Influenza vaccination in pregnant women: a systematic review

Hindawi Publishing Corporation ISRN Preventive Medicine Volume 2013, Article ID 879493, 8 pages http://dx.doi.org/10.5402/2013/879493 Research Article Influenza Vaccination in Pregnant Women: A Systematic Review Tais F. Galvao,1,2 Marcus T. Silva,3 Ivan R. Zimmermann,1 Luiz Antonio B. Lopes,4 Eneida F. Bernardo,4 and Mauricio G. Pereira1 1 Faculty of Medicine, University of Brasilia, Campus Universitario, Conj 16, Sala 77, 70904-970 Brasilia, DF, Brazil Getulio Vargas University Hospital, Federal University of Amazonas, Rua Apurina 4, Centro, 69020-170 Manaus, AM, Brazil 3 Faculty of Medicine, Federal University of Amazonas, Rua Afonso Pena 1053, Centro, 69020-160 Manaus, AM, Brazil 4 State Health Department, LACEN, Setor de Areas Isoladas Norte, Bloco B, 70086-900 Brasilia, DF, Brazil 2 Correspondence should be addressed to Tais F. Galvao; [email protected] Received 8 August 2013; Accepted 12 September 2013 Academic Editors: F. Pregliasco, H. Rashid, and S. H. Seo Copyright © 2013 Tais F. Galvao et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To assess the efects of the inactivated inluenza virus vaccine on inluenza outcomes in pregnant women and their infants. Methods. We performed a systematic review of the literature. We searched for randomized controlled trials and cohort studies in the MEDLINE, Embase, and other relevant databases (inception to September 2013). Two researchers selected studies and extracted the data independently. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the quality of the evidence. Results. We included eight studies out of 1,967 retrieved records. Inluenza vaccination in pregnant women signiicantly reduced the incidence of inluenza-like illness in mothers and their infants when compared with control groups (high-quality evidence) and reduced the incidence of laboratory-conirmed inluenza in infants (moderate-quality evidence). No diference was found with regard to inluenza-like illness with fever higher than 38∘ C (moderate-quality evidence) or upper respiratory infection (very-low-quality evidence) in mothers and infants. Conclusions. Maternal vaccination against inluenza was shown to prevent inluenza-like illness in women and infants; no diferences were found for other outcomes. As the quality of evidence was not high overall, further research is needed to increase conidence and could possibly change these estimates. 1. Introduction Pregnant women and neonates are at greater risk for influenza-related complications than the general population [1, 2]. Most institutions and organizations recommend that all pregnant women receive the trivalent inactivated inluenza virus vaccine [3–8]. Such endorsements rely on the immunogenic response of the mothers, the lack of teratogenicity, and the contrandication of immunization in children younger than six months [7, 9–11]. Despite the broad recommendation to vaccinate pregnant women against inluenza, coverage is still limited. A survey held by the Centers for Disease Control and Prevention involving women who were pregnant from October 2011 to January 2012 showed that only half of the respondents had been vaccinated and fewer than 10% had received the vaccine before giving birth [12]. Similar patterns were found in previous studies [13]. Although there is clear evidence of the eicacy of the inluenza vaccine for the general population [14], to our knowledge, a systematic approach with regard to the evidence of the therapeutic efects of inluenza vaccination in pregnant women is lacking. Our objective is to review the efects of inluenza vaccination in preventing inluenza-related outcomes in pregnant women and their infants. 2. Methods 2.1. Eligibility Criteria for the Included Studies. We selected randomized controlled trials or cohort studies that assessed the efects of inactivated inluenza vaccine in preventing inluenza-related outcomes in pregnant women and their ofspring compared with placebo, other vaccines, or no vaccines. We excluded studies that assessed monovalent vaccines, such as the H1N1 inluenza vaccine, because they are used for speciic epidemic situations. 