Abstract

Aims

To estimate the risk of congenital heart defects (CHD) associated with assisted reproductive technologies (ART).

Methods and results

We used data from the Paris Registry of Congenital Malformations on 5493 cases of CHD and 3847 malformed controls for which no associations with ART were reported in the literature. Assisted reproductive technologies included inductors of ovulation only, in vitro fertilization, and intracytoplasmic sperm injection. Exposure to ART was higher for cases than controls (4.7 vs. 3.6%, P= 0.008) and was associated with a 40% increase in the maternal age, socioeconomic factors, and year of birth-adjusted odds of CHD without chromosomal abnormalities [adjusted odds ratio (OR) 1.4, 95% confidence interval (CI) 1.1–1.7]. Assisted reproductive technologies were specifically associated with significant increases in the odds of malformations of the outflow tracts and ventriculoarterial connections (adjusted OR 1.7, 95% CI 1.2–2.4) and of cardiac neural crest defects and double outlet right ventricle (adjusted OR 1.7, 95% CI 1.1–2.7). In general, we found specific associations between methods of ART and subcategories of CHD.

Conclusion

Cases with CHD were more likely to have been conceived following ART when compared with malformed controls. This higher risk for CHD varied specifically according to the method of ART and the type of CHD and may be due to ART per se and/or the underlying infertility of couples.

Introduction

Congenital heart defects (CHD) are the most prevalent birth defects and comprise the most important cause of malformation-related infant mortality.1,2 Despite the progress in prenatal diagnosis, medical and surgical management of infants with CHD3,4 substantial risks of morbidity and mortality remain for severe cases of CHD. Risk factors of CHD include inherited5 and non-inherited causes,6 among which the role of assisted reproductive technologies (ART) remains uncertain.

Assisted reproductive technologies include various techniques used to achieve pregnancy in the case of male or female infertility and comprise inductors of ovulation, conventional in vitro fertilization (IVF), and IVF with intracytoplasmic sperm injection (ICSI). These techniques are increasingly used in many countries7,8 in part due to trends towards delayed childbearing.9 For example, in France, nearly 2.4% of all children born in 2006 were conceived following ART.10

Children conceived following ART are known to be at higher risk for adverse birth outcomes11–15 including those related to multiple births, preterm delivery, and intrauterine growth retardation. There are more uncertainties regarding the risks for birth defects,13,16–23 and in particular for specific defects such as CHD.12,24–26 The meta-analysis by Hansen et al.18 showed a moderate increase in the overall risk for birth defects in children born after IVF or ICSI compared with children born spontaneously [odds ratio (OR) = 1.40, 95% confidence interval (CI) 1.28–1.53]. However, insufficient data exist regarding specific risks for CHD that may be associated with ART.

Previous studies included a relatively small number of cases of CHD and showed inconsistent results for risks of CHD in relation to ART.12,24–26 Moreover, specific associations between subcategories of CHD and different methods of ART have not been adequately assessed in the literature. This is important as most known teratogens and risk factors for birth defects are associated with one or a few specific anomalies.

Using population-based data from the Paris Registry of Congenital Malformations including more than 5000 cases of CHD, we estimated the risk for CHD in relation to different methods of ART for: all CHD, CHD without chromosomal abnormalities, and subcategories of CHD defined based on anatomo-embryological criteria.

Methods

Data

We used data from the population-based Paris Registry of Congenital Malformations,4,27 which registers all cases of birth defects and chromosomal abnormalities among live-borns, still-borns (≥22 weeks of gestation), and pregnancy terminations. The Registry covers the population of women who live in Greater Paris area (Paris and its surrounding suburb) and deliver or have a pregnancy termination in a Parisian maternity unit. The annual number of deliveries in our population is about 38 000.

The Paris Registry is a member of the European Network of Registries of Congenital Malformations (EUROCAT) and of the International Clearinghouse for Birth Defects Surveillance and Research. The Registry follows the EUROCAT methodology and quality of data is routinely monitored by both EUROCAT1 and the National Committee of Registries in France. The review of procedures regarding confidentiality of data is overseen by both the National Committee of Registries and the National Committee of Informatics and Freedom. Data are based on medical records and are collected from several sources including maternity units, neonatology wards, and cytogenetic and pathology services.

Data for the study population corresponded to the period 1987–2006 as the first case of a malformation with exposure to IVF occurred in 1987 and 2006 was the last year for which data were available.

Methods

A case–control study with malformed controls was conducted to estimate the risk of CHD in relation to ART. Cases were children/foetuses with a diagnosis of CHD. For the malformed controls, following Hook's recommendations,28 we included a wide spectrum of malformations for which no association with ART was reported in the literature. The malformed controls were foetuses/children with isolated club-foot, angioma, skin abnormality, polydactyly, syndactyly, or congenital hip dislocation.

We estimated the risk (odds) of CHD when compared with malformed controls in relation to different methods of ART. This risk was estimated for the following outcomes: (i) all CHD combined, (ii) CHD without chromosomal abnormalities, (iii) CHD without chromosomal abnormalities and excluding isolated ventricular septal defects (VSD), and (iv) 10 mutually exclusive subcategories of CHD (Table 1, subcategories 1–10) defined based on anatomo-embryological criteria and classified by consensus by two paediatric cardiologists (L.H. and D.B.). Three additional subcategories (Table 1, subcategories 11–13) were defined by re-grouping, based on their common developmental and genetic origins,29 certain types of CHD included in the 10 preceding subcategories.

