ORIGINAL ARTICLES: ENVIRONMENT AND EPIDEMIOLOGY
Congenital anomalies in offspring of subfertile couples: a registry-based study in the northern Netherlands Jorien Seggers, M.D.,a Hermien E. K. de Walle, Ph.D.,b Jorieke E. H. Bergman, M.D., Ph.D.,b Henk Groen, M.D., Ph.D.,b Mijna Hadders-Algra, M.D., Ph.D.,a Marly E. Bos, B.Sc.,b Annemieke Hoek, M.D., Ph.D.,c and Maaike L. Haadsma, M.D., Ph.D.b a Division of Developmental Neurology, Department of Pediatrics, b Division of Eurocat Northern Netherlands, Department of Genetics, and c Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Objective: To study whether specific congenital anomalies occur more often with a history of subfertility and/or the use of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Design: Case-only analyses. Setting: Not applicable. Patient(s): We included live births, stillbirths, and terminated pregnancies with congenital anomalies without a known cause that had a birth year between 1997 and 2010 (n ¼ 4,525). A total of 4,185 malformed cases were born to fertile couples and 340 to subfertile couples, of whom 139 had conceived after IVF/ICSI and 201 had conceived naturally after >12 months. Intervention(s): None. Main Outcome Measure(s): The contribution, expressed in odds ratios (ORs), of a history of subfertility and IVF/ICSI to each specific type of congenital anomaly, imprinting disorder, and syndromal disorder. Result(s): We found subfertility to be associated with an increase in abdominal wall defects (adjusted OR [aOR] 2.43, 95% CI 1.05–5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58–27.04), right ventricular outflow tract obstruction (aOR 1.77, 95% CI 1.06–2.97), and methylation defects causing imprinting disorders (aOR 13.49, 95% CI 2.93–62.06). In vitro fertilization/ICSI was associated with an increased risk of polydactyly (OR 4.83, 95% CI 1.39–16.77) and more specifically polydactyly of the hands (OR 5.02, 95% CI 1.43–17.65). Conclusion(s): In our registry-based study, parental subfertility was associated with an increase in abdominal wall defects, penoscrotal hypospadia, right ventricular outflow tract obstruction, and methylation defects causing imprinting disorders. In vitro fertilization/ICSI was associated with an increase in polydactyly, mainly of the hands. (Fertil SterilÒ 2015;103: Use your smartphone 1001–10. Ó2015 by American Society for Reproductive Medicine.) to scan this QR code Key Words: In vitro fertilization, assisted reproductive technology, subfertility, congenital and connect to the anomalies, birth defects Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/seggersj-congenital-anomalies-offspring-netherlands/
T
he increasing use of in vitro fertilization (IVF), with or without intracytoplasmic sperm
injection (ICSI), has raised concerns about potential consequences for the resulting offspring, in particular the
Received September 17, 2014; revised December 5, 2014; accepted December 15, 2014; published online January 24, 2015. A.H. reports grants (outside the submitted work) from Ferring Farmaceutical NL BV, MSD, and the Netherlands Organization for Health Research and Development ZonMW (grant 50-50110-96-518); and speaker fees from MSD. J.S. has nothing to disclose. H.E.K.d.W. has nothing to disclose. J.E.H.B. has nothing to disclose. H.G. has nothing to disclose. M.H.-A. has nothing to disclose. M.E.B. has nothing to disclose. M.L.H. has nothing to disclose. The Department of Obstetrics and Gynecology of the University Medical Center Groningen received an unrestricted educational grant from Ferring Pharmaceutical BV, Netherlands. The Eurocat registry is financed by the Dutch Ministry of Public Health, Welfare and Sports. The sponsor of the study had no role in its design, data collection, data analysis, data interpretation, or in writing of the report. Reprint requests: Jorien Seggers, M.D., Developmental Neurology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands (E-mail: [email protected]). Fertility and Sterility® Vol. 103, No. 4, April 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.12.113 VOL. 103 NO. 4 / APRIL 2015
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putative effect on the prevalence of congenital anomalies. A recent metaanalysis showed that infants born after IVF/ICSI (n ¼ 92,671) had a relative risk of 1.32 (95% confidence interval [95% CI] 1.24–1.42) of having any birth defect compared with naturally conceived infants (n ¼ 3,870,760) (1). The increased number of birth defects in infants conceived via IVF/ICSI has been attributed both to the IVF/ ICSI procedure and the parent's underlying subfertility. A role for the IVF/ ICSI procedure is conceivable because natural selection of gametes is bypassed, early embryonic development 1001
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY takes place in vitro, and the embryo is transferred into an altered intrauterine environment due to ovarian hyperstimulation. There is also evidence for a role of the underlying subfertility: untreated subfertility and a longer time to pregnancy are associated with an increased rate of birth defects (2–4). In addition, an increased risk of imprinting disorders like Beckwith-Wiedemann syndrome and Angelman syndrome has been described after IVF/ICSI (5–7). There is evidence to suggest an adverse effect of the IVF/ICSI procedures (8–11), as well as of the underlying subfertility (12), on imprinting status. Previous studies often faced the limitation of either low numbers of specific congenital anomalies or the absence of information on a history of subfertility without IVF/ICSI treatment. In case of low numbers of specific anomalies, defects were grouped together in larger subgroups for power reasons. Associations have been reported between IVF/ICSI and cardiovascular anomalies, neural tube defects, urogenital anomalies, gastrointestinal anomalies, clefts, musculoskeletal anomalies, and limb anomalies (13–15). A disadvantage of using subgroups is that pathogenetically dissimilar congenital anomalies are pooled. This could explain why the studies provided an incoherent picture. For instance, some found an increased risk of musculoskeletal defects (2, 14, 16–18), whereas others did not (15, 19–22). These contradictions emphasize the necessity for a novel approach evaluating the increased risk for specific types of birth defects like hip dysplasia or a club foot, instead of larger subgroups of defects, such as musculoskeletal defects. In addition, knowledge about which birth defects occur more often after a history of subfertility without IVF/ICSI treatment is scarce. To address these issues, we analyzed data from Eurocat Northern Netherlands (Eurocat NNL), a voluntary population-based birth defects registry. Unlike previous studies that used non-malformed controls, we performed a case-only study: we studied the effects of subfertility and IVF/ICSI in a dataset of fetuses/children that all have a congenital anomaly. This approach precludes us from investigating the overall risk for a congenital anomaly but allows us to identify which specific congenital anomalies, imprinting disorders, and syndromal disorders with unknown etiology are associated with subfertility or IVF/ICSI.
MATERIALS AND METHODS Setting and Participants We used data from Eurocat NNL, which registers fetuses and children with congenital anomalies of mothers who lived in the registration area at the time of birth. An affected child can be registered up to the age of 10 years. Annually, Eurocat NNL monitors approximately 19,000 births in the northern Netherlands. Eurocat NNL uses multiple sources for active case ascertainment, in addition to notification by midwives, general practitioners, well-baby clinic doctors, and medical specialists. Live births, stillbirths, and pregnancies terminated due to congenital anomalies are notified on a voluntary basis. The staff of Eurocat NNL is actively involved in case ascertainment. The participation rate is stable at approximately 1002
80% for years. After consenting to registration, parents receive a questionnaire asking about their health, life style, use of medication, fertility, and pregnancy; another 80% completes the questionnaire. A telephone interview on the use of medication during pregnancy was conducted with all parents who submitted a questionnaire. If inconsistencies in the questionnaire were detected, the interviewer also asked questions about these inconsistencies in the same interview. Information on congenital anomalies is retrieved from medical files and includes results from genetic tests and pathology reports. Congenital anomalies are classified according to the 9th and 10th revisions of the World Health Organization International Classification of Diseases (ICD). The ICD-9 classification was used up to 2001 and ICD-10 from 2002 onward. Heart defects are further classified into septal defects, conotruncal defects, outflow tract anomalies, and other heart defects (23). Eurocat NNL does not collect information on non-malformed fetuses/children. An overview of the procedures and findings of Eurocat can be found at www.eurocat-network.eu/accessprevalencedata/prevalen cetables. Parents consented to the data being registered and used in studies on risk factors for congenital anomalies. Approval from the medical ethics board was not required. Cases born between 1997 and 2010 were divided into three fertility groups: [1] fertile parents, [2] subfertile parents who eventually conceived naturally (Sub-NC group), and [3] subfertile parents who conceived after IVF or ICSI. Parents were categorized into one of these groups depending on their answers to the questionnaire: they were asked whether they experienced any problem conceiving. If they answered ‘‘no,’’ they were considered fertile. If they answered ‘‘yes,’’ parents could fill out whether they used any fertility treatment and, if so, which treatment. We searched medical records of fertility clinics of all couples stating they had fertility problems. Couples were defined as subfertile after a time to pregnancy of at least 12 months. Cases were excluded if subfertility could not be confirmed (e.g., no medical records of fertility clinics were available or a time to pregnancy 12 mo D IVF/ICSI (n [ 340) Characteristic ICSI, n (%) Maternal age at conception (y) Maternal prepregnancy BMI (kg/m2) Pregestational diabetes Periconceptional smoking Correct use of folic acid DES daughter Maternal level of education Lowd Averagee Highf Multiple pregnancy Congenital anomaly discovered during pregnancy Pregnancy outcome Active termination of pregnancy Live birth Stillbirth Other
Fertile group (n [ 4,185)
Subfertile but natural conception (n [ 201)
Subfertile, conception after IVF/ICSI (n [ 139)
– 29.8 (24.0–35.4)a,b 23.3 (19.7–29.7) 3 (0) 1,024 (25) 1,507 (37)a,b 20 (1)b
– 32.7 (19.6–33.1)b 23.5 (19.6–33.09) 1 (1) 57 (30) 92 (48)a,c 4 (2)b
78 (56) 33.6 (27.6–38.8)a 22.7 (19.4–28.9) 0 (0) 30 (23) 95 (75)b,c 1 (1)
732 (18) 1,993 (50) 1,270 (32) 152 (4)b 1,796 (43)
45 (23) 95 (50) 52 (27) 10 (5)a 86 (43)
262 (6) 3,705 (89) 55 (1) 163 (4)
10 (5) 179 (89) 2 (1) 10 (5)
27 (22) 55 (44) 42 (34) 48 (35)a,b 60 (43) 9 (6) 117 (84) 1 (1) 12 (9)
Note: Values are n (%) or median (percentiles, 10–90). IVF ¼ in vitro fertilization; ICSI ¼ intracytoplasmic sperm injection. a,b,c Matching superscript letters indicate a statistically significant difference (P< .05). d Low level of education: no school, primary school, lower general secondary education, and lower vocational education. e Average level of education: higher general secondary education and intermediate vocational education. f High level of education: university, further tertiary college, and higher vocational education. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
group also reached statistical significance. Mothers in the Sub-NC group were more often DES daughters (2%) than fertile mothers (1%).
Frequencies of Congenital Anomalies, Recognized Syndromes with Unknown Etiology, and Imprinting Disorders Table 2 shows the number of congenital anomalies, recognized syndromes with unknown etiology, and imprinting disorders per fertility category. Congenital anomalies that occurred less than three times in the total subfertile group were not analyzed but are described in Supplemental Table 1 (available online). As an exception, we do show all imprinting disorders in Table 2, regardless of low numbers.
Differences in Congenital Anomalies per Fertility Category Table 3 shows crude and adjusted ORs resulting from the logistic regression analyses. In these multivariable regression analyses we always corrected for maternal age at conception and correct use of folic acid. In addition, we corrected for year of birth, multiple pregnancy, and defect-specific confounders where we found significant differences between the groups after correcting for maternal age and folic acid use; this was the case for the following congenital anomalies: abdominal wall defects, congenital hip dysplasia, limb anomalies, polydactyly, and preaxial polydactyly of the hands. As can be seen in Table 3, we found a history of subfertility to be associated with an increase in abdominal wall defects 1004
(adjusted OR [aOR] 2.43, 95% CI 1.05–5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58–27.04), and right ventricular outflow tract obstruction (RVOTO; aOR 1.77, 95% CI 1.05–2.96). In vitro fertilization/ICSI was associated with an increase in limb anomalies (aOR 3.31, 95% CI 1.31–8.38), polydactyly (aOR 4.83, 95% CI 1.39–16.77), and polydactyly of the hands (aOR 5.02, 95% CI 1.43–17.65). This association between IVF/ICSI and limb anomalies was attenuated when we excluded the cases with polydactyly from the cases with limb anomalies (aOR 1.83, 95% CI 0.48–6.99), indicating that the increased risk of limb anomalies was dominated by an increased risk of polydactyly. The legend of Table 3 shows the additional confounders. The rationale for selecting defect-specific confounders was as follows: in the analyses of genital anomalies we corrected for DES daughter and ICSI, because DES daughters more often give birth to a son with hypospadia (24), and ICSI may be associated with genital anomalies in the offspring (25). In the analysis of VOTOs, we also corrected for pregestational diabetes because heart defects occur more often in offspring of mothers with diabetes (26).
