Early Childhood Health OutcomesFollowing In Utero Exposure toInfluenza Vaccines: ASystematic ReviewDamien Y.P. Foo, BSc (Hons),a,b Mohinder Sarna, PhD,a,b Gavin Pereira, PhD,a,c,d Hannah C. Moore, PhD,b Deshayne B. Fell, PhD,e,f

Annette K. Regan, PhDa,b,g

abstractCONTEXT: Vaccination during pregnancy is an effective strategy for preventing infant disease;however, little is known about early childhood health after maternal vaccination.

OBJECTIVES: To systematically review the literature on early childhood health associated withexposure to influenza vaccines in utero.

DATA SOURCES: We searched CINAHL Plus, Embase, Medline, Scopus, and Web of Science forrelevant articles published from inception to July 24, 2019.

STUDY SELECTION: We included studies published in English reporting original data withmeasurement of in utero exposure to influenza vaccines and health outcomes among children,5 years of age.

DATA EXTRACTION: Two authors independently assessed eligibility and extracted data on studydesign, setting, population, vaccines, outcomes, and results.

RESULTS: The search yielded 3647 records, of which 9 studies met the inclusion criteria. Studiesexamined infectious, atopic, autoimmune, and neurodevelopmental outcomes, and all-causemorbidity and mortality. Authors of 2 studies reported an inverse association betweenpandemic influenza vaccination and upper respiratory tract infections and all-causehospitalizations, and authors of 2 studies reported modest increased association betweenseveral childhood disorders and pandemic or seasonal influenza vaccination, which, afteradjusting for confounding and multiple comparisons, were not statistically significant.

LIMITATIONS: Given the small number of studies addressing similarly defined outcomes, meta-analyses were deemed not possible.

CONCLUSIONS: Results from the few studies in which researchers have examined outcomes inchildren older than 6 months of age did not identify an association between exposure toinfluenza vaccines in utero and adverse childhood health outcomes.

aSchool of Public Health, Curtin University, Perth, Western Australia, Australia; bWesfarmers Centre of Vaccines & Infectious Diseases, cTelethon Kids Institute, The University of WesternAustralia, Perth, Western Australia, Australia; dCentre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; eSchool of Epidemiology and Public Health, University ofOttawa, Ottawa, Ontario, Canada; fChildren’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; and gSchool of Public Health, Texas A&M University, College Station, Texas

To cite: Foo DYP, Sarna M, Pereira G, et al. Early Childhood Health Outcomes Following In Utero Exposure to Influenza Vaccines: A Systematic Review. Pediatrics.2020;146(2):e20200375

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Influenza is a major respiratoryinfection that can lead to severeillness and death at any age,1 buthigh-risk populations such aspregnant women and infants,6 months of age have a greater riskof severe illness.2,3 No vaccines arecurrently licensed for infants in thisage group.4–6 Because maternalantibodies cross the placenta duringpregnancy,7 influenza vaccinesadministered to pregnant women arean effective means of protecting bothmothers and their infants frominfluenza infection.8–10 Given thesebenefits, the 2012 World HealthOrganization position paper oninfluenza vaccines recommendedpregnant women be considered thehighest priority risk group forcountries considering expansionof their seasonal influenzavaccination program.6 Globally,.50% of countries have policiesrecommending influenza vaccines topregnant women.6,11–14

Despite these widespreadrecommendations, vaccine uptake ispoor in many countries,15–22 withconcerns around vaccine safety citedas the most common reason forvaccine hesitancy.23 These concernsstand in contrast to the substantialevidence supporting the safety ofadministration of inactivatedinfluenza vaccines (IIVs) duringpregnancy on maternal, fetal, andearly infant outcomes. The safety ofinfluenza vaccination duringpregnancy has been consistentlyhighlighted in systematic reviewsand meta-analyses.24–26 Thesestudies concluded that influenzavaccination during pregnancy wasnot associated with increased riskof congenital anomalies, stillbirth,preterm birth, fetal growthrestriction, and/or low birthweight.24–27 Although a recentreview assessed influenza andother respiratory outcomes inearly childhood, no study hascomprehensively assessed longer-term child health outcomes in

association with in utero exposure toIIV.28

METHODS

We conducted a systematic review ofthe literature related to IIV duringpregnancy and childhood healthoutcomes, as guided by the minimumevidence-based set of items forreporting in systematic reviewsoutlined in the Preferred ReportingItems for Systematic Reviewsand Meta-Analyses (PRISMA)guidelines.29 The study protocol wasregistered with the National Institutefor Health Research internationalprospective register of systematicreviews (CRD42014014384) beforecommencing the review.

Data Sources and Search Strategy

We searched CINAHL Plus, Embase,Medline, Scopus, and Web of Sciencedatabases for peer-reviewedliterature from inception to July 24,2019, using a combination of medicalsubject headings and keywordsrelated to prenatal influenzavaccination and early childhoodhealth outcomes (SupplementalTables 6–10). Our search includedexperimental and observationalstudies, including cross-sectional,case-control, and cohort studies. Asrecommended,30,31 we consulted witha medical librarian to develop oursearch strategy.

Study Selection

Eligible studies included thoseinvestigating any mother–child pairpopulation, in which exposure toinfluenza vaccines in utero (pandemicor seasonal) was reported, anunexposed mother–child pair controlgroup is present, and $1 healthoutcome in children aged 6 months to5 years was investigated. We madethe following exclusions: articles notpublished in peer-reviewed journals,articles published in languages otherthan English, studies not conducted inhumans, reviews, editorials,commentaries, letters, case studies,

and case series. First, twoindependent reviewers (D.Y.P.F. andM.S.) screened and reviewed the titlesand abstracts of records retrievedduring the search for inclusioncriteria. Second, the reviewersscreened and reviewed the full-textarticles for eligibility in accordancewith study inclusion and exclusioncriteria. Studies deemed to meet theinclusion criteria by the tworeviewers were included in the finalreview. A third reviewer (A.K.R.)resolved any conflicts between thetwo reviewers during each screeningand review stage.

