%), and miscarriage rate ranged from 14% to

52% (mean 28%; median 25%). Until data from randomized controlled trials become

available, this review summarizes the best available evidence of the efficacy of PGS

versus natural conception. At present, there is insufficient evidence to recommend PGS

as a method to increase live birth rates in couples with unexplained RM.

Chapter 5 reviews the reproductive outcome after PGD in couples with RM carrying

a structural chromosome abnormality, as well as the reproductive outcome of these

couples after natural conception. MEDLINE, EMBASE and the Cochrane database were

searched until April 2009. Trials, patient series and case reports describing reproductive

outcome in couples with RM carrying a structural chromosome abnormality after

natural conception and/ or after PGD were included. Primary outcome measure was

live birth rate per couple. Secondary outcome measure was miscarriage rate per couple.

No randomized controlled trials or cohort studies comparing natural conception with

PGD in couples with RM carrying a structural chromosome abnormality were found.

Four observational studies reporting on the reproductive outcome of 469 couples

after natural conception and 21 studies reporting on the reproductive outcome of

126 couples after PGD were found. Live birth rate per couple after natural conception

varied between 33% and 60% (median 55.5%) and miscarriage rate ranged from 21%

to 40% (median 34%). Live birth rate per couple after PGD varied between 0% and

100% (median 31%), and miscarriage rate ranged from 0% to 50% (median 0%).

Currently, there is insufficient evidence to recommend PGD as a method to increase

live birth rates in couples with RM carrying a structural chromosome abnormality.

Chapter 6 presents an exploratory investigation of what women with unexplained RM

prefer as supportive care during their next pregnancy. What these women themselves

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150

prefer as supportive care in their next pregnancy has never been substantiated. We

performed explorative, semi-structured, in-depth interviews among 15 women with

unexplained RM who were actively seeking conception. The topic list and the open

questions in the interviews were based on information acquired at expert panel

meetings and supplemented with the sparse literature on this topic. Women identified

20 different supportive care options; 16 of these options were preferred for their

next pregnancy. Examples of the preferred supportive care were early and frequently

repeated ultrasounds, βHCG monitoring, practical advice concerning life style and

diet, emotional support in the form of counselling, a clear policy for the upcoming

12 weeks and medication. The four supportive care options that were not preferred

by the women were admittance to a hospital ward on the same gestational age as

previous miscarriages, Complementary Alternative Medicine, ultrasound every other

day and receiving supportive care from their general practitioner. Our study identified

several relevant preferences for supportive care in women with unexplained RM. Many

of these can be offered by the gynaecologist and will help in guaranteeing high quality

patient centred care.

Chapter 7 investigates which supportive care options are most frequently preferred

by women with RM in their next pregnancy and which patient characteristics predict

the need for supportive care. A questionnaire study was conducted in 266 women

with RM ( ≥ 2 miscarriages) in three hospitals in the Netherlands. Two-hundred-sixty-

six women diagnosed with RM were sent a questionnaire. The questionnaire assessed

characteristics of the women, quantified supportive care options identified by the

qualitative study presented in Chapter 6 and analysed women’s characteristics (age,

ethnicity, education level, parity, pregnancy during questionnaire and time passed

since last miscarriage) to elucidate the preferences of the different groups. In total 171

questionnaires were analysed. Women with RM preferred the following supportive

care options for their next pregnancy; a plan for the first trimester (80%) and care by

one doctor (70%) preferably a gynaecologist or doctor specialized in RM that shows

understanding (88%), takes them seriously (87%), has knowledge of their obstetric

history (86%), listens to them (86%) gives information about RM (84%), shows empathy

(76%), informs on progress (74%) and enquires about emotional needs (60%). Access

to ultrasound examination during symptoms (88%), directly after a positive pregnancy

test (67%) and every two weeks a repeat ultrasound (66%) were preferred by the

majority of women with RM. Finally, 61% of women would prefer to talk to a medical

or psychological professional after their next miscarriage. The majority of women did

not prefer admittance to a hospital ward at the same gestational age as previous

miscarriages (65%) nor bereavement therapy (66%).

