REFERAT RPL Final.docx

CHAPTER I

INTRODUCTION

Recurrent pregnancy loss (RPL) is always a traumatic experience for the patient,

and also the most difficult areas in reproductive medicine. According to the Royal

College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline No. 7 In

2011, miscarriage is the spontaneous loss of a pregnancy before the fetus reaches 24

weeks gestation.3 World Health Organization (WHO) recommends that in developing

countries, where the gestational age is often difficult to determine, the loss of pregnancy

when the fetus weighs under 500g is used to determine miscarriage.1 Ideally, a threshold

of three or more consecutive miscarriages should be used for epidemiological studies

while clinical evaluation may proceed following two first-trimester pregnancy losses.

RPL affects 0.5-1% of couples. 5 This figure turned out to be twice the incidence that may

occur by chance, thus showing that there is an abnormality that can occur. It has been

found that the factors that could cause RPL including cytogenetic factors, anatomical

factors, antiphosopholipid syndrome, thrombophilia’s, hormonal or metabolic disorders,

infectious, autoimmune, sperm quality and lifestyle issues. 1

Only little consensus exists on the investigation should be done to find the

etiology of RPL along with effective treatment, and only a few are evidence-based.1 This

paper aims to discuss the definition, epidemiology, etiology, investigation and

management in RPL.

1

CHAPTER II

LITERARY REVIEW

2.1 Definition

For the purposes of determining whether evaluation for RPL is appropriate,

pregnancy is defined as a clinical pregnancy documented by ultrasonography or

histopathological examination. 2 Williams Obstetrics 23rd edition defines RPL as three or

more consecutive pregnancy losses at 20 weeks or less with fetal weight less than 500

grams.5 World Health Organization (WHO) recommends to developing countries where

the gestational age is often difficult to determine, the loss of pregnancy when the fetus

weighs under 500g was used to determine miscarriage.1 Controversy has existed on the

number of miscarriages required to define RPL. 5 According to the Royal College of

Obstetricians and Gynecologists (RCOG) Green-top Guideline No. 7 in 2011,

miscarriage is defined as the spontaneous loss of a pregnancy before the fetus reaches 24

weeks of gestation. RPL is therefore defined by three or more consecutive misscariages. 3

In contrast, the American Society for Reproductive Medicine (ASRM) in 2012 has

defined RPL as a “distinct disorder defined by two or more failed clinical pregnancies”.

Jaslow et al, evaluated more than 1000 women with RPL and their study found no

difference in the frequency of abnormal diagnostic factors between women with two and

those with three or more miscarriages, and argued that full evaluations should be offered

to women who have experienced at least two consecutive losses. Ideally, a threshold of

three or more consecutive miscarriages should be used for epidemiological studies while

clinical evaluation may proceed following two first-trimester pregnancy losses.1 The

difficulty on handling RPL is for the clinician is to distinguish sporadic miscarriage of

RPL. Self-reported miscarriage are often inaccurate. In a case study, only 71% reported

miscarriages patients themselves could be verified through medical records. Therefore, to

determine whether the evaluation for RPL is required, the pregnancy must be defined as

clinical pregnancies recorded by ultrasound or histopathology examination. 2

RPL is a traumatic experience for the patient, and also the most difficult areas in

reproductive science. To date, there is little consensus on the necessary investigations to

identify the causes and management of effective, and very few are evidence based. 1

2

2.2 Epidemiology

RPL affects 0.5-1% of couples attempting to have children. 5 Identified causes

such as uterine malformations, antiphospholipid antibodies, parental cytogenetic

anomalies, endocrine disturbances and infection accounted for only 20-50% of RPL. 5

The risk of miscarriage increases with younger gestational age, with the majority

occuring in the first trimester. The prevalence of miscarriage increases with increasing

maternal age, this occurs due to increased chromosomal abnormalities, possibly due to

decreased oocyte quality, and decreased uterine and ovarian function. Increased paternal

age is also a risk factor for miscarriage. The highest risk of miscarriage in couples where

women over 35 and men over 40 years. The patients obstetric history may also increase

the risk of miscarriage. Retrospective and prospective studies have shown that the risk of

recurrent miscarriage increases after each miscarriage. RPL usually occurs at the same

gestational age. 1

Tabel 1: Risk of miscarriage at specific gestational ages 1

Gestation Risk of miscarriage (%)

