1. To synthesise the best available evidence on the effectiveness of influenza vaccination during pregnancy, for pregnant women, her foetus and the child up to six months of age.
2. To synthesise the best available evidence on the types and frequency of adverse events for pregnant women, her foetus and the child up to six months of age, associated with influenza vaccination during pregnancy.
1. What are the beneficial effects of influenza vaccination during pregnancy for pregnant women, her foetus and child up to six months of age?
2. What are the adverse effects of influenza vaccination during pregnancy for pregnant women, her foetus and child up to six months of age?
Description of the condition
Influenza occurs seasonally and in most cases causes an acute self-limiting respiratory infection, and febrile illness. It is sometimes accompanied with other symptoms such as myalgia, headache, malaise and fatigue. Even though the incidence of influenza in pregnant women is similar compared to non-pregnant women, they are at an increased risk of respiratory complications, hospital and intensive care admissions, especially in epidemic and pandemic years.1, 2, 3, 4 The increase in risk is thought to be due to the immunologic and physiologic changes that occur in pregnancy. The immune system in pregnant women changes so that they can tolerate a genetically foreign foetus, with half of the genes coming from the father. These changes are not well understood and are thought to result in a shift from cell-mediated immunity towards humoral immunity. Combined with changes with increased heart rate, oxygen consumption and decreased lung capacity, it is thought to make pregnant women more susceptible to infectious diseases, including influenza.5 These changes may also have an impact on the effectiveness of the influenza vaccine in preventing complications from infection. Pregnancy places women at even greater risk if they have a coexisting illness or risk factor, such as asthma or obesity. Women in this group were shown to have poorer outcomes during the H1N1 influenza pandemic of 2009.1
The effect of influenza on the foetus in mothers infected with influenza is not as clear, due to conflicting or incomplete outcomes from epidemiological studies. Overall the risk of transplacental transmission is thought to be low, despite case reports of in-utero infection confirmed with viral culture6. In times of pandemic it does appear that the risk of harm to the foetus of pregnant women rises. A retrospective cohort study during the H1N1 09 pandemic found that pregnant women infected with influenza had an increased risk of preterm delivery and perinatal mortality, when compared to non-infected pregnant women7. This finding is consistent with observations during the pandemic of 1918-20, where women with influenza complicated by pneumonia had increased rates of spontaneous abortion8.
Children under 6 months of age have an immature immune system and are susceptible to complications from influenza. Neonates have also not had the opportunity to develop immunity to infectious diseases, due to the lack of exposure to pathogens. Surveillance undertaken during the 2003-04 influenza season in America by the Centre for Disease Control documented that 18 children under the age of six months died due to complications of influenza, making it the highest mortality rate in children under 17 years9. Similar to pregnant women, children aged 0-6 months are more susceptible to complications from influenza if they have an underlying comorbidity, such as, heart, lung, neurological or neuromuscular conditions9, 10. For children under the age of 6 months it may be possible that influenza antibodies transferred by their mother may provide some protection for the first couple of months of life.
Description of the intervention
Influenza vaccination is the primary preventive measure to reduce complications from influenza. Mutation of the virus from antigenic drift means that the make up of the vaccine may need to change on a yearly basis, or more frequently in the case of a pandemic strain. The accuracy of the match of the vaccine strains to the circulating strain has been shown to be important in the effectiveness of vaccine11. Currently trivalent influenza vaccines are recommended in an attempt to provide protection against three different strains of influenza. During the 2009 H1N1 pandemic, a monovalent vaccine was manufactured and administered to pregnant women and the general population. Due to the potential risk to the foetus from live vaccines, inactivated influenza vaccine is recommended for use in pregnant women.
Children under 6 months are currently unable to be vaccinated as the vaccine is not licensed in this age group and young infants are likely to have a modest immune response to influenza vaccines12. Research into passive immunity following vaccination of their mothers has shown that it may provide protective antibodies13. It is not clear however, if vaccination of pregnant women reduces influenza or respiratory infection in their child, with some studies finding an effect14, 15, 16, whilst others finding no such decrease in influenza or illness17, 18, 19.
