Maternal influenza and birth outcomes: systematic review of comparative studies

Abstract

Background: Although pregnant women are considered at high risk for severe influenza disease, comparative studies of maternal influenza and birth outcomes have not been comprehensively summarised.

Objective: To review comparative studies evaluating maternal influenza disease and birth outcomes.

Search strategy: We searched bibliographic databases from inception to December 2014.

Selection criteria: Studies of preterm birth, small-for-gestational-age (SGA) birth or fetal death, comparing women with and without clinical influenza illness or laboratory-confirmed influenza infection during pregnancy.

Data collection and analysis: Two reviewers independently abstracted data and assessed study quality.

Main results: Heterogeneity across 16 studies reporting preterm birth precluded meta-analysis. In a subgroup of the highest-quality studies, two reported significantly increased preterm birth (risk ratios (RR) from 2.4 to 4.0) following severe 2009 pandemic H1N1 (pH1N1) influenza illness, whereas those assessing mild-to-moderate pH1N1 or seasonal influenza found no association. Five studies of SGA birth showed no discernible patterns with respect to influenza disease severity (pooled odds ratio 1.24; 95% CI 0.96-1.59). Two fetal death studies were of sufficient quality and size to permit meaningful interpretation. Both reported an increased risk of fetal death following maternal pH1N1 disease (RR 1.9 for mild-to-moderate disease and 4.2 for severe disease).

Conclusions: Comparative studies of preterm birth, SGA birth and fetal death following maternal influenza disease are limited in number and quality. An association between severe pH1N1 disease and preterm birth and fetal death was reported by several studies; however, these limited data do not permit firm conclusions on the magnitude of any association.

Tweetable abstract: Comparative studies are limited in quality but suggest severe pandemic H1N1 influenza increases preterm birth.

Keywords: Fetal death; influenza; pregnancy; preterm birth; small-for-gestational-age birth; systematic review.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram showing study selection process. ^aDescriptive studies and systematic reviews were screened as part of the overall evidence review, but are not reported in this publication. ^bYates et al. (2010)32 and Pierce et al. (2011)33 used the same study population, the former representing an earlier version of the study, published before full follow‐up had been completed. Only the Pierce et al. study33 is reported in this review. ^cSubsequent to the original screening, a placebo‐controlled randomised clinical trial (RCT) of influenza immunisation during pregnancy was included.11

Figure 2

Forest plot of individual study results for association between influenza illness during pregnancy and preterm birth. Small, black diamond markers indicate individual study point estimate, with corresponding 95% confidence intervals (CIs) represented by horizontal bars. ^aRisk of preterm birth per 100 women classified as having (exposed) or not having (unexposed) influenza illness/infection during pregnancy. ^bFor observational studies, ‘’ indicates a Newcastle‐Ottawa Score ≥8, risk of diagnostic ascertainment bias not rated as ‘very high’, and exposure not measured using self‐reported questionnaire. ^cCrude estimates were used in place of adjusted estimates when the latter were not provided. ^dHansen (2012)40 is shown twice: one estimate for 2009 A (pH1N1) and one for 2008–2009 influenza season. ^eHåberg (2013)39 did not provide the risk of preterm birth by exposure group. Overall risk in the study population was 5.4/100 singleton live births. ^fMorken (2011)41 studied spontaneous preterm birth only. ^gBaseline risk of preterm birth in the study population was not provided.44

Figure 3

Forest plot of individual study results for association between influenza illness during pregnancy and small‐for‐gestational‐age (SGA) birth. Small, black diamond markers indicate individual study point estimate, with corresponding 95% confidence intervals (CIs) represented by horizontal bars. ^aRisk of SGA birth per 100 women classified as having (exposed) or not having (unexposed) influenza illness/infection during pregnancy. ^b’’ indicates a Newcastle‐Ottawa Score ≥8, risk of diagnostic ascertainment bias not rated as ‘very high’, and exposure not measured using self‐reported questionnaire. ^cCrude estimates were used in place of adjusted estimates when the latter were not provided. ^dHansen (2012)40 is shown twice: one estimate for 2009 A (pH1N1) and one for 2008–2009 influenza season.

Figure 4

Forest plot of individual study results for association between influenza illness during pregnancy and fetal death. Small, black diamond markers indicate individual study point estimate, with corresponding 95% confidence intervals (CIs) represented by horizontal bars. ^aRisk of fetal death birth per 1000 women classified as having (exposed) or not having (unexposed) influenza illness/infection during pregnancy. ^bFor observational studies, ‘’ indicates a Newcastle‐Ottawa Score ≥8, risk of diagnostic ascertainment bias not rated as ‘very high’, and exposure not measured using self‐reported questionnaire. ^C Crude estimates were used in place of adjusted estimates when the latter were not provided. ^dNieto‐Pascual (2013)37 is shown twice: one estimate for abortion (RR: 0.40) and one for intrauterine fetal death (RR: 1.19). ^eNot further defined. ^fHåberg (2013)39 did not provide the risk of fetal death by exposure group. Overall risk in the study population was 4.3 fetal deaths per 1000 pregnancies. ^gBased on ICD‐9 diagnostic codes. ^hRisk of fetal death cannot be calculated because this was a case‐control study. ⁱIrving (2000)48 had no fetal death events among unexposed women and only one event among exposed women; therefore an effect estimate could not be computed.