In Vitro Fertilization and VACTERL Birth Defects

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Importance: The VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal defects, and limb defects) pattern of birth defects is a complex congenital condition with largely unknown causes. Studies suggest a link between in vitro fertilization (IVF) and birth defects, including VACTERL, but it remains unknown whether IVF has a unique association with VACTERL. Objective: To characterize the association between IVF and VACTERL. Design, Setting, and Participants: This cohort study included 1 555 936 live births in 4 US States (Massachusetts, New York, North Carolina, and Texas) between January 1, 2004, and December 31, 2018. A total of 175 161 births were IVF conceived, and 1 380 775 naturally conceived children were selected as a 10:1 comparison group. Births were linked to IVF cycle data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. Data were analyzed from August 2 to October 30, 2025. Exposures: Method of conception (IVF vs natural) and IVF treatment parameter information. Main Outcomes and Measures: VACTERL, defined as 3 or more of the defects included in the pattern. Multivariable logistic regression models were used to estimate adjusted odds ratios and 95% CIs. Results: A total of 1 555 936 live births were included in the analysis (796 892 males [51.2%]). The naturally conceived group included 1 380 775 children; the IVF-conceived group, 175 161. Approximately half of children were male in both groups, while IVF-conceived children were more often born to older mothers and those with a higher educational level and were from multiple-gestation pregnancies. Two hundred children with VACTERL (41 IVF and 159 non-IVF) were identified. The prevalence of VACTERL among IVF-conceived births was 2.3 (95% CI, 1.7-3.2) per 10 000 live births. After adjusting for demographic, socioeconomic, and pregnancy-related factors, IVF conception was associated with increased odds of VACTERL (adjusted odds ratio, 1.86; 95% CI, 1.16-2.98). Conclusions and Relevance: This population-based prospective cohort study identified an association of IVF with the multiple congenital anomaly pattern VACTERL. Although the absolute risk among live births remains low, these findings highlight the need for further investigations of child health outcomes by method of conception.

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