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).

TABLE 1

Risk of Selected Adverse Events After Measles-containing Vaccine in the First 24 Months of Life Among Children Exposed and Unexposed In Utero to BRM, Vaccine Safety Datalink 2006–2017

Exposed to BRM N = 954Unexposed to BRM N = 578760Exposed Versus Unexposed
OutcomeRisk Intervals (Days)Number of Cases in Risk IntervalPrevalence/10 000 PersonNumber of Cases in Risk IntervalPrevalence/10 000 PersonPrevalence Ratio (95% CI)Risk Difference (95% CI)
Fevera 7–10 10 105.00 (57.00 to 192.00) 5795 100 (98.00 to 103.00) 1.05 (0.56 to 1.94) 5.00 (–65.00 to 75.00) 
Febrile seizurea 7–10 0 (0.00 to 40.00) 240 4.20 (3.70 to 4.70) −4.20 (–10.00 to 1.60) 
Cerebellar ataxiab 1–14 0 (0.00 to 40.00) 120 2.10 (1.70 to 2.50) −2.10 (–7.70 to 3.50) 
 1–42 0 (0.00 to 40.00) 379 6.60 (5.90 to 7.20) –6.60 (–12.50 to -0.70) 
Hepatitisb 1–21 0 (0.00 to 40.00) 0.04 (0.00 to 0.13) −0.03 (–5.30 to 5.30) 
 1–42 0 (0.00 to 40.00) 0.09 (0.04 to 0.20) −0.09 (–5.40 to 5.20) 
Varicella pneumonitisa 1–21 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
 1–42 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
Acute disseminated encephalomyelitisb 3–21 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
 1–42 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
Encephalitis, myelitis, and encephalomyelitisb 3–21 0 (0.00 to 40.00) 0.10 (0.05 to 0.22) −0.10 (–50 to 5.20) 
 1–42 0 (0.00 to 40.00) 12 0.21 (0.12 to 0.36) −0.21 (–50 to 5.20) 
Exposed to BRM N = 954Unexposed to BRM N = 578760Exposed Versus Unexposed
OutcomeRisk Intervals (Days)Number of Cases in Risk IntervalPrevalence/10 000 PersonNumber of Cases in Risk IntervalPrevalence/10 000 PersonPrevalence Ratio (95% CI)Risk Difference (95% CI)
Fevera 7–10 10 105.00 (57.00 to 192.00) 5795 100 (98.00 to 103.00) 1.05 (0.56 to 1.94) 5.00 (–65.00 to 75.00) 
Febrile seizurea 7–10 0 (0.00 to 40.00) 240 4.20 (3.70 to 4.70) −4.20 (–10.00 to 1.60) 
Cerebellar ataxiab 1–14 0 (0.00 to 40.00) 120 2.10 (1.70 to 2.50) −2.10 (–7.70 to 3.50) 
 1–42 0 (0.00 to 40.00) 379 6.60 (5.90 to 7.20) –6.60 (–12.50 to -0.70) 
Hepatitisb 1–21 0 (0.00 to 40.00) 0.04 (0.00 to 0.13) −0.03 (–5.30 to 5.30) 
 1–42 0 (0.00 to 40.00) 0.09 (0.04 to 0.20) −0.09 (–5.40 to 5.20) 
Varicella pneumonitisa 1–21 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
 1–42 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
Acute disseminated encephalomyelitisb 3–21 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
 1–42 0 (0.00 to 40.00) 0 (0.00 to 0.07) — 0 (–0.50 to 5.20) 
Encephalitis, myelitis, and encephalomyelitisb 3–21 0 (0.00 to 40.00) 0.10 (0.05 to 0.22) −0.10 (–50 to 5.20) 
 1–42 0 (0.00 to 40.00) 12 0.21 (0.12 to 0.36) −0.21 (–50 to 5.20) 

—, not estimable.

a

First diagnosed in 30 d in any settings.

b

First time ever.

TABLE 2

Risk of Selected Adverse Events After Rotavirus Vaccine in the First 12 Months of Life Among Children Exposed and Unexposed In Utero to BRM, Vaccine Safety Datalink 2006–2017

