Hydroxychloroquine early in pregnancy and risk of birth defects

Abstract

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.

Maternal exposure to hydroxychloroquine and birth defects

“…Among women with rheumatic diseases, medication use, including HCQ, during pregnancy is recommended to decrease the occurrence of flares, as disease flares have been associated with poorer pregnancy outcomes (Clowse et al, 2006 ; Götestam Skorpen et al, 2016 ; Leroux et al, 2015 ). A recent study by Huybrechts et al ( 2020 ) presented a summary of existing literature surrounding HCQ and the risk of birth defects, noting that these studies have been small case series, small cohort studies of exposed pregnancies, and studies without controls. The authors used two large US claims databases to explore HCQ use and the risk of birth defects among 2,045 HCQ‐exposed and 3,198,589 unexposed pregnancies.…”

“…However, concerns about its safety in pregnancy exist given that HCQ crosses the placenta and data on the risks of birth defects associated with HCQ use are sparse (Costedoat‐Chalumeau et al, 2002 ). Though most existing studies have not identified specific signals for safety concerns, a recent cohort study using data from two pharmaceutical claims databases reported an increased risk for any birth defect among women filling prescriptions for HCQ with a daily dose ≥400 mg (Huybrechts et al, 2020 ). While unable to explore the risk of specific birth defects due to the small number of exposed cases, the authors found associations with large groupings of birth defects, including birth defects in the respiratory and urinary tract systems, and oral clefts (Huybrechts et al, 2020 ).…”

“…Though most existing studies have not identified specific signals for safety concerns, a recent cohort study using data from two pharmaceutical claims databases reported an increased risk for any birth defect among women filling prescriptions for HCQ with a daily dose ≥400 mg (Huybrechts et al, 2020 ). While unable to explore the risk of specific birth defects due to the small number of exposed cases, the authors found associations with large groupings of birth defects, including birth defects in the respiratory and urinary tract systems, and oral clefts (Huybrechts et al, 2020 ). We sought to describe all women who reported HCQ use in pregnancy and describe the presence of specific major birth defects in their offspring within two multi‐site, case–control studies of birth defects, the National Birth Defects Prevention Study (NBDPS) and the Slone Epidemiology Center Birth Defects Study (BDS).…”

Bilateral idiopathic club foot in baby of a rheumatoid mother: A rare case report and its management

“…Hence, we are reporting this rare case of bilateral clubfoot in RA's mother. 17 Ventricular septal defects and coarctation of the aorta have been described in babies born to mothers who have received sulfasalazine during pregnancy. However, musculoskeletal abnormalities have not yet been reported as their teratogenicity.…”

COVID-19 and pregnant women – An overview on diagnosis, treatment approach with limitation, and clinical management

“…Huybrechts et al reports quantified the risk of congenital malformations/birth defects related to early pregnancy administered with hydroxychloroquine and its potential use as prophylaxis were notable [76].…”