Recognized Syndromes with Unknown Etiology Of the recognized syndromes with unknown underlying cause, only VATER association was reported at least three times in the subfertile groups and is presented in Table 2. VATER was found four times in the IVF/ICSI group (3%) and once (1%) in the Sub-NC group; the difference was statistically not significant (P¼ .055). In the fertile group, VATER was also found in 1% (n¼23). VOL. 103 NO. 4 / APRIL 2015
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TABLE 2 Number of congenital anomalies per fertility category. Total subfertile group (n [ 340) Congenital anomaly Anomalies of the central nervous system Neural tube defect Anencephaly Hydrocephaly Eye anomaly Congenital cataract Ear anomaly Clefts Cleft lip with or without cleft palate Cleft lip without cleft palate Cleft lip with cleft palate Unilateral cleft lip and palate Cleft palate without cleft lip Anomalies of the respiratory tract Anomalies of the digestive tract Anomalies of the esophagus Hypertrophic pyloric stenosis Atresia of the small or large intestine Atresia of the small intestine Atresia of the large intestine Anorectal atresia Malrotation of the intestines Diaphragmatic hernia Abdominal wall defects Omphalocele Gastroschisis Anomalies of the genitals Epispadia Hypospadia Coronal and glandular hypospadia Penile hypospadia Penoscrotal hypospadia Anomalies of the urinary tract Renal agenesis (unilateral and bilateral) Cystic kidney disease Multicystic dysplastic kidney Renal dysplasia Hydronephrosis Stenosis ureter/pelviureteric junction Vesicoureteric reflux Musculoskeletal anomalies Congenital hip dysplasia Dislocation hip Club foot (neural tube defects excluded) Limb anomalies Polydactyly Polydactyly hand Preaxial polydactyly hands Postaxial polydactyly hands Syndactyly Syndactyly hands Reduction defect Reduction defect upper limb Reduction defect lower limbs Transverse reduction defect Heart anomalies Septal defect ASD VSD Muscular VSD Perimembraneous VSD AVSDs
Fertile group (n [ 4,185)
Natural conception after >12 mo (n [ 201)
Conception after IVF/ICSI (n [ 139)
290 (7) 148 (4) 49 (1) 53 (1) 108 (3) 47 (1) 18 (0) 368 (9) 250 (6) 94 (2) 156 (4) 46 (1) 118 (3) 76 (2) 531 (13) 44 (1) 224 (5) 78 (2) 29 (1) 51 (1) 48 (1) 33 (1) 45 (1) 38 (1) 21 (1) 17 (0) 354 (9) 8 (0) 328 (8) 184 (4) 114 (3) 14 (0) 402 (10) 82 (2) 65 (2) 48 (1) 45 (1) 76 (2) 61 (2) 54 (1) 889 (21) 621 (15) 128 (3) 171 (4) 252 (6) 106 (3) 83 (2) 18 (0) 38 (1) 45 (1) 27 (1) 69 (2) 46 (1) 27 (1) 53 (1) 1059 (26) 472 (11) 128 (3) 491 (12) 232 (6) 128 (3) 27 (1)
10 (5) 6 (3) 4 (2) 3 (2) 0 0 1 (1) 17 (9) 14 (7) 7 (4) 7 (4) 2 (1) 3 (2) 6 (3) 35 (18) 3 (2) 14 (7) 4 (2) 2 (1) 2 (1) 2 (1) 4 (2) 2 (1) 7 (4) 5 (3) 2 (1) 24 (12) 2 (1) 23 (11) 9 (5) 6 (3) 7 (4) 24 (12) 3 (2) 8 (4) 6 (3) 5 (3) 5 (3) 3 (2) 2 (1) 35 (17) 16 (8) 6 (3) 15 (8) 12 (6) 5 (3) 5 (3) 0 3 (2) 1 (1) 1 (1) 5 (3) 2 (1) 3 (2) 4 (2) 60 (30) 29 (14) 8 (4) 29 (14) 12 (6) 11 (6) 1 (1)
6 (4) 1 (1) 1 (1) 2 (1) 4 (3) 3 (2) 2 (2) 11 (8) 7 (7) 5 (4) 2 (1) 1 (1) 4 (3) 1 (1) 18 (13) 1 (1) 7 (5) 4 (3) 1 (1) 3 (2) 3 (2) 0 2 (1) 1 (1) 0 1 (1) 5 (4) 1 (1) 4 (3) 2 (1) 1 (1) 0 10 (7) 2 (1) 3 (2) 1 (1) 1 (1) 1 (1) 1 (1) 4 (3) 25 (19) 19 (14) 5 (4) 2 (1) 18 (13) 12 (9) 11 (8) 4 (3) 3 (2) 2 (1) 2 (1) 5 (4) 5 (4) 1 (1) 4 (3) 40 (30) 16 (12) 7 (5) 14 (10) 10 (7) 4 (3) 3 (2)
Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
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TABLE 2 Continued. Total subfertile group (n [ 340) Congenital anomaly Patent ductus arteriosus Conotruncal defects D-transposition great arteries Transposition great arteries Tetralogy of Fallot Outflow tract anomalies RVOTO Pulmonary valve atresia or stenosis LVOTO Bicuspid aortic valve Hypoplastic left heart syndrome Coarctation of the aorta Single ventricle Recognized syndromes with unknown etiology VATER association Imprinting disorders Any imprinting disorder Beckwith-Wiedemann syndrome Silver-Russell syndrome Prader-Willi syndrome Angelman syndrome Cause of imprinting disordera Primary methylation defect Microdeletion Uniparental disomy Other causesb
Fertile group (n [ 4,185)
Natural conception after >12 mo (n [ 201)
Conception after IVF/ICSI (n [ 139)
45 (1) 157 (4) 92 (2) 97 (2) 52 (1) 329 (8) 144 (3) 142 (3) 185 (4) 55 (1) 55 (1) 82 (2) 14 (0)
5 (3) 7 (4) 3 (2) 3 (2) 2 (1) 22 (11) 12 (6) 8 (4) 10 (5) 3 (2) 3 (2) 2 (1) 0
1 (1) 5 (4) 1 (1) 2 (1) 3 (2) 12 (9) 7 (5) 7 (5) 5 (4) 3 (2) 4 (3) 4 (3) 3 (2)
23 (1)
1 (1)
4 (3)
20 (1) 7 (0) 1 (0) 10 (0) 2 (0)
2 (1) 1 (1) 1 (1) 0 0
1 (1) 1 (1) 0 0 0
5 (0) 8 (0) 4 (0) 2 (0)
2 (1) 0 0 0
1 (1) 0 0 0
Note: Values are n (%). ASD ¼ atrial septal defects; AVSD ¼ atrioventricular septal defect; ICSI ¼ intracytoplasmic sperm injection; IVF ¼ in vitro fertilization; LVOTO ¼ left ventricular outflow tract obstruction; RVOTO ¼ right ventricular outflow tract obstruction; VATER ¼ nonrandom co-occurrence of at least three of the following: vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb anomalies; VSD ¼ ventricular septal defects. a In one child with Prader-Willi syndrome the underlying cause was unknown. b Other causes included a de novo mutation in the UBE3A gene in a child with Angelman syndrome and a translocation of chromosomes Y and 11 in a child with Beckwith-Wiedemann syndrome. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
Differences in Imprinting Disorders per Fertility Category Table 4 shows crude ORs for different types of imprinting disorders and their underlying causes, including primary methylation defects, microdeletions, or uniparental disomy. Imprinting disorders resulting from primary methylation defects occurred more often in the total subfertile group than in the fertile group (crude OR 6.12, 95% CI 1.54–24.90). After correcting for maternal age at conception, correct use of folic acid, year of birth, and multiple pregnancies, the difference remained significant: aOR 13.49, 95% CI 2.93–62.06.
DISCUSSION In this registry-based birth defect study we found an increased risk of abdominal wall defects, penoscrotal hypospadia, RVOTO, and methylation defects causing imprinting disorders in fetuses/children of subfertile parents (n ¼ 340) compared with those of fertile parents (n ¼ 4,185). We also found an increased risk of polydactyly (mainly of the hands) after IVF/ICSI (n ¼ 139) compared with the Sub-NC group (n ¼ 201). Some of our results are in line with the literature, whereas others are not. We found that abdominal wall defects occurred more often after subfertility. This is in line with studies 1006
reporting an increased risk of omphalocele (19) and blastogenesis birth defects, including abdominal wall defects, after IVF/ICSI (27). In these studies the role of the underlying subfertility could not be separately assessed, but a more general association between subfertility and anomalies of the digestive system has been reported (3). In our study, we found that penoscrotal hypospadia was associated with subfertility. Others have also found that of the different types of urogenital abnormalities, hypospadia in particular seems to be associated with IVF/ICSI (25, 28, 29). Links between paternal subfertility and hypospadia, as well as hormonal exposure during organogenesis, have been proposed as mediating factors (3, 19). Our study suggests that factors associated with subfertility are involved in the etiology of penoscrotal hypospadia, but we did not find evidence that ICSI plays a role. Our data further suggest that RVOTO is more common after a history of subfertility. Associations between IVF/ICSI and septal heart defects (15) and tetralogy of Fallot (30) have previously been reported, although neither study could disentangle how far the observed associations could be attributed to IVF/ICSI vs. the underlying subfertility. Our study allows us to separate these factors and suggests a role for a history of subfertility in RVOTO. We further found an association between IVF/ICSI and polydactyly (mainly of the VOL. 103 NO. 4 / APRIL 2015
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TABLE 3 ORs of congenital anomalies associated with fertility category. Total subfertile group vs. fertile group (reference)
IVF/ICSI vs. natural conception after >12 mo (reference)
Congenital anomaly
cOR
aOR (95% CI)
cOR
aOR (95% CI)
Anomalies of the central nervous system Neural tube defect Anencephaly Hydrocephaly Eye anomaly Congenital cataract Ear anomaly Clefts Cleft lip with or without cleft palate Cleft lip without cleft palate Cleft lip with cleft palate Unilateral cleft lip and palate Cleft palate without cleft lip Anomalies of the respiratory tract Anomalies of the digestive tract Anomalies of the oesophagus Hypertrophic pyloric stenosis Atresia of the small or large intestine Atresia of the small intestine Atresia of the large intestine Anorectal atresia Malrotation of the intestines Diaphragmatic hernia Abdominal wall defects Omphalocele Gastroschisis Anomalies of the genitals Epispadiac Hypospadiac Coronal and glandular hypospadiac Penile hypospadiac Penoscrotal hypospadiac Anomalies of the urinary tract Renal agenesis (unilateral and bilateral) Cystic kidney disease Multicystic dysplastic kidney Renal dysplasia Hydronephrosis Stenosis ureter/pelviureteric junction Vesicoureteral reflux Musculoskeletal anomalies Congenital hip dysplasia Dislocation hip Club foot (neural tube defects excluded) Limb anomalies Polydactyly Polydactyly hand Preaxial polydactyly hands Postaxial polydactyly hands Syndactyly Syndactyly hands Reduction defect Reduction defects upper limb Reduction defects lower limbs Transverse reduction defect Heart anomalies Septal defects ASD VSD Muscular VSD Perimembraneous VSD AVSDs