Exposed to BRM N = 929Unexposed to BRM N = 623 921Exposed Versus Unexposed
OutcomeRisk Interval (Days)Number of Cases in Risk IntervalPrevalence/10 000 Person (95% CI)Number of Cases in Risk IntervalPrevalence/10 000 Persons (95% CI)Prevalence Ratio (95% CI)Prevalence Difference (95% CI)
Diarrhea 1–14 54.00 (17.00 to 125.00) 2771 44.00 (43.00 to 46.00) 1.20 (0.50 to 2.90) 10.00 (–38.00 to 56.00) 
Bloody stool 1–14 11.00 (0.00 to 60.00) 965 15.00 (14 to 16.00) 0.70 (0.10 to 50) −4.00 (–31.00 to 22.00) 
Intussusception 1–7 0.00 (0.00 to 50.00) 12 0.20 (0.00 to 0.30) −0.20 (–6.00 to 5.00) 
 1–30 0.00 (0.00 to 50.00) 48 0.80 (0.60 to 1.00) −0.80 (–6.00 to 5.00) 
Vomiting 1–14 32.30 (6.20 to 99.00) 2854 45.70 (44.00 to 47.00) 0.70 (0.20 to 2.20) −13.00 (–55.00 to 29.00) 
Encephalitis, myelitis, and encephalomyelitis 3–21 0.00 (0.00 to 50.00) 11 0.20 (0.10 to 0.30) −0.20 (–6.00 to 5.00) 
1-42 0.00 (0.00 to 50.00) 24 0.40 (0.30 to 0.60) -0.40 (-6.00 to 5.00) 
Exposed to BRM N = 929Unexposed to BRM N = 623 921Exposed Versus Unexposed
OutcomeRisk Interval (Days)Number of Cases in Risk IntervalPrevalence/10 000 Person (95% CI)Number of Cases in Risk IntervalPrevalence/10 000 Persons (95% CI)Prevalence Ratio (95% CI)Prevalence Difference (95% CI)
Diarrhea 1–14 54.00 (17.00 to 125.00) 2771 44.00 (43.00 to 46.00) 1.20 (0.50 to 2.90) 10.00 (–38.00 to 56.00) 
Bloody stool 1–14 11.00 (0.00 to 60.00) 965 15.00 (14 to 16.00) 0.70 (0.10 to 50) −4.00 (–31.00 to 22.00) 
Intussusception 1–7 0.00 (0.00 to 50.00) 12 0.20 (0.00 to 0.30) −0.20 (–6.00 to 5.00) 
 1–30 0.00 (0.00 to 50.00) 48 0.80 (0.60 to 1.00) −0.80 (–6.00 to 5.00) 
Vomiting 1–14 32.30 (6.20 to 99.00) 2854 45.70 (44.00 to 47.00) 0.70 (0.20 to 2.20) −13.00 (–55.00 to 29.00) 
Encephalitis, myelitis, and encephalomyelitis 3–21 0.00 (0.00 to 50.00) 11 0.20 (0.10 to 0.30) −0.20 (–6.00 to 5.00) 
1-42 0.00 (0.00 to 50.00) 24 0.40 (0.30 to 0.60) -0.40 (-6.00 to 5.00) 
a

First time ever diagnosed.

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.710 

Our 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.

Drs Zerbo and Klein, and Mr Lewis conceptualized and designed the study, provided critical interpretation of the data, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Modaressi participated in data acquisition, conducted data analyses, and reviewed and revised the manuscript; Ms Goddard participated in data acquisition, coordinated all administrative work, related to this project, and critically reviewed and revised the manuscript; Drs Daley, Jackson, Donahue, Getahun, Palmsten, Fuller, Wodi, McNeil, and Mr Crane provided critical interpretation of the data, critically reviewed, and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

FUNDING: The study was funded in part by a contract from the Centers for Disease Control and Prevention (CDC). Dr Zerbo is also supported by career development grant K01AI139275 from the National Institute of Allergy and Infectious Diseases (NIAID). Dr Palmsten is supported by a career development grant R00HD082412 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).The study sponsor, CDC, participated as a co-investigator and contributed to protocol development; conduct of the study; interpretation of the data; review and revision of the manuscript; approval of the manuscript through official CDC scientific clearance processes; and the decision to submit the manuscript for publication. CDC authors must receive approval through the CDC scientific clearance process to submit an article for publication. Final decision to submit rests with the first author.

CONFLICT OF INTEREST DISCLOSURES: Dr Klein has received research support from Sanofi Pasteur, GSK, Merck, Pfizer, and Protein Sciences (now Sanofi Pasteur) for unrelated studies. Dr Getahun has received research grant support from NICHD, the Garfield Memorial Fund, Hologic Inc and Bayer for unrelated studies. Dr Donahue reports grants from Janssen Global Services, LLC, outside the submitted work. Dr Fuller has received research funding from Pfizer and Johnson & Johnson for unrelated studies.

     
  • AESI

    adverse effects of special interest

  •  
  • BLM

    biological response modifiers

  •  
  • CDC

    Center for Disease Control and Prevention

  •  
  • CI

    confidence interval

  •  
  • VSD

    Vaccine Safety Datalink

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Supplementary data