Before 6 weeks 22-57

6-10 weeks 15

After10 weeks 2-3

Tabel 2: Miscarriage rate according to maternal age 1

Maternal age at conception (years) Miscarriage rate (%)

20-24 9

25-29 11

30-34 15

35-39 25

40-44 51

>45 75

3

Tabel 3: Risk of miscarriage according to obstetric history 1

Consecutive pregnancies Risk of miscarriage (%)

First pregnancy 5-13

After 1 miscarriage 14-21

After 2 miscarriage 24-29

After 3 miscarriages 31-45

2.3 Etiology

It has been found that the factors that could cause RPL including cytogenetic

factors, anatomical factors, thrombophilic factors, antiphosopholipid syndrome,

immunologic factors, endocrine factors, environmentral factors, infection, male factors,

and unexplained RPL.

2.3.1 Cytogenetic Abnormalities

60% of miscarriage are associated with sporadic chromosomal anomalies,

especially trisomy partly related to age. In miscarriage with normal

karyotypes, multiple morphological abnormalities in the fetus were

diagnosed with transcervical embryoscopy. The risk of sporadic

miscarriage between 6-12 weeks of gestation in women less than 35 years

old is 9% -12%. This risk is increased in women over 35 years due to a

very significant increase of the incidence of trisomy pregnancy. In women

over 40 years, the risk of miscarriage sporadic reached 50%. Aneuploidy

risk at any age is lower in women with RPL compared experiencing

sporadic miscarriage. 1 The most common genetic cause of RPL is a

balanced reciprocal or robertsonian translocation. Other structural

abnormalities include chromosomal inversions, insertions, mosaicisms.

However, single gene defects such as seen in cystic fibrosis or sickle cell

anemia are seldom associated with RPL

4

2.3.2 Anatomical abnormalities

2.3.2.1 Congenital uterine anomalies

Congenital uterine malformations caused by disorders of

Müllerian duct development, fusion, canalization, and septal

resorption. Congenital anomalies of the uterus often cause miscarriage

in the second trimester, and in patients with RPL, the contribution of

congenital uterine anomalies are not clear. Septate uterus is uterine

abnormality most frequently associated with RPL with the worst

reproductive outcomes with the possibility of miscarriage more than

60%. A longer septum gives worse prognosis. 1

Figure 1.1: Disoders of mullerian duct development

2.3.2.2 Leiomyoma

The more important factor that plays a role in the

relationship between fibroids and fertility is more towards the

location rather than the size of the fibroids. The fibroids can

change the shape of the uterine cavity such as submucosal and

intramural fibroids with an intracavity component was found to

increase the risk of miscarriage. One study found that intramural

fibroids can decrease the implantation in each cycle. A meta-

analysis showed a decrease in the pregnancy rate with in vitro

5

fertilization (IVF), also with women with intramural fibroids that

does not change the shape of the cavity. 1

Figure 1.2 Uterine fibroid locations

2.3.2.3 Intra-uterine adhesions

Adhesion can occur due to intra-uterine trauma, such as

Asherman's syndrome that is caused by endometrial curettage. This

can cause miscarriage because the endometrium is not sufficient

for the development of the fetus, but there are no prospective

studies that may explain the relationship. In the developing

countries, intra-uterine adhesions can be caused genital

tuberculosis. 1

Figure1.2 Intrauterine adhesions

6

2.3.2.4 Cervical incompetence (insufficiency or dysfunction)

Cervical incompetence may cause repeated mid-trimester

miscarriage. 1

2.3.3 Thrombophilic factors

It is hypothesized that thrombophilic disorders can cause thrombosis of the

utero-placental vasculature (spiral arteries and intervillous space) due to an

increase in a hemostatic response. The subsequent impaired placental

perfusion may lead to RPL, fetal death, pre-eclampsia, intra-uterine growth

retardation (IUGR), and placental abruption. 1

Inherited thrombophilia is a genetic condition in which there is an

increased risk of venous thrombosis. The various types are:

Factor V leiden (FVL) mutation

7

Prothrombin G202110A gene mutation (PGM)

Protein S deficiency

Protein C deficiency

Antithrombin deficiency

Of the cases of inherited thrombophilia, 50-60% are due to the

FVL mutation and PGM. The literature on the association between

maternal inherited thrombophilia and RPL and mostly contradictory.

