CONTEXT:

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 with exposure to influenza vaccines in utero.

DATA SOURCES:

We searched CINAHL Plus, Embase, Medline, Scopus, and Web of Science for relevant articles published from inception to July 24, 2019.

STUDY SELECTION:

We included studies published in English reporting original data with measurement 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 study design, setting, population, vaccines, outcomes, and results.

RESULTS:

The search yielded 3647 records, of which 9 studies met the inclusion criteria. Studies examined infectious, atopic, autoimmune, and neurodevelopmental outcomes, and all-cause morbidity and mortality. Authors of 2 studies reported an inverse association between pandemic influenza vaccination and upper respiratory tract infections and all-cause hospitalizations, and authors of 2 studies reported modest increased association between several childhood disorders and pandemic or seasonal influenza vaccination, which, after adjusting 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 in children older than 6 months of age did not identify an association between exposure to influenza vaccines in utero and adverse childhood health outcomes.

Influenza is a major respiratory infection that can lead to severe illness and death at any age,1  but high-risk populations such as pregnant women and infants <6 months of age have a greater risk of severe illness.2,3  No vaccines are currently licensed for infants in this age group.46  Because maternal antibodies cross the placenta during pregnancy,7  influenza vaccines administered to pregnant women are an effective means of protecting both mothers and their infants from influenza infection.810  Given these benefits, the 2012 World Health Organization position paper on influenza vaccines recommended pregnant women be considered the highest priority risk group for countries considering expansion of their seasonal influenza vaccination program.6  Globally, >50% of countries have policies recommending influenza vaccines to pregnant women.6,1114 

Despite these widespread recommendations, vaccine uptake is poor in many countries,1522  with concerns around vaccine safety cited as the most common reason for vaccine hesitancy.23  These concerns stand in contrast to the substantial evidence supporting the safety of administration of inactivated influenza vaccines (IIVs) during pregnancy on maternal, fetal, and early infant outcomes. The safety of influenza vaccination during pregnancy has been consistently highlighted in systematic reviews and meta-analyses.2426  These studies concluded that influenza vaccination during pregnancy was not associated with increased risk of congenital anomalies, stillbirth, preterm birth, fetal growth restriction, and/or low birth weight.2427  Although a recent review assessed influenza and other respiratory outcomes in early childhood, no study has comprehensively assessed longer-term child health outcomes in association with in utero exposure to IIV.28 

We conducted a systematic review of the literature related to IIV during pregnancy and childhood health outcomes, as guided by the minimum evidence-based set of items for reporting in systematic reviews outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.29  The study protocol was registered with the National Institute for Health Research international prospective register of systematic reviews (CRD42014014384) before commencing the review.

We searched CINAHL Plus, Embase, Medline, Scopus, and Web of Science databases for peer-reviewed literature from inception to July 24, 2019, using a combination of medical subject headings and keywords related to prenatal influenza vaccination and early childhood health outcomes (Supplemental Tables 610). Our search included experimental and observational studies, including cross-sectional, case-control, and cohort studies. As recommended,30,31  we consulted with a medical librarian to develop our search strategy.

Eligible studies included those investigating any mother–child pair population, in which exposure to influenza vaccines in utero (pandemic or seasonal) was reported, an unexposed mother–child pair control group is present, and ≥1 health outcome in children aged 6 months to 5 years was investigated. We made the following exclusions: articles not published in peer-reviewed journals, articles published in languages other than English, studies not conducted in humans, reviews, editorials, commentaries, letters, case studies, and case series. First, two independent reviewers (D.Y.P.F. and M.S.) screened and reviewed the titles and abstracts of records retrieved during the search for inclusion criteria. Second, the reviewers screened and reviewed the full-text articles for eligibility in accordance with study inclusion and exclusion criteria. Studies deemed to meet the inclusion criteria by the two reviewers were included in the final review. A third reviewer (A.K.R.) resolved any conflicts between the two reviewers during each screening and review stage.

We developed a standardized data collection form to extract information on study characteristics, including study design, geographic location, participant demographics, definition and ascertainment of exposure and outcomes (including type of influenza vaccine), effect sizes and confidence intervals (CIs), and confounding variables. Two reviewers (D.Y.P.F. and M.S.) independently extracted information from each of the included articles.

For observational studies, we used the Newcastle–Ottawa scale to assess risk of bias (Tables 13).32  The Newcastle–Ottawa scale has a maximum score of 9, with a greater score indicating the lowest risk of bias. The scoring system is based on the following criteria: selection bias (maximum score: 4), comparability of study groups (maximum score: 2), and ascertainment of exposure for case-control studies or outcome for observational studies (maximum score: 3).32  Observational studies were considered at low risk of bias if they scored ≥8 and moderate-high risk of bias if they scored <8.

