Skip to Main Content

Skip Nav Destination

Article navigation

Research Briefs| June 09 2022

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

Ousseny Zerbo, PhD;

Ousseny Zerbo, PhD

aDivision of Research, Vaccine Study Center, Kaiser Permanente Northern California, Oakland, California

Address correspondence to Ousseny Zerbo, PhD, Kaiser Permanente Northern California, Division of Research, Vaccine Study Center, 1 Kaiser Plaza, 16th Floor, Oakland, CA 94612. E-mail: [email protected]

Search for other works by this author on:

PubMed

Google Scholar

Sharareh Modaressi, MD, MPH;

Sharareh Modaressi, MD, MPH

aDivision of Research, Vaccine Study Center, Kaiser Permanente Northern California, Oakland, California

Search for other works by this author on:

PubMed

Google Scholar

Kristin Goddard, MPH;

Kristin Goddard, MPH

aDivision of Research, Vaccine Study Center, Kaiser Permanente Northern California, Oakland, California

Search for other works by this author on:

PubMed

Google Scholar

Edwin Lewis, MPH;

Edwin Lewis, MPH

aDivision of Research, Vaccine Study Center, Kaiser Permanente Northern California, Oakland, California

Search for other works by this author on:

PubMed

Google Scholar

Darios Getahun, MD, PhD, MPH;

Darios Getahun, MD, PhD, MPH

bDepartment of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California

cDepartment of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California

Search for other works by this author on:

PubMed

Google Scholar

Kristin K. Palmsten, ScD;

Kristin K. Palmsten, ScD

dHealthPartners Institute, Minneapolis, Minnesota

Search for other works by this author on:

PubMed

Google Scholar

Candace C. Fuller, PhD, MPH;

Candace C. Fuller, PhD, MPH

eDepartment of Population Medicine, Harvard Medical School and the Harvard Pilgrim Health Care Institute, Boston, Massachusetts

Search for other works by this author on:

PubMed

Google Scholar

Bradley Crane, MS;

Bradley Crane, MS

fThe Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon

Search for other works by this author on:

PubMed

Google Scholar

James G. Donahue, DVM, PhD;

James G. Donahue, DVM, PhD

gCenter for Clinical Epidemiology & Population Health, Marshfield Clinic Research Institute, Marshfield, Wisconsin

Search for other works by this author on:

PubMed

Google Scholar

Matthew F. Daley, MD;

Matthew F. Daley, MD

hInstitute for Health Research, Kaiser Permanente Colorado, Denver, Colorado

Search for other works by this author on:

PubMed

Google Scholar

Lisa A. Jackson, MD, MPH;

Lisa A. Jackson, MD, MPH

iKaiser Permanente Washington Health Research Institute, Seattle, Washington

Search for other works by this author on:

PubMed

Google Scholar

A. Patricia Wodi, MD;

A. Patricia Wodi, MD

jImmunization Services Division

Search for other works by this author on:

PubMed

Google Scholar

Michael M. McNeil, MD, MPH;

Michael M. McNeil, MD, MPH

kImmunization Safety Office, Centers for Disease Control and Prevention, Atlanta, Georgia

Search for other works by this author on:

PubMed

Google Scholar

Nicola P. Klein, MD, PhD

Nicola P. Klein, MD, PhD

aDivision of Research, Vaccine Study Center, Kaiser Permanente Northern California, Oakland, California

Search for other works by this author on:

PubMed

Google Scholar

Address correspondence to Ousseny Zerbo, PhD, Kaiser Permanente Northern California, Division of Research, Vaccine Study Center, 1 Kaiser Plaza, 16th Floor, Oakland, CA 94612. E-mail: [email protected]

Pediatrics (2022) 150 (1): e2021056021.

https://doi.org/10.1542/peds.2021-056021

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.

Methods

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.