0.66 0.57 1.26 1.16 0.45 0.78 2.08 0.93 1.04 1.59 0.70 0.80 0.72 1.13 1.28 1.12 1.16 1.28 1.28 1.22 1.30 1.50 1.10 2.63 2.96 2.19 1.01 4.65 1.01 0.73 0.75 6.26 1.05 0.74 2.11 1.81 1.65 0.98 0.81 1.37 0.80 0.66 1.06 1.24 1.53 2.03 2.45 2.76 1.96 0.82 1.37 1.82 1.91 1.84 1.89 1.24 1.20 1.46 1.09 1.18 1.47 1.84
0.66 (0.39–1.13) 0.54 (0.24–1.25) 1.06 (0.37–3.02) 1.04 (0.40–2.68) 0.46 (0.17–1.28) 0.80 (0.24–2.65) 2.95 (0.82–10.69) 0.84 (0.55–1.30) 0.98 (0.60–1.60) 1.60 (0.83–3.07) 0.63 (0.30–1.31) 0.98 (0.30–3.24) 0.60 (0.26–1.39) 0.90 (0.36–2.29) 1.31 (0.94–1.81) 0.87 (0.26–2.89) 1.31 (0.82–2.11) 1.04 (0.47–2.32) 1.46 (0.43–4.98) 0.79 (0.28–2.26) 0.80 (0.28–2.29) 1.39 (0.41–4.67) 0.72 (0.22–2.40) 2.43 (1.05–5.62)a,b 2.14 (0.76–6.02) 3.60 (0.98–13.23) 1.06 (0.70–1.60) 3.99 (0.75–21.26)d 1.07 (0.70–1.64) 0.69 (0.36–1.32) 0.87 (0.40–1.91) 9.83 (3.58–27.04)a,d 0.99 (0.67–1.47) 0.69 (0.25–1.92) 2.01 (0.99–4.05) 1.54 (0.63–3.74) 1.29 (0.49–3.36) 1.01 (0.43–2.37) 0.84 (0.30–2.38) 1.05 (0.41–2.72) 0.85 (0.63–1.14) 0.71 (0.48–1.04)b 1.12 (0.59–2.13) 1.40 (0.82–2.36) 1.50 (0.98–2.30) 2.20 (1.24–3.89)a,b 2.78 (1.53–5.07)a,b 4.09 (1.24–13.45)a,b 2.13 (0.86–5.25) 0.62 (0.15–2.59) 1.16 (0.27–5.04) 1.62 (0.79–3.36) 1.71 (0.70–4.13) 1.14 (0.33–3.90) 1.66 (0.73–3.78) 1.27 (0.98–1.63) 1.32 (0.93–1.85) 1.66 (0.95–2.92) 1.13 (0.80–1.59) 1.26 (0.79–2.01) 1.51 (0.86–2.66) 1.69 (0.57–5.04)
0.86 0.24 0.36 0.96 na na 2.95 0.94 0.71 1.03 0.41 0.72 1.96 0.24 0.73 0.48 0.71 1.49 0.72 2.23 2.23 na 1.45 0.20 0.00 0.73 0.28 0.72 0.23 0.31 0.24 0.00 0.58 0.96 0.53 0.24 0.28 0.29 0.48 2.95 1.08 1.85 1.21 0.18 2.40 3.73 3.40 na 1.46 2.92 2.92 1.48 3.78 0.48 1.46 0.99 0.77 1.28 0.67 1.22 0.52 4.44
1.20 (0.39–3.63) 0.39 (0.04–3.57) 0.80 (0.07–8.97) 0.78 (0.12–4.94) na na 3.20 (0.26–39.75) 0.75 (0.31–1.84) 0.64 (0.23–1.81) 0.76 (0.21–2.75) 0.50 (0.09–2.74) 0.76 (0.06–10.03) 1.20 (0.23–6.32) 0.00 (0.00–na) 0.82 (0.43–1.58) 0.50 (0.04–5.67) 0.71 (0.27–1.88) 2.31 (0.47–11.35) 0.65 (0.05–7.97) 6.66 (0.61–72.15) 6.66 (0.61–72.15) na 4.79 (0.39–59.54) 0.18 (0.02–1.56) 0.00 (0.00–na) 0.70 (0.06–8.38) 0.55 (0.15–2.07)d 0.69 (0.05–8.96) 0.53 (0.14–2.00)d 0.18 (0.02–1.50) 0.21 (0.02–1.84) 0.00 (0.00–na) 0.68 (0.29–1.58) 1.25 (0.16–9.68) 0.62 (0.12–3.17) na 0.00 (0.00–na) 0.59 (0.06–5.65) 0.75 (0.07–8.02) 1.93 (0.30–12.43) 1.13 (0.62–2.08) 1.70 (0.80–3.62) 1.12 (0.32–3.92) 0.24 (0.05–1.12) 3.31 (1.31–8.38)a,b 4.83 (1.39–16.77)a,b 5.02 (1.43–17.65)a,b na 1.94 (0.33–11.93) na na 1.62 (0.41–6.48) 6.65 (0.73–60.76) 0.68 (0.06–8.19) 1.89 (0.39–9.14) 0.94 (0.57–1.58) 0.78 (0.39–1.54) 1.22 (0.41–3.62) 0.68 (0.34–1.39) 1.23 (0.49–3.04) 0.59 (0.17–1.99) 4.18 (0.39–44.74)
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TABLE 3 Continued. Total subfertile group vs. fertile group (reference)
IVF/ICSI vs. natural conception after >12 mo (reference)
Congenital anomaly
cOR
aOR (95% CI)
cOR
Patent ductus arteriosus Conotruncal defects D-transposition great arteries Transposition great arteries Tetralogy of Fallot Outflow tract anomalies RVOTO Pulmonary valve atresia or stenosis Pulmonary valve stenosis LVOTO Bicuspid aortic valve Hypoplastic left heart syndrome Coarctation of the aorta Single ventricle Recognized syndromes with unknown etiology VATER association
1.66 0.94 0.53 0.63 1.18 1.30 1.66 1.31 1.43 1.00 1.35 1.58 0.90 2.66
1.73 (0.66–4.51) 0.932 (0.51–1.72) 0.53 (0.19–1.48) 0.62 (0.25–1.56) 1.21 (0.47–3.12) 1.31 (0.89–1.92) 1.77 (1.06–2.97)a,e 1.31 (0.75–2.29) 1.43 (0.80–2.57) 0.97 (0.56–1.68) 1.10 (0.43–2.84) 1.44 (0.60–3.46) 0.80 (0.34–1.88) 2.63 (0.71–9.73)
0.29 1.03 0.48 0.97 2.20 0.77 0.84 1.28 1.09 0.71 1.46 1.96 2.95 na
na 1.36 (0.40–4.71) 0.42 (0.04–4.32) 0.79 (0.12–5.03) 7.82 (0.83–73.82) 0.71 (0.33–1.53) 0.88 (0.33–2.40) 1.35 (0.46–4.01) 1.19 (0.38–3.68) 0.57 (0.18–1.75) 0.62 (0.10–3.81) 1.19 (0.23–6.28) 2.47 (0.42–14.41) na
2.70
2.44 (0.79–7.53)
5.93
9.38 (0.86–102.04)
aOR (95% CI)
Note: The 95% CI excludes 1. Adjusted odds ratios (aOR) not further specified were all corrected for maternal age at conception and the correct use of folic acid. ASD ¼ atrial septal defects; ICSI ¼ intracytoplasmic sperm injection; IVF ¼ in vitro fertilization; LVOTO ¼ left ventricular outflow tract obstruction; na ¼ not applicable; cOR ¼ crude odds ratio; RVOTO ¼ right ventricular outflow tract obstruction; VATER ¼ nonrandom co-occurrence of at least three of the following: vertebral anomalies, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb anomalies; VSD ¼ ventricular septal defects. a Statistically significant result. b Corrected for maternal age, folic acid use, year of birth, and multiple pregnancy. c The control group consisted of both male and female infants in order to maintain uniformity of our methods. When limiting the analyses to male infants the results did not materially change. d Corrected for maternal age, folic acid use, year of birth, multiple pregnancy, ICSI, and DES daughters. e Corrected for maternal age, folic acid use, year of birth, multiple pregnancy, and pregestational diabetes. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
hands). We excluded monogenic causes of polydactyly and looked, in detail, into whether polydactyly after IVF/ICSI repeatedly occurred in combination with any other specific defect: it did not. Finally, we confirmed that a history of subfertility is associated with methylation defects that cause imprinting disorders. In an earlier Dutch study, the association between IVF/ ICSI and Beckwith-Wiedemann syndrome and Angelman syndrome disappeared after correction for subfertility (12). Imprinting disorders can occur owing to disturbed methylation, microdeletions, or uniparental disomy. We were able to analyze these different causes and found that a history of subfertility was associated with methylation defects. Because the effects of parental subfertility on the epigenetic makeup of offspring are largely unknown, this may contribute to generating new hypotheses. Genome-wide epigenetic alterations in phenotypically normal children born after IVF/ICSI have been described (31). It is possible that there is an epigenetic instability of the gametes or the early embryonic cells that results in both subfertility of the parents and adverse health outcomes in their offspring (6, 32). Other studies reported associations between IVF/ICSI and several subgroups of congenital anomalies that we were unable to confirm. The subgroups included musculoskeletal defects, neural tube defects, digestive tract atresia, cleft lip/ palate, and anomalies of the ear, eye, face, and neck (2, 3, 13–15, 19, 21). The fact that previous studies provide an incoherent picture of which subgroups of anomalies occur more often after IVF/ICSI might suggest that all anomalies occur more frequently after IVF. Additionally, because we combined all different causes of subfertility into one group, 1008
we were not able to further deduce whether specific causes of subfertility were associated with specific birth defects in our study. Furthermore, because Eurocat NNL does not include non-malformed controls, the risk increase for the overall group of congenital anomalies could not be analyzed. One of the main strengths of our study is inclusion of all types of births, regardless of gestational age. Unlike many other studies, terminations of pregnancy due to fetal anomalies were included in this study. This is important because subfertile women may less frequently decide to terminate their muchdesired pregnancies because of a congenital anomaly (14). The total subfertile group consisted of 340 children. This may seem a small group, but because they all had a congenital anomaly, this sample allowed for an adequate evaluation of most specific anomalies. All congenital anomalies that occurred at least three times in the total subfertile group were analyzed; the complete and detailed overview of all anomalies is regarded one of the main strengths of the study. Yet our power to detect associations with very rare congenital anomalies and syndromes with unknown etiology was probably insufficient. Another strength of our study is inclusion of children with congenital anomalies up to the age of 10 years and not just after birth. Furthermore, Eurocat NNL's long history allowed for large numbers of cases and enabled us to look at specific and pathogenetically similar types of congenital anomalies rather than larger heterogeneous subgroups. The detailed information from the parental questionnaire allowed us to adjust for a large variety of confounders. A final strength of our study is that we verified parental subfertility by searching medical records of fertility clinics. VOL. 103 NO. 4 / APRIL 2015
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TABLE 4 Crude odds ratios of imprinting disorders and their underlying causes associated with fertility category.