TABLE 1

Results of Risk-of-Bias Assessment for Cohort Studies

Cohort StudiesaOverall Risk-of-Bias scoreRisk of BiasbCriteria
SelectionComparabilitycOutcome
Representativeness of the Exposed CohortSelection of the Nonexposed CohortAscertainment of CasesOutcome of Interest Was Not Present at Start of StudyComparability of the Design and Analysis for CohortsAssessment of OutcomeSufficient Follow-up DurationAdequacy of Follow-up of Cohorts
van Santen et al33  (2013) 6 of 9 High — — 
Ludvigsson et al34  (2015) 8 of 9 Low XX — 
van der Maas et al35  (2016) 7 of 9 High — — XX 
Fell et al36  (2016) 8 of 9 Low XX — 
Zerbo et al37  (2017) 7 of 9 High — XX — 
Hviid et al38  (2017) 8 of 9 Low XX — 
Walsh et al39  (2019) 8 of 9 Low XX — 
Cohort StudiesaOverall Risk-of-Bias scoreRisk of BiasbCriteria
SelectionComparabilitycOutcome
Representativeness of the Exposed CohortSelection of the Nonexposed CohortAscertainment of CasesOutcome of Interest Was Not Present at Start of StudyComparability of the Design and Analysis for CohortsAssessment of OutcomeSufficient Follow-up DurationAdequacy of Follow-up of Cohorts
van Santen et al33  (2013) 6 of 9 High — — 
Ludvigsson et al34  (2015) 8 of 9 Low XX — 
van der Maas et al35  (2016) 7 of 9 High — — XX 
Fell et al36  (2016) 8 of 9 Low XX — 
Zerbo et al37  (2017) 7 of 9 High — XX — 
Hviid et al38  (2017) 8 of 9 Low XX — 
Walsh et al39  (2019) 8 of 9 Low XX — 
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 is 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 

TABLE 2

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

Case-Control StudiesaOverall Risk-of-Bias ScoreRisk of BiasbSelectionComparabilitycExposure
Representativeness of the CasesSelection of the ControlsAdequacy of Case DefinitionDefinition of ControlsComparability of the Design and Analysis for CohortsAscertainment of ExposureComparability of Ascertainment of Exposure for CohortsComparability of Nonresponse Rate for Cohorts
Benowitz et al40  (2010) 7 of 9 High — 
Case-Control StudiesaOverall Risk-of-Bias ScoreRisk of BiasbSelectionComparabilitycExposure
Representativeness of the CasesSelection of the ControlsAdequacy of Case DefinitionDefinition of ControlsComparability of the Design and Analysis for CohortsAscertainment of ExposureComparability of Ascertainment of Exposure for CohortsComparability of Nonresponse Rate for Cohorts
Benowitz et al40  (2010) 7 of 9 High — 
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 criterion is 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 

TABLE 3

Results of Risk-of-Bias Assessment for RCTs

RCTsaRisk of BiasbSelection BiasPerformance BiasAttrition BiasDetection BiasReporting Bias
Random Sequence GenerationAllocation ConcealmentBlinding of Participants and Personnel and Other Potential Threats to ValidityIncomplete Outcome DataBlinding of Outcome Assessment and Other Potential Threats to ValiditySelective Outcome Reporting
Bischoff et al41  (2015) High Low Low Low Low High High 
RCTsaRisk of BiasbSelection BiasPerformance BiasAttrition BiasDetection BiasReporting Bias
Random Sequence GenerationAllocation ConcealmentBlinding of Participants and Personnel and Other Potential Threats to ValidityIncomplete Outcome DataBlinding of Outcome Assessment and Other Potential Threats to ValiditySelective Outcome Reporting
Bischoff et 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 

For randomized controlled trials (RCTs), we used the Cochrane risk-of-bias tool to assess risk of bias.31  The Cochrane risk-of-bias tool addressed 5 major domains: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel and other potential threats to validity), detection bias (blinding of outcome assessment and other potential threats to validity), attrition bias (incomplete outcome data), and reporting bias (selective outcome reporting).31  Consistent with the Cochrane risk-of-bias tool scoring, articles were classified as low risk of bias, some concerns of bias, or high risk of bias.31  Two reviewers (D.Y.P.F. and M.S.) independently assessed the quality of case-control and cohort studies and RCTs using the Newcastle–Ottawa Scale42  and Cochrane risk-of-bias tool,43  respectively. Any conflicts between the two reviewers during the quality assessment process were resolved by a third reviewer (A.K.R.).

