Assisted Reproductive Technology And Birth Defects In A Prospective Cohort Study

【Background】 At present,assisted reproductive technology(ART)has evolved into the most effective treatment for thousands of families struggling with infertility,and the proportion of births after ART in mainland China was over 1%.With rapid development and its wide application of ART in clinical practice,more and more researchers begin to pay attention to whether these exogenous exposures including increased exogenous hormones,gamete operations,repeated ultrasounds and embryos freeze-thaw,as well as couple’s subfertility will have an impact on the health of ART population and their offspring and even the next generation.Emerging population studies suggest that in vitro fertilization and embryo transfer(IVF-ET)increases the risk of adverse perinatal outcomes,including birth defects.Birth defects have seriously affected the health and the quality of children,which have become an important public health issue.Categories of birth defect are diverse,and these birth defects currently without known etiology may result from parental or embryonic genetic factors,environmental exposures during pregnancy and the gene-environmental interactions.The characteristics of the infertile couples and various exposure factors in the ART process may affect the development of gametes and embryos,leading to the occurrence of birth defects in offspring.Although several systematic reviews have shown a significant increase in the risk of birth defects in infants after ART treatment,especially in singletons,we are still faced with challenges to make the assosiation clear.First of all,previous studies paid more attention to birth defects after birth and ignored prenatal screening and terminations of pregnancy due to birth defects,which could thus underestimate the rate of birth defects.Secondly,the definition and classification of birth defects in previous studies were confusing,and more attention was paid to major birth defects other than functional abnormalities.Thirdly,previous studies mostly included case-control studies or hospital-based retrospective cohort studies,but few prospective cohort studies have conducted to integrate all data sources and follow-up at various timing simultaneously,which can improve the detection rate and accuracy of birth defects,thereby improving the diagnosis and treatment of birth defects.Finally,the risk of birth defects in ART offspring could not be distinguished from the influence of parental characteristics relate to sterility and specific ART procedures,and to which extent the impact of ART on the risk of birth defects mediated by multiple births is less clear.The Jiangsu Birth Cohort Study is a large prospective and longitudinal population-based epidemiological study,which was conducted to elucidate heterogeneity between ART-conceived and spontaneous-conceived pregnancies regarding to their birth outcomes and pregnancy complications,and to systematically evaluate how clinical,environmental and genetic factors may influence the outcomes.Of note,present findings on this topic are primarily from researches conducted outside of China,and the prevalence of birth defects among ART pregnancies in China is sparsely studied.Given that many factors are potentially underlying the associations between ART use and birth defects,including parental characteristics relate to sterility and specific ART procedures,sufficient and accurate information collections are needed to evaluate the associations with comprehensive considerations of possible influencing factors.Therefore,we were based on the large prospective Jiangsu Birth Cohort to assess the prevalence of birth defects among births conceived using ART compared with their non-ART counterparts in China,and to investigate the risk of birth defects associated with different parental infertility diagnoses,and with specific ART procedures among ART-conceived births.【Method】 We conducted this prospective study within the Jiangsu Birth Cohort Study,we included all women who had pregnancies up to 20 weeks’ gestation(1825 ART-and 3483 spontaneous-pregnancies)between August 2016 and May 2019.We collected the exposure variables related to these infertility diagnoses and ART treatments by searching the clinical reproduction medicine management system.Birth outcomes were obtained by using hospital information system and birth registration system;Diagnoses of birth defects at each follow-up were obtained from hospital information system-inpatient system,hospital birth registration system,provincial birth defect registration system,provincial perinatal database,etc..Birth defects were coded and categorized into 13 subgroups according to the International Classification of Diseases,10 th edition(ICD-10 codes),including nervous system malformations,eye,ear,face and neck malformations,circulatory system malformations,respiratory system malformations,cleft lip and cleft palate,digestive system malformations,genital organs malformations,urinary system malformations,musculoskeletal system malformations,chromosomal abnormalities,metabolic abnormalities,hematologic abnormalities and other birth defects.Birth defects assessed in this study included both major and minor defects.We collected baseline and pregnancy information by on-site questionnaire follow-ups,hospital electronic medical record collection,and telephone follow-ups.Strict quality controls within the Jiangsu birth cohort and during the implementation of this study are the prerequisites to ensure the credibility of our results.We compared the distribution of maternal and offspring characteristics for all included ART pregnancies and natural pregnancies in this study.We assessed the prevalence of birth defects in infants who were ART-conceived and those who were naturally conceived,and analyzed the association between the use of ART and the risk of birth defects diagnosed prenatally,by 7 days after delivery,by 6 months and 1 year old after delivery.Risk ratio(RRs)and 