Table 1

Subcategories of congenital heart defects defined according to anatomo-embryological criteriaa

Subcategories of CHD Malformations included ICD 10 
Anomalies of heart position Heterotaxy syndromeb/isomerism of atrial appendages Q206 
Mirror-image arrangement Q893 

 
Malformations of the outflow tracts and ventriculoarterial connections Transposition of great arteries (complete) Q203 
Vascular malpositions  
 Double outlet right ventricle Q201 
 Double outlet left ventricle Q202 
Cardiac neural crest defects  
 Common arterial trunk Q200 
 Tetralogy of Fallot Q213 
 Aortopulmonary septal defect Q214 
 Pulmonary valve atresia + VSD Q220 + Q210 
 Atresia of pulmonary artery Q255 
 Interrupted aortic arch/atresia of aorta Q252 
 Overriding aorta Q2542 
Defects of aortic valves/left outflow tract  
 Stenosis of aortic valve Q230 
 Insufficiency of aortic valve Q231 
Defects of pulmonary valves/right outflow tract  
 Pulmonary valve atresia Q220 
 Pulmonary valve stenosis Q221 
 Pulmonary valve insufficiency Q222 
 Other defects of pulmonary valve Q223 
 Pulmonary infundibular stenosis Q243 
Other defects of great vessels Q258/Q259 

 
Malformations of the atrioventricular valves and atrioventricular connections Defects of tricuspid valve  
 Tricuspid valve stenosis/atresia Q224 
 Ebstein's anomaly Q225 
 Other defects of tricuspid valve Q228 
 Unspecified tricuspid valve defect Q229 
Defects of mitral valve  
 Mitral stenosis Q232 
 Mitral insufficiency Q233 
 Unspecified mitral defects Q239 
Common atrium/cor triloculare biventriculare Q2115 
Atrioventricular septal defects Q212 

 
Functionally univentricular CHD Double inlet ventricle Q204 
Hypoplastic left heart syndrome Q234 
Hypoplastic right ventricle  
 Hypoplastic right heart syndrome Q226 
 Cor biloculare Q208 

 
Anomalies of the great arteries Anomalies of ascending aorta  
 Hypoplasia of ascending aorta Q2540 
 Supravalvular aortic stenosis Q253 
 Aneurysm or dilatation of aorta Q2545 
 Aneurysm of sinus of Valsalva Q2543 
Coarctation of aorta Q251 
Anomalies of aortic arch Q2541/Q2544 
Anomalies of pulmonary artery  
 Stenosis of pulmonary artery Q256 
 Other defects of pulmonary artery Q257 

 
Anomalies of coronary vessels Defect of coronary vessels Q245 
Ventricular septal defects Ventricular septal defects Q210 

 
Anomalies of the atria and interatrial communications Cor triatrium Q242 
Interatrial communications Q2110/Q2112/Q2113/Q2114/Q2118 

 
Anomalies of venous connections Anomalous systemic venous connection  
 Persistent left superior vena cava Q261 
 Other defects of great veins Q260/Q265/Q266/Q268/Q269 
Anomalous pulmonary venous connection  
 Total anomalous pulmonary venous connection Q262 
 Partial anomalous pulmonary venous connection Q263 
 Unspecified anomalous pulmonary venous connection Q264 

 
Discordant atrioventricular connections Discordant atrioventricular connection Q205 
Unspecified defects of cardiac chamber and connections Q209 

 
TGA, heterotaxy syndromeb and discordant atrioventricular connections  Q206/Q203/Q205/Q209 

 
Cardiac neural crest defects and double outlet right ventricle without ventricular hypoplasia  Q200/Q213/Q214/Q220 + Q210/Q252/Q255/Q2542/Q201 without Q226 and Q234 

 
Isolated atrioventricular septal defects  Q212 
Subcategories of CHD Malformations included ICD 10 
Anomalies of heart position Heterotaxy syndromeb/isomerism of atrial appendages Q206 
Mirror-image arrangement Q893 

 
Malformations of the outflow tracts and ventriculoarterial connections Transposition of great arteries (complete) Q203 
Vascular malpositions  
 Double outlet right ventricle Q201 
 Double outlet left ventricle Q202 
Cardiac neural crest defects  
 Common arterial trunk Q200 
 Tetralogy of Fallot Q213 
 Aortopulmonary septal defect Q214 
 Pulmonary valve atresia + VSD Q220 + Q210 
 Atresia of pulmonary artery Q255 
 Interrupted aortic arch/atresia of aorta Q252 
 Overriding aorta Q2542 
Defects of aortic valves/left outflow tract  
 Stenosis of aortic valve Q230 
 Insufficiency of aortic valve Q231 
Defects of pulmonary valves/right outflow tract  
 Pulmonary valve atresia Q220 
 Pulmonary valve stenosis Q221 
 Pulmonary valve insufficiency Q222 
 Other defects of pulmonary valve Q223 
 Pulmonary infundibular stenosis Q243 
Other defects of great vessels Q258/Q259 