We developed a narrative description of the characteristics and results of included studies. Where possible, results were provided by trimester of vaccination and type of vaccine. To generate pooled effect estimates for each outcome, a random effects meta-analysis was planned a priori, dependent on whether a sufficient number of studies were retrieved using commonly defined end-points (n > 2).

This systematic review was supported in part by funding received from the National Health and Medical Research Council (GNT1141510), Curtin University Graduate Research School, and the Wesfarmers Centre of Vaccines & Infectious Diseases at the Telethon Kids Institute. The funders had no role in the design or implementation of the systematic review or the decision to publish findings from the review.

We identified 3647 records, of which 3551 were excluded after initial title and abstract screening. We reviewed 96 full-text articles, of which 9 were deemed eligible for inclusion (Fig 1). Reasons for exclusions included no measurement of influenza vaccination during pregnancy (n = 4), no reported outcome measure of early childhood health (n = 33), not a comparative observational study or RCT (n = 44), or not published in English (n = 6).

FIGURE 1

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

FIGURE 1

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

Close modal

Of the 9 included studies, methodology and study outcomes were highly diverse (Table 4). All of the studies originated from high-income countries in North America (n = 5) or Europe (n = 4), and study periods ranged between 1980 and 2012. Estimates from the same population were reported in 2 articles.33,37  One study was an RCT,41  5 studies were retrospective cohort studies, 33,35,36,38,39  and 2 were prospective cohort studies34,37 ; 1 study used a case-control design.40  Record linkage was used in most studies to measure prenatal influenza vaccination and early childhood health outcomes (n = 7). Studies ranged in sample size from 306 to 275 500 mother–infant pairs. With the exception of 1 study in which children 6 to 12 months of age were specifically examined,40  the follow-up period of included studies began at birth and ranged from 1 to 15 years of age.

TABLE 4

Characteristics of Studies Included in a Systematic Review of the Literature on Early Childhood Health Outcomes Associated With In Utero Exposure to Influenza Vaccines