2.3.4 Autoimmune factors

According to the RCOG, antiphospholipid syndrome is the most

important cause of RPL that can be cured. This syndrome is the only

autoimmune disease in which abortion is part of the diagnostic criteria.

Antiphospholipid antibodies (APAS), lupus anticoagulant, anticardiolipid

antibodies (ACAS) and anti-B2-glycoprotein I antibodies attack the

phospholipid-binding plasma proteins.1

Disorders of pregnancy can occur in the form of:

More than 3 consecutive miscarriages can not be explained

under the age of 10 weeks gestation

More than one dead fetus with normal morphology after 10

weeks' gestation

More than one preterm births under 34 weeks' gestation

because of pre-eclampsia, eclampsia or placental

insufficiency. 1

Figure 1.3 Antiphospholipid antibodies against the placenta

8

Antiphospholipid antibodies against trophoblasts has many effects

towards the placenta, including the inhibition of the differentiation of

villous cytotrophoblasts, extravillous cytotrophoblast invasion into

decidua, induction of apoptosis syncytiotrophoblast, and the initiation of

maternal inflammatory pathways on the surface of the

syncytiotrophoblast. 2

2.3.5 Allo-immune factors

9

The Hypothesis that some cases of RPL may be due to the failure

of maternal allo-immune recognition of the pregnancy has never been

proven. There is also no evidence to support the hypothesis that HLA

incompatibility between couples may lead to RPL.1

2.3.5.1 HLA Incompatibility

The human conceptus is a semi-allograft and hence

antigenically foreign to the mother. Therefore the process of

implantation may include mechanisms to prevent allograft

rejection, but once the immunological tolerance becomes

imbalanced, RPL may occur. The human leucocyte antigen (HLA-

G) seemed to play a major role in immune suppression at the

maternal-fetal interface and placental angiogenesis. HLA-G is

mainly expressed in extravillous trophoblasts (EVTs) of decidual

tissue, and has suppressive effects on NK cells, CD4+ and CD8+ T

cells, B lymphocyctes and antigen presenting cells such as

macrophages and dendritic cells. This interaction was essential for

the maternal-fetal immune balance needed for optimal trophoblast

invasion during implantation and placentation.

Recent evidences have indicated that HLA-G played an

important role in the pathogenesis of RPL. Although there were

some controversies, the overall picture in recent years was that

reduced or aberrant HLA-G expression (such as HLA-G

polymorphism) was associated with RPL. Complications during

pregnancy, such as preeclampsia, miscarriage, IUGR, and

premature birth were associated with low or undetectable levels of

soluble HLA-G in the maternal blood circulation. However, studies

that have examined the association between HLA-G 14-bp

insertion/deletion polymorphism and RPL have showed

inconsistent, even contradictory results. 5

In a comprehensive meta analysis by Wei Fan et al (2013),

it is shown that there was insufficient evidence to demonstrate a

10

conclusive association between HLA-G 14-bp insertion/deletion

polymorphism with the risk RPL, whereas a significant

heterogeneity was evident across the individual studies. The

subgroup analysis indicated that there was a significant association

between HLA-G 14-bp insertion/deletion polymorphic variation

and RPL risk in patients with three or more miscarriages. 5

2.3.5.2 Uterine natural killer (NK) cells

Some patients with RPL may lack essential component of

the networks that provide immunological protection for the

embryo. Uterine NK cells appear to regulate placental and

trophoblast growth and local immunomodulation, and control

trophoblast invasion. The relationship between uterine NK cells

and pregnancy outcome in patients with RPL is still under

investigation. 1

2.3.5.3 Granulocyte-macrophage colony stimulating factor (G-CSF)

G-CSF is a cytokine with an important regulatory role in

embryo implantation and subsequent development. G-CSF

deficiency in pregnancy adversely impacts on fetal and placental

development. Recent studies has shown that the highest quality

oocytes come from follicles with the highest levels of G-CSF.