 
Malformations of the atrioventricular valves and atrioventricular connections Defects of tricuspid valve  
 Tricuspid valve stenosis/atresia Q224 
 Ebstein's anomaly Q225 
 Other defects of tricuspid valve Q228 
 Unspecified tricuspid valve defect Q229 
Defects of mitral valve  
 Mitral stenosis Q232 
 Mitral insufficiency Q233 
 Unspecified mitral defects Q239 
Common atrium/cor triloculare biventriculare Q2115 
Atrioventricular septal defects Q212 

 
Functionally univentricular CHD Double inlet ventricle Q204 
Hypoplastic left heart syndrome Q234 
Hypoplastic right ventricle  
 Hypoplastic right heart syndrome Q226 
 Cor biloculare Q208 

 
Anomalies of the great arteries Anomalies of ascending aorta  
 Hypoplasia of ascending aorta Q2540 
 Supravalvular aortic stenosis Q253 
 Aneurysm or dilatation of aorta Q2545 
 Aneurysm of sinus of Valsalva Q2543 
Coarctation of aorta Q251 
Anomalies of aortic arch Q2541/Q2544 
Anomalies of pulmonary artery  
 Stenosis of pulmonary artery Q256 
 Other defects of pulmonary artery Q257 

 
Anomalies of coronary vessels Defect of coronary vessels Q245 
Ventricular septal defects Ventricular septal defects Q210 

 
Anomalies of the atria and interatrial communications Cor triatrium Q242 
Interatrial communications Q2110/Q2112/Q2113/Q2114/Q2118 

 
Anomalies of venous connections Anomalous systemic venous connection  
 Persistent left superior vena cava Q261 
 Other defects of great veins Q260/Q265/Q266/Q268/Q269 
Anomalous pulmonary venous connection  
 Total anomalous pulmonary venous connection Q262 
 Partial anomalous pulmonary venous connection Q263 
 Unspecified anomalous pulmonary venous connection Q264 

 
Discordant atrioventricular connections Discordant atrioventricular connection Q205 
Unspecified defects of cardiac chamber and connections Q209 

 
TGA, heterotaxy syndromeb and discordant atrioventricular connections  Q206/Q203/Q205/Q209 

 
Cardiac neural crest defects and double outlet right ventricle without ventricular hypoplasia  Q200/Q213/Q214/Q220 + Q210/Q252/Q255/Q2542/Q201 without Q226 and Q234 

 
Isolated atrioventricular septal defects  Q212 

aSee the Methods section for details.

bDefinition of heterotaxy syndrome was based on the article by Jacobs et al.44

The main predictor variable was exposure to ART, which included the following: inductors of ovulation only (IO), IVF, and ICSI. Exposure to ART was assessed: (i) as a binary (ART yes/no) variable and (ii) as a variable in four categories (no ART, IO, IVF, and ICSI), and for IVF and ICSI combined (IVF + ICSI).

Variables considered as potentially confounding factors included year of birth, maternal age, occupation, and geographic origin. These factors are known to be related to both exposure to ART and prevalence of birth defects22,30 even if their specific associations with CHD are not well documented. Maternal occupation was coded according to the French National Institute of Statistics and Economic studies (INSEE) classification: professional, intermediate, administrative/public service, other, and none. These categories represent a gradient from the highest to the lowest occupational group in France. The ‘other' group comprised: artisan/small business owner, shop keeper/shop assistant, service worker, skilled worker, and unskilled worker, for which each category represented a small number of deliveries in our population. Maternal geographic origin was coded as: French, North African, other African, and other countries.

Analyses for the largest three groups of cases (all CHD, CHD without chromosomal abnormalities, and CHD without chromosomal abnormalities and excluding isolated VSD) were also done separately for singletons.

Power

Assuming a type-I error of 0.05, we had a power of 80% to detect an OR of 1.5 for the overall risk of CHD in relation to IVF (exposure ≈2%). Assuming a case–control ratio of 1:4, we had a power of 80% to detect an OR of 2.0 associated with IVF exposure for subcategories of 1000 cases. For subcategories of 100 cases, we had an 80% power to detect an OR of 3.0 or more. For exposure to ICSI (≈0.6%), we had a power of 80% to detect an OR of 2.0 for the overall risk of CHD and 3.0 for subcategories of 1000 cases.

Statistical analyses

The odds of CHD in relation to ART was estimated using logistic regression models for each outcome, after taking into account year of birth, maternal age, occupation, and geographic origin. The adjustment for maternal age was made using fractional polynomials.31

Separate logistic regression models were estimated for each of the following outcomes: (i) all CHD, (ii) CHD without chromosomal abnormalities, (iii) CHD without chromosomal abnormalities and excluding VSD, and (iv) each of the 13 CHD subcategories that included at least 100 cases. The following CHD subcategories were not analysed separately as they included less than 100 cases: anomalies of heart position, anomalies of coronary arteries, anomalies of venous connections, discordant atrioventricular connections, and isolated atrioventricular septal defects. However, these cases were included in the analyses for all CHD/CHD without chromosomal abnormalities/excluding VSD.