Worldwide many health authorities including the World Health Organisation (WHO) recommend pregnant women receive an influenza vaccination during any trimester of pregnancy20. The practice of vaccination of pregnant women is not new and has been performed since 1950. The Advisory Committee on Immunisation Practices (ACIP) in America officially recommended the vaccine for pregnant women in 1997. Originally, the recommendation was for immunisation in the second and third trimester only, which changed in 2004 to include any trimester6. Other countries have gradually followed suit with the ACIP recommendations, some hastened by the H1N1 2009 pandemic. Countries such as Australia and the United Kingdom recommend the influenza vaccine for groups considered at higher risk, which includes pregnant women of any trimester. Other countries such as America and Canada recommend influenza vaccine for everyone over 6 months of age.
The safety of vaccines in pregnant women has long been a contentious issue, especially because of potential adverse reactions in both mother and foetus. Influenza vaccination has a long history, and the potential risk of harm from the vaccine is still listed as one of the main reasons women choose not to be vaccinated, or health professionals do not advocate for the vaccine26, 27, 28. There is mixed opinion in regards to the amount of evidence we have on the safety of the influenza vaccine. A pre H1N1 2009 review in the Lancet wrote “we only have a handful of studies on the safety of influenza vaccine in pregnancy”6, whilst other more recent articles post the H1N1 2009 pandemic, are prepared to say that the vaccine is categorically safe29.
Why it is important to do this review
The decision to recommend a vaccine requires weighing the evidence of benefit against the risk of harm. In a Cochrane review ‘Vaccines for preventing influenza in healthy adults’, Jefferson et al, noted that research on influenza vaccination had a high risk of bias30. No recent or underway systematic reviews were found in a search of JBI Library of Systematic Reviews, Cochrane Library, PubMed, Cinahl and Prospero. There are some thorough reviews and articles, but none have been done using published on this topic using systematic review methodology.
Since 2009, there have been many studies investigating influenza vaccine, due to the H1N1 2009 pandemic. The numbers of studies that look at effectiveness and safety in pregnant women have also increased, in part due to the severity of complications in pregnant women in the 2009 pandemic. This systematic review will accurately assess studies and provide clarity on the effectiveness and safety of vaccinating pregnant women.
Types of participants
This study will focus on pregnant women with or without risk factors for complications from influenza infection, their unborn child that is being carried at the time of the vaccination, and children up to the age of 6 months.
Types of intervention(s)
Inactivated influenza vaccination, irrespective of antigenic configuration or adjuvant, administered via any route, any dose, to pregnant women of any trimester.
Studies investigating the monovalent H1N1 vaccine will be assessed separately, as well as in combination with the standard trivalent vaccine.
Comparator: Pregnant women not vaccinated against influenza.
Types of outcomes
- Number and severity of influenza and influenza-like episodes and hospitalisation from influenza for pregnant women and their infant less than six months.
- Adverse effects for pregnant women, including but not limited to local reaction, fever, anaphylaxis, Guillain Barré Syndrome and maternal death.
- Effects on the foetus, including but not limited to spontaneous abortion, stillbirth, premature birth, birth weight, foetal growth and congenital malformation.
- Adverse effects of maternal immunisation on the infant up to six months of age.
The case definition of influenza will be accepted as a collection of respiratory and systemic symptoms as defined by the author, and/or laboratory confirmed influenza using viral isolation and/or serology.
Severity for the mother and infants will be assessed by hospitalisation and/or death, and/or severe disease such as pneumonia.
Types of studies
This review will consider both experimental and epidemiological study designs including randomised controlled trials, non-randomised controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies for inclusion.
The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilised in this review. An initial limited search of PUBMED and EMBASE will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English will be considered for inclusion in this review. Studies published from the inception of each database will be considered for inclusion in this review.
The databases to be searched include:
PUBMED, EMBASE, SCOPUS and Web of Science
The search for unpublished studies will include:
Scirus, MedNar, ProQuest Dissertations and Theses, Australian Digital Thesis program
Initial keywords to be used will be:
Influenza, Vaccine, Pregnancy
Assessment of methodological quality
Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardised critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.
Data will be extracted from papers included in the review using the standardised data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.
Quantitative data will, where possible be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.
Conflicts of interest
As this systematic review forms partial submission for the degree award of Masters of Clinical Sciences, a secondary reviewer will only be used for critical appraisal. Lynn Costi B Pharm, M Clin Sci candidate will conduct critical appraisal as secondary reviewer for this project.
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Appendix I: Appraisal instruments
MAStARI Appraisal instrument
Appendix II: Data extraction instruments
MAStARI data extraction instrument