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Birth defects after a history of subfertility: a registry ... Birth defects after a history of subfertility:

Feb 19, 2020




  • Birth defects after a history of subfertility:

    a registry-based case-control study in the

    Northern Netherlands

    M.E. Bos s1735187

    EUROCAT Northern Netherlands, UMCG

    Supervisors: dr. H.E.K. de Walle dept GENETICS

    dr. A. Hoek dept OBGYN, dr. M.L. Haadsma dept GENETICS

    Research period: August 2012 – December 2012

  • 1

    1 Abstract

    Background: In children conceived via assisted reproduction, an increased overall

    risk for birth defects has been described in literature. In these newborn, a specific

    increase has been reported for cardiovascular, musculoskeletal, urogenital and

    gastrointestinal abnormalities. It remains uncertain, however, whether the rise in

    occurrence of birth defects can be attributed to patient characteristics related to

    subfertility, or to the treatment itself. The primary aim of the study is to evaluate

    whether specific types of birth defects occur more often in offspring of subfertile

    couples rather than in the offspring of fertile couples. The secondary aim is to

    evaluate when birth defects are more likely to develop: after a history of subfertility

    compared to the offspring of couples who received in vitro fertilization (IVF) or

    intracytoplasmatic sperm injection (ICSI). The tertiary aim is to evaluate whether

    prolonged time to pregnancy (TTP) in the group of subfertile couples shows a positive

    correlation with regard to the prevalence of specific types of birth defects.

    Methods: For performing this case-control study we used data from EUROCAT –

    Northern Netherlands, a registry of birth defects. 4392 cases and 1456 (malformed)

    controls were identified. These subjects were born between 1997 and 2010, and were

    registered by EUROCAT. The cases were children and fetuses with major birth

    defects of a non-genetic origin. Controls were defined as children and fetuses with a

    chromosomal anomaly, a microdeletion or a monogenic anomaly. In the statistical

    analysis, three groups of children and fetuses were compared: Sub-NC (n=296),

    IVF/ICSI (n=174) and children and fetuses of fertile couples (n=5378).

    Results: Compared with fertile women, Sub-NC women were at an increased risk of

    having a child with a penoscrotal hypospadia (adjusted odds ratio [aOR]: 6.80; 95%

    confidence interval [CI]: 2.35 – 19.63). Subfertile women conceiving via IVF/ICSI

    were at an increased risk of having a child with a limb anomaly (aOR: 2.80; CI: 1.51 –

    5.20), especially polydactyly (aOR: 5.26; CI: 2.47 – 11.20). Compared to fertile

    women, the entire group of subfertile women (Sub-NC and IVF/ICSI) was at an

    additional increased risk of having a child with an epispadia (aOR: 4.28; CI: 1.04 –

    17.57) and cystic kidneys (aOR: 2.10; CI: 1.02 – 4.34). Surprisingly, Sub-NC women

    showed a significant decreased risk for having a child with a congenital anomaly in

    general, considering congenital anomalies occurring in all groups. Overall, a

    significantly decreased risk of having a child with a congenital hip dysplasia was seen

    in subfertile women, as was also described for the Sub-NC women alone.

    Conclusions: In this study, Sub-NC women were at an increased risk of having a

    child with specific major congenital anomalies, especially penoscrotal hypospadias.

    The results of this study may be of great importance for public health, since

    subfertility is a growing health issue since women are conceiving at older ages.

    Keywords: assisted reproductive techniques, IVF, ICSI, congenital abnormalities,

    history of subfertility

  • 2

    2 Preface

    This paper is intended as the final report of the science project for the Master in

    Medicine. The emphasis lies on whether there is a correlation between specific major

    congenital anomalies and subfertility. After the study was conducted, which greatly

    expanded my interest in this topic, I have the ambition to do more research within this


    The main objective of the science project is to improve different skills: scientific

    writing, critical reading and perform statistical analyses. This research is based on the

    analysis of data from fertile records of fourteen hospitals in the Dutch provinces

    Friesland, Groningen and Drenthe. Performing this research improved my ability to

    read and understand fertility- and gynaecology- records. Moreover, I became more

    experienced in communicating with gynaecologists.