We tested whether the effects associated with ART (specifically IO and IVF for which data were available for the entire study period) changed over time; i.e. we tested for interaction effects between IO/IVF and time using nested models with likelihood ratio tests. None of the interaction effects between ART and time were statistically significant (detailed results not shown; available from authors). We also tested for any interaction effects between ART and singleton/multiple births.

The statistical significance level was set at α = 0.05 and all tests were two-sided.

As recommended by Rothman32 and Savitz and Olshan33 in the case of observational studies, such as ours, aimed at detecting patterns of (specific) associations, no adjustment was made for multiple comparisons in analysing the associations between the a priori chosen subcategories of CHD and ART.

Analyses were done with Stata 9 software (Statacorp, TX, USA).

Results

Study population

After excluding data with missing information on ART (2% of cases), the study population included 5493 cases of CHD, 4459 cases of CHD without chromosomal abnormalities, and 3104 without chromosomal abnormalities and excluding VSD (Table 2).

Table 2

Number of cases and controls and proportions of children/foetuses conceived after assisted reproductive technologies

Categorya Subjects with complete data on ART (nExposure to ART (%) P-valueb 
Controls 3847 3.6  

 
All CHD 5493 4.7 0.008 
CHD without chromosomal abnormalities 4459 4.9 0.003 
CHD without chromosomal abnormalities and excluding VSD 3104 5.0 0.005 

 
Malformations of the outflow tracts and ventriculoarterial connections 1088 5.6 0.003 
Malformations of the atrioventricular valves and atrioventricular connections 608 2.6 0.231 
Functionally univentricular CHD 402 2.5 0.253 
Anomalies of the great arteries 371 5.6 0.331 
Ventricular septal defects 2248 5.0 0.006 
Anomalies of the atria and interatrial communications 124 4.8 0.463 
TGA, heterotaxy syndrome, and discordant atrioventricular connections 475 1.3 0.362 
Cardiac neural crest defects and double outlet right ventricle without ventricular hypoplasia 537 1.8 0.014 
Categorya Subjects with complete data on ART (nExposure to ART (%) P-valueb 
Controls 3847 3.6  

 
All CHD 5493 4.7 0.008 
CHD without chromosomal abnormalities 4459 4.9 0.003 
CHD without chromosomal abnormalities and excluding VSD 3104 5.0 0.005 

 
Malformations of the outflow tracts and ventriculoarterial connections 1088 5.6 0.003 
Malformations of the atrioventricular valves and atrioventricular connections 608 2.6 0.231 
Functionally univentricular CHD 402 2.5 0.253 
Anomalies of the great arteries 371 5.6 0.331 
Ventricular septal defects 2248 5.0 0.006 
Anomalies of the atria and interatrial communications 124 4.8 0.463 
TGA, heterotaxy syndrome, and discordant atrioventricular connections 475 1.3 0.362 
Cardiac neural crest defects and double outlet right ventricle without ventricular hypoplasia 537 1.8 0.014 

aSubcategories of CHD with less than 100 cases are not shown.

bComparison of the proportion of children/foetuses conceived after ART between the subcategory of CHD and the controls.

The subcategories of CHD comprised from 124 to 2248 cases (Table 2; subcategories of CHD with less than 100 cases are not shown—detailed data available from authors). The largest subcategory was the VSD (n= 2248) representing nearly 40% of all cases. The subcategory malformations of the outflow tracts and ventriculoarterial connections was the second largest subcategory and comprised 1088 cases.

After excluding controls with missing data for ART (3.5% of controls), the study population included a total of 3847 malformed controls, comprising isolated congenital hip dislocation (n= 1299), polydactyly (n= 769), club foot (n= 733), angioma (n= 515), skin abnormality (n= 367), or syndactyly (n= 164).

Maternal age was missing for 35 (0.6%) cases and 23 (0.6%) controls. Data on maternal geographic origin were missing for 1.7% of the cases and 2.1% of the controls, and information on maternal occupation was missing for 7.9% of the cases and 3.1% of the controls.

Most socio-demographic characteristics were different between cases and controls. Mothers of cases were older, less often of French origin, and were more likely to be in the occupational category ‘none' than mothers of controls. On the other hand, mothers who had conceived following ART were more likely to be of French origin and to be in the occupational category ‘professional' (highest category) than mothers who had conceived spontaneously (detailed results not shown; available from authors).

Risk of congenital heart defects associated with assisted reproductive technologies

Table 2 shows the proportions of cases and controls that were exposed to ART. Overall, CHD cases were more likely to have been conceived following ART when compared with controls (4.7 vs. 3.6%, respectively, P= 0.008). Exposure to the different methods of ART was also significantly different between cases and controls (P= 0.013); in particular, 1.9% of the cases were born following IVF vs. 1.3% of the controls and 0.6% of the cases were born following ICSI vs. 0.3% of the controls.

Table 3 shows the crude and adjusted associations between the overall risk of CHD and ART (all methods combined). Exposure to ART was associated with a 1.3-fold increase in the maternal age, socioeconomic factors, and year of birth-adjusted odds of all CHD (adjusted OR 1.3, 95% CI 1.0–1.6). For CHD without chromosomal abnormalities and CHD without chromosomal abnormalities and excluding isolated VSD, estimates were comparable to (slightly higher than) those observed for all CHD (adjusted OR 1.4, 95% CI 1.1–1.7 and adjusted OR 1.5, 95% CI 1.1–1.9, respectively).