Data Extraction and Risk-of-BiasAssessment

We developed a standardized datacollection form to extract informationon study characteristics, includingstudy design, geographic location,participant demographics, definitionand ascertainment of exposure andoutcomes (including type of influenzavaccine), effect sizes and confidenceintervals (CIs), and confoundingvariables. Two reviewers (D.Y.P.F.and M.S.) independently extractedinformation from each of the includedarticles.

For observational studies, we usedthe Newcastle–Ottawa scale to assessrisk of bias (Tables 1–3).32 TheNewcastle–Ottawa scale hasa maximum score of 9, with a greaterscore indicating the lowest risk ofbias. The scoring system is based onthe following criteria: selection bias(maximum score: 4), comparability ofstudy groups (maximum score: 2),and ascertainment of exposure forcase-control studies or outcome forobservational studies (maximumscore: 3).32 Observational studieswere considered at low risk of bias ifthey scored $8 and moderate-highrisk of bias if they scored ,8.

For randomized controlled trials(RCTs), we used the Cochrane risk-of-bias tool to assess risk of bias.31 TheCochrane risk-of-bias tool addressed5 major domains: selection bias

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(random sequence generation andallocation concealment), performancebias (blinding of participants andpersonnel and other potential threatsto validity), detection bias (blindingof outcome assessment and otherpotential threats to validity), attritionbias (incomplete outcome data), andreporting bias (selective outcomereporting).31 Consistent with theCochrane risk-of-bias tool scoring,articles were classified as low risk

of bias, some concerns of bias, orhigh risk of bias.31 Two reviewers(D.Y.P.F. and M.S.) independentlyassessed the quality of case-controland cohort studies and RCTsusing the Newcastle–Ottawa Scale42

and Cochrane risk-of-bias tool,43

respectively. Any conflicts betweenthe two reviewers during thequality assessment process wereresolved by a third reviewer(A.K.R.).

Data Synthesis and Analysis

We developed a narrative descriptionof the characteristics and results ofincluded studies. Where possible,results were provided by trimester ofvaccination and type of vaccine. Togenerate pooled effect estimates foreach outcome, a random effectsmeta-analysis was planned a priori,dependent on whether a sufficientnumber of studies were retrieved usingcommonly defined end-points (n . 2).

TABLE 1 Results of Risk-of-Bias Assessment for Cohort Studies

CohortStudiesa

OverallRisk-of-Biasscore

Riskof

Biasb

Criteria

Selection Comparabilityc Outcome

Representativenessof the Exposed

Cohort

Selection ofthe

NonexposedCohort

Ascertainmentof Cases

Outcome ofInterestWas NotPresent at

Startof Study

Comparabilityof the Designand Analysisfor Cohorts

Assessmentof Outcome

SufficientFollow-upDuration

Adequacyof Follow-

upof Cohorts

van Santenet al33

(2013)

6 of 9 High — X X X X X X —

Ludvigssonet al34

(2015)

8 of 9 Low X X X X XX X X —

van derMaaset al35

(2016)

7 of 9 High — X — X XX X X X

Fell et al36

(2016)8 of 9 Low X X X X XX X X —

Zerbo et al37

(2017)7 of 9 High — X X X XX X X —

Hviid et al38

(2017)8 of 9 Low X X X X XX X X —

Walsh et al39

(2019)8 of 9 Low X X X X XX X X —

a Cohort studies were assessed using the Newcastle–Ottawa scale. Each X represents whether an individual criterion is satisfied. Each — represents whether an individual criterion isnot satisfied.b Low risk of bias: overall risk of bias score $8; high risk of bias: overall risk of bias score ,8.c All criteria receives a maximum score of 1 X except for comparability of study groups where an additional X may be allocated for the control of additional important confounders.30

TABLE 2 Results of Risk-of-Bias Assessment for Case-Control Studies

Case-ControlStudiesa

OverallRisk-of-BiasScore

Riskof

Biasb

Selection Comparabilityc Exposure

Representativenessof the Cases

Selectionof theControls

Adequacyof CaseDefinition

Definitionof

Controls

Comparabilityof the Designand Analysisfor Cohorts

Ascertainmentof

Exposure

Comparability ofAscertainmentof Exposurefor Cohorts

Comparabilityof Nonresponse

Ratefor Cohorts

Benowitzet al40

(2010)

7 of 9 High X — X X X X X X

a Case-control studies were assessed using the Newcastle–Ottawa scale. Each X represents whether an individual criterion is satisfied. Each— represents whether an individual criterionis not satisfied.b Low risk of bias: overall risk of bias score $8; high risk of bias: overall risk of bias score ,8.c All criteria receives a maximum score of 1 X except for comparability of study groups where an additional X may be allocated for the control of additional important confounders.30

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Role of the Funding Source

This systematic review wassupported in part by funding receivedfrom the National Health and MedicalResearch Council (GNT1141510),Curtin University Graduate ResearchSchool, and the Wesfarmers Centreof Vaccines & Infectious Diseasesat the Telethon Kids Institute. Thefunders had no role in the design orimplementation of the systematicreview or the decision to publishfindings from the review.

RESULTS

Study Selection

We identified 3647 records, of which3551 were excluded after initial titleand abstract screening. We reviewed96 full-text articles, of which 9 weredeemed eligible for inclusion (Fig 1).Reasons for exclusions included nomeasurement of influenza vaccinationduring pregnancy (n = 4), no reportedoutcome measure of early childhoodhealth (n = 33), not a comparativeobservational study or RCT (n = 44),or not published in English (n = 6).