2 2.2. Data Sources and Search Strategy. We searched for eligible studies in the following databases (from inception to September 2013): MEDLINE, Embase, Scopus, Centre for Reviews and Dissemination (CRD), Cochrane Central Register of Controlled Trials (CENTRAL), metaRegister of Current Controlled Trials (mCRT), Latin American and Caribbean Center on Health Sciences Information (LILACS), and Scientiic Electronic Library Online (SciELO). References to relevant publications in the ield were also screened to identify potentially eligible studies. here were no restrictions on language, length of followup, publication date, or publication status. hose databases comprise the main sources of cohort studies and clinical trials. We used the following search terms to search MEDLINE (via PubMed) and adapted the strategy for the other databases: (“inluenza, human”[mesh] or “inluenza”[tiab] or “human lu”[tiab] or “inluenza”[tiab] or “inluenzas”[tiab] or “grippe”[tiab] or “lu”[tiab] or “cold”[tiab]) and (“inluenza vaccines”[mesh] or “inluenza vaccines”[tiab] or “vaccine” [tiab] or “vaccine”[tiab] or “vaccines”[tiab]) and (“mothers” [mesh] or “mothers”[tiab] or “pregnancy”[mesh] or “pregnancy”[tiab] or “gestation”[tiab] or “pregnant women”[mesh] or “pregnant women”[tiab] or “pregnant”[tiab]) and (“infant”[mesh] or “infant”[tiab] or “infants”[tiab] or “infant, newborn”[mesh] or “newborn”[tiab] or “newborns”[tiab] or “fetus”[mesh] or “fetus”[tiab] or “foetus”[tiab] or “fetal”[tiab] or pregnancy). 2.3. Study Selection and Data Collection Process. Two independent reviewers (EB and LABL) selected the studies by assessing titles and abstracts and extracted the data. Disagreements were resolved by consensus or a third reviewer (TFG). he extracted data consisted of the following: year, country, study design, gestational age, type of vaccine, posology, comparators, sample size, followup, and outcomes. When necessary, we contacted the corresponding authors for additional information. 2.4. Risk of Bias and Quality Assessment. To assess the risk of bias of randomized controlled trials (RCT), we used the Cochrane Collaboration tool [15], which includes judgments about the sequence generation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias. For observational studies, we evaluated the following: eligibility criteria, measurements of exposures and outcomes, control of confounding, and followup [16]. We assessed the quality of evidence for each relevant outcome with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) [17, 18]. For this evaluation, we separated the bodies of evidence into “experimental” and “observational” centered on RCT and cohort studies, respectively. Following the GRADE approach, RCT started the evaluation with “high quality” and cohort studies with low quality of evidence. hen, we assessed the evidence against ive items that could decrease its quality: limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias. Ater assessing these items, the resulting quality of evidence could be rated as high, moderate, low, or ISRN Preventive Medicine 1,967 retrieved records: 727 MEDLINE 53 SciELO 670 Scopus 17 CRD 393 mRCT 15 CENTRAL 83 Embase 9 LILACS 1,943 excluded records: 1,638 not eligible 305 duplicates 24 records selected for full-text assessment 15 records excluded: 7 study designs or samples not suitable [19–25] 5 interventions or outcomes not assessed [26–30] 2 interventions not suitable for the review [31, 32] 1 conference abstract without full text [33] 9 included records (8 studies) [34–42] Figure 1: he results of the search, selection and inclusion of studies. very low. When distinct levels of quality were available for the same outcome, we considered the experimental design (RCT) evidence in rating the quality. he inal judgments regarding the risk of bias and evidence quality were achieved by consensus. We considered the quality assessment results when interpreting the indings. 2.5. Data Analysis. he primary outcome was the incidence of inluenza-like illness, which was deined as fever and either cough or sore throat. For infants’ outcomes, we deined small for gestational age as a weight below the 10th percentile and prematurity as birth before a gestational age of 37 complete weeks. We extracted the estimates along with 95% conidence intervals (95% CI) according to the data available in the original studies (relative risk (RR), odds ratio (OR), or hazard ratio (HR)). If reported, we only considered the adjusted estimates and did not perform further calculation. We attempted to perform meta-analyses using random efects models, if numerical data from studies allowed a summarization. 3. Results Our search retrieved 1,967 records. Twenty-three records were selected for full-text assessment, and nine were included in the review. he reasons for exclusions are depicted in Figure 1 [19–33]. were related to eight unique studies that enrolled 182,820 pregnant women and 182,246 neonates [34– 42]. 