Author(s) (y), CountryStudy DesignAscertainment of ExposureType of VaccineStudy PeriodAge of Follow-upNo. ParticipantsTrimester of Exposure, n (%)Ascertainment of OutcomeOutcome(s)
ExposedUnexposedFirstSecondThird
Pandemic influenza vaccine             
 Bischoff et al41  (2015), Denmark Nested RCT Random allocation MF59-adjuvanted pandemic A/H1N1 influenza vaccine 2009–2010 0–1 y 51 332 Not specified Not specified Not specified Parent-reported daily diary cards reviewed by research doctor Infections (common cold, pharyngitis, otitis, pneumonia, fever, and gastrointestinal infection) 
 Ludvigsson et al34  (2015), Sweden Prospective cohort Register AS03-adjuvanted pandemic A/H1N1 influenza vaccine October 2, 2009, to November 26, 2010 0–6.4 y 41 183 234 317 Not specified Not specified Not specified Death register Mortality 
 van der Maas et al35  (2016), Netherlands Retrospective cohort Self-report MF59-adjuvanted pandemic A/H1N1 influenza vaccine November 2009 to December 2009 0–1 y 1357 669 — 1357 (100) across the second and third trimester 1357 (100) across the second and third trimester Register and medical records Infection-related primary care contact (fever, symptoms of infection of ≥1 organ system, or prescriptions for infectious symptoms) 
 Fell et al36  (2016), Canada Retrospective cohort Register Pandemic A/H1N1 influenza vaccinea November 2, 2009 to October 31, 2010 0–1 y 36 044 81 302 Not specified Not specified Not specified Medical records Influenza, combination of pneumonia and influenza 
 Hviid et al38  (2017), Denmark Retrospective cohort Register AS03-adjuvanted pandemic A/H1N1 influenza vaccine November 2, 2009 to March 31, 2010 0–5 y 6311 55 048 349 (5.5) 5962 (94.5) across the second and third trimester 5962 (94.5) across the second and third trimester Register and medical records Hospitalizations, infectious diseases, autoimmune diseases, neurologic diseases, behavioral disorders 
 Walsh et al39  (2019), Canada Retrospective cohort Register Pandemic A/H1N1 influenza vaccinea November 2, 2009 to October 31, 2010 0–5 y 31 295 72 954 Not specified Not specified Not specified Medical records Infectious diseases, atopic diseases, neoplasms, sensory disorders, urgent and inpatient health services use, complex chronic conditions, mortality 
Seasonal influenza vaccine             
 Benowitz et al40  (2010), United States Matched case-control Medical records IVV October 1, 2000 to April 30, 2009 0–1 y 113b 193 — 8 (22.2) 28 (77.8) Direct fluorescent antibody test Laboratory-confirmed influenza 
 van Santen et al33  (2013), United States Retrospective cohort Medical records Trivalent IVV June 2, 2002 to December 31, 2009 0–1 y 2416 7391 Not specified Not specified Not specified Medical records Acute otitis media, medically attended acute respiratory infections 
 Zerbo et al37  (2017), United States Prospective cohort Medical records IVVc 2000–2010 0–15 y 45 231 151 698 13 477 (29.8) 17 475 (38.6) 16 095 (35.6) Medical records Autism spectrum disorder 
Author(s) (y), CountryStudy DesignAscertainment of ExposureType of VaccineStudy PeriodAge of Follow-upNo. ParticipantsTrimester of Exposure, n (%)Ascertainment of OutcomeOutcome(s)
ExposedUnexposedFirstSecondThird
Pandemic influenza vaccine             
 Bischoff et al41  (2015), Denmark Nested RCT Random allocation MF59-adjuvanted pandemic A/H1N1 influenza vaccine 2009–2010 0–1 y 51 332 Not specified Not specified Not specified Parent-reported daily diary cards reviewed by research doctor Infections (common cold, pharyngitis, otitis, pneumonia, fever, and gastrointestinal infection) 
 Ludvigsson et al34  (2015), Sweden Prospective cohort Register AS03-adjuvanted pandemic A/H1N1 influenza vaccine October 2, 2009, to November 26, 2010 0–6.4 y 41 183 234 317 Not specified Not specified Not specified Death register Mortality 
 van der Maas et al35  (2016), Netherlands Retrospective cohort Self-report MF59-adjuvanted pandemic A/H1N1 influenza vaccine November 2009 to December 2009 0–1 y 1357 669 — 1357 (100) across the second and third trimester 1357 (100) across the second and third trimester Register and medical records Infection-related primary care contact (fever, symptoms of infection of ≥1 organ system, or prescriptions for infectious symptoms) 
 Fell et al36  (2016), Canada Retrospective cohort Register Pandemic A/H1N1 influenza vaccinea November 2, 2009 to October 31, 2010 0–1 y 36 044 81 302 Not specified Not specified Not specified Medical records Influenza, combination of pneumonia and influenza 
 Hviid et al38  (2017), Denmark Retrospective cohort Register AS03-adjuvanted pandemic A/H1N1 influenza vaccine November 2, 2009 to March 31, 2010 0–5 y 6311 55 048 349 (5.5) 5962 (94.5) across the second and third trimester 5962 (94.5) across the second and third trimester Register and medical records Hospitalizations, infectious diseases, autoimmune diseases, neurologic diseases, behavioral disorders 
 Walsh et al39  (2019), Canada Retrospective cohort Register Pandemic A/H1N1 influenza vaccinea November 2, 2009 to October 31, 2010 0–5 y 31 295 72 954 Not specified Not specified Not specified Medical records Infectious diseases, atopic diseases, neoplasms, sensory disorders, urgent and inpatient health services use, complex chronic conditions, mortality 
Seasonal influenza vaccine             
 Benowitz et al40  (2010), United States Matched case-control Medical records IVV October 1, 2000 to April 30, 2009 0–1 y 113b 193 — 8 (22.2) 28 (77.8) Direct fluorescent antibody test Laboratory-confirmed influenza 
 van Santen et al33  (2013), United States Retrospective cohort Medical records Trivalent IVV June 2, 2002 to December 31, 2009 0–1 y 2416 7391 Not specified Not specified Not specified Medical records Acute otitis media, medically attended acute respiratory infections 
 Zerbo et al37  (2017), United States Prospective cohort Medical records IVVc 2000–2010 0–15 y 45 231 151 698 13 477 (29.8) 17 475 (38.6) 16 095 (35.6) Medical records Autism spectrum disorder 

—, indicates no participants in the exposure group.

a

Study did not distinguish between non-adjuvanted pandemic influenza vaccine (targeted at pregnant women) and AS03-adjuvanted pandemic influenza vaccine (targeted at the general population).

b

Number of case participants (infants hospitalized for laboratory-confirmed influenza).

c

Study included the 2009 A/H1N1 pandemic year; investigators did not distinguish between the seasonal trivalent influenza vaccine from the pandemic monovalent vaccine during this period of time.