Research has been done to investigate the effectiveness of

administering G-CSF in preventing embryo death in women with

RPL. Most of the data show that G-CSF may be effective in the

treatment of unexplained RPL. However further studies are needed

to confirm the effectiveness of this treatment.

2.3.6 Endocrine factors

2.3.6.1 Diabetes Mellitus

Several studies have found that the value of glycosylated

hemoglobin (HbA1C) is high (> 8%) in early pregnancy can

increase early pregnancy loss and congenital malformations. There

11

is no risk of miscarriage in women with well-controlled diabetes

mellitus. 1

2.3.6.2 Polycystic ovarian syndrome (PCOS)

Recent studies have shown that reproductive outcome did

not differ between patients diagnosed with PCOS and healthy

controls. The two groups had similar live birth and miscarriage

rates.1

2.3.6.3 Thyroid antibodies and disease

There are many conflicting reports, and evidence is still

lacking with regard to the role of thyroid disease. Although the

mechanism is still unclear, it was found that increased serum

thyroid antibodies (thyroid peroxidase or thyroglobulin) are

associated with spontaneous RPL. Hyperthyroidism (Graves'

disease) can cause miscarriage, premature contractions, low fetal

weight, and perinatal mortality. Hypothyroidism can cause

infertility and miscarriage in the first trimester, as well as perinatal

morbidity and mortality. 1

2.3.6.4 luteal phase defect and deficiency of progesterone

A functional corpus luteum is essential for successful

implantation and maintenance of early pregnancy, primarily

through progesterone production. A luteal phase defect (defect in

corpus luteum function) with insufficient progesterone production

results in endometrial development unsuitable for embryonic

implantation and is associated with RPL. The existence for this

luteal phase defect is controversial, whether or not it is related to

RPL, mainly because there are inconsistencies in diagnosis and

management. There is no evidence that could be found in literature

regarding a possible association of anti-Mullerian hormone

deficiency and RPL. 1

2.3.7 Environmental factors

12

No high quality evidence shows the relationship between RPL and

occupational factors, stress, chemical exposure to light, smoke, or

caffeine. Medium-heavy alcohol consumption may increase the risk of

sporadic miscarriage. Physical activity does not increase the risk of RPL.

Recent retrospective study found that obesity is a risk factor for infertility,

miscarriage sporadic, RPL, and pregnancy complications. 1

2.3.8 Infection

No infectious agent has been proven to cause RPL. Ureaplasma

urealyticum, Mycoplasma hominus, chlamydia, Listera monocytogenes,

Toxoplasma gondii, rubella, cytomegalovirus, herpes virus, and other less

frequent pathogens have been identified more frequently in vaginal and

cervical cultures and serum from women with sporadic miscarriages.

However, there are no convincing data that infections cause recurrent

pregnancy loss, therefore there are no clear indications for routinely

testing these organisms for RPL evaluation. Therefore, use of any

antibiotics are nit supported by evidence.2 Pregnancies complicated by

untreated syphilis may lead to RPL if it remains untreated in the

subsequent pregnancy, this usually presents with recurrent mid-trimester

miscarriage with a macerated fetus. Genital tuberculosis may cause

implantation failure or early embryonic rejection, leading to RPL and

ectopic pregnancy. 1

2.3.9. Male factors

Standard semen parameters, including sperm morphology, do not

appear to be predictive of RPL. Sperm aneuploidy and DNA

fragmentation have been studied in couples with RPL. Abormal DNA

fragmentation may be seen in advanced paternal age or result from

correctable environmental factors, such as exogenous heat, toxic

exposures, varicoceles, or increased reactive oxygen species in semen.

Although increased rates of sex chromosome disomy have been seen in

sperm from the male partner in couples with recurrent miscarriage,

cytogenic analysis of the products of conception from couples with RPL

13

does not reveal an increased rate of sex chromosome aneuploidy, thus

suggesting that such cytogenetically abnormal sperm may be selected

against during fertilization. Therefore routine testing for spermploidy or

DNA fragmentation is not recommended.

2.3.10 Unexplained recurrent pregnancy loss

No apparent causative factor is identified in 50%-70% of couples

with RPL. However is it important to emphasize to patients with

unexplained RPL that chance for a future successful pregnancy can exceen

50%-60% depending on maternal age and parity.