Imprinting disorder Any imprinting disorder Beckwith-Wiedemann syndrome Silver Russell syndrome Prader-Willi syndrome Angelman syndrome Cause of imprinting disordera Primary methylation defect Microdeletion Uniparental disomy Other causec
Total subfertile group vs. fertile group (reference)
Total subfertile group Fertile group (n [ 340) (n [ 4,185)
IVF/ICSI vs. Subfertile, natural natural conception IVF/ICSI conception after >12 mo (n [ 139) (n [ 201) (reference)
3 2
20 7
1.85 (0.55–6.27) 3.53 (0.73–17.07)
1 1
2 1
0.72 (0.07–8.03) 1.45 (0.09–23.37)
1 0 0
1 10 2
12.34 (0.77–197.76) na na
0 0 0
1 0 0
na na na
3
5
6.12 (1.54–24.90)b
1
2
0.72 (0.07–8.03)
0 0 0
8 4 2
na na na
0 0 0
0 0 0
na na na
Note: Values are n or crude OR (95% CI). 95% CI excludes 1. ICSI ¼ intracytoplasmic sperm injection; IVF ¼ in vitro fertilization. a In one child with Prader-Willi syndrome the underlying cause was unknown. b Statistically significant result. After correction for maternal age at conception, the correct use of folic acid, year of birth, and multiple pregnancies, the difference remained statistically significant: aOR 13.49, 95% CI 2.93–62.06. c Other causes included a de novo mutation in the UBE3A gene in a child with Angelman syndrome and a translocation of chromosomes Y and 11 in a child with Beckwith-Wiedemann syndrome. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
However, searching the fertility records could also be regarded as a limitation, because we lost data by excluding those with unconfirmed subfertility. The loss of these data reduced the study power but increased the certainty of evaluating the effect of IVF/ICSI and subfertility on congenital anomalies. Other limitations that should be noted are related to the case-only design. Because Eurocat NNL does not collect information on non-malformed controls, fetuses/children with another congenital anomaly than the one studied in that specific analysis served as the control group. This means that the control group changes for the analyses of different anomalies, making the ORs derived not readily comparable to each other. The ORs can, however, be used to estimate the effect of IVF/ICSI and subfertility on that specific defect. Furthermore, when studying a specific defect with a caseonly design, pathogenetically similar defects may be included in the control group. For example, when studying ventricular septal defects (VSDs), atrial septal defects (ASDs) are included in the control group. Because VSDs and ASDs may share a common etiology, this may dilute the effect of IVF/ICSI and subfertility on VSDs. Yet, because many more other congenital anomalies are included in the control group, the diluting effect (of ASDs in this example) is thought to be small. Nevertheless, these disadvantages of a case-only design should be kept in mind. Another limitation of our study is that information on fertility status and pregnancy details was obtained retrospectively with a questionnaire up to the age of 10 years, so the couples could have a problem with the recall of these details. However, problems with recall are expected to be the same for all groups, and most questionnaires were returned within the first 2 years after the child's birth (median 1.40 years, SD 2.11 years). Another limitation is that we were not certain that fertile couples were indeed fertile according to the definition of a time to pregnancy of 12 mo + IVF/ICSI (N [ 340)
Congenital anomalies Central nervous system Neural tube defect Anencephaly Spina bifida Thoracal spina bifida Lumbar spina bifida Encephalocele Iniencephaly Craniorachischisis Arhinencephaly/holoprosencephaly Microcephaly Hydrocephaly Eye Anophthalmia Microphthalmia Congenital glaucoma Congenital cataract Coloboma of the iris Ear Anotia Microtia Misshapen ear Clefts Cleft lip with or without cleft palate Cleft lip without cleft palate Bilateral cleft lip Central cleft lip Cleft lip with cleft palate Unilateral cleft lip and palate Bilateral cleft lip and palate Cleft palate without cleft lip Respiratory tract Choanal atresia Lung hypoplasia Digestive tract Anomalies of the oesophagus Hypertrophic pyloric stenosis Atresia of the small or large intestine Atresia/stenosis of the small intestine Artresia duodenum Atresia jejunum Atresia ileum Atresia/stenosis of the large intestine Anorectal atresia Hirschsprung's disease Malrotation of the intestines Abdominal wall defects Diaphragmatic hernia Omphalocele Gastroschisis Genitals Epispadia Hypospadia Coronaral and glandular hypospadia Penile hypospadia Penoscrotal hypospadia Indeterminate gender Urinary tract Renal agenesis (unilateral and bilateral) Bilateral renal agenesis Unilateral renal agenesis
Fertile group (N [ 4,185), N (%)
Subfertile but natural conception (N [ 201), N (%)
Subfertile, conception after IVF/ICSI (N [ 139), N (%)
290 (7) 148 (4) 49 (1) 89 (2) 26 (1) 51 (1) 10 (0) 2 (0) 5 (0) 10 (1) 25 (1) 53 (1) 108 (3) 2 (0) 17 (0) 7 (0) 47 (1) 15 (0) 18 (0) 11 (0) 2 (0) 2 (0) 368 (9) 250 (6) 94 (2) 9 (0) 2 (0) 156 (4) 46 (1) 52 (1) 118 (3) 76 (2) 12 (0) 29 (1) 531 (13) 44 (1) 224 (5) 78 (2) 29 (1) 11 (0) 8 (0) 10 (0) 51 (1) 48 (1) 28 (1) 33 (1) 38 (1) 45 (1) 21 (1) 17 (0) 354 (9) 8 (0) 328 (8) 184 (4) 114 (3) 14 (0) 5 (0) 402 (10) 82 (2) 24 (1) 31 (1)
10 (5) 6 (3) 4 (2) 2 (1) 0 2 (1) 0 0 0 1 (1) 0 3 (2) 0 0 0 0 0 0 1 (1) 0 0 0 17 (9) 14 (7) 7 (4) 0 1 (1) 7 (4) 2 (1) 1 (1) 3 (2) 6 (3) 0 2 (1) 35 (18) 3 (2) 14 (7) 4 (2) 2 (1) 1 (1) 0 1 (1) 2 (1) 2 (1) 0 4 (2) 7 (4) 2 (1) 5 (3) 2 (1) 24 (12) 2 (1) 23 (11) 9 (5) 6 (3) 7 (4) 1 (1) 24 (12) 3 (2) 2 (1) 0
6 (4) 1 (1) 1 (1) 0 0 0 0 0 0 1 (1) 0 2 (1) 4 (3) 0 0 0 3 (2) 0 2 (2) 1 (1) 0 0 11 (8) 7 (7) 5 (4) 2 (1) 0 2 (1) 1 (1) 1 (1) 4 (3) 1 (1) 0 0 18 (13) 1 (1) 7 (5) 4 (3) 1 (1) 1 (1) 0 0 3 (2) 3 (2) 1 (1) 0 1 (1) 2 (1) 0 1 (1) 5 (4) 1 (1) 4 (3) 2 (1) 1 (1) 0 1 (1) 10 (7) 2 (1) 0 1 (1)
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SUPPLEMENTAL TABLE 1 Continued. Total subfertile group, natural conception > 12 mo + IVF/ICSI (N [ 340)
Congenital anomalies Cystic kidney disease Simple renal cyst Multicystic dysplastic kidney Renal dysplasia Hydronephrosis Stenosis ureter/pelviureteric junction Megaloureter/hydroureter Horseshoe kidney Vesicoureteral reflux Exstrophy of bladder or cloaca Atresia of the urethra and bladder neck Musculoskeletal Congenital hip dysplasia Dislocation hip Subluxation hip Club foot (neural tube defects excluded) Limbs Polydactyly Polydactyly hands Preaxial polydactyly hands Postaxial polydactyly hands Polydactyly feet Preaxial polydactyly feet Postaxial polydactyly feet Syndactyly Syndactyly hands Syndactyly feet Reduction defect Reduction defect upper limb Reduction defect lower limb Transverse reduction defect Preaxial reduction defect Postaxial reduction defect Intercalary reduction defect Congenital deformity hand or arm Congenital deformity leg or unspecified limb Rockerbottom feet Heart Septal defect ASD VSD Muscular VSD Perimembraneous VSD AVSDs Persistent truncus arteriosus Patent foramen ovale Patent ductus arteriosus Conotruncal defects D-transposition great arteries Transposition great arteries Tetralogy of Fallot Outflow tract anomalies Double outlet right ventricle RVOTO Pulmonary valve atresia or stenosis Pulmonary valve atresia Pulmonary valve stenosis Anomalies pulmonary artery
Fertile group (N [ 4,185), N (%)
Subfertile but natural conception (N [ 201), N (%)
Subfertile, conception after IVF/ICSI (N [ 139), N (%)
65 (2) 1 (0) 48 (1) 45 (1) 76 (2) 61 (2) 55 (1) 9 (0) 54 (1) 9 (0) 36 (1) 889 (21) 621 (15) 128 (3) 16 (0) 171 (4) 252 (6) 106 (3) 83 (2) 18 (0) 38 (1) 19 (1) 2 (0) 10 (0) 45 (1) 27 (1) 14 (0) 69 (2) 46 (1) 27 (1) 53 (1) 8 (0) 25 (1) 2 (0) 12 (0) 12 (0)
8 (4) 0 6 (3) 5 (3) 5 (3) 3 (2) 2 (1) 1 (1) 2 (1) 0 2 (1) 35 (17) 16 (8) 6 (3) 2 (1) 15 (8) 12 (6) 5 (3) 5 (3) 0 3 (2) 0 0 0 1 (1) 1 (1) 0 5 (3) 2 (1) 3 (2) 4 (2) 0 1 (1) 0 0 0
3 (2) 0 1 (1) 1 (1) 1 (1) 1 (1) 0 0 4 (3) 0 0 25 (19) 19 (14) 5 (4) 0 2 (1) 18 (13) 12 (9) 11 (8) 4 (3) 3 (2) 2 (1) 0 1 (1) 2 (1) 2 (1) 0 5 (4) 5 (4) 1 (1) 4 (3) 2 (2) 0 0 0 0
1 (0) 1059 (26) 472 (11) 128 (3) 491 (12) 232 (6) 128 (3) 27 (1) 9 (0) 18 (0) 45 (1) 157 (4) 92 (2) 97 (2) 52 (1) 329 (8) 23 (1) 144 (3) 142 (3) 20 (1) 122 (3) 21 (1)
0 60 (30) 29 (14) 8 (4) 29 (14) 12 (6) 11 (6) 1 (1) 1 (1) 0 5 (3) 7 (4) 3 (2) 3 (2) 2 (1) 22 (11) 1 (1) 12 (6) 8 (4) 0 8 (4) 2 (1)
0 40 (30) 16 (12) 7 (5) 14 (10) 10 (7) 4 (3) 3 (2) 0 1 (1) 1 (1) 5 (4) 1 (1) 2 (1) 3 (2) 12 (9) 0 7 (5) 7 (5) 1 (1) 6 (4) 0
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SUPPLEMENTAL TABLE 1 Continued. Total subfertile group, natural conception > 12 mo + IVF/ICSI (N [ 340)
Congenital anomalies LVOTO Aortic valve stenosis Bicuspid aortic valve Hypoplastic left heart syndrome Coarctation of the aorta Interrupted aortic arch Tricuspid atresia or stenosis Mitral valve stenosis Mitral valve insufficiency Single ventricle Ebstein anomaly Recognized syndromes with unknown aetiology VATER association OAVS Limb body wall complex Amniotic band syndrome FFU complex Poland syndrome Pierre Robin sequence Prune belly syndrome Imprinting disorders Any imprinting disorder Beckwith Wiedemann syndrome Silver Russell syndrome Prader Willi syndrome Angelman syndrome Cause of imprinting disordera Primary methylation defect Microdeletion Uniparental disomy Other causeb
Fertile group (N [ 4,185), N (%)
Subfertile but natural conception (N [ 201), N (%)
Subfertile, conception after IVF/ICSI (N [ 139), N (%)
185 (4) 20 (1) 55 (1) 55 (1) 82 (2) 7 (0) 12 (0) 10 (0) 17 (0) 14 (0) 12 (0)
10 (5) 2 (1) 3 (2) 3 (2) 2 (1) 0 0 0 1 (1) 0 1 (1)
5 (4) 0 3 (2) 4 (3) 4 (3) 0 2 (1) 0 1 (1) 3 (2) 0
23 (1) 18 (0) 3 (0) 10 (0) 5 (0) 6 (0) 20 (1) 5 (0)
1 (1) 0 0 0 1 (1) 0 1 (1) 0
4 (3) 1 (1) 2 (1) 1 (1) 0 0 1 (1) 0
20 (1) 7 (0) 1 (0) 10 (0) 2 (0)
2 (1) 1 (1) 1 (1) 0 0
1 (1) 1 (1) 0 0 0
5 (0) 8 (0) 4 (0) 2 (0)
2 (1) 0 0 0
1 (1) 0 0 0
Note: As syndromes and imprinting disorders are very rare, we decided that they had to occur at least five times in the total database to be shown in the appendix. ASD ¼ atrial septal defect; VSD ¼ ventricular septal defect; AVSD ¼ atrioventricular septal defect; RVOTO ¼ right ventricular outflow tract obstruction; LVOTO ¼ left ventricular outflow tract obstruction;VATER association ¼ non-random association of vertebral anomalies, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies and limb anomalies; OAVS ¼ oculo-auriculo-vertebral spectrum; FFU complex ¼ femur-fibula-ulna complex. a In one child with Prader Willi syndrome the underlying cause was unknown. b Other causes included a de novo mutation in the UBE3A gene in a child with Angelman syndrome and a translocation of chromosomes Y and 11 in a child with Beckwith-Wiedemann syndrome. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
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Congenital anomalies in offspring of subfertile couples: a registry-based study in the northern Netherlands Jorien Seggers, M.D.,a Hermien E. K. de Walle, Ph.D.,b Jorieke E. H. Bergman, M.D., Ph.D.,b Henk Groen, M.D., Ph.D.,b Mijna Hadders-Algra, M.D., Ph.D.,a Marly E. Bos, B.Sc.,b Annemieke Hoek, M.D., Ph.D.,c and Maaike L. Haadsma, M.D., Ph.D.b a Division of Developmental Neurology, Department of Pediatrics, b Division of Eurocat Northern Netherlands, Department of Genetics, and c Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Objective: To study whether specific congenital anomalies occur more often with a history of subfertility and/or the use of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Design: Case-only analyses. Setting: Not applicable. Patient(s): We included live births, stillbirths, and terminated pregnancies with congenital anomalies without a known cause that had a birth year between 1997 and 2010 (n ¼ 4,525). A total of 4,185 malformed cases were born to fertile couples and 340 to subfertile couples, of whom 139 had conceived after IVF/ICSI and 201 had conceived naturally after >12 months. Intervention(s): None. Main Outcome Measure(s): The contribution, expressed in odds ratios (ORs), of a history of subfertility and IVF/ICSI to each specific type of congenital anomaly, imprinting disorder, and syndromal disorder. Result(s): We found subfertility to be associated with an increase in abdominal wall defects (adjusted OR [aOR] 2.43, 95% CI 1.05–5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58–27.04), right ventricular outflow tract obstruction (aOR 1.77, 95% CI 1.06–2.97), and methylation defects causing imprinting disorders (aOR 13.49, 95% CI 2.93–62.06). In vitro fertilization/ICSI was associated with an increased risk of polydactyly (OR 4.83, 95% CI 1.39–16.77) and more specifically polydactyly of the hands (OR 5.02, 95% CI 1.43–17.65). Conclusion(s): In our registry-based study, parental subfertility was associated with an increase in abdominal wall defects, penoscrotal hypospadia, right ventricular outflow tract obstruction, and methylation defects causing imprinting disorders. In vitro fertilization/ICSI was associated with an increase in polydactyly, mainly of the hands. (Fertil SterilÒ 2015;103: Use your smartphone 1001–10. Ó2015 by American Society for Reproductive Medicine.) to scan this QR code Key Words: In vitro fertilization, assisted reproductive technology, subfertility, congenital and connect to the anomalies, birth defects Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/seggersj-congenital-anomalies-offspring-netherlands/