Researchers in 6 studies investigated pandemic34,36,38,39,41  influenza vaccines, and researchers in 3 investigated seasonal33,37,40  influenza vaccines (Table 4). Of the 6 studies on 2009 monovalent pandemic influenza A virus subtype H1N1 (A/H1N1) vaccines, researchers of 4 studies exclusively investigated adjuvanted vaccines (MF59-adjuvant: n = 235,41 ; AS03-adjuvant: n = 234,38 ). Vaccination status during pregnancy was ascertained by self-report (n = 1),35  random allocation (n = 1),41  written or electronic health records (n = 3),33,37,40  and registry information (n = 4).34,36,38,39 

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 or infectious conditions included influenza, pneumonia, otitis media, sepsis, acute respiratory infections, gastrointestinal infections, viral infections, and all-cause infection-related primary care contact. Atopic conditions included asthma. Autoimmune conditions included celiac disease, ulcerative colitis, Crohn disease, juvenile arthritis, Sjögren syndrome, vasculitis, reactive arthropathy, idiopathic thrombocytopenic purpura, type-1 diabetes, Bell palsy, and Guillain-Barré syndrome. Neurodevelopmental conditions included epilepsy, autism spectrum disorder, intellectual disability, and sensory disorders. All-cause morbidity outcomes included 1-year all-cause hospitalization, 3-year all-cause hospitalization, 5-year all-cause hospitalization, urgent and inpatient health services used, and pediatric complex chronic conditions. International Classification of Diseases (ICD) clinical diagnosis codes were used in the majority of studies (n = 5) to identify outcomes.

TABLE 5

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

Author(s) (y)Outcome AssessedEffect Estimate for Vaccination at Any Time During PregnancyEffect Estimate by Trimester
First TrimesterSecond TrimesterThird Trimester
Pandemic influenza vaccine      
 Bischoff et al41  (2015) All infections (common cold, pharyngitis, otitis, pneumonia, fever, gastrointestinal infection) aIRR: 0.99 (0.84–1.18) — — — 
 Ludvigsson et al34  (2015) Mortality aHR: 0.97 (0.69–1.36) vs sibling 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 der Maas et al35  (2016) Infection-related primary care contact 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 pandemic period 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 season     
  2009 A/H1N1 pandemic season aIRR: 1.04 (0.84–1.29) — — — 
  Post 2009 A/H1N1 pandemic period 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)b aRR: 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)b aRR: 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)b aRR: 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)b aRR: 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) 
 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 health services used aIRR: 0.99 (0.98–1.01) — — — 
 Pediatric complex chronic conditions aRR: 0.98 (0.80–1.20) — — — 
 5-y mortality aHR: 0.83 (0.64–1.08) — — — 
Seasonal influenza vaccine      
 Benowitz et al40  (2010) Laboratory-confirmed influenza VE: −41.4% (−2257.4% to 91.5%) — — — 
 van Santen et al33  (2013) Acute otitis media aVE: 47.9% (42.0% to 53.3%) — — — 
 Medically attended acute respiratory infections aVE: 39.6% (31.6% to 46.7%) — — — 
 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) 
Author(s) (y)Outcome AssessedEffect Estimate for Vaccination at Any Time During PregnancyEffect Estimate by Trimester
First TrimesterSecond TrimesterThird Trimester
Pandemic influenza vaccine      
 Bischoff et al41  (2015) All infections (common cold, pharyngitis, otitis, pneumonia, fever, gastrointestinal infection) aIRR: 0.99 (0.84–1.18) — — — 
 Ludvigsson et al34  (2015) Mortality aHR: 0.97 (0.69–1.36) vs sibling 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 der Maas et al35  (2016) Infection-related primary care contact 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 pandemic period 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 season     
  2009 A/H1N1 pandemic season aIRR: 1.04 (0.84–1.29) — — — 
  Post 2009 A/H1N1 pandemic period 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)b aRR: 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)b aRR: 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)b aRR: 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)b aRR: 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) 
 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 health services used aIRR: 0.99 (0.98–1.01) — — — 
 Pediatric complex chronic conditions aRR: 0.98 (0.80–1.20) — — — 
 5-y mortality aHR: 0.83 (0.64–1.08) — — — 
Seasonal influenza vaccine      
 Benowitz et al40  (2010) Laboratory-confirmed influenza VE: −41.4% (−2257.4% to 91.5%) — — — 
 van Santen et al33  (2013) Acute otitis media aVE: 47.9% (42.0% to 53.3%) — — — 
 Medically attended acute respiratory infections aVE: 39.6% (31.6% to 46.7%) — — — 
 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.

Given the small number of studies in which similarly defined outcomes were addressed, meta-analyses were deemed not possible.

