Updated guidance on influenza vaccination during pregnancy

On this page

• Preamble
• Summary of information contained in this statement
• Introduction
  • Background on influenza vaccines, immunization programs and recommendations during pregnancy in Canada
  • Guidance objective
  • A note on language
• Methods
• Epidemiology
  • Estimated burden of influenza among pregnant persons
  • Estimated impact of influenza on perinatal outcomes
  • Estimated burden of influenza among infants under 6 months of age
  • Influenza vaccination coverage among pregnant persons in Canada
• Vaccine
  • Concurrent administration with other vaccines
  • Efficacy and effectiveness
  • Vaccine safety
• Ethics, equity, feasibility and acceptability considerations
  • Ethics considerations
  • Equity considerations
  • Feasibility considerations
  • Acceptability considerations
• Discussion
• Recommendations
• Research priorities
• Surveillance priorities
• Tables
• List of abbreviations
• Acknowledgements
• Appendix A: Review update methods
• Appendix B: Prisma flow diagram for review update
• References

Preamble

The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.

In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.

The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.

This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge.

This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Summary of information contained in this statement

The following highlights key information for immunization providers. Please refer to the remainder of the statement for details.

What

Seasonal influenza infection is a respiratory illness that can lead to serious complications and adverse outcomes, particularly for pregnant individuals, the developing fetus, and infants under 6 months old. Influenza vaccination is safe and the best way to prevent infection in both pregnant people and infants under 6 months old. Pregnant individuals are prioritized to receive influenza vaccines because of the increased risks of severe disease during pregnancy; despite this, influenza vaccination uptake among this group remains suboptimal.

The following recommendations for influenza vaccination in pregnancy supplement NACI's overarching recommendations for influenza vaccination, which are available in the NACI seasonal influenza vaccine statement. NACI recommends that individuals at any stage of pregnancy should receive an age-appropriate inactivated unadjuvanted (IIV) or recombinant influenza vaccine (RIV) each influenza season.

Who

This supplemental statement provides an evidence summary on the safety and vaccine effectiveness (VE) of influenza vaccination in pregnant individuals, and the benefits and risks to the developing fetus and infants under 6 months of age.

How

IIV or RIV should be offered annually, at any gestational age, during pregnancy. Influenza vaccination may be given at the same time as, or at any time before or after administration of another vaccine, including the COVID-19 or pertussis vaccine.

Why

Pregnant people, their fetuses, and infants are at high risk of complications from influenza; therefore, annual influenza vaccination during pregnancy is strongly recommended. Influenza vaccination during pregnancy has consistently been shown to be safe and is supported by numerous studies, moreover vaccination has been shown to reduce the morbidity and mortality associated with influenza infection. Additionally, since influenza-related outcomes experienced during pregnancy can negatively impact the development of the fetus, vaccination of the pregnant person helps protect the fetus. Furthermore, passive transfer of antibodies from vaccination during pregnancy protects newborns during their first months of life when they are at high risk of complications from influenza infection, and too young to be immunized. Overall, the evidence supports the safety and VEs of influenza vaccines during pregnancy.

Introduction

Background on influenza vaccines, immunization programs and recommendations during pregnancy in Canada

Prior to the COVID-19 pandemic, influenza viruses caused approximately 40,000 laboratory-confirmed influenza (LCI) cases, 12,200 hospitalizations, and 3,500 deaths among Canadians each year^{Footnote 1Footnote 2Footnote 3}. As such, NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have a contraindication to the vaccine. NACI has also identified groups at higher risk of influenza complications for whom influenza vaccination is particularly recommended (Strong NACI recommendation).

NACI has identified pregnant individuals as one of the high-risk groups for whom influenza immunization is particularly important. Because of pregnancy-related changes in anatomy and the immune and cardiovascular systems, pregnant individuals are at higher risk for severe influenza disease and related complications such as pneumonia, hospitalization, and death compared to non-pregnant individuals^{Footnote 4Footnote 5Footnote 6}. Influenza infection during pregnancy not only affects pregnant persons, but can also impact the developing fetus, and increases the risk of late-stage pregnancy loss, still birth, low birth weight and pre-term birth^{Footnote 6Footnote 7}. Therefore, immunizing pregnant persons against influenza is strongly recommended to protect both them and their infants from severe disease, especially as infants under 6 months of age are not eligible for influenza vaccination.

