Increased risk of congenital anomalies after fertility treatment is partially mediated by multiple birth: a population-based cohort study.

study questionTo what extent does multiple birth mediate the association between fertility treatment and congenital anomalies? SUMMARY ANSWER: Multiple birth explained only a modest proportion of the increased risk of congenital anomalies associated with fertility treatment, suggesting that most of the excess risk is independent of multiple birth. WHAT IS KNOWN ALREADY: Fertility treatments have been associated with an increased risk of congenital anomalies. Because fertility treatment also increases the probability of multiple birth, it remains unclear whether the observed increase in congenital anomalies is attributable to treatment itself, multiple gestation, or underlying infertility. STUDY DESIGN, SIZE, DURATION: Population-based cohort study of all live and stillbirths delivered ≥22 weeks' gestation from 2006 to 2021 among women with a history of infertility diagnosis in Ontario, Canada. PARTICIPANTS/MATERIALS, SETTING,

methodsData were obtained from administrative health records routinely collected within a universal healthcare system for epidemiological surveillance. Exposure was defined as (1) infertility without fertility treatment, (2) ovulation induction (OI) or IUI, and (3) IVF or ICSI. Congenital anomalies were categorized as (1) any anomaly, (2) organ system, and (3) specific anomalies. Modified Poisson regression models generated adjusted relative risks (aRR). For statistically significant aRR > 1, causal mediation was used to decompose the total effect into direct and mediated effects to estimate proportion mediated by multiple birth. MAIN RESULTS AND THE ROLE OF CHANCE: There were 274 893 births included in the cohort, of which 229 932 (83.6%) occurred among women with infertility who did not receive fertility treatment, 20 525 (7.5%) after OI/IUI, and 24 536 (8.9%) after IVF/ICSI. Multiple birth rates were 2.3%, 7.2%, and 13.3%, respectively. Compared with infertility without treatment, the aRR of any anomaly was 1.11 (95% CI 1.05-1.17) after OI/IUI and 1.28 (95% CI 1.22-1.34) after IVF/ICSI. Mediation analyses demonstrated that multiple birth accounted for only a minority of the excess risk, although the proportion mediated varied by anomaly type. The greatest mediation was observed for pulmonary artery stenosis, where multiple birth explained 33.9% of the association after OI/IUI and 44.4% after IVF/ICSI. LIMITATIONS, REASONS FOR CAUTION: As with all studies using administrative health data, our findings are subject to potential misclassification of infertility status based on billing codes, particularly when consultations do not reflect a confirmed diagnosis, as well as residual confounding from unmeasured factors. . WIDER IMPLICATIONS OF THE

findingsThis study suggests that multiple birth explains only part of the increased risk of congenital anomalies observed after fertility treatment. While continued efforts to decrease multiple pregnancy remain important, future research should focus on disentangling the contribution of specific infertility diagnoses and treatment-related factors to the risk of congenital anomalies.

fundingThis study was funded by grant MFM-146444 from the Canadian Institutes of Health Research Institute of Human Development, Child & Youth Health, Clinician-Investigator Teams in Obstetrics and Maternal-Fetal Medicine. Bailey Milne received funding for this project from the Queen's University Dean's Doctoral Award. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from ©Canada Post Corporation and Statistics Canada. Parts of this material are based on data and/or information compiled and provided by CIHI, the Ontario Ministry of Health, and the Better Outcomes Registry & Network ('BORN'), part of the Children's Hospital of Eastern Ontario. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. DISCLOSURES: The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.