In Utero Azathioprine Exposure and Increased Utilization of Special Educational Services in Children Born to Mothers With Systemic Lupus Erythematosus

Abstract

Objective Azathioprine (AZA) is recognized among immunosuppressive medications as relatively safe during pregnancy for women with systemic lupus erythematosus (SLE) requiring aggressive treatment. This pilot study aimed to determine whether SLE therapy during pregnancy was associated with developmental delays in offspring. Methods This cohort study included SLE patients with at least one live birth post-diagnosis. Medical histories were obtained via interviews and chart review. Multiple logistic regression was used to examine associations between SLE therapy during pregnancy and maternal report of special educational (SE) requirements (as proxy for developmental delays) among offspring. Propensity scoring (incorporating corticosteroid use, lupus flare, and lupus nephritis) was used to account for disease severity. Results Of 60 eligible offspring from 38 mothers, 15 required SE services, the most common indication for which was speech delay. 7 of the 13 (54%) children with in utero AZA exposure utilized SE services versus 8 of 47 (17%) non-exposed (p<0.05). After adjustment for pregnancy duration, small for gestational age, propensity score, maternal education and antiphospholipid antibody syndrome, AZA was significantly associated with SE utilization occurring from age 2 onward (OR 6.6, 95% CI 1.0, 43.3), and bordered significance for utilization at any age or age <2 years. Conclusions AZA exposure during SLE pregnancy was independently associated with increased SE utilization in offspring, after controlling for confounders. Further research is indicated to fully characterize developmental outcomes among offspring with in utero AZA exposure. Vigilance and early interventions for suspected developmental delays among exposed offspring may be warranted.

Pregnancy and autoimmune connective tissue diseases

“…Potential rare side effects in the newborn may include transient hypogammaglobulinemia and pancytopenias, which tend to normalize within 10 weeks of birth [120–124]; a complete blood count in newborns and vigilance for neonatal infection after in utero AZA exposure has been recommended by some [116,117]. Recent data also suggest a potential association with developmental delays in offspring [125], which warrants vigilance in the pediatric setting given the clear benefit of early interventions. It should be emphasized that given strong evidence that active maternal disease is associated with adverse maternal and fetal outcomes, the benefits of AZA treatment outweigh potential risks, and this medication should not be withheld during pregnancy.…”

Azathioprine during pregnancy in systemic lupus erythematosus patients is not associated with poor fetal outcome

“…In fact, a recent study found an increase in the use of special educational services, particularly those for delayed speech, in the offspring of mothers who took this drug during pregnancy [26]. These findings suggest the need for a longterm follow-up of infants whose mothers take azathioprine during pregnancy.…”

Managing lupus patients during pregnancy

“…The dose should be limited to maximum of 2mg/kg/day, to avoid risk of fetal cytopenias and immune suppression [38]. An association between maternal azathioprine therapy during pregnancy and late developmental delays in offspring was suggested by a recent study [47]. However, the confidence intervals were very wide and the study had serious limitations (small sample size, retrospective nature, lack of validated measures).…”