Safety of Live-Attenuated Vaccines in Children Exposed to Biologic Response Modifiers in Utero

Biological response modifiers (BRM), also known as immunomodulators or cytokine inhibitors, are immunosuppressive substances that are increasingly being used to treat various autoimmune diseases,1 including during pregnancy. Some BRM are actively transported across the placenta barrier and can remain in infants for up to 12 months after birth,2,3 raising concerns that infants exposed to BRM in utero may be at increased risk of infections and adverse events after immunization with live attenuated vaccines.We conducted a retrospective cohort study among children born 2006 to 2017 at 6 sites within the Vaccine Safety Datalink (VSD), a collaboration between the Centers for Disease Control and Prevention (CDC) and 9 integrated health care systems across the United States.4 We compared clinical outcomes (neutropenia, immune thrombocytopenia, pneumonia, rotavirus, varicella, pertussis, and measles infections during the first 6 months and 12 months of life), live-attenuated vaccination coverage (measles-containing vaccine [MCV] and rotavirus vaccines), and adverse events of special interest (AESI) in children exposed and unexposed in utero to BRM. AESI included fever, febrile seizure, cerebellar ataxia, hepatitis, pneumonitis, acute disseminated encephalomyelitis, encephalitis, myelitis, diarrhea, bloody stool, and vomiting during prespecified risk intervals. Outcomes were identified using International Classification of Disease codes, ninth or 10th revision, in outpatient, emergency department or inpatient setting.Maternal BRM use was based on dispensed medication, or a prescription recorded in electronic health records 30 days before pregnancy onset through the pregnancy outcome date.The study was approved by the institutional review board at each VSD site and CDC.Among 582 759 infants who remained a VSD member for at least 6 months after birth, 960 (16 per 10 000) were exposed to BRM in utero. BRM use during pregnancy varied by year (Supplemental Figure 1). The most frequently prescribed BRM were etanercept, anakinra, adalimumab, and infliximab (Supplemental Table 3).The proportions of clinical outcomes diagnosed in any setting were small (0% to 4%) and similar among in-utero BRM-exposed and unexposed children (Supplemental Table 4).MCV uptake in the first 24 months of life was higher among BRM-exposed than unexposed children (87.06% vs 83.71%; adjusted odds ratio [OR] = 1.30, 95% confidence interval [CI] 1.10 to 1.69). However, receipt of the recommended number of doses of rotavirus vaccines in the first year of life was lower among BRM-exposed than among unexposed children (81.00% vs 85.20%, adjusted OR = 0.74, 95% CI 0.61 to 0.90: Supplemental Table 5).AESI after MCV or rotavirus vaccines were similarly rare between BRM-exposed and unexposed children. After receipt of a MCV, there were no cases of febrile seizure, cerebellar ataxia, hepatitis, pneumonitis, acute disseminated encephalomyelitis or encephalitis and myelitis during the risk intervals among children exposed to BRM in utero (Table 1). After rotavirus vaccination, diagnoses of diarrhea (54 per 10 000 vs 44 per 10 000), bloody stool (11 per 10 000 vs 15 per 10 000), and vomiting (32.3 per 10 000 vs 45.7 per 10 000) were similar between children exposed and unexposed to BRM, respectively, and there were no cases of intussusception or encephalitis, myelitis, or encephalomyelitis among children exposed to BRM (Table 2).In this multisite study, we found that children exposed in utero to BRM who received live-attenuated rotavirus vaccine in their first year or MCV during their first 24 months were not at increased risk of prespecified adverse events compared to unexposed children. Children exposed to BRMs were also less likely to have received all recommended doses of rotavirus vaccine compared to unexposed children. Our results, combined with those of previous studies,5,6 provide reassuring evidence that live-attenuated rotavirus and measles-containing vaccines can be given to infants exposed to BRM in utero.7–10Our study was strengthened by use of electronic health record data to define exposure and outcomes rather than self-reported data. However, the study was limited by the inability to assess outcomes by trimester of BRM exposure because the outcomes of interest were rare and sample size was small. Additional limitations include the inability to adjust for maternal autoimmune disease severity, and possible misclassification of BRM orders or prescriptions that could not be confirmed as actually used.Our data provide some reassurance to parents and pediatricians regarding live-attenuated vaccines for children exposed to BRM in utero. Professional societies may want to consider reevaluating their live-attenuated vaccines recommendations for these children as new safety data accumulates.