Summary

1519Chapter

The mean preference on a scale from 1-10 for supportive care was 8.0 for women

with RM. Ethnicity, education level, parity, pregnancy at the time of the survey and

time passed since the last miscarriage proved to be predictors in the preference of

different supportive care options, female age did not. These results show that women

with RM preferred several types of medical supportive care from a gynaecologist or

doctor specialized in RM who takes them seriously. Women from ethnic minorities and

women who were not pregnant during the questionnaire were the two patient groups

that preferred the highest number of supportive care options. These data allow for

tailor made supportive care in women with RM.

In Chapter 8 the findings of this thesis are discussed, clinical implications are given and

future research recommendations are made.

9Samenvatting

Samenvatting

1559Chapter

Wereldwijd krijgen vrouwen hun eerste kind op steeds latere leeftijd. Het uitstellen

van de kinderwens heeft grote gevolgen, omdat bij het ouder worden de kans op

reproductieve problemen zoals leeftijdsgerelateerde subfertiliteit en miskramen

toeneemt.

Omdat oudere vrouwen een lagere kans op natuurlijke conceptie hebben, doen zij een

beroep op kunstmatige voortplantingstechnieken, maar worden dan geconfronteerd

met het feit dat ook voor IVF geldt dat de leeftijd van de vrouw de belangrijkste

voorspeller is voor de kans op succes. Eén van de gevolgen van verhoogde ‘maternale’

leeftijd bij IVF is een geringe respons op ovariële hyperstimulatie door de fysiologische

vermindering van primordiale follikels (i.e. geringe ovariële reserve). Bij jonge vrouwen

treedt incidenteel een geringe respons op ovariële hyperstimulatie op, door een

pathologische daling van het aantal en de kwaliteit van primordiale follikels. Er is

bewijs dat de toevoeging van recombinant luteïniserend hormoon (rLH) gedurende

gecontroleerde ovariële hyperstimulatie (COS) een toename geeft van het aantal

doorgaande zwangerschappen bij vrouwen met een verlaagde ovariële reserve.

Als deze vrouwen zwanger worden, na IVF of na natuurlijke conceptie, is het volgende

obstakel het risico op een miskraam. Drie procent van alle vrouwen zal twee of

meer miskramen meemaken vóór 20 weken zwangerschap. Herhaalde miskramen

veroorzaken veel stress bij de patiënt en haar partner. De arts staat veelal machteloos,

omdat meestal geen effectieve therapie bestaat. Pre-implantatie genetische screening

(PGS) en pre-implantatie genetische diagnostiek (PGD) zijn interventies waarvan wordt

gesuggereerd dat ze de kans op zwangerschap verhogen en de kans op miskramen

verlagen bij vrouwen met herhaalde miskramen.

Naast deze medisch-technische opties, wordt ondersteunende zorg voor vrouwen met

herhaalde miskramen aanbevolen. Wat de vrouwen zelf aan ondersteunende zorg

willen, is nooit onderzocht.

In dit proefschrift was onze hypothese dat de hogere doorgaande zwangerschapscijfers

beschreven bij vrouwen met een geringe ovariële reserve na toevoeging van rLH

met recombinant follikel stimulerend hormoon (rFSH) vergeleken met rFSH alleen in

COS verklaard kunnen worden door een verhoging van het aantal embryo’s van top

kwaliteit.

We onderzochten het effect van rLH-toevoeging aan COS op de kwaliteit van embryo’s

van vrouwen met een geringe ovariële reserve (vrouwen van 35 tot 41 jaar oud en

vrouwen jonger dan 35 jaar oud met een FSH spiegel van >12 IU/ml en een ‘antrale

follikel count’ (AFC) ≤ 5).