T
he increasing use of in vitro fertilization (IVF), with or without intracytoplasmic sperm
injection (ICSI), has raised concerns about potential consequences for the resulting offspring, in particular the
Received September 17, 2014; revised December 5, 2014; accepted December 15, 2014; published online January 24, 2015. A.H. reports grants (outside the submitted work) from Ferring Farmaceutical NL BV, MSD, and the Netherlands Organization for Health Research and Development ZonMW (grant 50-50110-96-518); and speaker fees from MSD. J.S. has nothing to disclose. H.E.K.d.W. has nothing to disclose. J.E.H.B. has nothing to disclose. H.G. has nothing to disclose. M.H.-A. has nothing to disclose. M.E.B. has nothing to disclose. M.L.H. has nothing to disclose. The Department of Obstetrics and Gynecology of the University Medical Center Groningen received an unrestricted educational grant from Ferring Pharmaceutical BV, Netherlands. The Eurocat registry is financed by the Dutch Ministry of Public Health, Welfare and Sports. The sponsor of the study had no role in its design, data collection, data analysis, data interpretation, or in writing of the report. Reprint requests: Jorien Seggers, M.D., Developmental Neurology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands (E-mail: [email protected]). Fertility and Sterility® Vol. 103, No. 4, April 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.12.113 VOL. 103 NO. 4 / APRIL 2015
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putative effect on the prevalence of congenital anomalies. A recent metaanalysis showed that infants born after IVF/ICSI (n ¼ 92,671) had a relative risk of 1.32 (95% confidence interval [95% CI] 1.24–1.42) of having any birth defect compared with naturally conceived infants (n ¼ 3,870,760) (1). The increased number of birth defects in infants conceived via IVF/ICSI has been attributed both to the IVF/ ICSI procedure and the parent's underlying subfertility. A role for the IVF/ ICSI procedure is conceivable because natural selection of gametes is bypassed, early embryonic development 1001
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY takes place in vitro, and the embryo is transferred into an altered intrauterine environment due to ovarian hyperstimulation. There is also evidence for a role of the underlying subfertility: untreated subfertility and a longer time to pregnancy are associated with an increased rate of birth defects (2–4). In addition, an increased risk of imprinting disorders like Beckwith-Wiedemann syndrome and Angelman syndrome has been described after IVF/ICSI (5–7). There is evidence to suggest an adverse effect of the IVF/ICSI procedures (8–11), as well as of the underlying subfertility (12), on imprinting status. Previous studies often faced the limitation of either low numbers of specific congenital anomalies or the absence of information on a history of subfertility without IVF/ICSI treatment. In case of low numbers of specific anomalies, defects were grouped together in larger subgroups for power reasons. Associations have been reported between IVF/ICSI and cardiovascular anomalies, neural tube defects, urogenital anomalies, gastrointestinal anomalies, clefts, musculoskeletal anomalies, and limb anomalies (13–15). A disadvantage of using subgroups is that pathogenetically dissimilar congenital anomalies are pooled. This could explain why the studies provided an incoherent picture. For instance, some found an increased risk of musculoskeletal defects (2, 14, 16–18), whereas others did not (15, 19–22). These contradictions emphasize the necessity for a novel approach evaluating the increased risk for specific types of birth defects like hip dysplasia or a club foot, instead of larger subgroups of defects, such as musculoskeletal defects. In addition, knowledge about which birth defects occur more often after a history of subfertility without IVF/ICSI treatment is scarce. To address these issues, we analyzed data from Eurocat Northern Netherlands (Eurocat NNL), a voluntary population-based birth defects registry. Unlike previous studies that used non-malformed controls, we performed a case-only study: we studied the effects of subfertility and IVF/ICSI in a dataset of fetuses/children that all have a congenital anomaly. This approach precludes us from investigating the overall risk for a congenital anomaly but allows us to identify which specific congenital anomalies, imprinting disorders, and syndromal disorders with unknown etiology are associated with subfertility or IVF/ICSI.
MATERIALS AND METHODS Setting and Participants We used data from Eurocat NNL, which registers fetuses and children with congenital anomalies of mothers who lived in the registration area at the time of birth. An affected child can be registered up to the age of 10 years. Annually, Eurocat NNL monitors approximately 19,000 births in the northern Netherlands. Eurocat NNL uses multiple sources for active case ascertainment, in addition to notification by midwives, general practitioners, well-baby clinic doctors, and medical specialists. Live births, stillbirths, and pregnancies terminated due to congenital anomalies are notified on a voluntary basis. The staff of Eurocat NNL is actively involved in case ascertainment. The participation rate is stable at approximately 1002
80% for years. After consenting to registration, parents receive a questionnaire asking about their health, life style, use of medication, fertility, and pregnancy; another 80% completes the questionnaire. A telephone interview on the use of medication during pregnancy was conducted with all parents who submitted a questionnaire. If inconsistencies in the questionnaire were detected, the interviewer also asked questions about these inconsistencies in the same interview. Information on congenital anomalies is retrieved from medical files and includes results from genetic tests and pathology reports. Congenital anomalies are classified according to the 9th and 10th revisions of the World Health Organization International Classification of Diseases (ICD). The ICD-9 classification was used up to 2001 and ICD-10 from 2002 onward. Heart defects are further classified into septal defects, conotruncal defects, outflow tract anomalies, and other heart defects (23). Eurocat NNL does not collect information on non-malformed fetuses/children. An overview of the procedures and findings of Eurocat can be found at www.eurocat-network.eu/accessprevalencedata/prevalen cetables. Parents consented to the data being registered and used in studies on risk factors for congenital anomalies. Approval from the medical ethics board was not required. Cases born between 1997 and 2010 were divided into three fertility groups: [1] fertile parents, [2] subfertile parents who eventually conceived naturally (Sub-NC group), and [3] subfertile parents who conceived after IVF or ICSI. Parents were categorized into one of these groups depending on their answers to the questionnaire: they were asked whether they experienced any problem conceiving. If they answered ‘‘no,’’ they were considered fertile. If they answered ‘‘yes,’’ parents could fill out whether they used any fertility treatment and, if so, which treatment. We searched medical records of fertility clinics of all couples stating they had fertility problems. Couples were defined as subfertile after a time to pregnancy of at least 12 months. Cases were excluded if subfertility could not be confirmed (e.g., no medical records of fertility clinics were available or a time to pregnancy 12 mo D IVF/ICSI (n [ 340) Characteristic ICSI, n (%) Maternal age at conception (y) Maternal prepregnancy BMI (kg/m2) Pregestational diabetes Periconceptional smoking Correct use of folic acid DES daughter Maternal level of education Lowd Averagee Highf Multiple pregnancy Congenital anomaly discovered during pregnancy Pregnancy outcome Active termination of pregnancy Live birth Stillbirth Other
Fertile group (n [ 4,185)
Subfertile but natural conception (n [ 201)
Subfertile, conception after IVF/ICSI (n [ 139)
– 29.8 (24.0–35.4)a,b 23.3 (19.7–29.7) 3 (0) 1,024 (25) 1,507 (37)a,b 20 (1)b
– 32.7 (19.6–33.1)b 23.5 (19.6–33.09) 1 (1) 57 (30) 92 (48)a,c 4 (2)b
78 (56) 33.6 (27.6–38.8)a 22.7 (19.4–28.9) 0 (0) 30 (23) 95 (75)b,c 1 (1)
732 (18) 1,993 (50) 1,270 (32) 152 (4)b 1,796 (43)
45 (23) 95 (50) 52 (27) 10 (5)a 86 (43)
262 (6) 3,705 (89) 55 (1) 163 (4)
10 (5) 179 (89) 2 (1) 10 (5)
27 (22) 55 (44) 42 (34) 48 (35)a,b 60 (43) 9 (6) 117 (84) 1 (1) 12 (9)
Note: Values are n (%) or median (percentiles, 10–90). IVF ¼ in vitro fertilization; ICSI ¼ intracytoplasmic sperm injection. a,b,c Matching superscript letters indicate a statistically significant difference (P< .05). d Low level of education: no school, primary school, lower general secondary education, and lower vocational education. e Average level of education: higher general secondary education and intermediate vocational education. f High level of education: university, further tertiary college, and higher vocational education. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
group also reached statistical significance. Mothers in the Sub-NC group were more often DES daughters (2%) than fertile mothers (1%).
Frequencies of Congenital Anomalies, Recognized Syndromes with Unknown Etiology, and Imprinting Disorders Table 2 shows the number of congenital anomalies, recognized syndromes with unknown etiology, and imprinting disorders per fertility category. Congenital anomalies that occurred less than three times in the total subfertile group were not analyzed but are described in Supplemental Table 1 (available online). As an exception, we do show all imprinting disorders in Table 2, regardless of low numbers.
Differences in Congenital Anomalies per Fertility Category Table 3 shows crude and adjusted ORs resulting from the logistic regression analyses. In these multivariable regression analyses we always corrected for maternal age at conception and correct use of folic acid. In addition, we corrected for year of birth, multiple pregnancy, and defect-specific confounders where we found significant differences between the groups after correcting for maternal age and folic acid use; this was the case for the following congenital anomalies: abdominal wall defects, congenital hip dysplasia, limb anomalies, polydactyly, and preaxial polydactyly of the hands. As can be seen in Table 3, we found a history of subfertility to be associated with an increase in abdominal wall defects 1004
(adjusted OR [aOR] 2.43, 95% CI 1.05–5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58–27.04), and right ventricular outflow tract obstruction (RVOTO; aOR 1.77, 95% CI 1.05–2.96). In vitro fertilization/ICSI was associated with an increase in limb anomalies (aOR 3.31, 95% CI 1.31–8.38), polydactyly (aOR 4.83, 95% CI 1.39–16.77), and polydactyly of the hands (aOR 5.02, 95% CI 1.43–17.65). This association between IVF/ICSI and limb anomalies was attenuated when we excluded the cases with polydactyly from the cases with limb anomalies (aOR 1.83, 95% CI 0.48–6.99), indicating that the increased risk of limb anomalies was dominated by an increased risk of polydactyly. The legend of Table 3 shows the additional confounders. The rationale for selecting defect-specific confounders was as follows: in the analyses of genital anomalies we corrected for DES daughter and ICSI, because DES daughters more often give birth to a son with hypospadia (24), and ICSI may be associated with genital anomalies in the offspring (25). In the analysis of VOTOs, we also corrected for pregestational diabetes because heart defects occur more often in offspring of mothers with diabetes (26).