    Performing this science project and writing this report have been made

    possible with the help of my supervisors, Hermien de Walle, Annemieke Hoek and

    Maaike Haadsma.

    Marly Bos


  • 3


    1 Abstract 1

    2 Preface 2

    3 Introduction 4

    3.1 Congenital anomalies 4

    3.2 Assisted reproductive technology 5

    3.3 IVF and ICSI procedures 5

    3.4 Perinatal risks and congenital anomalies associated with ART 6

    3.5 The role of subfertility in increasing birth defects rates 7

    3.6 The aim of the present study 8

    4 Methods 9

    4.1 EUROCAT 9

    4.2 Study population 10

    4.3 Definitions and recruitment 10

    4.4 Methods 11

    4.5 Statistical analysis 11

    5 Results 13

    5.1 General 13

    5.2 Characteristics 14

    5.3 Fertility status in two and three categories 15

    5.4 Time to pregnancy 18

    6 Discussion and Conclusion 20

    6.1 Main results 20

    6.2 Strengths and weaknesses 21

    6.3 Potential underlying mechanisms 22

    6.4 Further research 23

    6.5 Public health implications 24

    6.6 Conclusion 24

    7 Acknowledgments 25

    8 References 26

    9 Nederlandse samenvatting (Dutch summary) 30

    Appendix 32

  • 4

    3 Introduction

    3.1 Congenital anomalies

    The term congenital anomaly refers to a broad spectrum of defects in body structures.

    Congenital anomalies can be divided into anomalies of a genetic nature or anomalies

    of a non-genetic nature. Genetic anomalies include chromosomal disorders (e.g.,

    Down syndrome); single gene (monogenic) disorders, including those that are

    autosomal recessive (e.g., cystic fibrosis), automosal dominant (e.g., Marfan

    syndrome), or X-linked (e.g., hemophilia); as well as multifactorial disorders which

    result from the interaction of multiple genetic and environmental factors. The latter

    include birth defects such as a cleft lip/palate, congenital heart disease, and neural

    tube defects. Non-genetic etiologies include environmental factors. Examples of non-

    genetic defects are maternal phenylketonuria (PKU) or diabetes, teratogens (e.g.,

    alcohol consumption) and infections. An important cause of perinatal mortality are

    congenital anomalies, where 6-12% of stillbirths are attributed to a congenital


    Congenital anomalies can be classified into four different categories. They can

    be subdivided according to their presumed pathogenesis into malformations,

    deformations, disruptions and dysplasias. Malformations are caused by an intrinsically

    abnormal developmental process which leads to defects of organs or certain body

    parts. Generally, malformations already occur in the first eight weeks of gestation and

    are the result of a defect in embryonic development. Common occurring

    malformations are neural tube defects and congenital heart defects. Deformations,

    however, are not caused by intrinsically abnormal development, but are rather

    produced by abnormal mechanical forces which distort otherwise normal structures

    and could develop at any time in gestation. Oligohydramnion, for instance, may lead

    to a child being born with an abnormal foot position. Unlike malformations or

    deformations, disruptions results from an extrinsic disturbance leading to a

    morphologic anomaly to an organ or body part. Anomalies caused by extrinsic

    disturbance are typically caused by adverse environmental factors such as teratogenic

    drugs, compression or strangulation. Anomalies can also appear as the result of

    abnormal organization or function of cells into tissues, called dysplasias. When cells

    are not correctly organized, this may lead to abnormal growth, resulting, for instance,

    in skeletal dysplasia(2).

    While congenital anomalies can be classified by the suspected underlying

    cause, they may also be subdivided according to severity; as are major or minor

    anomalies. The difference between major- and minor anomalies is that the former

    have medical and/or social implications and often require surgery to be corrected,

    while the latter generally at most have a cosmetic impact. Though minor anomalies

    may be associated with a disorder or disability, they generally do not