Omdat de toevoeging van rLH een extra subcutane injectie betekent en kosten met

zich meebrengt vroegen wij de vrouwen wat zij vonden van een extra injectie van rLH

met betrekking tot doorgaande zwangerschapscijfers en kosten.

Chapter 9

156

Om te achterhalen of de technieken PGS en PGD leidden tot meer levendgeborenen

en minder miskramen bij vrouwen met herhaalde miskramen, is systemisch

literatuuronderzoek verricht.

Ten slotte hebben we onderzocht wat vrouwen met herhaalde miskramen ervaren als

ondersteunende zorg en waar ze behoefte aan hebben.

Hoofdstuk 1 geeft een beschrijving van de achtergrond en doelstellingen van dit

proefschrift.

Hoofdstuk 2 geeft de resultaten weer van een gerandomiseerde onderzoek

die onderzoekt of het toevoegen van recombinant luteiniserend hormoon (rLH)

aan recombinant follikel stimulerend hormoon (rFSH) bij ovariële hyperstimulatie

leidt tot een betere embryokwaliteit bij vrouwen met geringe ovariële reserve. Er

was bewijs dat de toevoeging van rLH tijdens ovariële hyperstimulatie een gunstig

effect heeft op het aantal doorgaande zwangerschappen bij vrouwen met geringe

ovariële reserve. Gezien de rol van rLH tijdens de rijping van de eicel en het effect

op embryokwaliteit, kan het voordeel van rLH op de zwangerschapspercentages bij

vrouwen met een geringe ovariële reserve mogelijk worden veroorzaakt door een

toename in embryokwaliteit. Voor de publicatie beschreven in dit hoofdstuk waren

er geen gerandomiseerd onderzoeken dat het effect van rLH op embryokwaliteit

bij vrouwen met een geringe ovariële reserve onderzochten. Twee-honderd-vier-en-

veertig vrouwen met een geringe ovariële reserve lootten voor een IVF behandeling

met recombinant follikel stimulerend hormoon (rFSH) en rLH (2:1 ratio) of rFSH alleen

(controle groep); 116 vrouwen werden gerandomiseerd voor de rLH groep en 128

vrouwen werden gerandomiseerd voor de controle groep. De primaire uitkomstmaat

was de verhouding embryo’s van top kwaliteit per vrouw (aantal top embryo’s/ totaal

aantal embryo’s per vrouw). De analyse werd gedaan volgens het intention to treat

principe. De verhouding top kwaliteit embryo’s per vrouw was 17% in de rLH groep

en 11% in de controlegroep (gemiddelde verschil 0.06; 95%CI -0.01 to 0.14). Uit deze

gegevens concluderen wij dat er een niet significante toename is in de verhouding top

kwaliteit embryo’s per vrouw na de toevoeging van rLH in vergelijking met rFSH alleen

tijdens ovariële hyperstimulatie bij vrouwen met geringe ovariële reserve.

Hoofdstuk 3 onderzoekt de mening van vrouwen over een extra injectie met rLH met

betrekking tot de kans op een levendgeboren kind en eigen financiële bijdrage in een

discreet keuze experiment (DCE). Naast een eventueel gunstig effect van het toevoegen

van rLH tijdens de ovariële stimulatie, zijn er twee mogelijke nadelen van het toevoegen

van rLH; vrouwen moeten een extra subcutane injectie toedienen en dagelijkse rLH

injecties zorgen voor extra kosten van de behandeling. Twee honderd-vier-en-dertig

Samenvatting

1579Chapter

vrouwen die in aanmerking kwamen voor IVF werden gevraagd te kiezen tussen

hypothetische IVF behandelingen die verschilden in de kans op een levendgeboren

kind na één IVF-cyclus, de hoeveelheid subcutane injecties die toegediend werden en

de eigen bijdrage voor de injecties. In totaal werden 206 vragenlijsten geanalyseerd.