Study Characteristics

Of the 9 included studies,methodology and study outcomeswere highly diverse (Table 4). All ofthe studies originated from high-income countries in North America(n = 5) or Europe (n = 4), and studyperiods ranged between 1980 and2012. Estimates from the samepopulation were reported in 2articles.33,37 One study was an RCT,41

5 studies were retrospective cohortstudies, 33,35,36,38,39 and 2 wereprospective cohort studies34,37; 1study used a case-control design.40

Record linkage was used in moststudies to measure prenatal influenzavaccination and early childhoodhealth outcomes (n = 7). Studiesranged in sample size from 306 to275 500 mother–infant pairs. Withthe exception of 1 study in whichchildren 6 to 12 months of age werespecifically examined,40 the follow-upperiod of included studies began atbirth and ranged from 1 to 15 yearsof age.

Exposure Assessment

Researchers in 6 studies investigatedpandemic34,36,38,39,41 influenzavaccines, and researchers in 3investigated seasonal33,37,40 influenzavaccines (Table 4). Of the 6 studies on2009 monovalent pandemic influenzaA virus subtype H1N1 (A/H1N1)vaccines, researchers of 4 studiesexclusively investigated adjuvantedvaccines (MF59-adjuvant: n = 235,41;AS03-adjuvant: n = 234,38).Vaccination status during pregnancywas ascertained by self-report (n =1),35 random allocation (n = 1),41

written or electronic health records(n = 3),33,37,40 and registryinformation (n = 4).34,36,38,39

Outcome Assessment

Outcomes included infectious (n = 7),atopic (n = 2), autoimmune (n = 2),and neurodevelopmental (n = 3)conditions, neoplasms (n = 1), and all-cause morbidity (n = 2) and mortality

(n = 2) (Table 5). Infections orinfectious conditions includedinfluenza, pneumonia, otitis media,sepsis, acute respiratory infections,gastrointestinal infections, viralinfections, and all-cause infection-related primary care contact. Atopicconditions included asthma.Autoimmune conditions includedceliac disease, ulcerative colitis,Crohn disease, juvenile arthritis,Sjögren syndrome, vasculitis,reactive arthropathy, idiopathicthrombocytopenic purpura, type-1diabetes, Bell palsy, and Guillain-Barré syndrome.Neurodevelopmental conditionsincluded epilepsy, autism spectrumdisorder, intellectual disability, andsensory disorders. All-causemorbidity outcomes included 1-yearall-cause hospitalization, 3-year all-cause hospitalization, 5-year all-causehospitalization, urgent and inpatienthealth services used, and pediatriccomplex chronic conditions.International Classification ofDiseases (ICD) clinical diagnosiscodes were used in the majority ofstudies (n = 5) to identify outcomes.

Given the small number of studies inwhich similarly defined outcomeswere addressed, meta-analyses weredeemed not possible.

Confounder Assessment

Among the 9 included studies, severalmaternal and child characteristicswere included as potentialconfounders (SupplementalTable 11). Maternal characteristics

TABLE 3 Results of Risk-of-Bias Assessment for RCTs

RCTsa Risk ofBiasb

Selection Bias PerformanceBias

AttritionBias

DetectionBias

ReportingBias

RandomSequenceGeneration

AllocationConcealment

Blinding of Participants andPersonnel and Other Potential

Threatsto Validity

IncompleteOutcomeData

Blinding of OutcomeAssessment and Other Potential

Threatsto Validity

SelectiveOutcomeReporting

Bischoffet al41

(2015)

High Low Low Low Low High High

a RCTs were assessed using the Cochrane risk-of-bias tool. Each risk of bias item receives a judgement on risk of bias.b Risk of bias judgement given by algorithm.31

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included maternal age (n = 6),ethnicity (n = 2), place of birth(n = 3), place of residence (n = 3),socioeconomic status and income(n = 4), education (n = 3), BMI (n = 2),parity (n = 5), medical comorbidities(n = 5), pregnancy complications (n =3), multiple gestations and/or births(n = 3), smoking during pregnancy(n = 4), season of conception (n = 2),and gestational age (n = 2). Childcharacteristics mostly included sex(n = 4). Other characteristics, such asmarital status, calendar year ofconception, use of antenatal care,medication use, the child’s ethnicity,

and other birth outcomes, wereless commonly controlled for asconfounders (n = 1) (SupplementalTable 11). One study accounted forthe potential influence of childhoodinfluenza immunization by censoringat age at influenza vaccination.33

Infectious Conditions

In the 2 studies in which researchersexamined influenza infection,infection status was ascertainedeither by a positive result by directfluorescent antibody test (forlaboratory-confirmed influenza)40 orby using primary or secondary

diagnostic codes for (1) influenzaalone or (2) influenza andpneumonia.36 Outcome measureswere expressed as vaccineeffectiveness (VE; calculated as [1 2odds ratio comparing the odds ofinfection in exposed versusunexposed] 3 100%) or crudeincidence rates for influenza infectionamong children exposed to IIV inutero versus unexposed. Benowitzet al40 assessed laboratory-confirmedinfluenza and did not identify anassociation between IIV exposure inutero and VE in infants aged$6 months (unadjusted VE: 241.4%;95% CI: 22257.4% to 91.5%)(Table 5). However, as noted byBenowitz et al,40 because of the smallsample size of infants aged $6months, there was low statisticalpower to assess VE. In a study thatfollowed infants #1 year of age, Fellet al36 observed incidence rates ofinfluenza that did not differ betweenchildren exposed to IIV in uterocompared with unexposed childrenfor each influenza time periodexamined, including the 2009A/H1N1 pandemic season (incidencerate ratio: 0.61; 95% CI: 0.32 to 1.17)and the post-2009 A/H1N1 pandemicperiod (adjusted incidence rate ratio[aIRR]: 1.05; 95% CI: 0.81 to 1.37).Incidence rates for influenza andpneumonia were significantly higheramong infants exposed to IIV in uterocompared with unexposed infants inthe post-2009 A/H1N1 pandemicperiod (aIRR: 1.17; 95% CI: 1.05 to1.31). However, incidence rates forinfluenza and pneumonia did notdiffer significantly during the 2009A/H1N1 pandemic season (aIRR:1.04; 95% CI: 0.84 to 1.29) (Table 5).