Table 3

Logistic regression analyses of the associations between assisted reproductive technologies (all methods combined) and congenital heart defects

 Cases Crude ORa 95% CI Adjustedb ORa 95% CI 
All All CHD 1.0 Ref. 1.0 Ref. 
1.3 1.1–1.6 1.3 1.0–1.6 
CHD without chromosomal abnormalities 1.0 Ref. 1.0 Ref. 
1.4 1.1–1.7 1.4 1.1–1.7 
CHD without chromosomal abnormalities and excluding VSD 1.0 Ref. 1.0 Ref. 
1.4 1.1–1.8 1.5 1.1–1.9 

 
Singletons only All CHD 1.0 Ref. 1.0 Ref. 
1.1 0.8–1.5 1.1 0.8–1.5 
CHD without chromosomal abnormalities 1.0 Ref. 1.0 Ref. 
1.1 0.8–1.5 1.2 0.9–1.6 
CHD without chromosomal abnormalities and excluding VSD 1.0 Ref. 1.0 Ref. 
1.1 0.8–1.5 1.2 0.8–1.6 
 Cases Crude ORa 95% CI Adjustedb ORa 95% CI 
All All CHD 1.0 Ref. 1.0 Ref. 
1.3 1.1–1.6 1.3 1.0–1.6 
CHD without chromosomal abnormalities 1.0 Ref. 1.0 Ref. 
1.4 1.1–1.7 1.4 1.1–1.7 
CHD without chromosomal abnormalities and excluding VSD 1.0 Ref. 1.0 Ref. 
1.4 1.1–1.8 1.5 1.1–1.9 

 
Singletons only All CHD 1.0 Ref. 1.0 Ref. 
1.1 0.8–1.5 1.1 0.8–1.5 
CHD without chromosomal abnormalities 1.0 Ref. 1.0 Ref. 
1.1 0.8–1.5 1.2 0.9–1.6 
CHD without chromosomal abnormalities and excluding VSD 1.0 Ref. 1.0 Ref. 
1.1 0.8–1.5 1.2 0.8–1.6 

aOdds ratios represent the odds of a birth (including live births, stillbirths, and pregnancy terminations) with congenital heart disease (cases) relative to the odds of a birth with one of the malformed controls (see the Methods section for details).

bAdjusted for maternal age, geographic origin, occupation, and year of birth.

Table 4 shows the crude and adjusted ORs between the risk of CHD and the different methods of ART. The adjusted ORs for IVF and ICSI were similar and the combined IVF + ICSI exposure was associated with a 1.4-fold increase in the odds of CHD (adjusted OR 1.4, 95% CI 1.0–2.9). The combined IVF + ICSI exposure was also associated with a 1.5-fold increase in the odds of CHD without chromosomal abnormalities (adjusted OR 1.5 95% CI 1.1–2.1) and a 1.7-fold increase in the odds of CHD without chromosomal abnormalities and excluding VSD (adjusted OR 1.7 95% CI 1.2–2.4). In contrast, we did not find any statistically significant association between IO and CHD with or without chromosomal abnormalities.

Table 4

Logistic regression analyses of the associations between different methods of assisted reproductive technologies and congenital heart defects

Cases method of ART crude ORa 95% CI adjustedb ORa 95% CI 
All      
 All CHD None 1.0 Ref. 1.0 Ref. 
Inductors of ovulation only 1.1 0.8–1.5 1.2 0.9–1.6 
IVF 1.4 1.0–2.0 1.4 1.0–2.0 
ICSI 2.3 1.1–4.4 1.4 0.7–2.7 
IVF + ICSI 1.6 1.2–2.1 1.4 1.0–1.9 
 CHD without chromosomal abnormalities None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 1.2 0.9–1.6 1.2 0.9–1.7 
IVF 1.5 1.1–2.1 1.6 1.1–2.3 
ICSI 2.4 1.2–4.8 1.4 0.7–2.9 
IVF + ICSI 1.7 1.2–2.3 1.5 1.1–2.1 
 CHD without chromosomal abnormalities and excluding VSD None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 1.1 0.8–1.6 1.3 0.9–1.8 
IVF 1.6 1.1–2.3 1.7 1.2–2.6 
ICSI 2.5 1.2–5.2 1.5 0.7–3.2 
IVF + ICSI 1.7 1.3–2.4 1.7 1.2–2.4 