Among the 9 included studies, several maternal and child characteristics were included as potential confounders (Supplemental Table 11). Maternal characteristics 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). Child characteristics mostly included sex (n = 4). Other characteristics, such as marital status, calendar year of conception, use of antenatal care, medication use, the child’s ethnicity, and other birth outcomes, were less commonly controlled for as confounders (n = 1) (Supplemental Table 11). One study accounted for the potential influence of childhood influenza immunization by censoring at age at influenza vaccination.33 

In the 2 studies in which researchers examined influenza infection, infection status was ascertained either by a positive result by direct fluorescent antibody test (for laboratory-confirmed influenza)40  or by using primary or secondary diagnostic codes for (1) influenza alone or (2) influenza and pneumonia.36  Outcome measures were expressed as vaccine effectiveness (VE; calculated as [1 − odds ratio comparing the odds of infection in exposed versus unexposed] × 100%) or crude incidence rates for influenza infection among children exposed to IIV in utero versus unexposed. Benowitz et al40  assessed laboratory-confirmed influenza and did not identify an association between IIV exposure in utero and VE in infants aged ≥6 months (unadjusted VE: −41.4%; 95% CI: −2257.4% to 91.5%) (Table 5). However, as noted by Benowitz et al,40  because of the small sample size of infants aged ≥6 months, there was low statistical power to assess VE. In a study that followed infants ≤1 year of age, Fell et al36  observed incidence rates of influenza that did not differ between children exposed to IIV in utero compared with unexposed children for each influenza time period examined, including the 2009 A/H1N1 pandemic season (incidence rate ratio: 0.61; 95% CI: 0.32 to 1.17) and the post-2009 A/H1N1 pandemic period (adjusted incidence rate ratio [aIRR]: 1.05; 95% CI: 0.81 to 1.37). Incidence rates for influenza and pneumonia were significantly higher among infants exposed to IIV in utero compared with unexposed infants in the post-2009 A/H1N1 pandemic period (aIRR: 1.17; 95% CI: 1.05 to 1.31). However, incidence rates for influenza and pneumonia did not differ significantly during the 2009 A/H1N1 pandemic season (aIRR: 1.04; 95% CI: 0.84 to 1.29) (Table 5).

Researchers of two studies assessed infection-related primary care contact (fever, symptoms of infection of ≥1 organ system, or prescriptions for infectious symptoms) by examining medical records given by primary care providers35  and infections (common cold, pharyngitis, otitis, pneumonia, and gastrointestinal infection) or fever by parent-reported daily diary cards reviewed by a research doctor.41  Neither van der Maas et al35  (aIRR: 1.07; 95% CI: 0.91 to 1.28) nor Bischoff et al41  (aIRR: 0.99; 95% CI: 0.84 to 1.18) found a difference in incidence of infections between children of vaccinated and unvaccinated mothers in their studies (Table 5).

Studies in which upper respiratory tract infections, lower respiratory tract infections, and all-cause infections were examined found a statistically significant reduction in risk 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 lower respiratory tract infections (Table 5).38,39  Hviid et al38  observed an inverse association with upper respiratory tract infections and all-cause infections in children whose mothers were vaccinated with pandemic influenza vaccine in the second or third trimester and in the first trimester, respectively. However, after adjusting for multiplicity using a Bonferroni correction, these associations were no longer significant. Data from one of 2 studies33,39  that investigated otitis media in infants ≤1 year of age reported a lower absolute adjusted VE (calculated as 1 – the ratio of the incidence of otitis media in exposed versus unexposed children) for children whose mothers received a pneumococcal conjugate vaccine while pregnant (37.6%; 95% CI: 23.1 to 49.4) than children whose mothers received a pneumococcal conjugate vaccine and trivalent IIV while pregnant (47.9%; 95% CI: 42.0 to 53.3), as compared with the children whose mothers received no vaccines during pregnancy.33  The second study, by Walsh et al,39  followed offspring ≤5 years of age and found no difference in incidence rates between children exposed to IIV in utero and unexposed children (aIRR: 1.03; 95% CI: 1.00 to 1.06). Walsh et al39  and Hviid et al38  each observed a statistically significant reduction in the 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 association in children whose mothers were vaccinated in either the second or third trimester but not in the first trimester. Second or thirdtrimester prenatal influenza vaccination was also associated with a significant increase in risk of sepsis (aRR: 1.96; 95% CI: 1.26 to 3.05).38  However, after taking multiple comparisons into account using Bonferroni-corrected CIs, associations for gastrointestinal infections and sepsis were not significant and could have been due to chance (Table 5).38,39 

In the 2 studies in which asthma was examined, asthma status was identified from a regional asthma database39  or by using primary or secondary ICD diagnostic codes.38,39  Walsh et al39  reported a small, but significant, increase in asthma among children exposed to IIV in utero compared with unexposed children (aHR: 1.05; 95% CI: 1.02 to 1.09) (Table 5). However, results were no longer statistically significant after adjusting for multiplicity using Bonferroni correction (aHR: 1.05; 95% CI: 1.00 to 1.11).39  Hviid et al38  reported no significant difference in asthma for first trimester vaccination (aRR: 1.50; 95% CI: 0.99 to 2.29) or second or third trimester vaccination (aRR: 1.02; 95% CI: 0.89 to 1.16).