2.4 Diagnosis

They who suggested to take the medical examinations are woman who had two or

three miscarriage in a row.

2.4.1 History Taking

Comprehensive evaluation to establish the diagnosis should be

made, including about the history of her disease . Some questions

including age, obstetrics history, gynecology history, past medical

history and hereditary diseases, including family illness, a history of

previous surgery, genetic disorders, and social status .

Besides history taking, physical examination are also required

precise and meticulous. A complete history of previous

miscarriages events is important, including gestational age when

past miscarriage occurs. When a miscarriage in the second

trimester, any information that could support or rule out the

possibility of cervical incompetence, whether or not the fetus is

macerated and good discovery in the evaluation of uterine

abnormalities, all of them should be reviewed and recorded in the

medical record. The results of investigations that have been done

before, including blood tests, pathology and imaging should also be

obtained.

14

Table 4. Evaluation of a woman with RPL

Here are some methods to investigate the

occurrence of RPL :

Karyotiping

Karyotiping from the conseptional’s products

Cytogenic analysis should be carried out on the products of

conception in all patients with RPL. Normal karyotype

usually indicates a better prognosis for the next

pregnancy.4 Structural rearrangements of chromosomes in

the fetus can be inherited or sporadic, and is an indication

for karyotyping parents. The role of pre - implantational

genetic diagnosis ( PGD ) with IVF has been reviewed and

15

has been found not to be cost effective in the management

of RPL.5 In patients with RPL, spontaneous birth rate was

50 % ; with PGD miscarriage rate may be decreased , but

only 33 % of women who get pregnant after a cycle of PGD

/ IVF .

Karyotyping from parental’s peripheral blood

Proper selective parental karyotyping performed in cases

where chromosomal abnormalities identified in the results

conception.4 Conception should be noted that the

investigation is expensive and has limited prognostic

value, low yields for detect any disorders, and it is not an

effective routine to perform karyotyping of all couples with

RPL. The aim is to detect the balance of reciprocal or

Robertsonian translocation, or mosaicism bias that is not

inherited by the balance on the fetus. However,

chromosomal abnormalities found in the peripheral blood

of the parents are indirect indicators and limited for fetal

karyotype .

Uterus Assessment

According to the RCOG , all women with RPL in the first

trimester or with one or more of the second trimester

should perform a pelvic ultrasound examination to assess

the uterus anatomy.4 After that , if there is a suspicion of

uterine anomalies, further investigations may be

performed to confirm the diagnosis, using hysteroscopy,

laparoscopic or pelvic three-dimensional ultrasound. Other

diagnostic modalities are sonohysterography,

hysterosalpingography and magnetic resonance imaging

( MRI ). MRI is rarely used because it is more expensive.

Hysteroscopy is seen as the gold standard for the diagnosis

of intrauterine anomalies, most disorders can also be

16

treated during the examination procedure.6

Sonohysterography provides a description of the internal

contours of the uterus, as well as the outer surface and the

walls of the uterus. In one study, sonohysterography

provide more accurate results when compared to

hysterosalpingography.7

Hereditary Thrombophilia

Testing for hereditary thrombophilia in women with a

history of idiopathic RPL is still controversial. No

randomized clinical trials with placebo control to establish

the effectiveness of anticoagulation therapy in preventing

RPL quality. Evidence to help guide the process of

screening is also limited conditions.

According to the American College of Obstetricians and

Gynecologists Practuce Bulletin No. 124, hereditary

thrombophilia testing is not recommended for women with

a history of RPL or placental abruption, because it is

unclear whether anticoagulation reduces recurrence (level

B recommendation).8 Screening with fasting homocysteine

levels or methylenetetrahydrofolate reductase mutation

analysis also not recommended (level B recommendation).

Examinations should be done is to assess the FVL and

PGM, and antithrombin, protein C and protein S deficiency

(level of recommendation C). Screening it self is still

controversial, and only useful if the results will affect

management decisions, and not for the treatment

indicated for other risk factors.

RCOG recommends that women with RPL in the second

trimester, should be screened for hereditary thrombophilia.