 
Singletons only 
 All CHD None 1.0 Ref. 1.0 Ref. 
Inductors of ovulation only 0.9 0.6–1.4 1.0 0.7–1.5 
IVF 1.4 0.8–2.4 1.2 0.7–2.1 
ICSI 1.4 0.6–3.2 1.2 0.5–2.7 
IVF+ICSI 1.4 0.9–2.2 1.2 0.8–1.9 
 CHD without chromosomal abnormalities None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 1.0 0.7–1.4 1.1 0.7–1.6 
IVF 1.4 0.8–2.4 1.3 0.7–2.3 
ICSI 1.5 0.6–3.4 1.3 0.5–3.0 
IVF + ICSI 1.4 0.9–2.2 1.3 0.8–2.1 
 CHD without chromosomal abnormalities and excluding VSD None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 0.8 0.6–1.3 1.0 0.7–1.6 
IVF 1.4 0.8–2.5 1.5 0.8–2.7 
ICSI 1.4 0.6–3.4 1.2 0.5–3.1 
IVF + ICSI 1.4 0.9–2.3 1.4 0.8–2.3 
Cases method of ART crude ORa 95% CI adjustedb ORa 95% CI 
All      
 All CHD None 1.0 Ref. 1.0 Ref. 
Inductors of ovulation only 1.1 0.8–1.5 1.2 0.9–1.6 
IVF 1.4 1.0–2.0 1.4 1.0–2.0 
ICSI 2.3 1.1–4.4 1.4 0.7–2.7 
IVF + ICSI 1.6 1.2–2.1 1.4 1.0–1.9 
 CHD without chromosomal abnormalities None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 1.2 0.9–1.6 1.2 0.9–1.7 
IVF 1.5 1.1–2.1 1.6 1.1–2.3 
ICSI 2.4 1.2–4.8 1.4 0.7–2.9 
IVF + ICSI 1.7 1.2–2.3 1.5 1.1–2.1 
 CHD without chromosomal abnormalities and excluding VSD None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 1.1 0.8–1.6 1.3 0.9–1.8 
IVF 1.6 1.1–2.3 1.7 1.2–2.6 
ICSI 2.5 1.2–5.2 1.5 0.7–3.2 
IVF + ICSI 1.7 1.3–2.4 1.7 1.2–2.4 

 
Singletons only 
 All CHD None 1.0 Ref. 1.0 Ref. 
Inductors of ovulation only 0.9 0.6–1.4 1.0 0.7–1.5 
IVF 1.4 0.8–2.4 1.2 0.7–2.1 
ICSI 1.4 0.6–3.2 1.2 0.5–2.7 
IVF+ICSI 1.4 0.9–2.2 1.2 0.8–1.9 
 CHD without chromosomal abnormalities None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 1.0 0.7–1.4 1.1 0.7–1.6 
IVF 1.4 0.8–2.4 1.3 0.7–2.3 
ICSI 1.5 0.6–3.4 1.3 0.5–3.0 
IVF + ICSI 1.4 0.9–2.2 1.3 0.8–2.1 
 CHD without chromosomal abnormalities and excluding VSD None 1.0 ref. 1.0 ref. 
Inductors of ovulation only 0.8 0.6–1.3 1.0 0.7–1.6 
IVF 1.4 0.8–2.5 1.5 0.8–2.7 
ICSI 1.4 0.6–3.4 1.2 0.5–3.1 
IVF + ICSI 1.4 0.9–2.3 1.4 0.8–2.3 

aOdds ratios represent the odds of a birth (including live births, stillbirths, and pregnancy terminations) with congenital heart disease (cases) relative to the odds of a birth with one of the malformed controls (see the Methods section for details).

bAdjusted for maternal age, geographic origin, occupation, and year of birth.

When analyses were restricted to singletons, ORs for IVF and ICSI remained >1, but the magnitude of associations decreased and CIs included the null value (Tables 3 and 4). However, test of the interaction effect between ART and singleton/multiple births was not statistically significant (P = 0.67).

Analyses for subcategories of congenital heart defects defined according to anatomo-embryological criteria

Table 5 shows the results of the analyses for the subcategories of CHD. Assisted reproductive technologies were associated with significant increases in the odds of malformations of the outflow tracts and ventriculoarterial connections (adjusted OR 1.7, 95% CI 1.2–2.4) and of cardiac neural crest defects and double outlet right ventricle (adjusted OR 1.7, 95% CI 1.1–2.7).

Table 5

Logistic regression analyses of the associations between assisted reproductive technologies (all methods combined) and subcategories of congenital heart defects

Subcategories Crude ORa 95% CI Adjustedb ORa 95% CI 
Malformations of the outflow tracts and ventriculoarterial connections 1.0 Ref. 1.0 Ref. 
1.6 1.2–2.2 1.7 1.2–2.4 
Malformations of the atrioventricular valves and atrioventricular connections 1.0 Ref. 1.0 Ref. 
0.7 0.4–1.2 0.6 0.4–1.2 
Functionally univentricular CHD 1.0 Ref. 1.0 Ref. 
0.7 0.4–1.3 0.6 0.3–1.3 
Anomalies of the great arteries 1.0 Ref. 1.0 Ref. 
1.3 0.8–2.2 1.3 0.8–2.3 
Ventricular septal defects 1.0 Ref. 1.0 Ref. 
1.4 1.1–1.8 1.3 1.0–1.6 
Anomalies of the atria and interatrial communications 1.0 Ref. 1.0 Ref. 
1.4 0.6–3.2 2.0 0.8–5.0 
TGA, heterotaxy syndrome, and discordant atrioventricular connections 1.0 Ref. 1.0 Ref. 
1.2 0.8–2.0 1.3 0.8–2.3 
Cardiac neural crest defects and double outlet right ventricle without ventricular hypoplasia 1.0 Ref. 1.0 Ref. 
1.6 1.1–2.5 1.7 1.1–2.7 
Subcategories Crude ORa 95% CI Adjustedb ORa 95% CI 
Malformations of the outflow tracts and ventriculoarterial connections 1.0 Ref. 1.0 Ref. 
1.6 1.2–2.2 1.7 1.2–2.4 
Malformations of the atrioventricular valves and atrioventricular connections 1.0 Ref. 1.0 Ref. 
0.7 0.4–1.2 0.6 0.4–1.2 
Functionally univentricular CHD 1.0 Ref. 1.0 Ref. 
0.7 0.4–1.3 0.6 0.3–1.3 
Anomalies of the great arteries 1.0 Ref. 1.0 Ref. 
1.3 0.8–2.2 1.3 0.8–2.3 
Ventricular septal defects 1.0 Ref. 1.0 Ref. 
1.4 1.1–1.8 1.3 1.0–1.6 
Anomalies of the atria and interatrial communications 1.0 Ref. 1.0 Ref. 
1.4 0.6–3.2 2.0 0.8–5.0 
TGA, heterotaxy syndrome, and discordant atrioventricular connections 1.0 Ref. 1.0 Ref. 
1.2 0.8–2.0 1.3 0.8–2.3 
Cardiac neural crest defects and double outlet right ventricle without ventricular hypoplasia 1.0 Ref. 1.0 Ref. 
1.6 1.1–2.5 1.7 1.1–2.7 