Recognized Syndromes with Unknown Etiology Of the recognized syndromes with unknown underlying cause, only VATER association was reported at least three times in the subfertile groups and is presented in Table 2. VATER was found four times in the IVF/ICSI group (3%) and once (1%) in the Sub-NC group; the difference was statistically not significant (P¼ .055). In the fertile group, VATER was also found in 1% (n¼23). VOL. 103 NO. 4 / APRIL 2015
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TABLE 2 Number of congenital anomalies per fertility category. Total subfertile group (n [ 340) Congenital anomaly Anomalies of the central nervous system Neural tube defect Anencephaly Hydrocephaly Eye anomaly Congenital cataract Ear anomaly Clefts Cleft lip with or without cleft palate Cleft lip without cleft palate Cleft lip with cleft palate Unilateral cleft lip and palate Cleft palate without cleft lip Anomalies of the respiratory tract Anomalies of the digestive tract Anomalies of the esophagus Hypertrophic pyloric stenosis Atresia of the small or large intestine Atresia of the small intestine Atresia of the large intestine Anorectal atresia Malrotation of the intestines Diaphragmatic hernia Abdominal wall defects Omphalocele Gastroschisis Anomalies of the genitals Epispadia Hypospadia Coronal and glandular hypospadia Penile hypospadia Penoscrotal hypospadia Anomalies of the urinary tract Renal agenesis (unilateral and bilateral) Cystic kidney disease Multicystic dysplastic kidney Renal dysplasia Hydronephrosis Stenosis ureter/pelviureteric junction Vesicoureteric reflux Musculoskeletal anomalies Congenital hip dysplasia Dislocation hip Club foot (neural tube defects excluded) Limb anomalies Polydactyly Polydactyly hand Preaxial polydactyly hands Postaxial polydactyly hands Syndactyly Syndactyly hands Reduction defect Reduction defect upper limb Reduction defect lower limbs Transverse reduction defect Heart anomalies Septal defect ASD VSD Muscular VSD Perimembraneous VSD AVSDs
Fertile group (n [ 4,185)
Natural conception after >12 mo (n [ 201)
Conception after IVF/ICSI (n [ 139)
290 (7) 148 (4) 49 (1) 53 (1) 108 (3) 47 (1) 18 (0) 368 (9) 250 (6) 94 (2) 156 (4) 46 (1) 118 (3) 76 (2) 531 (13) 44 (1) 224 (5) 78 (2) 29 (1) 51 (1) 48 (1) 33 (1) 45 (1) 38 (1) 21 (1) 17 (0) 354 (9) 8 (0) 328 (8) 184 (4) 114 (3) 14 (0) 402 (10) 82 (2) 65 (2) 48 (1) 45 (1) 76 (2) 61 (2) 54 (1) 889 (21) 621 (15) 128 (3) 171 (4) 252 (6) 106 (3) 83 (2) 18 (0) 38 (1) 45 (1) 27 (1) 69 (2) 46 (1) 27 (1) 53 (1) 1059 (26) 472 (11) 128 (3) 491 (12) 232 (6) 128 (3) 27 (1)
10 (5) 6 (3) 4 (2) 3 (2) 0 0 1 (1) 17 (9) 14 (7) 7 (4) 7 (4) 2 (1) 3 (2) 6 (3) 35 (18) 3 (2) 14 (7) 4 (2) 2 (1) 2 (1) 2 (1) 4 (2) 2 (1) 7 (4) 5 (3) 2 (1) 24 (12) 2 (1) 23 (11) 9 (5) 6 (3) 7 (4) 24 (12) 3 (2) 8 (4) 6 (3) 5 (3) 5 (3) 3 (2) 2 (1) 35 (17) 16 (8) 6 (3) 15 (8) 12 (6) 5 (3) 5 (3) 0 3 (2) 1 (1) 1 (1) 5 (3) 2 (1) 3 (2) 4 (2) 60 (30) 29 (14) 8 (4) 29 (14) 12 (6) 11 (6) 1 (1)
6 (4) 1 (1) 1 (1) 2 (1) 4 (3) 3 (2) 2 (2) 11 (8) 7 (7) 5 (4) 2 (1) 1 (1) 4 (3) 1 (1) 18 (13) 1 (1) 7 (5) 4 (3) 1 (1) 3 (2) 3 (2) 0 2 (1) 1 (1) 0 1 (1) 5 (4) 1 (1) 4 (3) 2 (1) 1 (1) 0 10 (7) 2 (1) 3 (2) 1 (1) 1 (1) 1 (1) 1 (1) 4 (3) 25 (19) 19 (14) 5 (4) 2 (1) 18 (13) 12 (9) 11 (8) 4 (3) 3 (2) 2 (1) 2 (1) 5 (4) 5 (4) 1 (1) 4 (3) 40 (30) 16 (12) 7 (5) 14 (10) 10 (7) 4 (3) 3 (2)
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TABLE 2 Continued. Total subfertile group (n [ 340) Congenital anomaly Patent ductus arteriosus Conotruncal defects D-transposition great arteries Transposition great arteries Tetralogy of Fallot Outflow tract anomalies RVOTO Pulmonary valve atresia or stenosis LVOTO Bicuspid aortic valve Hypoplastic left heart syndrome Coarctation of the aorta Single ventricle Recognized syndromes with unknown etiology VATER association Imprinting disorders Any imprinting disorder Beckwith-Wiedemann syndrome Silver-Russell syndrome Prader-Willi syndrome Angelman syndrome Cause of imprinting disordera Primary methylation defect Microdeletion Uniparental disomy Other causesb
Fertile group (n [ 4,185)
Natural conception after >12 mo (n [ 201)
Conception after IVF/ICSI (n [ 139)
45 (1) 157 (4) 92 (2) 97 (2) 52 (1) 329 (8) 144 (3) 142 (3) 185 (4) 55 (1) 55 (1) 82 (2) 14 (0)
5 (3) 7 (4) 3 (2) 3 (2) 2 (1) 22 (11) 12 (6) 8 (4) 10 (5) 3 (2) 3 (2) 2 (1) 0
1 (1) 5 (4) 1 (1) 2 (1) 3 (2) 12 (9) 7 (5) 7 (5) 5 (4) 3 (2) 4 (3) 4 (3) 3 (2)
23 (1)
1 (1)
4 (3)
20 (1) 7 (0) 1 (0) 10 (0) 2 (0)
2 (1) 1 (1) 1 (1) 0 0
1 (1) 1 (1) 0 0 0
5 (0) 8 (0) 4 (0) 2 (0)
2 (1) 0 0 0
1 (1) 0 0 0
Note: Values are n (%). ASD ¼ atrial septal defects; AVSD ¼ atrioventricular septal defect; ICSI ¼ intracytoplasmic sperm injection; IVF ¼ in vitro fertilization; LVOTO ¼ left ventricular outflow tract obstruction; RVOTO ¼ right ventricular outflow tract obstruction; VATER ¼ nonrandom co-occurrence of at least three of the following: vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb anomalies; VSD ¼ ventricular septal defects. a In one child with Prader-Willi syndrome the underlying cause was unknown. b Other causes included a de novo mutation in the UBE3A gene in a child with Angelman syndrome and a translocation of chromosomes Y and 11 in a child with Beckwith-Wiedemann syndrome. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
Differences in Imprinting Disorders per Fertility Category Table 4 shows crude ORs for different types of imprinting disorders and their underlying causes, including primary methylation defects, microdeletions, or uniparental disomy. Imprinting disorders resulting from primary methylation defects occurred more often in the total subfertile group than in the fertile group (crude OR 6.12, 95% CI 1.54–24.90). After correcting for maternal age at conception, correct use of folic acid, year of birth, and multiple pregnancies, the difference remained significant: aOR 13.49, 95% CI 2.93–62.06.
DISCUSSION In this registry-based birth defect study we found an increased risk of abdominal wall defects, penoscrotal hypospadia, RVOTO, and methylation defects causing imprinting disorders in fetuses/children of subfertile parents (n ¼ 340) compared with those of fertile parents (n ¼ 4,185). We also found an increased risk of polydactyly (mainly of the hands) after IVF/ICSI (n ¼ 139) compared with the Sub-NC group (n ¼ 201). Some of our results are in line with the literature, whereas others are not. We found that abdominal wall defects occurred more often after subfertility. This is in line with studies 1006
reporting an increased risk of omphalocele (19) and blastogenesis birth defects, including abdominal wall defects, after IVF/ICSI (27). In these studies the role of the underlying subfertility could not be separately assessed, but a more general association between subfertility and anomalies of the digestive system has been reported (3). In our study, we found that penoscrotal hypospadia was associated with subfertility. Others have also found that of the different types of urogenital abnormalities, hypospadia in particular seems to be associated with IVF/ICSI (25, 28, 29). Links between paternal subfertility and hypospadia, as well as hormonal exposure during organogenesis, have been proposed as mediating factors (3, 19). Our study suggests that factors associated with subfertility are involved in the etiology of penoscrotal hypospadia, but we did not find evidence that ICSI plays a role. Our data further suggest that RVOTO is more common after a history of subfertility. Associations between IVF/ICSI and septal heart defects (15) and tetralogy of Fallot (30) have previously been reported, although neither study could disentangle how far the observed associations could be attributed to IVF/ICSI vs. the underlying subfertility. Our study allows us to separate these factors and suggests a role for a history of subfertility in RVOTO. We further found an association between IVF/ICSI and polydactyly (mainly of the VOL. 103 NO. 4 / APRIL 2015
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TABLE 3 ORs of congenital anomalies associated with fertility category. Total subfertile group vs. fertile group (reference)
IVF/ICSI vs. natural conception after >12 mo (reference)
Congenital anomaly
cOR
aOR (95% CI)
cOR
aOR (95% CI)
Anomalies of the central nervous system Neural tube defect Anencephaly Hydrocephaly Eye anomaly Congenital cataract Ear anomaly Clefts Cleft lip with or without cleft palate Cleft lip without cleft palate Cleft lip with cleft palate Unilateral cleft lip and palate Cleft palate without cleft lip Anomalies of the respiratory tract Anomalies of the digestive tract Anomalies of the oesophagus Hypertrophic pyloric stenosis Atresia of the small or large intestine Atresia of the small intestine Atresia of the large intestine Anorectal atresia Malrotation of the intestines Diaphragmatic hernia Abdominal wall defects Omphalocele Gastroschisis Anomalies of the genitals Epispadiac Hypospadiac Coronal and glandular hypospadiac Penile hypospadiac Penoscrotal hypospadiac Anomalies of the urinary tract Renal agenesis (unilateral and bilateral) Cystic kidney disease Multicystic dysplastic kidney Renal dysplasia Hydronephrosis Stenosis ureter/pelviureteric junction Vesicoureteral reflux Musculoskeletal anomalies Congenital hip dysplasia Dislocation hip Club foot (neural tube defects excluded) Limb anomalies Polydactyly Polydactyly hand Preaxial polydactyly hands Postaxial polydactyly hands Syndactyly Syndactyly hands Reduction defect Reduction defects upper limb Reduction defects lower limbs Transverse reduction defect Heart anomalies Septal defects ASD VSD Muscular VSD Perimembraneous VSD AVSDs