The NACI recommendations for the use of influenza vaccines in pregnancy and breastfeeding have evolved over time. Prior to 2007, NACI encouraged all pregnant people to be vaccinated against influenza but did not identify pregnant people without comorbidities as a priority group for vaccination programs. In 2007, NACI revised its recommendation to identify all pregnant individuals as a group for whom influenza vaccine is particularly recommended by nature of being at high-risk of influenza-related complications. NACI now also highlights that influenza vaccination in pregnancy protects both pregnant individuals and their newborn infants with passive immunity via transplacentally-transferred antibodies from the pregnant person up to the time infants can receive the vaccine themselves.

Despite pregnant people being prioritized to receive influenza vaccines because of the increased risks of severe disease, vaccine uptake remains lower compared to the non-pregnant population. Further, a disproportionate burden of disease and low uptake is observed among populations who are pregnant and racialized, Indigenous, younger, and/or have lower household income^{Footnote 8Footnote 9Footnote 10Footnote 11}.

More literature continues to be published on the safety, efficacy, and effectiveness of influenza vaccines in pregnancy. The need for this NACI Supplemental Statement on the use of influenza vaccines during pregnancy was triggered by a study identifying a potential risk of increased early spontaneous abortion in pregnant people who received influenza vaccines in 2010 and 2011^{Footnote 12}. Since then, several studies have been published finding no association of influenza vaccines administered during pregnancy and adverse outcomes in pregnant persons or infants^{Footnote 13Footnote 14Footnote 15Footnote 16}. NACI has taken this opportunity to review the safety, efficacy, and effectiveness of influenza vaccine in pregnancy. Moreover, this statement aims to synthesize the key information and evidence to support provincial and territorial vaccine programs and primary care providers in offering influenza vaccine to pregnant individuals.

The beneficial effects of immunization during pregnancy for the fetus as well as the newborn infant have been well documented. Vaccination during pregnancy has consistently been shown to be safe and protects the pregnant individual from vaccine-preventable diseases that may otherwise be acquired and transmitted to the fetus or infant. In addition, protective concentrations of antibodies are transferred to the fetus transplacentally, which usually results in infant protection from infection in the first few months of life. For information on the benefits and safety of recommended vaccines during pregnancy and breastfeeding, refer to the immunization in pregnancy and breastfeeding chapter in the Canadian Immunization Guide (CIG).

Guidance objective

The following advisory committee statement on influenza vaccination in pregnancy supplements NACI's overarching recommendations for influenza vaccination, which are available in the NACI seasonal influenza vaccine statement. The objective of this supplemental statement is to provide updated guidance on the use of influenza vaccination during pregnancy. The statement describes the disproportionate risk of morbidity and mortality for pregnant individuals and infants under 6 months old who acquire influenza compared to the general population; reviews the available evidence on the efficacy, effectiveness, and safety of influenza vaccination during pregnancy; and explores the EEFA considerations of immunizing pregnant people against influenza. Based on this body of evidence, the supplemental statement reaffirms the safety and importance of influenza vaccination during pregnancy.

Breastfeeding

It is recognized that pregnant and breastfeeding individuals are closely overlapping populations; however, there are differences in the considerations of vaccination for each. The purpose of this supplemental statement is to examine influenza vaccination in pregnancy specifically, given an identified possible concern regarding its safety. Therefore, this supplemental statement does not examine the safety and effectiveness of influenza vaccination during breastfeeding.

As stated in the NACI Seasonal Influenza Vaccine Statement, annual influenza vaccination is recommended during breastfeeding, and either non-live influenza vaccines or live attenuated influenza vaccine (LAIV) can be administered to breastfeeding individuals. There have been no identified safety signals for influenza vaccination in breastfeeding, and no hypothesized biological mechanism for a safety issue with currently authorized products. For more information on this topic, please see the aforementioned Statement and CIG chapter on immunization in pregnancy and breastfeeding.

