Risk of congenital anomalies among infants of patients with endometriosis: a population-based cohort study

Background — Maternal chronic conditions are implicated as risk factors for congenital anomalies, but few studies have assessed reproductive conditions such as endometriosis. Given the association between endometriosis and infertility requiring fertility treatments, we sought to estimate risks of congenital anomalies in infants of patients with endometriosis and mediation by subfertility and fertility treatments.

Methods — We conducted a population-based study of births in Ontario (Apr. 7, 2006, to Mar. 31, 2021) to identify infants born at 20 weeks’ gestation or later to patients aged 15 to 50 years. We analyzed associations of endometriosis in the patient before conception with congenital anomalies in their infant. We determined the proportion of these associations mediated by subfertility, ovulation induction or intrauterine insemination, and in vitro fertilization or intracytoplasmic sperm injection.

Results — Among 1 460 564 eligible births, 33 619 (2.3%) patients had endometriosis. Congenital anomalies occurred in 2120 (6.3%) infants of patients with endometriosis and 77 094 (5.4%) infants of patients without endometriosis. Endometriosis in the patient was independently associated with a higher risk of any congenital anomaly (adjusted relative risk [RR] 1.16, 95% confidence interval [CI] 1.12 to 1.21). Specific anomalies with the highest associated risks included unspecified cleft palate (adjusted RR 1.52, 95% CI 1.03 to 2.25), hypospadias (adjusted RR 1.47, 95% CI 1.04 to 2.09), and pulmonary artery stenosis (adjusted RR 1.41, 95% CI 1.03 to 1.94). Endometriosis was an independent risk factor for any congenital anomaly, with only 11.0% of the associated risk mediated by in vitro fertilization or intracytoplasmic injection; subfertility, ovulation induction, and intrauterine insemination did not mediate the association between endometriosis and anomalies.

Interpretation — Endometriosis in the patient is associated with small but significantly increased risks of congenital anomalies among offspring, partially mediated by fertility treatment. The potential mechanisms remain to be identified.