Subfertility and congenital anomalies: a systematic review and meta-analysis

Importance Fertility treatments have been associated with increased risks of adverse birth outcomes, including congenital anomalies. However, confounding by indication related to underlying infertility independent of fertility treatment has not been consistently accounted for in previous meta-analyses. Objective Fertility treatments have been associated with increased risks of adverse birth outcomes, including congenital anomalies. However, confounding by indication related to underlying infertility independent of fertility treatment has not been consistently accounted for in previous meta-analyses. This systematic review and meta-analysis aimed to quantify the association between subfertility and risk of congenital anomalies compared to unassisted conception. Evidence Review A systematic search of English-language studies was performed on OVID MEDLINE, Embase, and PubMed databases for studies published from earliest availability to June 30, 2025. Search terms included combinations of the following medical subject headings and keywords: congenital anomalies, subfertility, and fertility treatment. Results Of 2,778 unique records identified, 23 studies met inclusion criteria, representing 9,355,843 infants. Thirteen studies contributed to the meta-analysis of any anomaly, five studies to major anomalies, and two to five studies to specific anomalies. Compared to unassisted conception, offspring of women with subfertility had slightly higher odds of any congenital anomaly (OR 1.19; 95% CI, 1.14–1.24) and major anomalies (OR 1.08; 95% CI, 0.99–1.17). Among the few studies that assessed specific anomalies, higher odds of gastrointestinal anomalies (OR 1.31, 95% CI 1.13–1.50) and cleft anomalies (OR 1.24; 95% CI, 1.05–1.47) were observed. There was no evidence of publication bias. Conclusions and relevance Subfertility was associated with higher odds of congenital anomalies, including major and select organ-system and specific anomalies. These findings support the use of a subfertile comparator groups when evaluating the safety of assisted reproductive technologies to reduce confounding from infertility.