Researchers of two studies assessedinfection-related primary care contact(fever, symptoms of infection of $1organ system, or prescriptions forinfectious symptoms) by examiningmedical records given by primarycare providers35 and infections(common cold, pharyngitis, otitis,pneumonia, and gastrointestinal

FIGURE 1Flow diagram of study selection process for systematic review of the literature on early childhoodhealth outcomes associated with in utero exposure to influenza vaccines.

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TABLE4Characteristicsof

StudiesIncluded

inaSystem

aticReview

oftheLiterature

onEarlyChildhood

Health

Outcom

esAssociated

With

InUteroExposure

toInfluenzaVaccines

Author(s)(y),Country

StudyDesign

Ascertainm

entof

Exposure

Type

ofVaccine

StudyPeriod

Ageof

Follow-

upNo.Participants

Trimesterof

Exposure,n

(%)

Ascertainm

entof

Outcom

eOutcom

e(s)

Exposed

Unexposed

First

Second

Third

Pandem

icinfluenza

vaccine

Bischoffet

al41

(2015),D

enmark

Nested

RCT

Random

allocation

MF59-adjuvanted

pandem

icA/H1N1

influenzavaccine

2009–2010

0–1y

51332

Notspecified

Notspecified

Notspecified

Parent-reported

daily

diarycards

review

edby

research

doctor

Infections

(com

mon

cold,

pharyngitis,otitis,

pneumonia,fever,and

gastrointestinal

infection)

Ludvigsson

etal34

(2015),Sweden

Prospectivecohort

Register

AS03-adjuvanted

pandem

icA/H1N1

influenzavaccine

October2,2009,

toNovember

26,2010

0–6.4y

41183

234317

Notspecified

Notspecified

Notspecified

Deathregister

Mortality

vanderMaaset

al35

(2016),

Netherlands

Retrospectivecohort

Self-report

MF59-adjuvanted

pandem

icA/H1N1

influenzavaccine

November2009

toDecember

2009

0–1y

1357

669

—1357

(100)across

thesecond

and

thirdtrimester

1357

(100)across

thesecond

and

thirdtrimester

Register

andmedical

records

Infection-relatedprimary

care

contact(fever,

symptom

sof

infection

of$1organsystem

,or

prescriptions

for

infectious

symptom

s)Fellet

al36(2016),

Canada

Retrospectivecohort

Register

Pandem

icA/H1N1

influenzavaccinea

November2,

2009

toOctober

31,2010

0–1y

36044

81302

Notspecified

Notspecified

Notspecified

Medical

records

Influenza,combinationof

pneumonia

and

influenza

Hviid

etal38(2017),

Denm

ark

Retrospectivecohort

Register

AS03-adjuvanted

pandem

icA/H1N1

influenzavaccine

November2,

2009

toMarch

31,2010

0–5y

6311

55048

349(5.5)

5962

(94.5)

across

thesecond

and

thirdtrimester

5962

(94.5)

across

thesecond

and

thirdtrimester

Register

andmedical

records

Hospitalizations,

infectious

diseases,

autoimmunediseases,

neurologicdiseases,

behavioral

disorders

Walsh

etal39(2019),

Canada

Retrospectivecohort

Register

Pandem

icA/H1N1

influenzavaccinea

November2,

2009

toOctober

31,2010

0–5y

31295

72954

Notspecified

Notspecified

Notspecified

Medical

records

Infectious

diseases,atopic

diseases,n

eoplasms,

sensorydisorders,

urgent

andinpatient

health

services

use,

complex

chronic

conditions,mortality

Seasonal

influenza

vaccine

Benowitz

etal40

(2010),U

nited

States

Matched

case-

control

Medical

records

IVV

October1,2000

toApril30,

2009

0–1y

113b

193

—8(22.2)

28(77.8)

Direct

fluorescent

antibodytest

Laboratory-confirm

edinfluenza

vanSanten

etal33

(2013),U

nited

States

Retrospectivecohort

Medical

records

TrivalentIVV

June

2,2002

toDecember31,

2009

0–1y

2416

7391

Notspecified

Notspecified

Notspecified

Medical

records

Acuteotitismedia,

medicallyattended

acuterespiratory

infections

Zerboet

al37(2017),

UnitedStates

Prospectivecohort

Medical

records

IVVc

2000–2010

0–15

y45

231

151698

13477(29.8)

17475(38.6)

16095(35.6)

Medical

records

Autismspectrum

disorder

—,indicates

noparticipants

intheexposure

group.

aStudydidnotdistinguishbetweennon-adjuvanted

pandem

icinfluenzavaccine(targetedat

pregnant

wom

en)andAS03-adjuvantedpandem

icinfluenzavaccine(targetedat

thegeneralpopulation).

bNumberof

case

participants

(infants

hospitalized

forlaboratory-confirm

edinfluenza).

cStudyincluded

the2009

A/H1N1

pandem

icyear;investigatorsdidnotdistinguishbetweentheseasonal

trivalentinfluenzavaccinefrom

thepandem

icmonovalentvaccineduring

thisperiod

oftim

e.