Eén extra dagelijkse subcutane injectie beïnvloedde de voorkeuren van de vrouwen

niet. De kans op een levendgeboren kind en de kosten beïnvloedden de voorkeur

van vrouwen significant (p<0,001). Patiëntenkarakteristieken, zoals leeftijd, pariteit,

duur van de subfertiliteit en inkomen beïnvloedden het effect van de kosten op de

voorkeur van vrouwen significant. Afhankelijk van deze kenmerken, waren vrouwen

bereid om een eigen bijdrage van 1000 euro te betalen, indien hier een kans op een

levendgeboren kind tegen over stond variërend van 5% tot 14%. Deze resultaten tonen

aan dat het toevoegen van een extra dagelijkse injectie de keuzes van een vrouw voor

een bepaalde IVF behandeling niet beïnvloedt. De eigen bijdrage en de last van de

extra dagelijkse injectie moet bij de vrouwen leiden tot een kans op een levendgeboren

kind van tenminste 6% .

Hoofdstuk 4 presenteert een systematisch overzicht van de literatuur betreffende

reproductieve uitkomsten na pre-implantatie genetische screening (PGS) of natuurlijke

conceptie (NC) bij paren met onverklaarde herhaalde miskramen. MEDLINE, EMBASE

en de Cochrane database werden doorzocht tot december 2009. Gerandomiseerde

onderzoeken en cohort onderzoeken die de reproductieve uitkomsten beschreven na

PGS en /of na NC bij paren met onverklaarde RM werden geïncludeerd. De primaire

uitkomstmaat was het percentage levendgeboren kinderen per paar. De secundaire

uitkomstmaat was het percentage miskramen per paar. Omdat er geen onderzoeken

werden gevonden die de reproductieve uitkomst van beide groepen vergeleken,

werd voor beide groepen een aparte zoekstrategie uitgevoerd. Vier observationele

onderzoeken die de reproductieve uitkomst beschreven van 181 paren na PGS en

zeven onderzoeken die de reproductieve uitkomst beschreven van 261 paren na NC

werden geïncludeerd. Na PGS varieerde het percentage levendgeboren kinderen per

paar van 19% tot 46% (gemiddeld 35%; mediaan 40%), en het miskraampercentage

per paar van 0% tot 10% (gemiddeld 9%; mediaan 9%). Na NC varieerde het

percentage levendgeboren kinderen per paar tussen 11% en 61% (gemiddeld 41%;

mediaan 36%), en het miskraampercentage per paar van 14% tot 52% (gemiddeld

28%; mediaan 25%). Totdat gegevens uit gerandomiseerde onderzoeken beschikbaar

zijn, geeft dit literatuuroverzicht het best beschikbare bewijs over de werkzaamheid

van PGS versus NC. Op dit moment is er onvoldoende bewijs om PGS aan te bevelen

om een toename van het aantal levendgeborenen te bewerkstelligen bij paren met

onverklaarde herhaalde miskramen.

Chapter 9

158

Hoofdstuk 5 laat aan de hand van een systematisch literatuuroverzicht zien wat de

reproductieve uitkomst is na pre-implantatie genetische diagnostiek (PGD) bij paren

met herhaalde miskramen en dragerschap van een structurele chromosoomafwijking,

evenals de reproductieve uitkomst van deze paren na natuurlijke conceptie (NC).

In MEDLINE, EMBASE en de Cochrane database werden doorzocht tot april 2009.

Trials, patiëntenseries en case reports die de reproductieve uitkomst beschreven

na PGD en / of na NC bij paren met herhaalde miskraam en dragerschap van een

structurele chromosoomafwijking werden geïncludeerd. Primaire uitkomstmaat was

het percentage levendgeboren kinderen per paar. Secundaire uitkomstmaat was het

percentage miskramen per paar. Omdat er geen onderzoeken werden gevonden die

de reproductieve uitkomst van beide groepen vergeleken, werd voor beide groepen

een aparte zoekstrategie uitgevoerd. Vier observationele onderzoeken rapporteerden