Estimates on rates of autism spectrum disorder were provided in 2 studies, of which 1 group evaluated pandemic influenza vaccine39  and the other evaluated seasonal influenza vaccine.37  For both studies, autism spectrum disorder was identified using ICD diagnostic codes. Zerbo et al37  reported a slightly elevated risk of autism spectrum disorder after prenatal influenza vaccination in the first trimester (aHR: 1.20; 95% CI: 1.04 to 1.39) but not in the second or third trimester (Table 5). However, this association was no longer significant after adjusting for multiplicity using a Bonferroni correction (P = .1). Hviid et al38  found no significant association between IIV exposure in utero and autism spectrum disorder. Additionally, Hviid et al38  observed an increase of risk in Sjögren syndrome, only after prenatal influenza vaccination in the second or third trimester (aRR: 1.59; 95% CI: 1.04 to 2.44) but not in the first trimester. After adjusting for multiplicity using a Bonferroni correction, this association for Sjögren syndrome was no longer significant (aRR: 1.59; 95% CI: 0.82 to 3.11).

Across all studies, there were no other significant associations between prenatal influenza vaccination and celiac disease,38  Crohn disease,38  ulcerative colitis,38  juvenile arthritis,38  vasculitis,38  reactive arthropathy,38  idiopathic thrombocytopenic purpura,38  idiopathic urticaria,38  type-1 diabetes,38  Bell palsy,38  epilepsy,38  Guillain-Barré syndrome,38  intellectual disability,38  neoplasms,39  and sensory disorders (Table 5).39 

All-cause childhood morbidity outcomes included all-cause hospitalizations and urgent care services; researchers in 1 study examined a nonspecific outcome, including a complex of pediatric chronic conditions.39  Walsh et al39  found no significant associations between IIV exposure in utero and urgent and inpatient health services used39  or the nonspecific complex of chronic conditions (Table 5).39  Hviid et al38  observed a statistically significant reduction in the risk of 1-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-cause hospitalization (aHR: 0.95; 95% CI: 0.91 to 0.99) in children whose mothers were vaccinated in the second or third trimester.

Pediatric mortality was defined as death occurring from birth through 5 years of age39  or from 7 days to 4.6 years of age.34  No significant associations were identified in the 2 studies that examined mortality as an outcome. Although Walsh et al39  reported a reduced association between pandemic influenza vaccine given during pregnancy and pediatric mortality (aHR: 0.83; 95% CI: 0.64 to 1.08), this result was not statistically significant (Table 5). Similarly, Ludvigsson et al34  reported no significant association between pandemic influenza vaccine during pregnancy and pediatric mortality overall (aHR: 0.97; 95% CI: 0.69 to 1.36) 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; third trimester: aHR: 0.93; 95% CI: 0.54 to 1.60). Secondary analyses, using unvaccinated siblings as controls, also revealed no significant associations (overall: aHR: 0.78; 95% CI: 0.52 to 1.19; first trimester: aHR: 0.47; 95% CI: 0.22 to 1.01; second trimester: aHR: 1.44; 95% CI: 0.74 to 2.78; third trimester: aHR; 0.65; 95% CI: 0.30 to 1.39).34 

For observational studies, risk of bias scores ranged from 6 to 8 on the Newcastle–Ottawa scale, of which 4 studies were deemed to be at low risk of bias,34,36,38,39  and 4 studies were deemed to be at moderate-high risk of bias (Tables 13).33,35,37,40  Common causes of potential bias included inadequate representativeness of the exposed cohort (n = 3)33,35,37  and inadequately described follow-up of exposed and nonexposed cohorts (n = 6). The 1 RCT included was deemed to be at high risk of bias because of the lack of blinding of outcome assessment (detection bias) and inadequate ascertainment of outcomes (reporting bias).41 

Although there has been increasing interest in the potential impacts of IIV exposure in utero on later child health, we identified relatively few studies in which health outcomes through the age of 5 years have been evaluated. In this systematic review, we summarized results from 9 studies including information on over 750 000 children, 163 924 of whom were exposed to IIV in utero. Researchers in 2 studies suggested lower risk of upper respiratory tract infection, all-cause hospitalization, and gastrointestinal infection associated with pandemic IIV exposure in utero. While the data from some studies suggested a potential increase in the risk of asthma, sepsis, and Sjögren syndrome after exposure to pandemic IIV in utero and an increased risk of autism spectrum disorder after exposure to seasonal IIV in utero, after adjusting for multiple comparisons using Bonferroni-corrected CIs, these associations were no longer statistically significant.