Including tests for FVL, PGM and protein S deficiency (level

D recommendation) .4 It is based on the results of a meta-

17

analysis of retrospective studies that show a strong

association between miscarriage in the second trimester

and hereditary thrombophilia.

Antiphospolipid Syndrome

All women with RPL should be screened for

antiphospholipid syndrome before the next pregnancy.9

This test included to test the ACA IgG and IgM, and lupus

anticoagulant ( LA ); testing should be done twice, with a

distance of 6-8 weeks, to rule out false positive results.

Diagnosis of antiphospholipid syndrome requires at least

two positive results both for LA or ACA IgG or IgM. Women

with a positive test result and the second negative test

result should have a third test to confirm the diagnosis.

False-positive results may be due to infection, suboptimal

methods of sample collection and preparation, and the lack

of standardization of laboratory testing.

The cause of infection

A recent review article concludes that most patients with a

history of RPL is not affected by the treatment of extensive

infections.10 Exception of the untreated syphilis .

Thyroid function

Thyroid function should be assessed in women who have a

history of thyroid disease or with the clinical

manifestations. The American Thyroid Association

recommends measurement of serum thyroid- stimulating

hormone in pregnant women with the following conditions: 11

Symptoms of thyroid disease

From the area that known as iodine drficiency

History of thyroid disease in family or personal

Thyroid peroxides antibody +

18

Type 1 diabetes

History of premature birth or miscarriage

History of head and neck radiation

Morbid obesity

Infertility

Age over 30 years

Screening in women without symptoms of subclinical

thyroid disease is controversial. When screening for thyroid

disease of all women planning a pregnancy is not

recommended, because there is no data to confirm that

the screening had significant results. However, certain

researchers recommend measuring thyroid peroxidase

antibodies in patients with RPL or premature birth, in which

no other cause can be identified.12

Evaluation of ovarian reverse

Taking blood sample to measure the follicle- stimulating

hormone ( FSH ) level on day 3 of the menstrual cycle can

be considered in the evaluation of RPL in women of all age

groups. In a retrospective analysis comparison, serum FSH

day 3 or estradiol, or both, was found to increase as much

as 58 % of women with idiopathic RPL.13

Defect in luteal phase

There is no standard method for diagnostic that available

to assess the actual occurrence and effect of luteal phase

defect. Endometrium biopsy is not recommended, because

studies have shown that it does not predict the fertility

status. Measurement of serum progesterone also

unreliable, and can not predict the final outcome of

pregnancy.14

Enforce the medical diagnosis

19

Laboratory tests may be indicated in women with clinical

manifestations or a history of medical disorders that lead

to RPL

Table 5. Evidence-based approach to the work-up of couples with RPL, to identify a possible underlying

cause

Table 6. Controversial factors in the work-up and management of RPL

2.5 1Management

Treatments for recurrent miscarriage is based on the etiology.

However, all couples must be treated sensitively , sympathetic , and

20

with the proper emotional support. The best practice is to refer the

couple to a specialist clinic.

2.5.1 Anatomical

Correction of septate defect in particular may have beneficial effects and should

be considered in woman with RPL. Clinical management with Asherman

syndrome or intrauterine synechiae, uterine fibroids, and uterine polyps remain

controversial, some data showed that surgical treatment did not reduces the risk of

pregnancy loss. Cerclage cervix is recommended to be done at

gestational age 14-16 weeks in the case of cervical

incompetence.

2.5.2 Autoimmune

Women with persistent lupus anticoagulant, anticardiolipin

antibodies and hereditary trombophilia can be treated with low -

dose aspirin (81 mg) and enoxaparin (40 mg subcutaneously),

during subsequent pregnancies.

2.5.3 Alloimmune

Immunomodulatory treatments for RPL in the setting of one or more finding have

not been proven effective. Treatment with intravenous immunoglobulin (IVIG)

has also been proposed for unexplained pregnancy loss. However, several trials

and meta-analyses conclude that IVIG is ineffective for primary RPL, thus this

treatment is not recommended.

2.5.4 Endocrine

In women with PCOS, the risk of RPL may be reduced by giving

1700 mg metformin daily. Ultrasound examination can also be

carried out to assess the presence of PCOS and uterine

abnormalities.