3.1. Study Characteristics. Table 1 describes the main characteristics of the included studies. Except for one, all studies ISRN Preventive Medicine 3 Table 1: Main characteristics of the included studies. Study Period of enrollment Country Hulka 1964 [34] 1962-1963 USA Inluenza vaccine group (�) Polyvalent inactivated Prospective cohort (363) Trivalent inactivated Retrospective cohort (3,707) Matched Trivalent inactivated retrospective cohort (225) Matched Trivalent inactivated retrospective cohort (3,160) Study design Black et al. 2004 [35] Munoz et al. 2005 [36] France et al. 2006 [37] 1997–2002 USA 1998–2003 USA 1995–2001 USA Zaman et al. 2008 [38, 39] 2004-2005 Bangladesh Randomized controlled trial 2002–2005 USA Prospective cohort 2004–2006 USA Retrospective cohort 2003–2008 USA Retrospective cohort Eick et al. 2011 [40] Omer et al. 2011 [41] Sheield et al. 2012 [42] Trivalent inactivated (172) Trivalent inactivated (573) Trivalent inactivated (578) Trivalent inactivated (8,690) Control group (�) Placebo (181) No vaccine (45,878) No vaccine (826) No vaccine (37,969) Pneumococcal vaccine (168) No vaccine (587) No vaccine (3,590) No vaccine (76,153) Gestational month at immunization >3rd∗ 7th–9th 4th–9th 4th–9th 7th–9th 4th–9th 1st–9th 1st–9th† ∗ Data assumed by the authors from information available in the paper. From October 2003 through March 2004, women were vaccinated in the second and third trimesters. From October 2004 through March 2008, women were vaccinated in all three trimesters. �: number of pregnant women in each group. USA: United States of America. † were published from 1990 to 2012. We identiied one RCT conducted in Bangladesh and seven cohort studies performed in the United States. he trivalent inactivated vaccine was the most common intervention and was assessed in seven studies [35–41]. One cohort used the polyvalent inactivated vaccine [34]. Newborns were not vaccinated. Only the RCT had an active control group (pneumococcal vaccine) [38]. Nearly the entire sample of pregnant women came from three retrospective cohorts [35, 37, 41]. he data in the retrospective studies came from medical records. he length of followup of each outcome varied among studies and lasted up to 36 weeks. Some studies adjusted their results for confounding factors, such as the women’s age, week of delivery, infant’s gender, and gestational age. Observational studies that compared baseline characteristics of the groups showed that most variables did not difer between the groups. Some studies showed that vaccinated women had a worse proile than unvaccinated women, which were of higher risk for complications [37], were older, and had higher body mass index, higher parity, and more multiple gestation [42]. One study observed that vaccinated mothers had more health insurance than unvaccinated ones [41]. All studies controlled the identiied confounding through multivariable analysis. 3.2. Outcomes and Quality of Evidence. We could not perform meta-analysis because the studies used diferent measures of association for the same outcome; the estimates are presented as available in the studies. Table 2 depicts the results of each outcome and the quality assessment. Mothers who received the inluenza vaccine had a lower incidence of inluenza-like illness, as did their infants (high-quality evidence), but there was no diference found for inluenza-like illness with fever higher than 38∘ C (moderatequality evidence). A lower incidence of inluenza in infants, as conirmed by laboratory tests, was also observed (moderatequality evidence). Very-low-quality evidence showed no diference between comparisons with regard to the incidence of upper respiratory infection, hospitalization, and medical visits for inluenza-like illness in mothers and infants. Two studies found no diference in the incidence of hospitalization for inluenza-like illness in infants [35, 37]; in one study, the reduction in the rate of hospital admission was signiicant [40]. With regard to medical visits for inluenzalike illness in infants, the observational studies showed no signiicant diferences [35, 37, 40], and the RCT showed a reduction in such rate [38] (moderate-quality evidence). For the outcomes prematurity and small for gestational age, conlicting results were found across the studies. One single cohort [42] indicated signiicant reduction in stillbirth and neonatal death among the inluenza-vaccinated group (moderate-quality evidence). We did not assess the incidence of adverse reactions because the included studies did not systematically evaluate this outcome. In general, inluenza vaccination had no association with local or minor systemic efects, fever, Apgar score at one minute, hyperbilirubinemia, or major malformations. 