Background: Hydroxychloroquine (HCQ) is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to HCQ is important both in the context of its ongoing use for rheumatological disorders as well as its potential future use for COVID-19 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for COVID-19 treatment having been negative.
Objective: The study objective was to evaluate the risk of major congenital malformations associated with exposure to HCQ during the first trimester, the period of organogenesis.
Study design: We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2,045 HCQ exposed and 3,198,589 unexposed pregnancies continuously enrolled in their respective insurance program from 3 months before the last menstrual period through at least one month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women with HCQ use during the first trimester versus no use, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (N= 1,867 HCQ exposed; 19,080 unexposed pregnancies). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery, and specific malformation types for which there were at least 5 exposed events: oral clefts, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects.
Results: Overall, 54.8 per 1,000 infants exposed to HCQ were born with a major congenital malformation versus 35.3 per 1,000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% CI, 1.27-1.81). Patient characteristics were balanced in the restricted, propensity score matched cohort. The adjusted relative risk was 1.26 (1.04-1.54); it was 1.33 (1.08-1.65) for a daily dose ≥400mg and 0.95 (0.60-1.50) for <400mg. Among the different malformation groups considered, more substantial increases in the risk for oral clefts, respiratory anomalies and urinary defects were observed, although estimates were imprecise. No pattern of malformations was identified.
Conclusions: Our findings suggest a small increase in the risk of malformations associated with first trimester HCQ use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If HCQ were shown to be effective for COVID-19 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.