95% confidence intervals(CIs)were calculated with the use of logistic generalized estimating equations.Stratification analyses were conducted according to plurity,organ system and severity of birth defects.In children conceived by ART,we investigated the risk of birth defects associated with parental infertility diagnosis characteristics,and with specific ART procedures among ART-conceived births after adjustment for maternal age,parity,maternal pre-pregnancy BMI,diseases during pregnancy(diabetes and hypertension).When maternal characteristics and potential influencing factors were considered,multivariable logistic regression analysis was used to assess the independent effects of specific ART characteristics on birth defects.To assess the possible role of multiple births in the association between ART and birth defects,we assessed potential mediation effect of twin status using methods published by Valeri and Vander Weele.As birth defects of circulatory system account for the largest proportion of all birth defects,we also conducted the above association analyses and mediation analysis for circulatory system malformations.Finally,the heterogeneity P values were calculated to compare the differences in the association between birth defects diagnosed within 7 days of birth and those diagnosed after 7 days of birth with ART-related characteristics.【Results】A total of 1,790 ART-and 3,400 spontaneous-pregnancies were included in final analysis.We found the general characteristics of other pregnant women were significantly different between ART-and spontaneous-pregnancies except for tobacco use during pregnancy.24.6% of ART treated women and 1.0% of non-ART women were pregnant with twins.When stratified by plurality,the frequencies of adverse birth outcomes were more in ART singletons,while ART twins were only found more likely to be born before term.Our results showed that the prevalence of birth defects of the fetes conceived by ART and naturally conceived fetes were 2.2% vs.1.2% at prenatal,4.9% vs.2.9% by 7 days after birth,10.4% vs.5.3% by 6 months,and 13.9% vs.7.0% by 1 year after delivery.The cumulative rate of birth defects gradually increased,and the similarly robust risk was observed associated with ART at each follow-up.When restricted to singleton births,those conceived with ART were 1.85-fold(1.38-2.48)as likely as naturally conceived births to have 1 or multiple birth defects diagnosed by one year old.In contrast,an inverse but insignificant pattern was observed in twins.Stratified by severity of conditions,ART use increased major birth defects,while regarding to minor defects,we did not find significant association until 6 months after birth.Children born to parents with the 6 infertility diagnoses including polycystic ovary syndrome(PCOS),ovarian dysfunction,infertility due to pelvic or tubal factor,uterine factor,thyroid factor,and due to sperm disorder were all at higher risk of developing birth defects vs.those born to naturally conceived parents,whereas no individual subfertility cause displayed excess risk as compared with other causes.When assessing specific ART procedures,births born to mothers receiving diverse regimens of ovulation induction displayed differential risk of birth defects,with the prevalence of birth defects increased for births born to mothers using regimens of Gn RH antagonist(a RR 1.48,1.05-2.09)and microstimulation(a RR 2.11,1.13-3.93)as compared to those born to mothers using agonist regimen.In the multivariable model,when maternal characteristics and potential influencing factors were considered,regimen of Gn RH antagonist remained significant association with increased risk of birth defects in the ART-births(Multivariable Model: a RR 1.47,1.04-2.07).In the analyses of birth defects by organ system,significant increased risk was detected for the association between ART and circulatory malformations by 1 year of age(7.4% vs.3.7%,P < 0.001 after adjustment by false discovery rate(FDR)).In the multiple logistic regression analysis,only growth hormone use increased the risk of birth defects of the circulatory system,but showed no significant difference(a RR: 2.13,95%CI: 0.97-4.65,P = 0.059).The association between ART and the risk of birth defects was mediated in part by twins,and twin pregnancies after ART explained 31.1% of the relative effect of ART on birth defects and 39.6% on congenital heart disease in our data.In the ART offspring,twin pregnancy mainly increased the risk of birth defects diagnosed after 7 days of birth(mostly minor birth defects)(heterogeneity P < 0.001),and the use of h MG in ovulation induction regimen mainly increased the birth defects diagnosed within 7days of birth(heterogeneity P = 0.028).【Conclusion】This study is a prospective cohort study.These results of long-term synchronous follow-up at different timings suggest that ART use confers an increased risk for birth defects.The risk is partly attributable to infertility characteristics,certain ovulation induction regimen,including Gn RH antagonist regimen and the use of growth hormone.In addition,we demonstrate that the risk of ART use on birth defects is,to some extent,mediated by twinning.Our findings highlight the importance of long-term follow-up of children conceived via ART for health conditions including both major and minor birth defects.In particular,we emphasize close attention to ART women with twin pregnancies,and support the implementation of single embryo transfer and the enhancement of prenatal screening for twins.With the continuous increase in ART use,it is critical to determine the safety of ART approaches,including the number of embryo transfer and the regimen of ovulation induction.Our findings enrich the understanding of ART on the risk of birth defects,provide a theoretical basis for optimizing the selection of assisted program,an evidence-based basis for public health decision-making and are of great significance for drawing more attention to the health of ART offspring in various fields.