over de reproductieve uitkomsten van 469 paren na NC en 21 onderzoeken

rapporteerden over de reproductieve uitkomsten van 126 paren na PGD: het

percentage levendgeboren kinderen per paar na NC varieerde tussen 33% en 60%

(mediaan 55.5%), en het percentage miskramen per paar varieerde van 21% tot 40%

(mediaan 34%). Het percentage levendgeboren kinderen per paar na PGD varieerde

van 0% en tot 100% (mediaan 31%), en het miskraampercentage per paar varieerde

van 0% tot 50% (mediaan 0%). Momenteel is er onvoldoende bewijs om PGD aan te

bevelen als een methode die het aantal levendgeborenen verhoogt bij paren met RM

die drager zijn van een structurele chromosoomafwijking.

Hoofdstuk 6 presenteert een verkennend onderzoek naar de wensen van vrouwen

met onverklaarde herhaalde miskramen ten aanzien van ondersteunende zorg

tijdens hun volgende zwangerschap. Dit is niet eerder onderzocht. Exploratieve

semigestructureerde diepte-interviews werden afgenomen bij 15 vrouwen met

onverklaarde herhaalde miskramen en actieve kinderwens. De interviews werden

opgezet met behulp van informatie verkregen tijdens vergaderingen met experts en

aangevuld met de literatuur over dit onderwerp, die overigens beperkt was. Vrouwen

noemden 20 verschillende opties aan ondersteunende zorg; zestien van deze opties

werden verkozen als gewenst tijdens hun volgende zwangerschap; bijvoorbeeld een

echoscopisch onderzoek zo vroeg mogelijk in de volgende zwangerschap, meerdere

echoscopische onderzoeken, serum βHCG vervolgen, het ontvangen van praktische

adviezen met betrekking tot levensstijl en voeding, emotionele ondersteuning in de

vorm van begeleiding, een duidelijk beleidsplan voor de eerste 12 weken en medicatie.

De vier ondersteunende opties waar de voorkeur van de vrouwen niet naar uitging,

waren ziekenhuisopname tijdens dezelfde zwangerschapsduur als bij de vorige

miskramen, alternatieve geneeskunde, echoscopisch onderzoek om de dag en het

ontvangen van ondersteunende zorg van hun huisarts. Dit onderzoek identificeerde

Samenvatting

1599Chapter

verschillende relevante ondersteunende zorg opties die vrouwen met onverklaarde

herhaalde miskramen wensen. Veel van deze zorg opties kunnen worden aangeboden

door de gynaecoloog en helpt bij het leveren van goede patiëntgerichte zorg.

Hoofdstuk 7 onderzoekt aan welke ondersteunende zorg vrouwen met herhaalde

miskramen het meest behoefte hebben tijdens hun volgende zwangerschap. Een

vragenlijstonderzoek werd uitgevoerd onder 266 vrouwen met herhaalde miskramen (≥

2 miskramen) in drie ziekenhuizen in Nederland. Alle vrouwen die tussen januari 2010

en december 2010 gediagnosticeerd werden met herhaalde miskramen ontvingen een

vragenlijst. Met behulp van de vragenlijst kwantificeerden we de ondersteunde zorg

opties van Hoofdstuk 6, onderzochten we de gemiddelde voorkeur op een schaal van 1-10

voor ondersteunende zorg en analyseerde de associatie tussen patientkarakteristieken

(leeftijd, etniciteit, opleidingsniveau, pariteit, zwangerschap tijdens de vragenlijst en de

tijd sinds laatste miskraam) en de voorkeur voor een bepaalde ondersteunende zorg.