Results

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 = 954		Unexposed to BRM N = 578760		Exposed Versus Unexposed
Outcome	Risk Intervals (Days)	Number of Cases in Risk Interval	Prevalence/10 000 Person	Number of Cases in Risk Interval	Prevalence/10 000 Person	Prevalence Ratio (95% CI)	Risk Difference (95% CI)
Fever^a	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 seizure^a	7–10	0	0 (0.00 to 40.00)	240	4.20 (3.70 to 4.70)	0	−4.20 (–10.00 to 1.60)
Cerebellar ataxia^b	1–14	0	0 (0.00 to 40.00)	120	2.10 (1.70 to 2.50)	0	−2.10 (–7.70 to 3.50)
	1–42	0	0 (0.00 to 40.00)	379	6.60 (5.90 to 7.20)	0	–6.60 (–12.50 to -0.70)
Hepatitis^b	1–21	0	0 (0.00 to 40.00)	2	0.04 (0.00 to 0.13)	0	−0.03 (–5.30 to 5.30)
	1–42	0	0 (0.00 to 40.00)	5	0.09 (0.04 to 0.20)	0	−0.09 (–5.40 to 5.20)
Varicella pneumonitis^a	1–21	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
	1–42	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
Acute disseminated encephalomyelitis^b	3–21	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
	1–42	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
Encephalitis, myelitis, and encephalomyelitis^b	3–21	0	0 (0.00 to 40.00)	6	0.10 (0.05 to 0.22)	0	−0.10 (–50 to 5.20)
	1–42	0	0 (0.00 to 40.00)	12	0.21 (0.12 to 0.36)	0	−0.21 (–50 to 5.20)

		Exposed to BRM N = 954		Unexposed to BRM N = 578760		Exposed Versus Unexposed
Outcome	Risk Intervals (Days)	Number of Cases in Risk Interval	Prevalence/10 000 Person	Number of Cases in Risk Interval	Prevalence/10 000 Person	Prevalence Ratio (95% CI)	Risk Difference (95% CI)
Fever^a	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 seizure^a	7–10	0	0 (0.00 to 40.00)	240	4.20 (3.70 to 4.70)	0	−4.20 (–10.00 to 1.60)
Cerebellar ataxia^b	1–14	0	0 (0.00 to 40.00)	120	2.10 (1.70 to 2.50)	0	−2.10 (–7.70 to 3.50)
	1–42	0	0 (0.00 to 40.00)	379	6.60 (5.90 to 7.20)	0	–6.60 (–12.50 to -0.70)
Hepatitis^b	1–21	0	0 (0.00 to 40.00)	2	0.04 (0.00 to 0.13)	0	−0.03 (–5.30 to 5.30)
	1–42	0	0 (0.00 to 40.00)	5	0.09 (0.04 to 0.20)	0	−0.09 (–5.40 to 5.20)
Varicella pneumonitis^a	1–21	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
	1–42	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
Acute disseminated encephalomyelitis^b	3–21	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
	1–42	0	0 (0.00 to 40.00)	0	0 (0.00 to 0.07)	—	0 (–0.50 to 5.20)
Encephalitis, myelitis, and encephalomyelitis^b	3–21	0	0 (0.00 to 40.00)	6	0.10 (0.05 to 0.22)	0	−0.10 (–50 to 5.20)
	1–42	0	0 (0.00 to 40.00)	12	0.21 (0.12 to 0.36)	0	−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 = 929		Unexposed to BRM N = 623 921		Exposed Versus Unexposed
Outcome	Risk Interval (Days)	Number of Cases in Risk Interval	Prevalence/10 000 Person (95% CI)	Number of Cases in Risk Interval	Prevalence/10 000 Persons (95% CI)	Prevalence Ratio (95% CI)	Prevalence Difference (95% CI)
Diarrhea	1–14	5	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	1	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	0.00 (0.00 to 50.00)	12	0.20 (0.00 to 0.30)	0	−0.20 (–6.00 to 5.00)
	1–30	0	0.00 (0.00 to 50.00)	48	0.80 (0.60 to 1.00)	0	−0.80 (–6.00 to 5.00)
Vomiting	1–14	3	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	0.00 (0.00 to 50.00)	11	0.20 (0.10 to 0.30)	0	−0.20 (–6.00 to 5.00)
Encephalitis, myelitis, and encephalomyelitis	1-42	0	0.00 (0.00 to 50.00)	24	0.40 (0.30 to 0.60)	0	-0.40 (-6.00 to 5.00)