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TABLE 5 Adjusted Effect Estimates of Early Childhood Health Outcomes Associated With In Utero Exposure to Influenza Vaccine, by Pandemic and SeasonalInfluenza Vaccines

Author(s) (y) Outcome Assessed Effect Estimate forVaccination at Any

Time During Pregnancy

Effect Estimate by Trimester

First Trimester Second Trimester Third Trimester

PandemicinfluenzavaccineBischoff

et al41

(2015)

All infections (common cold,pharyngitis, otitis, pneumonia,fever, gastrointestinal infection)

aIRR: 0.99 (0.84–1.18) — — —

Ludvigssonet al34

(2015)

Mortality aHR: 0.97 (0.69–1.36) vssibling control: aHR:0.78 (0.52–1.19)a

aHR: 0.86 (0.51–1.47)versus sibling control:aHR: 0.47 (0.22–1.01)a

aHR: 1.10 (0.69–1.76)versus sibling control:aHR: 1.44 (0.74–2.78)a

aHR: 0.93 (0.54–1.60)versus sibling control:aHR: 0.65 (0.30–1.39)a

van derMaaset al35

(2016)

Infection-related primary carecontact

aIRR: 1.07 (0.91–1.28) — — —

Fell et al36

(2016)Influenza, by season

2009 A/H1N1 pandemic season IRR: 0.61 (0.32–1.17) — — —

Post 2009 A/H1N1 pandemicperiod

aIRR: 1.05 (0.81–1.37) — — —

Pre-2010–2011 period aIRR: 1.08 (0.80–1.44) — — —

2010–2011 period aIRR: 0.88 (0.76–1.02) — — —

Post-2010–2011 period aIRR: 0.72 (0.50–1.04) — — —

Pre-2011–2012 period — — — —

Influenza and pneumonia, by season2009 A/H1N1 pandemic season aIRR: 1.04 (0.84–1.29) — — —

Post 2009 A/H1N1 pandemicperiod

aIRR: 1.17 (1.05–1.31) — — —

Pre-2010–2011 period aIRR: 1.07 (0.93–1.25) — — —

2010–2011 period aIRR: 0.99 (0.92–1.07) — — —

Post-2010–2011 period aIRR: 1.00 (0.85–1.17) — — —

Pre-2011–2012 period aIRR: 0.81 (0.38–1.70) — — —

Hviid et al38

(2017)1-y hospitalization aHR: 1.10 (0.89–1.37);

aRR: 1.15 (0.90–1.48)aHR: 0.94 (0.89–0.99);aRR: 0.93 (0.87–0.99)

aHR: 0.94 (0.89–0.99);aRR: 0.93 (0.87–0.99)

3-y hospitalization aHR: 1.15 (0.97–1.37);aRR: 1.21 (0.98–1.50)

aHR: 0.95 (0.90–0.99);aRR: 0.96 (0.90–1.01)

aHR: 0.95 (0.90–0.99);aRR: 0.96 (0.90–1.01)

5-y hospitalization aHR: 1.13 (0.96–1.32);aRR: 1.17 (0.94–1.45)

aHR: 0.95 (0.91–0.99);aRR: 0.93 (0.87–0.99)

aHR: 0.95 (0.91–0.99);aRR: 0.93 (0.87–0.99)

Upper respiratory tract infections — aRR: 1.08 (0.80–1.46) aRR: 0.92 (0.85–0.99);aRR: 0.92 (0.81–1.03)b

aRR: 0.92 (0.85–0.99);aRR: 0.92 (0.81–1.03)b

Lower respiratory tract infections — aRR: 0.90 (0.63–1.28) aRR: 0.92 (0.84–1.00) aRR: 0.92 (0.84–1.00)Gastrointestinal infections aRR:1.03 (0.68–1.55) aRR: 0.84 (0.74–0.94);

aRR: 0.84 (0.70–1.00)baRR: 0.84 (0.74–0.94);aRR: 0.84 (0.70–1.00)b

Meningitis — — aRR: 1.17 (0.61–2.24) aRR: 1.17 (0.61–2.24)Sepsis — — aRR: 1.96 (1.26–3.05);

aRR: 1.96 (0.98–3.91)baRR: 1.96 (1.26–3.05);aRR: 1.96 (0.98–3.91)b

Viral infections — aRR: 1.20 (0.82–1.73) aRR: 0.91 (0.82–1.00) aRR: 0.91 (0.82–1.00)Other infections — aRR: 1.71 (1.08–2.73);

aRR: 1.71 (0.83–3.56)baRR: 0.92 (0.81–1.05) aRR: 0.92 (0.81–1.05)

Asthma — aRR: 1.50 (0.99–2.29) aRR: 1.02 (0.89–1.16) aRR: 1.02 (0.89–1.16)Celiac disease — — aRR: 0.81 (0.31–2.12) aRR: 0.81 (0.31–2.12)Crohn disease — — aRR: 1.24 (0.31–11.90) aRR: 1.24 (0.31–11.90)Ulcerative colitis — — aRR: 2.48 (0.41–14.82) aRR: 2.48 (0.41–14.82)Juvenile arthritis — — aRR: 0.60 (0.23–1.54) aRR: 0.60 (0.23–1.54)Sjögren syndrome aRR: 1.15 (0.24–5.53) aRR: 1.59 (1.04–2.44);

aRR: 1.59 (0.82–3.11)baRR: 1.59 (1.04–2.44);aRR: 1.59 (0.82–3.11)b

Vasculitis — — — —

Reactive arthropathy — aRR: 0.80 (0.09–6.88) aRR: 1.40 (0.96–2.05) aRR: 1.40 (0.96–2.05)Idiopathic thrombocytopenic

purpura— — aRR: 0.68 (0.15–3.05) aRR: 0.68 (0.15–3.05)

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infection) or fever by parent-reporteddaily diary cards reviewed bya research doctor.41 Neither van derMaas et al35 (aIRR: 1.07; 95% CI: 0.91to 1.28) nor Bischoff et al41 (aIRR:0.99; 95% CI: 0.84 to 1.18) founda difference in incidence of infectionsbetween children of vaccinated andunvaccinated mothers in their studies(Table 5).