In totaal werden 171 vragenlijsten geanalyseerd. Vrouwen met herhaalde miskramen

hadden een voorkeur voor de volgende ondersteunende zorg opties: vrouwen wilden

een beleidsplan maken met één dokter die begrip toont, hun serieus neemt, op de

hoogte is van de obstetrische voorgeschiedenis, naar hun luistert, informatie geeft

over herhaalde miskramen, medeleven toont, vraagt hoe het gaat en vraagt over

emotionele belasting. Verder willen vrouwen een echoscopisch onderzoek bij klachten

direct aansluitend na een positieve zwangerschapstest en daarna elke twee weken. Tot

slot, hadden vrouwen behoefte om bij een eventuele volgende miskraam een gesprek

met een medisch of psychologische professional te krijgen. De meeste van de vrouwen

hadden geen behoefte aan een ziekenhuisopname bij dezelfde zwangerschapsduur als

de vorige miskraam, noch aan rouwverwerkingtherapie. De gemiddelde voorkeur voor

ondersteunende zorg was 8.0 (op een schaal van 1-10). Etniciteit, opleidingsniveau,

pariteit, zwangerschap tijdens de vragenlijst en de tijdsduur sinds de laatste miskraam

waren geassocieerd met behoefte aan specifieke ondersteunde zorg opties. Er

was geen associatie met de leeftijd van de vrouw. Deze resultaten tonen aan dat

vrouwen met herhaalde miskramen behoefte hebben aan een beleidsplan, één

dokter, echoscopisch onderzoek, goede communicatieve vaardigheden van artsen

en nazorg na de miskraam. Vrouwen uit etnische minderheden en vrouwen die niet

zwanger waren tijdens het invullen van de vragenlijst hadden de meeste behoefte aan

specifieke ondersteunende zorg opties. Wij adviseren het aanbieden van individuele

ondersteunende zorg bij vrouwen met herhaalde miskramen.

Hoofdstuk 8 geeft een algemene bespreking van de resultaten in dit proefschrift,

schetst de klinische implicaties en doet aanbevelingen voor toekomstig onderzoek.

Dankwoord

Dankwoord

163

Allereerst wil ik de vrouwen bedanken die belangeloos hebben meegewerkt aan de

onderzoeken. Het spreekt voor zich dat zonder hun deelname er geen proefschrift was

geweest.

Fulco, door je rechtlijnigheid en ‘geen concessies’ attitude heb je ervoor gezorgd dat

ik een onderzoeker ben geworden. Jij hebt me geleerd om een helder doel te hebben

en ‘to the point’ te schrijven. Hiërarchie in de wetenschap bestaat niet volgens jou,

daarom heerst er een open sfeer op het CVV en is alles mogelijk. Je snelle reactie, je

creatieve denkvermogen en je ‘birds eye view’ zijn eigenschappen die ik hoop verder

te ontwikkelen. Dank!

Lieve Mariëtte, jij hebt me echt onder je vleugels genomen. Voordat ik het wist was ik

een onderdeel van het herhaalde miskraam team. Ik heb veel van je geleerd en ik ben je

erg dankbaar voor je enorme betrokkenheid bij mijn proefschrift. Door jouw intensieve

begeleiding hebben we dit proefschrift in stroom versnelling af kunnen maken!

Sjoerd, vanaf dag één wist ik: “Bij hem moet ik zijn”. Je bent echt een top wetenschapper,

visionair en nog steeds helemaal in contact met het hier en nu. Jij hebt in de eerste

dagen, toen er nog veel onduidelijk was, in mij geïnvesteerd. Dat zal ik nooit vergeten

en ik denk dat je de juiste beslissing hebt genomen.

Lieve Monique, een super multi-tasker ben jij: van het verbouwen van het CVV tot een

gynaecoloog die alleen maar mannen behandelt (TESE). Het stokje van de L-AGE heb ik

van je overgenomen, door jouw inzet en betrokkenheid zijn de inclusies snel gedaan!

Dank voor al je werk en je begeleiding.

Lieve Elies, De eindsprint is door jou ingezet en inspireerde mij. Jij hebt altijd tijd om

met mij te sparren over ideeën van wetenschap tot privé. Je bent een warme, attente

vriendin met een aanstekelijke schaterlach die ik nog heel vaak hoop te horen! Zo

ontzettend fijn dat je naast me staat vandaag!

