A population-based study of the co-occurrence of hypospadias and congenital heart defects among boys conceived with in vitro fertilization†.

study questionIs there an association of co-occurring hypospadias and congenital heart defects (CHD) with method of conception? SUMMARY ANSWER: There is a small excess risk for co-occurring hypospadias and CHD among boys conceived through in vitro fertilization (IVF) not fully explained by other risk factors. WHAT IS KNOWN ALREADY: We previously reported a higher prevalence of major CHDs among boys born with hypospadias. Our previous analyses leveraged 3.7 million pregnancies recorded through birth defect registries in 11 US states but could not evaluate the role of IVF in the risks for these pregnancy outcomes. Simultaneously, in registry data linked to fertility parameters, we observed excess risk for hypospadias and CHD with conception by IVF. The rarity of co-occurring birth defects requires large sample sizes with key information on both IVF treatment parameters and maternal characteristics to differentiate their roles in birth defects. STUDY DESIGN, SIZE, DURATION: We conducted a population-based study of live births in four US states (Massachusetts, New York, North Carolina, and Texas) from 2004 to 2018 and linked to IVF cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS). Information on the treatment cycle included the use of autologous or donor oocytes, fresh or frozen embryos, male infertility diagnosis, and the use of ICSI. Non-IVF births were sampled 10:1 at the time of IVF births. For the purposes of evaluating isolated and co-occurring hypospadias and CHD, our study included 731 838 boys born over the study period. PARTICIPANTS/MATERIALS, SETTING,

methodsState birth defect registries reporting British Pediatric Association codes were used to identify major birth defects. We formed four outcome groups: (i) boys with CHD alone, (ii) boys with hypospadias alone, (iii) boys with both (hypospadias-CHD), and (iv) boys without birth defects (comparison group). We used unadjusted and adjusted logistic regression to associate IVF conception with each outcome group relative to the common comparison group. Adjustments in each outcome model included backward elimination for birth year, plurality, maternal race/ethnicity, age, education, diabetes, hypertension, and parity. We additionally calculated the prevalence of CHD and hypospadias by IVF treatment parameters. MAIN RESULTS AND THE ROLE OF CHANCE: Among 731 838 boys, we identified 267 who had both hypospadias and a major CHD, 65 conceived through IVF and 202 controls. We observed strong unadjusted associations of IVF with hypospadias (OR 1.49, 95% CI 1.37-1.62), CHD (OR 1.64, 95% CI 1.49-1.81), and hypospadias-CHD (OR 2.63, 95% CI 1.39-4.69). The associations of IVF with isolated hypospadias and isolated CHD were attenuated, but not fully explained, after adjustment for key covariates (hypospadias adjusted OR 1.15, 95% CI 1.03-1.28; CHD adjusted OR 1.14, 95% CI 1.003-1.29). The adjusted association of IVF with hypospadias-CHD suggests a stronger association than for either defect alone (OR 2.16, 95% CI 1.17-3.99), and calculating the observed-expected multiplicative effect supports an excess risk for hypospadias-CHD co-occurrence among boys conceived through IVF (observed ratio 1.65 > expected ratio 1). Among boys with hypospadias, 4.4% (95% CI 4.0-4.8) of boys conceived without IVF also had a CHD, whereas 6.9% (95% CI 5.8-8.0) of boys conceived using IVF also had a CHD. We found that prevalence of CHD was highest among boys with the most severe form of hypospadias among those conceived with IVF (14.1% with CHD, 95% CI 5.5-22.6) or naturally conceived (10.8% with CHD, 95% CI 6.6-15.0). Calculating number needed to screen (NNS) suggests that incorporating information on hypospadias and method of conception could allow for targeted CHD screening opportunities (NNS range: 8-99). Description of fertility treatment parameters suggests the prevalence of hypospadias or CHD among boys conceived using frozen embryos (autologous or donor oocytes) is 2.8%, and is 2.7% among boys whose fathers were diagnosed with male infertility. For co-occurring hypospadias-CHD, the prevalence was highest among boys conceived using donor oocytes (both fresh or frozen embryos) and among boys whose fathers were diagnosed with male infertility, though the absolute risk remained low (0.09-0.12%). When further evaluating male infertility by the use of ICSI, we found that ICSI use increased the risk for isolated or co-occurring defects regardless of an underlying diagnosis of male infertility. LIMITATIONS, REASONS FOR CAUTION: Based on the rarity of co-occurring birth defects (0.08% prevalence of hypospadias-CHD among boys conceived using IVF), we were not able to fully evaluate IVF treatment parameters or subfertility for their role in the co-occurrence of hypospadias and CHD. However, we adjusted for maternal characteristics related to both birth defect risks and fertility. We further sought to characterize treatment parameters that warrant follow-up in future studies of health outcomes among children conceived using IVF. WIDER IMPLICATIONS OF THE

findingsThe use of IVF is associated with increased risk for co-occurrence of two of the most common birth defects in boys, hypospadias and CHD, but the absolute risk remains low. Additional investigations of combinations of birth defects, other childhood outcomes in relationship to method of conception, and mechanisms to explain these associations are warranted. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD112081 from the National Institute of Child Health and Human Development, USA (Barbara Luke and Philip Lupo, Multiple Principal Investigators). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any State Departments of Health which contributed data. M.L.E. declares stock/shares from their role as advisor to Swim Club, VSeat, Doveras, Legacy, Illumicell, Hannah, and HisTurn. E.W. is employed by Redshift Technologies, Inc., which is the data vendor for SART, and has received consulting fees from SART. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.