Studies in which upper respiratorytract infections, lower respiratorytract infections, and all-causeinfections were examined founda statistically significant reduction inrisk of upper respiratory tract

infections (adjusted rate ratio [aRR]:0.92; 95% CI: 0.85 to 0.99)38 and all-cause infections (aRR: 1.71; 95% CI:1.08 to 2.44)38 but not lowerrespiratory tract infections(Table 5).38,39 Hviid et al38 observedan inverse association with upperrespiratory tract infections and all-cause infections in children whosemothers were vaccinated withpandemic influenza vaccine in thesecond or third trimester and in thefirst trimester, respectively. However,after adjusting for multiplicity usinga Bonferroni correction, theseassociations were no longersignificant. Data from one of 2

studies33,39 that investigated otitismedia in infants #1 year of agereported a lower absolute adjustedVE (calculated as 1 – the ratio of theincidence of otitis media in exposedversus unexposed children) forchildren whose mothers receiveda pneumococcal conjugate vaccinewhile pregnant (37.6%; 95% CI: 23.1to 49.4) than children whose mothersreceived a pneumococcal conjugatevaccine and trivalent IIV whilepregnant (47.9%; 95% CI: 42.0 to53.3), as compared with the childrenwhose mothers received no vaccinesduring pregnancy.33 The secondstudy, by Walsh et al,39 followed

TABLE 5 Continued

Author(s) (y) Outcome Assessed Effect Estimate forVaccination at Any

Time During Pregnancy

Effect Estimate by Trimester

First Trimester Second Trimester Third Trimester

Idiopathic urticaria — — aRR: 1.03 (0.38–2.78) aRR: 1.03 (0.38–2.78)Type-1 diabetes — — aRR: 0.80 (0.23–2.77) aRR: 0.80 (0.23–2.77)Bell palsy — — aRR: 1.24 (0.34–4.57) aRR: 1.24 (0.34–4.57)Epilepsy — aRR: 1.01 (0.21–4.74) aRR: 0.86 (0.58–1.27) aRR: 0.86 (0.58–1.27)Guillain-Barré syndrome — — — —

Autism spectrum disorder — — aRR: 1.22 (0.79–1.86) aRR: 1.22 (0.79–1.86)Intellectual disability — — aRR: 0.66 (0.28–1.56) aRR: 0.66 (0.28–1.56)

Walsh et al39

(2019)Upper respiratory tract infections aIRR: 1.01 (0.98–1.03) — — —

Lower respiratory tract infections aIRR: 0.99 (0.95–1.03) — — —

Gastrointestinal infections aIRR: 0.94 (0.91–0.98);aIRR: 0.94 (0.88–1.00)b

— — —

Otitis media aIRR: 1.03 (1.00–1.06) — — —

All infections aIRR: 1.01 (0.98–1.03) — — —

Asthma aHR: 1.05 (1.02–1.09);aHR: 1.05 (1.00–1.11)b

— — —

Neoplasms aHR: 1.12 (0.79–1.59) — — —

Sensory disorders aHR: 0.94 (0.67–1.33) — — —

Urgent and inpatient healthservices used

aIRR: 0.99 (0.98–1.01) — — —

Pediatric complex chronicconditions

aRR: 0.98 (0.80–1.20) — — —

5-y mortality aHR: 0.83 (0.64–1.08) — — —

SeasonalinfluenzavaccineBenowitz

et al40

(2010)

Laboratory-confirmed influenza VE: 241.4% (22257.4%to 91.5%)

— — —

van Santenet al33

(2013)

Acute otitis media aVE: 47.9% (42.0% to53.3%)

— — —

Medically attended acuterespiratory infections

aVE: 39.6% (31.6% to46.7%)

— — —

Zerbo et al37

(2017)Autism spectrum disorder aHR: 1.10 (1.00–1.21) aHR: 1.20 (1.04–1.39) aHR: 1.03 (0.90–1.19) aHR: 1.03 (0.90–1.20)

aIRR, adjusted incidence rate ratio; aHR, adjusted hazard ratio; aRR, adjusted rate ratio; aVE, adjusted vaccine effectiveness; VE, unadjusted vaccine effectiveness; —, not applicable.a Overall estimates are compared with unexposed children; an additional comparison with unexposed siblings also provided.b Adjusted for multiplicity using Bonferroni correction.

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offspring #5 years of age and foundno difference in incidence ratesbetween children exposed to IIV inutero and unexposed children (aIRR:1.03; 95% CI: 1.00 to 1.06). Walshet al39 and Hviid et al38 each observeda statistically significant reduction inthe risk of gastrointestinal infections(adjusted hazard ratio [aHR]: 0.94;95% CI: 0.91 to 0.98 and aRR: 0.84;95% CI: 0.74 to 0.94, respectively).Hviid et al38 observed this associationin children whose mothers werevaccinated in either the second orthird trimester but not in the firsttrimester. Second or thirdtrimesterprenatal influenza vaccination wasalso associated with a significantincrease in risk of sepsis (aRR: 1.96;95% CI: 1.26 to 3.05).38 However,after taking multiple comparisonsinto account using Bonferroni-corrected CIs, associations forgastrointestinal infections and sepsiswere not significant and could havebeen due to chance (Table 5).38,39

Atopic, Autoimmune, andNeurodevelopmental Conditions

In the 2 studies in which asthma wasexamined, asthma status wasidentified from a regional asthmadatabase39 or by using primary orsecondary ICD diagnostic codes.38,39

Walsh et al39 reported a small, butsignificant, increase in asthma amongchildren exposed to IIV in uterocompared with unexposed children(aHR: 1.05; 95% CI: 1.02 to 1.09)(Table 5). However, results were nolonger statistically significant afteradjusting for multiplicity usingBonferroni correction (aHR: 1.05;95% CI: 1.00 to 1.11).39 Hviid et al38

reported no significant differencein asthma for first trimestervaccination (aRR: 1.50; 95% CI: 0.99to 2.29) or second or third trimestervaccination (aRR: 1.02; 95% CI: 0.89to 1.16).