aOdds ratios represent the odds of a birth (including live births, stillbirths, and pregnancy terminations) with congenital heart disease (cases) relative to the odds of a birth with one of the malformed controls (see the Methods section for details).

bAdjusted for maternal age, geographic origin, occupation, and year of birth.

The adjusted ORs for ICSI were in general similar to those for IVF except for the subcategories malformations of atrioventricular valves and atrioventricular connections, functionally univentricular CHD and transposition of the great arteries (TGA), heterotaxy syndrome, and discordant atrioventricular connection. The combined IVF + ICSI category was associated with a 1.8-fold increase in the odds of malformations of the outflow tracts and ventriculoarterial connections (adjusted OR 1.7 95% CI 1.1–2.8) and a 1.8-fold increase in the odds of cardiac neural crest defects and double outlet right ventricle without ventricular hypoplasia (adjusted OR 1.8 95% CI 1.0–3.3). IO were associated with a 2.5-fold higher odds of anomalies of atria and interatrial communications (adjusted OR 2.5, 95% CI 0.7–8.7). In general, the estimates of the associations between the different methods of ART and CHD subcategories varied across the different subcategories. However, CIs for smaller subcategories were wide, reflecting the relative imprecision of the estimates (detailed results of the associations between different methods of ART and subcategories of CHD are not shown in the printed version; these results are available from authors/or as Supplementary material online, Table S3).

Discussion

On the basis of data from the Paris Registry of Congenital Malformations including more than 5000 cases of CHD, we found a 40% increase in the overall risk of CHD without chromosomal abnormalities in children conceived following ART after taking into account maternal age, socioeconomic factors, and year of birth. Our results also suggest that specific associations exist between ART and subcategories of CHD. Moreover, although IVF and ICSI were associated with significant increases in the risk of CHD, we did not find a significant association between IO and the overall risk of CHD.

When analyses were restricted to singletons only, the ORs decreased and the CIs included the null value. This suggests that any effect of ART on CHD may be in part due to multiple births. On the other hand, test of the interaction effect between ART and singletons/multiple was not statistically significant, although this may have been due to limited power of our study for detecting any interaction effects that may have existed. In any case, it is certainly possible that multiple births may be on the causal pathway between ART and CHD. This hypothesis is consistent with Reefhuis's26 finding that ‘multiple births were more likely to have birth defects, regardless of conception mode'. It should be noted however that the public health impact of ART on the risk for birth defects includes all (singleton and multiple) births.

On the basis of our findings, we calculated attributable risk fractions, which would represent the proportion of cases that may be caused by ART, or equivalently, the proportion of cases that would be avoided were the exposure to ART removed ceteris paribus, ‘if' the associations we found between the risk of CHD and ART can be assumed to represent causal relations (this may of course not be the case for reasons that are discussed further below). The attributable risk fraction estimates suggest in particular that around 2% of the CHD without chromosomal abnormalities may be caused by ART and 1.2% by IVF + ICSI. These proportions are similar to those calculated for certain other major risk factors of CHD34 and may increase as exposure to ART is likely to increase over time.

To our knowledge, there are no embryological or physiopathological hypotheses to explain the specific associations between ART and the subcategories of CHD that we found in our study. In particular, genomic imprinting disorders found in children born after ART35 seem unlikely to explain all of the observed associations. Moreover, our results for CHD without chromosomal abnormalities suggest that associations between CHD and ART are not due to the association of the latter with chromosomal abnormalities. Our results may be helpful for generating hypotheses regarding underlying mechanisms for the association between the risk of CHD and different methods of ART.

Our study has certain limitations. Although our study included a large number of cases of CHD, exposure to ART, and particularly to ICSI, remains infrequent in the general population and in our Registry data. Consequently, the CIs for the estimates of the associations between subcategories of CHD and IVF and more so ICSI were wide, indicating the limited precision of some of our estimates.