A note on language

NACI recognizes that not all people giving birth or breastfeeding will identify as women or mothers. Much of the research available currently refers only to "women" when discussing pregnancy. When citing research, NACI refers to the language used in the study. In these cases, "woman" refers to someone who was assigned female at birth and "maternal" is used to identify the person who is pregnant or postpartum. For the purposes of this statement, the terms "woman", "women", and "maternal" should be considered to also apply to those individuals who do not specifically identify as female gender but are the parent gestating the fetus or breastfeeding/chestfeeding the infant.

Methods

In brief, the broad stages in the preparation of a NACI statement are:

1. Knowledge synthesis: retrieval and summary of literature, assessment of the quality of the evidence (summarized in Table 1. Summary of evidence).
2. Synthesis of the body of evidence: benefits (efficacy and effectiveness) and potential harms (safety), considering the quality of the synthesized evidence and, where applicable, the magnitude of effects observed across the studies.
3. Use of a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to EEFA are systematically assessed and integrated into the guidance^{Footnote 17}. Completion of health economic analyses as needed.
4. Use of the evidence to inform recommendations.

Further information on NACI's process and procedures is available elsewhere.

To meet the objectives of this statement, a de novo systematic review (SR) was conducted to gather evidence to inform NACI's recommendations regarding the use of influenza vaccines during pregnancy. The methodology was specified a priori in a written protocol^{Footnote 18}. The review protocol and knowledge synthesis were developed and performed in collaboration with the Methods and Applications Group for Indirect Comparisons (MAGIC) through the Drug Safety and Effectiveness Network (DSEN) and supervised by the NACI Influenza Working Group (IWG). An update to the literature search was completed by the NACI Secretariat in conjunction with a librarian from the Health Library of Health Canada and PHAC. A health economic analysis was not conducted as it was not deemed necessary for this statement. The evidence and proposed recommendations were presented to NACI for deliberation on April 27, 2023, and approved following a thorough review of the evidence. Relevant considerations, rationale for specific decisions, and knowledge gaps are described in the following sections.

For a comprehensive description of the review methods, including details on the study eligibility, literature search, study selection, data collection and statistical methods, please refer to Wolfe et al. (2020)^{Footnote 18}. Methods related to the review update completed by the NACI Secretariat are reported in Appendix A.

The policy question addressed in this statement is: Should pregnancy (regardless of gestational age) continue to be listed as one of the risk categories for priority influenza vaccination?

To meet the objective of this statement, other informal literature reviews were conducted as needed to gather data and information including:

• Epidemiology and estimated burden of influenza illness among pregnant persons and infants under 6 months of age;
• An environmental scan of recommendations and considerations for use of influenza vaccines during pregnancy in Canadian provinces and territories and in other high-income countries.

To develop comprehensive and appropriate immunization program recommendations, NACI considers several factors. In addition to critically appraising evidence on burden of disease and vaccine characteristics such as safety, efficacy, immunogenicity and effectiveness, NACI applies the EEFA framework with accompanying evidence-informed tools (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) to systematically consider these programmatic factors for the development of clear, comprehensive, appropriate recommendations for timely and transparent decision-making^{Footnote 19}. For details on the development and application of NACI's EEFA Framework and aforementioned evidence-informed tools, please see Ismail et al. (2020)^{Footnote 19}.

Epidemiology

Estimated burden of influenza among pregnant persons

Pregnant individuals are more susceptible to severe influenza illness throughout pregnancy, notably in the third trimester^{Footnote 20Footnote 21Footnote 22Footnote 23Footnote 24}. A 2019 meta-analysis (MA) on seasonal and pandemic (H1N1) influenza found that pregnant persons had a 7-times higher risk of influenza-associated hospital admission compared to non-pregnant persons (odds ratio [OR]=6.80; 95% confidence interval [CI]: 6.02-7.68), but were not at higher risk for intensive care unit (ICU) admission or death^{Footnote 22}. During the 2009 H1N1 pandemic however, a SR demonstrated that pregnant persons had a greater risk of influenza-related hospitalization, ICU admission, and death compared to non-pregnant persons^{Footnote 25}. Particularly, the median relative risk of influenza infection was 6.8 (range 3.5-25.3) compared to the general population.