Lieve Laura, maatjes vanaf jouw eerste dag op het CVV! Zo ontzettend, onvergetelijk

veel gelachen. Door jouw enorme intelligentie, vastberadenheid, en zelfvertrouwen

weet ik zeker dat als ik bezwijk vandaag dat jij glansrijk mijn hele proefschrift zou

kunnen verdedigen. Je bent een lieve vriendin en ik ben trots dat je vandaag naast me

staat!

Lieve Lex en Em, wat ben ik blij dat jullie van Groningen naar Amsterdam zijn gekomen!

Jullie zijn beiden de meest attente mensen die ik ooit ontmoet heb! Dank voor all the

Dankwoord

164

good times in H4-240. Lex, wat een feest om met jou in het jaar te zitten, leuk om met

jou dit mee te maken! Em, mijn RM vraagbaken en heerlijk dat ik na één gesprek met

jou op de hoogte ben van alles en iedereen! Stef! Wat heb ik genoten van onze één-

tweetjes. Je onuitputtelijke positieve energie en humor maakten elke dag een feest.

Lieve Norah, samen van T-onderwijs tot AIOS naar fertiliteits specialisten... Jouw rust,

flexibiliteit en aanpakkers mentaliteit zijn aanstekelijk!

Marsha, Menkie, Arianne, Wouter, Inge, Moniek, Sebastiaan, Liesbeth v L, Liesbeth

V, Noortje, Marjet, Femke M, Femke K, Femke M, Mohammed, Hooman, Bita, Lobke,

Marleen, Katrien, Margreet, Evelien, Jelle, Marloes, Sophie, Rosa, Floortje, Fleur,

Maureen, Emily onderzoekers van de eerste tot de laatste dag, dank voor al jullie

gezelligheid en tips&tricks!

Thea en Mojca beiden heel veel dank voor al jullie zichtbare en onzichtbare werk! En

voor jullie betrokkenheid en interesse!

Lieve Collega’s van het OLVG, alle verpleegkundigen, verloskundigen, secretaresses,

arts-assistenten en gynaecologen vanaf dag één voel ik me OLVG-er en heel erg

welkom. Dank voor jullie interesse in mijn onderzoek en de inclusies! Dick, dank voor

your famous words: “Het heet niet voor niets een proefschrift” Die woorden hebben

me door de laatste maanden heen gesleept!

Lieve Nino, you are the one and only “doctor Feel Good”! Ik heb heel veel van je geleerd

en nog meer met je gelachen. Zonder jou geen CVV. Fijn dat je ook een “nieuwe Nino”

voor me hebt geregeld in het OLVG!!

Team CVV: Juliette, Brigitte, Manon, Leonie, Lonneke, Ragna, José, Tessa, Sara en

Germine jullie maken het CVV zo een warme persoonlijke omgeving. Ik heb me altijd

heel welkom en gewaardeerd gevoeld door jullie. Keep up the good work: jullie maken

het verschil!

Lieve Jolan, Jorien, Naan, Lisette, Peike, Val, Jamie, Lou, Annelies, Roos, Dana, Vanessa,

Soof, Vanesse, Floor, Allison, Armand, Machteld, Bob, Michiel, Otto en Quinten dank

voor jullie luisterend oor, interesse en afleiding! Lieve Jolan, jij bent altijd de eerste die

ik bel voor ruggespraak en advies. Ik waarder je sterke relativeringsvermogen en je

gave om te luisteren.

Dankwoord

165

Lieve Ruud, Cisca, Simone en Dagmar vanaf het eerste begin waren jullie betrokken

mijn promotie onderzoek. Cis het was erg fijn om in het begin met jou over mijn

onderwerpen te discussiëren.