		Exposed to BRM N = 929		Unexposed to BRM N = 623 921		Exposed Versus Unexposed
Outcome	Risk Interval (Days)	Number of Cases in Risk Interval	Prevalence/10 000 Person (95% CI)	Number of Cases in Risk Interval	Prevalence/10 000 Persons (95% CI)	Prevalence Ratio (95% CI)	Prevalence Difference (95% CI)
Diarrhea	1–14	5	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	1	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	0.00 (0.00 to 50.00)	12	0.20 (0.00 to 0.30)	0	−0.20 (–6.00 to 5.00)
	1–30	0	0.00 (0.00 to 50.00)	48	0.80 (0.60 to 1.00)	0	−0.80 (–6.00 to 5.00)
Vomiting	1–14	3	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	0.00 (0.00 to 50.00)	11	0.20 (0.10 to 0.30)	0	−0.20 (–6.00 to 5.00)
Encephalitis, myelitis, and encephalomyelitis	1-42	0	0.00 (0.00 to 50.00)	24	0.40 (0.30 to 0.60)	0	-0.40 (-6.00 to 5.00)

a

First time ever diagnosed.

Discussion

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.^7–10

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

References

1

Davis

BP

,

Ballas

ZK

.

Biologic response modifiers: indications, implications, and insights

.

J Allergy Clin Immunol

.

2017

;

139

(

5

):

1445

–

1456

2

Julsgaard

M

,

Christensen

LA

,

Gibson

PR

, et al.

Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection

.

Gastroenterology

.

2016

;

151

(

1

):

110

–

119

3

Mahadevan

U

,

Long

MD

,

Kane

SV

, et al;

Crohn’s Colitis Foundation Clinical Research Alliance

.

Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease

.

Gastroenterology

.

2021

;

160

(

4

):

1131

–

1139

4

McNeil

MM

,

Gee

J

,

Weintraub

ES

, et al.

The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety

.

Vaccine

.

2014

;

32

(

42

):

5390

–

5398

5

Beaulieu

DB

,

Ananthakrishnan

AN

,

Martin

C

,

Cohen

RD

,

Kane

SV

,

Mahadevan

U

.

Use of biologic therapy by pregnant women with inflammatory bowel disease does not affect infant response to vaccines

.

Clin Gastroenterol Hepatol

.

2018

;

16

(

1

):

99

–

105

6

Chiarella-Redfern

H

,

Lee

S

,

Jubran

B

, et al.

Suboptimal vaccination administration in mothers with inflammatory bowel disease and their biologic-exposed infants

.

Inflamm Bowel Dis

.

2021

7

Mahadevan

U

,

Robinson

C

,

Bernasko

N

, et al.

Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group

.

Gastroenterology

.

2019

;

156

(

5

):

1508

–

1524

8

Nguyen

GC

,

Seow

CH

,

Maxwell

C

, et al;

IBD in Pregnancy Consensus Group

;

Canadian Association of Gastroenterology

.

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

.

Gastroenterology

.

2016

;

150

(

3

):

734

–

757.e1

9

Puchner

A

,

Gröchenig

HP

,

Sautner

J

, et al.

Immunosuppressives and biologics during pregnancy and lactation : A consensus report issued by the Austrian Societies of Gastroenterology and Hepatology and Rheumatology and Rehabilitation

.

Wien Klin Wochenschr

.

2019

;

131

(

1–2

):

29

–

44

10

van der Woude

CJ

,

Ardizzone

S

,

Bengtson

MB

, et al;

European Crohn’s and Colitis Organization

.

The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease

.

J Crohn’s Colitis

.

2015

;

9

(

2

):

107

–

124

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits noncommercial distribution and reproduction in any medium, provided the original author and source are credited.

Comments

1 Comment

Be careful with T cell deficiency newborns

July 17 2022

Javier Chinen

Baylor College of Medicine

I am concerned regarding the broad conclusions of this study. Remarkably, this study does not mention that all US newborns are currently screened for T cell deficiency, due to a genetic cause or due to secondary causes, including the use of immunosuppressive drugs. These newborns with abnormal screening results for T cell deficiency would be recommended to avoid live viral vaccines, unless immuno competence is determined. These babies would not be counted in the study. The statement: "..live attenuated rotavirus and measles-containing vaccines can be given to infants exposed to BRM in utero" may need be followed by a statement such as "unless the newborn has an abnormal newborn screening for T cell deficiency"

Submitted on July 17 2022