Moreover, we made no adjustment for multiple comparisons in analysing the associations between the a priori chosen subcategories of CHD and ART. Although this is consistent with the recommendations by Rothman32 and Savitz and Olshan33 in the case of observational studies, such as ours, aimed at detecting patterns of specific associations, controversies remain among experts as to the right statistical approach to multiple comparisons. In any case, the specific associations we found can only be considered exploratory and need to be further investigated.

The choice of malformed controls may have been a source of selection bias36,37 due to associations that may exist between exposure to ART and malformations included as controls. In order to minimize such bias, following Hook's recommendations,28 we selected a wide spectrum of malformations for which no associations with ART were described in the literature. This methodology is often used in the field of birth defects38 and in particular in assessing the teratogenic effects of medications.39,40

Although this approach of choosing a heterogeneous group of malformations as controls can lower the risk of selection bias by diluting any effects due to unknown (i.e. hitherto unreported in the literature) associations that may exist between ART and one or more of the malformations selected as controls, the possibility of residual bias cannot be excluded. This bias may result in an underestimation of the true association (i.e. what one would observe with an ideal set of non-malformed controls) between ART and CHD if ART is associated with an increase in the risk of the malformations included as controls. Conversely, the overestimation of the associations between ART and CHD can occur if ART is associated with a decrease in the risk of malformations included as controls, although such an association seems unlikely. Moreover, a differential misclassification bias for exposure assessment cannot be excluded if exposure to ART is ascertained in a different way in the case of CHD compared with the malformations included as controls. However, we are not aware of any a priori reason or empirical evidence to suggest that such a bias may exist for ART.

The frequency of missing data on exposure was different between cases and controls. This may have resulted in biased (over or under) estimates of the associations between CHD and ART if the distribution of exposure was different between subjects with complete data and those with missing data. Nevertheless, the overall frequency of missing data in this study was low and we have no reason to believe that the distribution of exposure was indeed different for cases and controls with missing data.

We explored specific associations that may exist between different types of CHD and ART by conducting separate analyses for subcategories of CHD defined a priori based on anatomic and/or embryological criteria. An important caveat that needs to be considered is that our criteria for defining these subcategories can be arguable; alternative and equally, if not more, valid subcategories may be envisaged. Notwithstanding these considerations, our results suggest that indeed specific associations may exist between ART and risk of specific CHD subcategories, without necessarily implying that the subcategories investigated in our study are the most appropriate ones to use in this setting.

Another potential limit of our study is related to the effects of possible confounding factors that could not be taken into account.41 In particular, we did not have adequate data for folic acid and/or multivitamins intake for women in our population. Lack of adjustment for multivitamins use could have resulted in an underestimation of the risks associated with ART as: (i) multivitamins/folic acid intake has been shown to be associated with a lower risk of CHD42 and (ii) a higher proportion of women who conceived after ART may have had an adequate multivitamins/folic acid intake.26

Another potentially important confounding variable that we could not adjust for was paternal age. As paternal age is correlated with maternal age, we partially adjusted for paternal age by taking maternal age into account. Nevertheless, lack of full adjustment for paternal age may have resulted in an overestimation of risks, particularly for ICSI that is used more often, although not exclusively, in the case of male infertility.8

More broadly, in the association between ART and CHD, the question of the role of underlying infertility vs. that of any treatment effects of ART per se remains an open one.14,16,17,43 Some studies have attempted to separate the effects of underlying infertility from any treatment effects due to ART by adjusting for the duration of infertility/involuntary childlessness.17 This strategy has been criticized by Hansen et al.19 as this variable may be ‘synonymous with exposure'. This is consistent with the data from our Registry in which 99% of the cases/controls with exposure to ART had a duration of infertility of 2 years or more.

Although for most subcategories of CHD the associations between IVF and ICSI were similar, our findings suggest that ICSI may be associated with a higher risk for some subcategories of CHD when compared with conventional IVF. However, CIs for the estimates of the risks associated with ICSI for subcategories of CHD were wide. Hence, while suggestive, our results cannot lead to a definitive conclusion regarding higher risks due to ICSI vs. IVF for certain subcategories of CHD.

In conclusion, we found that cases with CHD were more likely to have been conceived following ART when compared with malformed controls. In particular, IVF and ICSI were associated with a 1.5-fold increase in the odds of CHD without chromosomal abnormalities after adjustment for year of birth, maternal age, occupation, and geographic origin. In contrast, we did not find a significant association between IO (alone) and the overall risk of CHD. In general, estimates suggested that there may be specific associations between different methods of ART and subcategories of CHD classified based on anatomo-embryological criteria. Such specific associations may reflect causal effects due to ART and/or the underlying infertility of couples who conceive following ART.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

This work was supported in part by grants from the Assistance Publique—Hôpitaux de Paris Fonds d'Etude et de Recherche du Corps Médical (Paris, France) (to K.T.) and the Agence de Biomédecine (Saint-Denis La Plaine, France) (to B.K.). The Paris Registry of Congenital Malformations received financial support from INSERM (Paris, France) and the Institut de Veille Sanitaire (Saint-Maurice, France).

Conflict of interest: none declared.

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Gaynor
JW
Krogmann
ON
Kurosawa
H
Maruszewski
B
Stellin
G
Elliott
MJ
The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy
Cardiol Young
 , 
2007
, vol. 
17
 
Suppl. 2
(pg. 
1
-
28
)

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