Estimates on rates of autismspectrum disorder were provided in 2studies, of which 1 group evaluatedpandemic influenza vaccine39 and the

other evaluated seasonal influenzavaccine.37 For both studies, autismspectrum disorder was identifiedusing ICD diagnostic codes. Zerboet al37 reported a slightly elevatedrisk of autism spectrum disorder afterprenatal influenza vaccination in thefirst trimester (aHR: 1.20; 95% CI:1.04 to 1.39) but not in the second orthird trimester (Table 5). However,this association was no longersignificant after adjusting formultiplicity using a Bonferronicorrection (P = .1). Hviid et al38 foundno significant association between IIVexposure in utero and autismspectrum disorder. Additionally, Hviidet al38 observed an increase of risk inSjögren syndrome, only after prenatalinfluenza vaccination in the second orthird trimester (aRR: 1.59; 95% CI:1.04 to 2.44) but not in the firsttrimester. After adjusting formultiplicity using a Bonferronicorrection, this association forSjögren syndrome was no longersignificant (aRR: 1.59; 95% CI: 0.82to 3.11).

Across all studies, there were noother significant associationsbetween prenatal influenzavaccination and celiac disease,38

Crohn disease,38 ulcerative colitis,38

juvenile arthritis,38 vasculitis,38

reactive arthropathy,38 idiopathicthrombocytopenic purpura,38

idiopathic urticaria,38 type-1diabetes,38 Bell palsy,38 epilepsy,38

Guillain-Barré syndrome,38

intellectual disability,38 neoplasms,39

and sensory disorders (Table 5).39

All-Cause and Nonspecific ChildhoodMorbidity

All-cause childhood morbidityoutcomes included all-causehospitalizations and urgent careservices; researchers in 1 studyexamined a nonspecific outcome,including a complex of pediatricchronic conditions.39 Walsh et al39

found no significant associationsbetween IIV exposure in utero andurgent and inpatient health services

used39 or the nonspecific complex ofchronic conditions (Table 5).39 Hviidet al38 observed a statisticallysignificant reduction in the risk of1-year all-cause hospitalization (aHR:0.94; 95% CI: 0.89 to 0.99), 3-year all-cause hospitalization (aHR: 0.95; 95%CI: 0.90 to 0.99), and 5-year all-causehospitalization (aHR: 0.95; 95% CI:0.91 to 0.99) in children whosemothers were vaccinated in thesecond or third trimester.

Pediatric Mortality

Pediatric mortality was defined asdeath occurring from birth through5 years of age39 or from 7 days to4.6 years of age.34 No significantassociations were identified in the 2studies that examined mortality as anoutcome. Although Walsh et al39

reported a reduced associationbetween pandemic influenza vaccinegiven during pregnancy and pediatricmortality (aHR: 0.83; 95% CI: 0.64 to1.08), this result was not statisticallysignificant (Table 5). Similarly,Ludvigsson et al34 reported nosignificant association betweenpandemic influenza vaccine duringpregnancy and pediatric mortalityoverall (aHR: 0.97; 95% CI: 0.69 to1.36) or by trimester of vaccination(first trimester: aHR: 0.86; 95% CI:0.51 to 1.47; second trimester: aHR:1.10; 95% CI: 0.69 to 1.76; thirdtrimester: aHR: 0.93; 95% CI: 0.54 to1.60). Secondary analyses, usingunvaccinated siblings as controls, alsorevealed no significant associations(overall: aHR: 0.78; 95% CI: 0.52 to1.19; first trimester: aHR: 0.47; 95%CI: 0.22 to 1.01; second trimester:aHR: 1.44; 95% CI: 0.74 to 2.78; thirdtrimester: aHR; 0.65; 95% CI: 0.30 to1.39).34

Risk of Bias

For observational studies, risk of biasscores ranged from 6 to 8 on theNewcastle–Ottawa scale, of which 4studies were deemed to be at low riskof bias,34,36,38,39 and 4 studies weredeemed to be at moderate-high riskof bias (Tables 1–3).33,35,37,40

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Common causes of potential biasincluded inadequaterepresentativeness of the exposedcohort (n = 3)33,35,37 andinadequately described follow-up ofexposed and nonexposed cohorts (n =6). The 1 RCT included was deemedto be at high risk of bias because ofthe lack of blinding of outcomeassessment (detection bias) andinadequate ascertainment ofoutcomes (reporting bias).41

DISCUSSION

Although there has been increasinginterest in the potential impacts of IIVexposure in utero on later childhealth, we identified relatively fewstudies in which health outcomesthrough the age of 5 years have beenevaluated. In this systematic review,we summarized results from 9studies including information on over750 000 children, 163 924 of whomwere exposed to IIV in utero.Researchers in 2 studies suggestedlower risk of upper respiratory tractinfection, all-cause hospitalization,and gastrointestinal infectionassociated with pandemic IIVexposure in utero. While the datafrom some studies suggesteda potential increase in the risk ofasthma, sepsis, and Sjögren syndromeafter exposure to pandemic IIV inutero and an increased risk of autismspectrum disorder after exposure toseasonal IIV in utero, after adjustingfor multiple comparisons usingBonferroni-corrected CIs, theseassociations were no longerstatistically significant.