Narrative synthesis of these few studies indicates there is limited evidence evaluating health outcomes through the age of 5 years after exposure to IIV in utero, particularly for seasonal IIVs. Existing studies assessed a range of outcomes and the majority examined exposure to pandemic influenza vaccines. Only 3 studies on seasonal influenza vaccines in children were identified, and these were prone to bias; additional high-quality studies are warranted. Furthermore, given seasonal IIV is recommended in all trimesters of pregnancy and fetal development varies by gestational age, outcomes should be assessed according to gestational age at vaccination. Only 3 studies assessed outcomes by trimester of vaccination, of which 1 study combined second and third trimesters. The number of vaccinated individuals, particularly in the first trimester, was small and consequently limited the statistical power to detect differences between the children in the exposed and unexposed group. Differences in study quality, exposure ascertainment, vaccine type (ie, pandemic or seasonal, adjuvanted or nonadjuvanted, monovalent or trivalent), and study outcomes and outcome ascertainment, made it difficult to compare results across studies and precluded statistical pooling of results. These differences may have also influenced the reliability of findings. For example, diagnoses recorded in medical records and not using a validated standardized clinical assessment could lead to potential outcome misclassification.

Importantly, while the potential confounding influence of maternal age, parity, and pre-existing medical conditions was accounted for in most studies, the study by van Santen et al33  was the only one that factored for receipt of childhood immunizations as a potential confounding variable by censoring children after receiving their own influenza vaccine.33  No study factored for receipt of other recommended childhood vaccines. Given that receipt of vaccines during pregnancy may be predictive of childhood vaccination as well as other health behaviors,44  it is possible that residual bias in the observational studies identified may have influenced findings, especially the observed protective associations. Future studies should aim to account for childhood immunization status as a potential confounding variable.

Finally, there was little geographic variation in the geographic location of studies identified. All included studies were conducted in high-income countries in North America or Europe, and thus these findings may not generalize to children in low and middle-income countries, whose population demographics and risk profiles differ markedly. Research on the safety of influenza vaccination during pregnancy from low and middle-income countries would be useful for guiding future vaccine policies and programs in these settings.

Maternal influenza vaccination is a growing public health tool for improving the health of mothers and their infants. Despite long-standing recommendations, maternal influenza immunization policies were not widely adopted until the 2009 influenza A/H1N1 pandemic, and, as identified as part of this review, the long-term health effects of in utero exposure of influenza vaccines in children >6 months of age are underinvestigated. We identified relatively few studies in which early childhood health outcomes were evaluated in children aged >6 months of age in maternally vaccinated and unvaccinated children, and the same outcomes were rarely measured in the few existing studies. This made formal meta-analyses impractical. Although our review indicates that exposure to IIV in utero is not associated with adverse health outcomes in childhood, additional epidemiological studies of early childhood health outcomes after maternal influenza vaccination are still needed to address this gap. Future well-controlled research in which seasonal IIV administered in different trimesters and in different settings is considered is required to provide a stronger evidence-base for the long-term safety of maternal influenza vaccination. Notwithstanding the need for additional research in this area, the results of the studies to-date have not revealed any adverse effect of maternal influenza vaccination on childhood health outcomes during the first 5 years. These findings are reassuring and can help support health care providers and pregnant women in making decisions about influenza vaccination during pregnancy.

The authors would like to acknowledge contributions made by Ms Diana Blackwood, a research librarian of the Faculty of Health Sciences, who provided guidance with the literature search strategy.

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.

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).

     
  • A/H1N1

    influenza A virus subtype H1N1

  •  
  • aHR

    adjusted hazard ratio

  •  
  • aIRR

    adjusted incidence rate ratio

  •  
  • aRR

    adjusted rate ratio

  •  
  • CI

    confidence interval

  •  
  • IIV

    inactivated influenza vaccine

  •  
  • ICD

    International Classification of Diseases

  •  
  • RCT

    randomized controlled trial

  •  
  • VE

    vaccine effectiveness

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Competing Interests

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

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

Supplementary data