0.66 0.57 1.26 1.16 0.45 0.78 2.08 0.93 1.04 1.59 0.70 0.80 0.72 1.13 1.28 1.12 1.16 1.28 1.28 1.22 1.30 1.50 1.10 2.63 2.96 2.19 1.01 4.65 1.01 0.73 0.75 6.26 1.05 0.74 2.11 1.81 1.65 0.98 0.81 1.37 0.80 0.66 1.06 1.24 1.53 2.03 2.45 2.76 1.96 0.82 1.37 1.82 1.91 1.84 1.89 1.24 1.20 1.46 1.09 1.18 1.47 1.84
0.66 (0.39–1.13) 0.54 (0.24–1.25) 1.06 (0.37–3.02) 1.04 (0.40–2.68) 0.46 (0.17–1.28) 0.80 (0.24–2.65) 2.95 (0.82–10.69) 0.84 (0.55–1.30) 0.98 (0.60–1.60) 1.60 (0.83–3.07) 0.63 (0.30–1.31) 0.98 (0.30–3.24) 0.60 (0.26–1.39) 0.90 (0.36–2.29) 1.31 (0.94–1.81) 0.87 (0.26–2.89) 1.31 (0.82–2.11) 1.04 (0.47–2.32) 1.46 (0.43–4.98) 0.79 (0.28–2.26) 0.80 (0.28–2.29) 1.39 (0.41–4.67) 0.72 (0.22–2.40) 2.43 (1.05–5.62)a,b 2.14 (0.76–6.02) 3.60 (0.98–13.23) 1.06 (0.70–1.60) 3.99 (0.75–21.26)d 1.07 (0.70–1.64) 0.69 (0.36–1.32) 0.87 (0.40–1.91) 9.83 (3.58–27.04)a,d 0.99 (0.67–1.47) 0.69 (0.25–1.92) 2.01 (0.99–4.05) 1.54 (0.63–3.74) 1.29 (0.49–3.36) 1.01 (0.43–2.37) 0.84 (0.30–2.38) 1.05 (0.41–2.72) 0.85 (0.63–1.14) 0.71 (0.48–1.04)b 1.12 (0.59–2.13) 1.40 (0.82–2.36) 1.50 (0.98–2.30) 2.20 (1.24–3.89)a,b 2.78 (1.53–5.07)a,b 4.09 (1.24–13.45)a,b 2.13 (0.86–5.25) 0.62 (0.15–2.59) 1.16 (0.27–5.04) 1.62 (0.79–3.36) 1.71 (0.70–4.13) 1.14 (0.33–3.90) 1.66 (0.73–3.78) 1.27 (0.98–1.63) 1.32 (0.93–1.85) 1.66 (0.95–2.92) 1.13 (0.80–1.59) 1.26 (0.79–2.01) 1.51 (0.86–2.66) 1.69 (0.57–5.04)
0.86 0.24 0.36 0.96 na na 2.95 0.94 0.71 1.03 0.41 0.72 1.96 0.24 0.73 0.48 0.71 1.49 0.72 2.23 2.23 na 1.45 0.20 0.00 0.73 0.28 0.72 0.23 0.31 0.24 0.00 0.58 0.96 0.53 0.24 0.28 0.29 0.48 2.95 1.08 1.85 1.21 0.18 2.40 3.73 3.40 na 1.46 2.92 2.92 1.48 3.78 0.48 1.46 0.99 0.77 1.28 0.67 1.22 0.52 4.44
1.20 (0.39–3.63) 0.39 (0.04–3.57) 0.80 (0.07–8.97) 0.78 (0.12–4.94) na na 3.20 (0.26–39.75) 0.75 (0.31–1.84) 0.64 (0.23–1.81) 0.76 (0.21–2.75) 0.50 (0.09–2.74) 0.76 (0.06–10.03) 1.20 (0.23–6.32) 0.00 (0.00–na) 0.82 (0.43–1.58) 0.50 (0.04–5.67) 0.71 (0.27–1.88) 2.31 (0.47–11.35) 0.65 (0.05–7.97) 6.66 (0.61–72.15) 6.66 (0.61–72.15) na 4.79 (0.39–59.54) 0.18 (0.02–1.56) 0.00 (0.00–na) 0.70 (0.06–8.38) 0.55 (0.15–2.07)d 0.69 (0.05–8.96) 0.53 (0.14–2.00)d 0.18 (0.02–1.50) 0.21 (0.02–1.84) 0.00 (0.00–na) 0.68 (0.29–1.58) 1.25 (0.16–9.68) 0.62 (0.12–3.17) na 0.00 (0.00–na) 0.59 (0.06–5.65) 0.75 (0.07–8.02) 1.93 (0.30–12.43) 1.13 (0.62–2.08) 1.70 (0.80–3.62) 1.12 (0.32–3.92) 0.24 (0.05–1.12) 3.31 (1.31–8.38)a,b 4.83 (1.39–16.77)a,b 5.02 (1.43–17.65)a,b na 1.94 (0.33–11.93) na na 1.62 (0.41–6.48) 6.65 (0.73–60.76) 0.68 (0.06–8.19) 1.89 (0.39–9.14) 0.94 (0.57–1.58) 0.78 (0.39–1.54) 1.22 (0.41–3.62) 0.68 (0.34–1.39) 1.23 (0.49–3.04) 0.59 (0.17–1.99) 4.18 (0.39–44.74)
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TABLE 3 Continued. Total subfertile group vs. fertile group (reference)
IVF/ICSI vs. natural conception after >12 mo (reference)
Congenital anomaly
cOR
aOR (95% CI)
cOR
Patent ductus arteriosus Conotruncal defects D-transposition great arteries Transposition great arteries Tetralogy of Fallot Outflow tract anomalies RVOTO Pulmonary valve atresia or stenosis Pulmonary valve stenosis LVOTO Bicuspid aortic valve Hypoplastic left heart syndrome Coarctation of the aorta Single ventricle Recognized syndromes with unknown etiology VATER association
1.66 0.94 0.53 0.63 1.18 1.30 1.66 1.31 1.43 1.00 1.35 1.58 0.90 2.66
1.73 (0.66–4.51) 0.932 (0.51–1.72) 0.53 (0.19–1.48) 0.62 (0.25–1.56) 1.21 (0.47–3.12) 1.31 (0.89–1.92) 1.77 (1.06–2.97)a,e 1.31 (0.75–2.29) 1.43 (0.80–2.57) 0.97 (0.56–1.68) 1.10 (0.43–2.84) 1.44 (0.60–3.46) 0.80 (0.34–1.88) 2.63 (0.71–9.73)
0.29 1.03 0.48 0.97 2.20 0.77 0.84 1.28 1.09 0.71 1.46 1.96 2.95 na
na 1.36 (0.40–4.71) 0.42 (0.04–4.32) 0.79 (0.12–5.03) 7.82 (0.83–73.82) 0.71 (0.33–1.53) 0.88 (0.33–2.40) 1.35 (0.46–4.01) 1.19 (0.38–3.68) 0.57 (0.18–1.75) 0.62 (0.10–3.81) 1.19 (0.23–6.28) 2.47 (0.42–14.41) na
2.70
2.44 (0.79–7.53)
5.93
9.38 (0.86–102.04)
aOR (95% CI)
Note: The 95% CI excludes 1. Adjusted odds ratios (aOR) not further specified were all corrected for maternal age at conception and the correct use of folic acid. ASD ¼ atrial septal defects; ICSI ¼ intracytoplasmic sperm injection; IVF ¼ in vitro fertilization; LVOTO ¼ left ventricular outflow tract obstruction; na ¼ not applicable; cOR ¼ crude odds ratio; RVOTO ¼ right ventricular outflow tract obstruction; VATER ¼ nonrandom co-occurrence of at least three of the following: vertebral anomalies, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb anomalies; VSD ¼ ventricular septal defects. a Statistically significant result. b Corrected for maternal age, folic acid use, year of birth, and multiple pregnancy. c The control group consisted of both male and female infants in order to maintain uniformity of our methods. When limiting the analyses to male infants the results did not materially change. d Corrected for maternal age, folic acid use, year of birth, multiple pregnancy, ICSI, and DES daughters. e Corrected for maternal age, folic acid use, year of birth, multiple pregnancy, and pregestational diabetes. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
hands). We excluded monogenic causes of polydactyly and looked, in detail, into whether polydactyly after IVF/ICSI repeatedly occurred in combination with any other specific defect: it did not. Finally, we confirmed that a history of subfertility is associated with methylation defects that cause imprinting disorders. In an earlier Dutch study, the association between IVF/ ICSI and Beckwith-Wiedemann syndrome and Angelman syndrome disappeared after correction for subfertility (12). Imprinting disorders can occur owing to disturbed methylation, microdeletions, or uniparental disomy. We were able to analyze these different causes and found that a history of subfertility was associated with methylation defects. Because the effects of parental subfertility on the epigenetic makeup of offspring are largely unknown, this may contribute to generating new hypotheses. Genome-wide epigenetic alterations in phenotypically normal children born after IVF/ICSI have been described (31). It is possible that there is an epigenetic instability of the gametes or the early embryonic cells that results in both subfertility of the parents and adverse health outcomes in their offspring (6, 32). Other studies reported associations between IVF/ICSI and several subgroups of congenital anomalies that we were unable to confirm. The subgroups included musculoskeletal defects, neural tube defects, digestive tract atresia, cleft lip/ palate, and anomalies of the ear, eye, face, and neck (2, 3, 13–15, 19, 21). The fact that previous studies provide an incoherent picture of which subgroups of anomalies occur more often after IVF/ICSI might suggest that all anomalies occur more frequently after IVF. Additionally, because we combined all different causes of subfertility into one group, 1008
we were not able to further deduce whether specific causes of subfertility were associated with specific birth defects in our study. Furthermore, because Eurocat NNL does not include non-malformed controls, the risk increase for the overall group of congenital anomalies could not be analyzed. One of the main strengths of our study is inclusion of all types of births, regardless of gestational age. Unlike many other studies, terminations of pregnancy due to fetal anomalies were included in this study. This is important because subfertile women may less frequently decide to terminate their muchdesired pregnancies because of a congenital anomaly (14). The total subfertile group consisted of 340 children. This may seem a small group, but because they all had a congenital anomaly, this sample allowed for an adequate evaluation of most specific anomalies. All congenital anomalies that occurred at least three times in the total subfertile group were analyzed; the complete and detailed overview of all anomalies is regarded one of the main strengths of the study. Yet our power to detect associations with very rare congenital anomalies and syndromes with unknown etiology was probably insufficient. Another strength of our study is inclusion of children with congenital anomalies up to the age of 10 years and not just after birth. Furthermore, Eurocat NNL's long history allowed for large numbers of cases and enabled us to look at specific and pathogenetically similar types of congenital anomalies rather than larger heterogeneous subgroups. The detailed information from the parental questionnaire allowed us to adjust for a large variety of confounders. A final strength of our study is that we verified parental subfertility by searching medical records of fertility clinics. VOL. 103 NO. 4 / APRIL 2015
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TABLE 4 Crude odds ratios of imprinting disorders and their underlying causes associated with fertility category.