Narrative synthesis of these fewstudies indicates there is limitedevidence evaluating health outcomesthrough the age of 5 years afterexposure to IIV in utero, particularlyfor seasonal IIVs. Existing studiesassessed a range of outcomes and themajority examined exposure topandemic influenza vaccines. Only 3studies on seasonal influenzavaccines in children were identified,

and these were prone to bias;additional high-quality studies arewarranted. Furthermore, givenseasonal IIV is recommended in alltrimesters of pregnancy and fetaldevelopment varies by gestationalage, outcomes should be assessedaccording to gestational age atvaccination. Only 3 studies assessedoutcomes by trimester of vaccination,of which 1 study combined secondand third trimesters. The number ofvaccinated individuals, particularly inthe first trimester, was small andconsequently limited the statisticalpower to detect differences betweenthe children in the exposed andunexposed group. Differences instudy quality, exposureascertainment, vaccine type (ie,pandemic or seasonal, adjuvanted ornonadjuvanted, monovalent ortrivalent), and study outcomes andoutcome ascertainment, made itdifficult to compare results acrossstudies and precluded statisticalpooling of results. These differencesmay have also influenced thereliability of findings. For example,diagnoses recorded in medicalrecords and not using a validatedstandardized clinical assessmentcould lead to potential outcomemisclassification.

Importantly, while the potentialconfounding influence of maternalage, parity, and pre-existing medicalconditions was accounted for in moststudies, the study by van Santenet al33 was the only one thatfactored for receipt of childhoodimmunizations as a potentialconfounding variable by censoringchildren after receiving their owninfluenza vaccine.33 No study factoredfor receipt of other recommendedchildhood vaccines. Given that receiptof vaccines during pregnancy may bepredictive of childhood vaccination aswell as other health behaviors,44 it ispossible that residual bias in theobservational studies identifiedmay have influenced findings,especially the observed protective

associations. Future studies shouldaim to account for childhoodimmunization status as a potentialconfounding variable.

Finally, there was little geographicvariation in the geographic location ofstudies identified. All included studieswere conducted in high-incomecountries in North America orEurope, and thus these findings maynot generalize to children in low andmiddle-income countries, whosepopulation demographics and riskprofiles differ markedly. Research onthe safety of influenza vaccinationduring pregnancy from low andmiddle-income countries would beuseful for guiding future vaccinepolicies and programs in thesesettings.

CONCLUSIONS

Maternal influenza vaccination isa growing public health tool forimproving the health of mothers andtheir infants. Despite long-standingrecommendations, maternal influenzaimmunization policies were notwidely adopted until the 2009influenza A/H1N1 pandemic, and, asidentified as part of this review, thelong-term health effects of in uteroexposure of influenza vaccines inchildren .6 months of age areunderinvestigated. We identifiedrelatively few studies in which earlychildhood health outcomes wereevaluated in children aged.6 months of age in maternallyvaccinated and unvaccinatedchildren, and the same outcomeswere rarely measured in the fewexisting studies. This made formalmeta-analyses impractical. Althoughour review indicates that exposure toIIV in utero is not associated withadverse health outcomes inchildhood, additional epidemiologicalstudies of early childhood healthoutcomes after maternal influenzavaccination are still needed toaddress this gap. Future well-controlled research in which seasonal

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IIV administered in differenttrimesters and in different settings isconsidered is required to providea stronger evidence-base for the long-term safety of maternal influenzavaccination. Notwithstanding theneed for additional research in thisarea, the results of the studies to-datehave not revealed any adverse effectof maternal influenza vaccination onchildhood health outcomes during thefirst 5 years. These findings arereassuring and can help support

health care providers and pregnantwomen in making decisions aboutinfluenza vaccination during pregnancy.

ACKNOWLEDGMENTS

The authors would like toacknowledge contributions made byMs Diana Blackwood, a researchlibrarian of the Faculty of HealthSciences, who provided guidancewith the literature searchstrategy.

ABBREVIATIONS

A/H1N1: influenza A virussubtype H1N1

aHR: adjusted hazard ratioaIRR: adjusted incidence rate ratioaRR: adjusted rate ratioCI: confidence intervalIIV: inactivated influenza vaccineICD: International Classification of

DiseasesRCT: randomized controlled trialVE: vaccine effectiveness

Mr Foo led the development and registration of the original protocol, performed data collection, analysis, and interpretation of findings, drafted the initial

manuscript, and reviewed and revised the manuscript critically for important intellectual content; Dr Regan conceptualized and designed the study, contributed to

the data collection and analysis and interpretation of data, and revised the manuscript critically for important intellectual content; Dr Sarna contributed to the

development of the original protocol, contributed to data collection, analysis and interpretation of data, and revised the manuscript critically for important

intellectual content; Drs Fell, Moore, and Pereira advised on the development of the original protocol, contributed to the interpretation of results, and revised the

manuscript critically for important intellectual content; and all authors have approved the final version of the manuscript for publication and agree to be

accountable for all aspects of the work related to the accuracy or integrity of the research.

DOI: https://doi.org/10.1542/peds.2020-0375

Accepted for publication May 7, 2020

Address correspondence to Damien Y.P. Foo, School of Public Health, Curtin University, GPO Box U1987, Perth 6845, Western Australia. E-mail: damien.foo@

postgrad.curtin.edu.au

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2020 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Supported by a Curtin University Postgraduate Award, a postgraduate top-up scholarship from the Wesfarmers Centre of Vaccines and Infectious

Diseases, Telethon Kids Institute (to Mr Foo), and the National Health and Medical Research Council (GNT114150 to Drs Regan and Pereira; GNT1099655 and

GNT1173991 to Dr Pereira; GNT1034254 to Dr Moore).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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