Lieve Reinier, Marieke, Joce en Ewout, thanks for the support! Lieve Reinier en Joce het

is zo ontnuchterend om twee niet medische siblings te hebben, daardoor blijf je met je

beide benen op de grond. Jullie zijn naast familie ook vrienden waar ik alles mee kan

delen en de enigen die mijn dutch-english moeiteloos verstaan en spreken.

Dear Grandma en Grandpa, first of all thank you so much for sending your daughter

to the Netherlands. You two are very dear to me, thank you for always making me feel

special.

Lieve Mamma en Pappa. ‘Musters-en kunnen… ALLES!!’ en ‘Always be honest en kind’.

Wat heb ik het getroffen met jullie! Gedurende mijn hele leven staan jullie altijd als

twee enthousiastelingen mij toe te juichen. There is no problem too big or too small. Ik

hoop dat ik later ook zo op mijn gezin kan terug kijken!

Lieve Jesper en Victoria, woorden kunnen niet uitdrukken hoe blij en dankbaar ik ben

dat jullie in mijn leven zijn! Jep eigenlijk is dit boek ook aan jou te danken! Dank voor je

hulp, geduld, suggesties en alle uren dat je naar ‘proef’ praatjes heb geluisterd. Soms

vraag ik me af of ik niet de gelukkigste vrouw in de wereld ben met jullie bij me.

List of other publications

List of other publications

169

Musters AM, Twisk M, Leschot NJ, Oosterwijk C, Korevaar JC, Repping S, van der Veen F, Goddijn M. Perspectives of couples with high risk of transmitting genetic disorders. Fertil Steril. 2010 Sep; 94 :1239-43.

Musters AM, Goddijn M, Korevaar JC, van der Veen F, Mastenbroek S, Repping S. Benefits of PGD in patients with recurrent miscarriages? Fertil Steril. 2008 Jul;90(1):240-1; author reply 241-2.

Musters AM, Oosterwijk C, Repping S, Twisk M, Goddijn M, Korevaar JC, van der Veen F Leschot NJ. Onbekendheid over pre-implantatie genetische diagnostiek (PGD) is groot: onderzoek van het Centrum voor Voortplantingsgeneeskunde van het AMC en de patiëntenvereniging VSOP. MC 23 - 6 juni 2008. (not peer-reviewed)

van Wering HM, Bosse T, Musters A, de Jong E, de Jong N, Hogen Esch CE, Boudreau F, Swain GP, Dowling LN, Montgomery RK, Grand RJ, Krasinski SD. Complex regulation of the lactase-phlorizin hydrolase promoter by GATA-4. Am J Physiol Gastrointest Liver Physiol. 2004 Oct;287(4):G899-909.

About the author

About the author

173

Anna Musters was born on Sunday the 3rd of December 1978 in Bussum, the

Netherlands. She lived in Bussum for the first 3 years of her life and then moved to

Mexico, the United States, the United Kingdom and finally back to the Netherlands.

She graduated from the Alberdingk Thijm College (Internationaal Baccalaureate) in

1997.

She was able to travel to Mexico in 1997 and study Psychology in 1998 and she started

medical school at the Academic Medical Centre in Amsterdam in 1999.

In July 2006 she started working at the Centre for Reproductive Medicine of the AMC

as an IVF doctor. In 2007 Fulco van der Veen, Mariette Goddijn and Sjoerd Repping

gave her the opportunity to start the Ph.D. project ‘Reproductive choices in women

with poor ovarian reserve and recurrent miscarriages’. During the first 3 years of this

project she continued to work part-time as an IVF doctor in the AMC.

In July 2011 she started her residency in Obstetrics and Gynaecology at the Onze Lieve

Vrouwe Gasthuis in Amsterdam (Head of the Department: D.J. Bekedam M.D. Ph.D.).

Anna Musters lives with Jesper Padmos and their daughter Victoria in Amsterdam.

UvA-DARE (Digital Academic Repository) …Reproductive choices in women with poor ovarian reserve and recurrent miscarriages PhD Thesis, University of Amsterdam, The Netherlands ©

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