Imprinting disorder Any imprinting disorder Beckwith-Wiedemann syndrome Silver Russell syndrome Prader-Willi syndrome Angelman syndrome Cause of imprinting disordera Primary methylation defect Microdeletion Uniparental disomy Other causec
Total subfertile group vs. fertile group (reference)
Total subfertile group Fertile group (n [ 340) (n [ 4,185)
IVF/ICSI vs. Subfertile, natural natural conception IVF/ICSI conception after >12 mo (n [ 139) (n [ 201) (reference)
3 2
20 7
1.85 (0.55–6.27) 3.53 (0.73–17.07)
1 1
2 1
0.72 (0.07–8.03) 1.45 (0.09–23.37)
1 0 0
1 10 2
12.34 (0.77–197.76) na na
0 0 0
1 0 0
na na na
3
5
6.12 (1.54–24.90)b
1
2
0.72 (0.07–8.03)
0 0 0
8 4 2
na na na
0 0 0
0 0 0
na na na
Note: Values are n or crude OR (95% CI). 95% CI excludes 1. ICSI ¼ intracytoplasmic sperm injection; IVF ¼ in vitro fertilization. a In one child with Prader-Willi syndrome the underlying cause was unknown. b Statistically significant result. After correction for maternal age at conception, the correct use of folic acid, year of birth, and multiple pregnancies, the difference remained statistically significant: aOR 13.49, 95% CI 2.93–62.06. c Other causes included a de novo mutation in the UBE3A gene in a child with Angelman syndrome and a translocation of chromosomes Y and 11 in a child with Beckwith-Wiedemann syndrome. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
However, searching the fertility records could also be regarded as a limitation, because we lost data by excluding those with unconfirmed subfertility. The loss of these data reduced the study power but increased the certainty of evaluating the effect of IVF/ICSI and subfertility on congenital anomalies. Other limitations that should be noted are related to the case-only design. Because Eurocat NNL does not collect information on non-malformed controls, fetuses/children with another congenital anomaly than the one studied in that specific analysis served as the control group. This means that the control group changes for the analyses of different anomalies, making the ORs derived not readily comparable to each other. The ORs can, however, be used to estimate the effect of IVF/ICSI and subfertility on that specific defect. Furthermore, when studying a specific defect with a caseonly design, pathogenetically similar defects may be included in the control group. For example, when studying ventricular septal defects (VSDs), atrial septal defects (ASDs) are included in the control group. Because VSDs and ASDs may share a common etiology, this may dilute the effect of IVF/ICSI and subfertility on VSDs. Yet, because many more other congenital anomalies are included in the control group, the diluting effect (of ASDs in this example) is thought to be small. Nevertheless, these disadvantages of a case-only design should be kept in mind. Another limitation of our study is that information on fertility status and pregnancy details was obtained retrospectively with a questionnaire up to the age of 10 years, so the couples could have a problem with the recall of these details. However, problems with recall are expected to be the same for all groups, and most questionnaires were returned within the first 2 years after the child's birth (median 1.40 years, SD 2.11 years). Another limitation is that we were not certain that fertile couples were indeed fertile according to the definition of a time to pregnancy of 12 mo + IVF/ICSI (N [ 340)
Congenital anomalies Central nervous system Neural tube defect Anencephaly Spina bifida Thoracal spina bifida Lumbar spina bifida Encephalocele Iniencephaly Craniorachischisis Arhinencephaly/holoprosencephaly Microcephaly Hydrocephaly Eye Anophthalmia Microphthalmia Congenital glaucoma Congenital cataract Coloboma of the iris Ear Anotia Microtia Misshapen ear Clefts Cleft lip with or without cleft palate Cleft lip without cleft palate Bilateral cleft lip Central cleft lip Cleft lip with cleft palate Unilateral cleft lip and palate Bilateral cleft lip and palate Cleft palate without cleft lip Respiratory tract Choanal atresia Lung hypoplasia Digestive tract Anomalies of the oesophagus Hypertrophic pyloric stenosis Atresia of the small or large intestine Atresia/stenosis of the small intestine Artresia duodenum Atresia jejunum Atresia ileum Atresia/stenosis of the large intestine Anorectal atresia Hirschsprung's disease Malrotation of the intestines Abdominal wall defects Diaphragmatic hernia Omphalocele Gastroschisis Genitals Epispadia Hypospadia Coronaral and glandular hypospadia Penile hypospadia Penoscrotal hypospadia Indeterminate gender Urinary tract Renal agenesis (unilateral and bilateral) Bilateral renal agenesis Unilateral renal agenesis
Fertile group (N [ 4,185), N (%)
Subfertile but natural conception (N [ 201), N (%)
Subfertile, conception after IVF/ICSI (N [ 139), N (%)
290 (7) 148 (4) 49 (1) 89 (2) 26 (1) 51 (1) 10 (0) 2 (0) 5 (0) 10 (1) 25 (1) 53 (1) 108 (3) 2 (0) 17 (0) 7 (0) 47 (1) 15 (0) 18 (0) 11 (0) 2 (0) 2 (0) 368 (9) 250 (6) 94 (2) 9 (0) 2 (0) 156 (4) 46 (1) 52 (1) 118 (3) 76 (2) 12 (0) 29 (1) 531 (13) 44 (1) 224 (5) 78 (2) 29 (1) 11 (0) 8 (0) 10 (0) 51 (1) 48 (1) 28 (1) 33 (1) 38 (1) 45 (1) 21 (1) 17 (0) 354 (9) 8 (0) 328 (8) 184 (4) 114 (3) 14 (0) 5 (0) 402 (10) 82 (2) 24 (1) 31 (1)
10 (5) 6 (3) 4 (2) 2 (1) 0 2 (1) 0 0 0 1 (1) 0 3 (2) 0 0 0 0 0 0 1 (1) 0 0 0 17 (9) 14 (7) 7 (4) 0 1 (1) 7 (4) 2 (1) 1 (1) 3 (2) 6 (3) 0 2 (1) 35 (18) 3 (2) 14 (7) 4 (2) 2 (1) 1 (1) 0 1 (1) 2 (1) 2 (1) 0 4 (2) 7 (4) 2 (1) 5 (3) 2 (1) 24 (12) 2 (1) 23 (11) 9 (5) 6 (3) 7 (4) 1 (1) 24 (12) 3 (2) 2 (1) 0
6 (4) 1 (1) 1 (1) 0 0 0 0 0 0 1 (1) 0 2 (1) 4 (3) 0 0 0 3 (2) 0 2 (2) 1 (1) 0 0 11 (8) 7 (7) 5 (4) 2 (1) 0 2 (1) 1 (1) 1 (1) 4 (3) 1 (1) 0 0 18 (13) 1 (1) 7 (5) 4 (3) 1 (1) 1 (1) 0 0 3 (2) 3 (2) 1 (1) 0 1 (1) 2 (1) 0 1 (1) 5 (4) 1 (1) 4 (3) 2 (1) 1 (1) 0 1 (1) 10 (7) 2 (1) 0 1 (1)
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SUPPLEMENTAL TABLE 1 Continued. Total subfertile group, natural conception > 12 mo + IVF/ICSI (N [ 340)
Congenital anomalies Cystic kidney disease Simple renal cyst Multicystic dysplastic kidney Renal dysplasia Hydronephrosis Stenosis ureter/pelviureteric junction Megaloureter/hydroureter Horseshoe kidney Vesicoureteral reflux Exstrophy of bladder or cloaca Atresia of the urethra and bladder neck Musculoskeletal Congenital hip dysplasia Dislocation hip Subluxation hip Club foot (neural tube defects excluded) Limbs Polydactyly Polydactyly hands Preaxial polydactyly hands Postaxial polydactyly hands Polydactyly feet Preaxial polydactyly feet Postaxial polydactyly feet Syndactyly Syndactyly hands Syndactyly feet Reduction defect Reduction defect upper limb Reduction defect lower limb Transverse reduction defect Preaxial reduction defect Postaxial reduction defect Intercalary reduction defect Congenital deformity hand or arm Congenital deformity leg or unspecified limb Rockerbottom feet Heart Septal defect ASD VSD Muscular VSD Perimembraneous VSD AVSDs Persistent truncus arteriosus Patent foramen ovale Patent ductus arteriosus Conotruncal defects D-transposition great arteries Transposition great arteries Tetralogy of Fallot Outflow tract anomalies Double outlet right ventricle RVOTO Pulmonary valve atresia or stenosis Pulmonary valve atresia Pulmonary valve stenosis Anomalies pulmonary artery
Fertile group (N [ 4,185), N (%)
Subfertile but natural conception (N [ 201), N (%)
Subfertile, conception after IVF/ICSI (N [ 139), N (%)
65 (2) 1 (0) 48 (1) 45 (1) 76 (2) 61 (2) 55 (1) 9 (0) 54 (1) 9 (0) 36 (1) 889 (21) 621 (15) 128 (3) 16 (0) 171 (4) 252 (6) 106 (3) 83 (2) 18 (0) 38 (1) 19 (1) 2 (0) 10 (0) 45 (1) 27 (1) 14 (0) 69 (2) 46 (1) 27 (1) 53 (1) 8 (0) 25 (1) 2 (0) 12 (0) 12 (0)
8 (4) 0 6 (3) 5 (3) 5 (3) 3 (2) 2 (1) 1 (1) 2 (1) 0 2 (1) 35 (17) 16 (8) 6 (3) 2 (1) 15 (8) 12 (6) 5 (3) 5 (3) 0 3 (2) 0 0 0 1 (1) 1 (1) 0 5 (3) 2 (1) 3 (2) 4 (2) 0 1 (1) 0 0 0
3 (2) 0 1 (1) 1 (1) 1 (1) 1 (1) 0 0 4 (3) 0 0 25 (19) 19 (14) 5 (4) 0 2 (1) 18 (13) 12 (9) 11 (8) 4 (3) 3 (2) 2 (1) 0 1 (1) 2 (1) 2 (1) 0 5 (4) 5 (4) 1 (1) 4 (3) 2 (2) 0 0 0 0
1 (0) 1059 (26) 472 (11) 128 (3) 491 (12) 232 (6) 128 (3) 27 (1) 9 (0) 18 (0) 45 (1) 157 (4) 92 (2) 97 (2) 52 (1) 329 (8) 23 (1) 144 (3) 142 (3) 20 (1) 122 (3) 21 (1)
0 60 (30) 29 (14) 8 (4) 29 (14) 12 (6) 11 (6) 1 (1) 1 (1) 0 5 (3) 7 (4) 3 (2) 3 (2) 2 (1) 22 (11) 1 (1) 12 (6) 8 (4) 0 8 (4) 2 (1)
0 40 (30) 16 (12) 7 (5) 14 (10) 10 (7) 4 (3) 3 (2) 0 1 (1) 1 (1) 5 (4) 1 (1) 2 (1) 3 (2) 12 (9) 0 7 (5) 7 (5) 1 (1) 6 (4) 0
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SUPPLEMENTAL TABLE 1 Continued. Total subfertile group, natural conception > 12 mo + IVF/ICSI (N [ 340)
Congenital anomalies LVOTO Aortic valve stenosis Bicuspid aortic valve Hypoplastic left heart syndrome Coarctation of the aorta Interrupted aortic arch Tricuspid atresia or stenosis Mitral valve stenosis Mitral valve insufficiency Single ventricle Ebstein anomaly Recognized syndromes with unknown aetiology VATER association OAVS Limb body wall complex Amniotic band syndrome FFU complex Poland syndrome Pierre Robin sequence Prune belly syndrome Imprinting disorders Any imprinting disorder Beckwith Wiedemann syndrome Silver Russell syndrome Prader Willi syndrome Angelman syndrome Cause of imprinting disordera Primary methylation defect Microdeletion Uniparental disomy Other causeb
Fertile group (N [ 4,185), N (%)
Subfertile but natural conception (N [ 201), N (%)
Subfertile, conception after IVF/ICSI (N [ 139), N (%)
185 (4) 20 (1) 55 (1) 55 (1) 82 (2) 7 (0) 12 (0) 10 (0) 17 (0) 14 (0) 12 (0)
10 (5) 2 (1) 3 (2) 3 (2) 2 (1) 0 0 0 1 (1) 0 1 (1)
5 (4) 0 3 (2) 4 (3) 4 (3) 0 2 (1) 0 1 (1) 3 (2) 0
23 (1) 18 (0) 3 (0) 10 (0) 5 (0) 6 (0) 20 (1) 5 (0)
1 (1) 0 0 0 1 (1) 0 1 (1) 0
4 (3) 1 (1) 2 (1) 1 (1) 0 0 1 (1) 0
20 (1) 7 (0) 1 (0) 10 (0) 2 (0)
2 (1) 1 (1) 1 (1) 0 0
1 (1) 1 (1) 0 0 0
5 (0) 8 (0) 4 (0) 2 (0)
2 (1) 0 0 0
1 (1) 0 0 0
Note: As syndromes and imprinting disorders are very rare, we decided that they had to occur at least five times in the total database to be shown in the appendix. ASD ¼ atrial septal defect; VSD ¼ ventricular septal defect; AVSD ¼ atrioventricular septal defect; RVOTO ¼ right ventricular outflow tract obstruction; LVOTO ¼ left ventricular outflow tract obstruction;VATER association ¼ non-random association of vertebral anomalies, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies and limb anomalies; OAVS ¼ oculo-auriculo-vertebral spectrum; FFU complex ¼ femur-fibula-ulna complex. a In one child with Prader Willi syndrome the underlying cause was unknown. b Other causes included a de novo mutation in the UBE3A gene in a child with Angelman syndrome and a translocation of chromosomes Y and 11 in a child with Beckwith-Wiedemann syndrome. Seggers. Congenital anomalies after subfertility. Fertil Steril 2015.
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