Any disorder that associated with thyroid hormone can be

detected and treated with ease. First we try to maintain the TSH

values in 4.0-5.0 mIU/L, but if the TSH was not in the range, we

can maintain it by giving thyroid hormone replacement. As for

21

women who are suspected of suffering from diabetes mellitus,

glucose and hemoglobin AIC monitoring can be done.

2.5.5 Infections

Routine serological tests, cultures cervical and endometrial

biopsy to detect the presence of infection in women with a

history of RPL is not recommended. Evaluation should be

performed only on those who are clinically suffering from

cervicitis, chronic or recurrent bacterial vaginosis or complaints

of pelvic infection.

2.5.6 Unexplained etiology

Aspirin and low-molecular-weight heparin are prescribed for

woman with unexplained RPL, with the goal of improving the rate

of live births.

Table 7. Therapeutic Interventions for RPL based on Etiology

22

Generally, as many as 70-75 % of women who had a history of

RPL can be successful in the next pregnancy, except in those with

impaired or incompetent cervix antiphospholipid antibodies.

Table 8. Suspected cause of RPL

Table 9. Treatment for RPL

Etiology Treatment Outcome

Anatomical15 Transabdominal

Cervicoisthmus Cerclage

(TCC) has been advocated as

a treatment for second-

trimester miscarriage and

prevention of early preterm

labour in selected woman

with a previous failed

transvaginal cerclage and/or a

very short and scarred cervix

- 25% had two

successful consecutive

pregnancies after TCC

- Fetal survival after this

procedures was 85,2%

Antiphospolipid

Syndrome16,17,18

81 mg aspirin once daily

orally plus LMWH

enoxaparin 40 mg

- Rate of miscarriage

9%

23

subcutaneously / day - Live birth 91%

- Rate of pre-eclampsia

7%

5 mg folic acid daily before

conception, low dose aspirin,

40 mg/day of enoxaparin

subcutaneously

Live birth rate of woman

treated with enoxaparin

was 86% compared with

29% woman taking low

dose aspirin alone

Hormonal disorder19,20 Progesterone supplementation

10 mg/day

No statistically

difference in the risk of

miscarriage between

control and trial group

(OR 0,38, 95% CI 0,2-

0,7)

Metformin supllementation

1700-3000 mg/day in woman

PCOS until the entire

pregnancy

Diminished incidences

of fetal growth

restriction, preterm

labor, early pregnancy

loss and increased live

birth rates.

Alloimmune21,22 IVIg 500mg/kg/month until

18-20 weeks of gestation,

approximate total dose of

150-180 g

Live birth rate was

14,7%

Unexplained RPL23,24 80 mg of aspirin daily plus

subcutaneous nadroparin

(2850 IU)

- 54,5% gave birth to

live infant

- Woman who pregnant,

live birth rates were

69,1%

24

CHAPTER III

CONCULSION

RPL is spontaneous abortion that occurs three times or more in a row. This

situation is a problem that requires special attention. Etiology of RPL is cytogenetic

factors , anatomical , antiphosopholipid syndrome, thrombophilias , hormonal or

metabolic disorders , infectious , autoimmune , sperm quality and lifestyle issues .

Some proper handling and safe to overcome the incidence of RPL had been

discovered. Since a woman is diagnosed RPL, she should do some medical

examination to prevent the miscarriages and eventually gave birth to the fetus is

viable. Some tests that could be done including genetic examination, anatomy,

endocrinology and immunology factors. Generally the management of RPL is based

on the underlying etiology. Examination using ultrasound can help review the

development of the fetus in the uterus.

25

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Medicine.

3. “The Investigation and Treatment of Couples with Recurrent Firsttrimester and

Second-trimester Miscarriage.” Green-top Guideline No. 173 (2011): 1-18. Royal

College of Obstetricians and Gynaecologists.

4. Cunningham, F Gary, et al. 2010. Obstetri Williams 23rd ed. USA : The McGraw-

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5. Fan Wei, Shangwei Li, Zhongying Huang, Qiong Chen. Relationship between

HLA-G polymorphism and susceptibility to recurrent miscarriage: a meta analysis

of non family based studies. J Assist Reprod Genet (2014) 31: 173-184.

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