4. Discussion he inluenza vaccine was found to reduce the risk of inluenza-like illness in mothers and infants as well as the risk of laboratory-conirmed inluenza in infants. Such indings 4 Table 2: Outcomes and the quality of evidence of inluenza vaccination in pregnant women. Outcome Population Mothers Inluenza-like illness Inluenza-like illness with fever >38 C Infants Mothers Infants Laboratory-conirmed inluenza Infants ∘ Mothers Acute upper respiratory tract infection Infants Mothers Hospitalization for inluenza-like illness Infants Mothers Medical visit for inluenza-like illness Infants Prematurity Infants Infants Stillbirths Neonatal death Infants Infants Followup (weeks) 12 to 30 24 to 36∗ 24 24 to 36∗ 24 24 26 1.1 to 26 5 to 26 ≤13 6 ≤17 1.1 to 26 ≤13 26 16 or less 1.1 to 26 24 to 36∗ ≤17 ≤13 24 26 At birth At birth At birth At birth At birth At birth At birth At birth All months All months Measure of association RR IRR IRR IRR IRR IRR RR RR RR RR RR HR RR RR RR HR RR IRR HR RR IRR RR RR OR OR OR OR OR OR OR OR OR Result (95% CI) 0.56 (0.35–0.91)† 0.64 (0.43–0.96)† 0.71 (0.54–0.93)† 0.57 (0.30–1.09)† 0.72 (0.49–1.05)† 0.37 (0.15–0.95)† 0.59 (0.37–0.93) 1.84 (0.87–3.87)† 1.13 (0.87–1.44)† 0.83 (0.64–1.08)† 3.67 (0.23–58.47)† 0.63 (0.30–1.29) 3.73 (0.23–59.39)† 1.39 (0.42–4.58)† 0.61 (0.45–0.84) 1.00 (0.84–1.20) 1.35 (1.02–1.78)† 0.75 (0.39–1.44)† 0.96 (0.89–1.03) 0.96 (0.86–1.07) 0.58 (0.41–0.82)† 0.92 (0.73–1.16) 1.10 (0.97–1.23)† 0.67 (0.32–1.32) 0.48 (0.08–2.74) 0.60 (0.38–0.94) 0.86 (0.78–0.95) 0.44 (0.19–0.99) 0.74 (0.47–1.15) 1.00 (0.93–1.07) 0.61 (0.42–0.88) 0.55 (0.35–0.88) Quality of evidence High High Moderatea Moderatea Moderatea Very lowa,b Very lowa,b Very lowa,b Very lowa,b,c Moderatea Moderatea Very lowa,b Moderatea Moderatea Moderatea Moderatea IRR: incidence rate ratio; RR: relative risk; HR: hazard ratio; OR: odds ratio. Notes: ∗ women were followed during pregnancy, beginning at two weeks ater vaccination until delivery and continuing for 24 weeks ater delivery. † Data calculated by the authors from information available in the paper. ‡ Outcome measured at the peak of the inluenza season. Reasons for rating down the on-the-quality assessment using the GRADE approach. a Serious imprecision: low number of events. b he study design was observational. c Serious inconsistency: results vary greatly across studies. ISRN Preventive Medicine Small for gestational age Study Hulka 1964 [34] Zaman et al. 2008 [38] Zaman et al. 2008 [38] Zaman et al. 2008 [38] Zaman et al. 2008 [38] Zaman et al. 2008 [38] Eick et al. 2011 [40] Munoz et al. 2005 [36] Munoz et al. 2005 [36] France et al. 2006 [37] Munoz et al. 2005 [36] Black et al. 2004 [35] Munoz et al. 2005 [36] France et al. 2006 [37] Eick et al. 2011 [40] Black et al. 2004 [35] Munoz et al. 2005 [36]† Zaman et al. 2008 [38] Black et al. 2004 [35] France et al. 2006 [37] Zaman et al. 2008 [38] Eick et al. 2011 [40] Black et al. 2004 [35] Munoz et al. 2005 [36] Zaman et al. 2008 [38, 39] Omer et al. 2011 [41]‡ Sheield et al. 2012 [42]† Zaman et al. 2008 [38, 39] Omer et al. 2011[41]‡ Sheield et al. 2012 [42]† Sheield et al. 2012 [42]† Sheield et al. 2012 [42]† ISRN Preventive Medicine are supported by high- and moderate-quality evidence. Other outcomes showed no signiicant diferences between the compared groups. Adverse reactions were not systematically assessed across the studies, but there was no evidence of increase in clinically relevant risk related to inluenza vaccination during pregnancy. A big cohort study that focused on the safety of trivalent inactivated inluenza vaccine, however, did not ind any increased risk of adverse events and adverse obstetric events in the vaccinated mothers, when compared to unvaccinated pregnant women [43, 44]. Other factors can prevent inluenza in infants such as the efect of breast-feeding [45] and immunization of all the infant’s close contacts, also known as cocooning [46]. To avoid confounding and enable comparison, groups should be set by randomization. In the present review, however, only one RCT was identiied and included. Although most observational studies performed multivariate analyses, residual confounding may remain even ater adjustment because this statistical procedure cannot control for all biological variabilities [47]. Controversy may rise about the possible diferences between the groups from observational studies. Women receiving inluenza vaccine would have more medical attention and be healthier than unvaccinated pregnant women; thus, the result found would be attributed to the health proile of vaccinated women rather than to the vaccine itself. However, some studies reported that vaccinated women were at high risk during gestation, and this diference was also statistically controlled [37, 42]. Studies consistently reported that the patients and the clinicians made the decision about taking inluenza vaccine or not. Surveys about attitudes and beliefs of these actors regarding inluenza vaccination in pregnancy show that the proportion of people who do not believe vaccine is safe is still high [48, 49]. Another limitation of our review is the absence of the systematic reporting of adverse reactions. Although the incidence of adverse reaction was not shown to be a concern in the included studies, this lack of evidence may inadvertently lead to the conclusion that this risk is minimal or nonexistent [50]. Individuals with egg allergy, for example, require caution when receiving trivalent inactivated inluenza vaccine [7]. Previous narrative reviews concluded that inluenza vaccination is safe, that there has been no evidence of teratogenicity, and that many countries recommend inluenza vaccination among women with both healthy and high-risk pregnancies [9, 51–56]. he role of education of patients and doctors in increasing adherence to maternal vaccination was also emphasized [57–59]. One systematic review assessed the beneits and dangers of the inluenza vaccine in special populations—pregnant women included—but limited the eligible studies to RCTs only [60]. Another study reviewed the beneicial efects on the inluenza vaccine on infants only [61]. Some barriers still persist to the implementation of inluenza vaccine during pregnancy. Apprehensions about the use of thimerosal-containing inluenza vaccines, based on theoretical risk of harm to the fetal brain, were widely spread in scientiic and lay communities during the past 5 years [55, 62]. Subsequent research proved that no causal relation existed between immunization with vaccine containing thimerosal preservative—including exposure during pregnancy—and neuropsychological outcomes [63, 64]. he most recent report of the Global Advisory Committee on Vaccine Safety of the World Health Organization considered that available evidence strongly supports the safety of the use of thimerosal as a preservative for inactivated vaccines [65]. It is expected that with the availability of higher-quality evidence, such concerns can be demystiied. Attending to claims for more evidence [66, 67], several RCTs assessing inluenza vaccination in pregnancy are planned and some are ongoing [68–77]. Such RCTs focus on diferent populations, such as HIV-positive mothers, and factors that interfere with immunization coverage. We expect that, following the publication of these trials, the availability and quality of the evidence will radically improve. Additionally, the issue about the comparability between the vaccinated and unvaccinated groups will be more properly addressed. 5. Conclusion Maternal immunization for inluenza signiicantly reduced the incidence of inluenza-like illness in women and infants. For clinical practice, the indings reinforce the current recommendations to vaccinate all pregnant women against inluenza. We are not conident in making conclusions about other outcomes. Further studies should address this lack of evidence and enhance the overall quality of the outcomes. Conflict of Interests he authors declare that they have no conlict of interests. Acknowledgments he authors specially thank Andressa Waneska Martins da Silva for helping with the adaptation of this text and thier librarians: Bianca Lorrani Reis and Kenya Laura Barbosa for helping in the search update of the review. his research was partially funded by a public research agency (Brazilian National Research Council, CNPq). References [1] J. Lai, K. E. Fay, and J. A. Bocchini, “Update on childhood and adolescent immunizations: selected review of US recommendations and literature: part 2,” Current Opinion in Pediatrics, vol. 23, no. 4, pp. 470–481, 2011. [2] S. A. Rasmussen, D. J. Jamieson, and T. M. Uyeki, “Efects of inluenza on pregnant women and infants,” American Journal of Obstetrics and Gynecology, vol. 207, pp. S3–S8, 2012. [3] C. D. C. 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