Estimated impact of influenza on perinatal outcomes

Influenza infection during pregnancy can result in serious perinatal outcomes. A 2021 meta-analysis of worldwide studies on seasonal and pandemic (H1N1) influenza reported that pregnant individuals had a 3-times higher risk of stillbirth following influenza infection (risk ratio [RR]=3.62; 95% CI: 1.60 to 8.20)^{Footnote 26}. Studies from Australia, India, Peru, and Thailand also discovered a significant link between seasonal influenza infection during pregnancy to lower birth weight and late pregnancy loss^{Footnote 6Footnote 27}. Moreover, a 2017 SR reported limited, mixed evidence when evaluating the risk of adverse birth outcomes, including preterm birth, small-for-gestational-age (SGA) birth, or fetal death, in individuals with clinical influenza disease or LCI infection during pregnancy compared to those without influenza^{Footnote 28}. Although a small subgroup of higher-quality studies reported an association between pandemic H1N1 influenza (pH1N1) disease and preterm birth (with RRs ranging from 2.4 to 4.0 for severe disease) and fetal death (RR of 1.9 for mild-to-moderate disease and 4.2 for severe disease), no firm conclusions about the magnitude of the association can be drawn at this time based on these limited data.

Estimated burden of influenza among infants under 6 months of age

Young infants are particularly vulnerable to influenza infection and its complications due to their underdeveloped immune systems and ineligibility for the influenza vaccine. Influenza is a leading cause of respiratory infection among children under age 1 year and causes approximately 280,000 respiratory hospitalizations globally in those under 6 months old each year (95% CI: 150,000 to 344,000)^{Footnote 7Footnote 29Footnote 30Footnote 31}. In 2018, hospital admissions and in-hospital deaths due to seasonal influenza in children under 5 years of age occurred disproportionately in infants under 6 months old (23% and 36%, respectively) and predominantly in low and lower-middle-income countries^{Footnote 32}. In Canada, a national active surveillance study of pediatric influenza admissions revealed that infants under 6 months old accounted for 13.5% of children under 16 years of age admitted for influenza during 2010-2011 to 2020-2021, emphasizing the significant burden of influenza and its associated complications for this age group^{Footnote 33}. Furthermore US surveillance data from 2004-2012 reported that infants under 3 months of age were 40% more likely while those aged 3-6 months were 45% more likely to be admitted to the ICU with LCI compared to infants aged 6-12 months (OR=1.40; 95% CI: 1.04 to 1.88 and OR=1.45; 95% CI: 1.03 to 2.04, respectively)^{Footnote 29}. The influenza-associated mortality rate was estimated at 0.66 (95% CI: 0.53 to 0.82)^{Footnote 34}. During the 2009 H1N1 pandemic, a U.S. study reported a LCI hospitalization rate of 20.2 per 10,000 infants under 6 months of age^{Footnote 35}.

Influenza vaccination coverage among pregnant persons in Canada

In Canada, influenza vaccination coverage in pregnancy increased from 45.0% in 2019 to 52.7% in 2021^{Footnote 36}. However, coverage varied by province/territory; in 2021, Nova Scotia had the highest vaccination rate (82.5%) and Quebec had the lowest (44.2%). Overall, vaccination coverage increased in all jurisdictions from 2019 to 2021, except Saskatchewan (64.9% to 64.8%, respectively) and the Northwest Territories (84.8% to 71.7%, respectively). Vaccination coverage also varied by Indigenous status and income. The gap in influenza vaccination coverage between Indigenous pregnant people and non-Indigenous pregnant people increased in 2021 (vaccination coverage of 28% vs. 54% respectively) compared with 2019 (vaccination coverage of 35% vs. 46% respectively)^{Footnote 36}. As well, those in lower income groups (household income under $80,000) had lower vaccination rates against influenza relative to those in the highest household income group^{Footnote 36}.

Vaccine

Concurrent administration with other vaccines

Influenza vaccines may be administered concurrently with (i.e., same day), or at any time before or after, other vaccines recommended during pregnancy. Current evidence suggests that administering recommended vaccines concurrently during pregnancy is safe, despite the potential increase in local and systemic adverse reactions, including fever. There is no evidence to support adverse pregnancy sequelae from fever related to vaccine reactogenicity. A cohort study conducted in Australia involving 1,851 participants who received both IIV3 and tetanus toxoid, reduced diphtheria toxoid and reduced acellular pertussis (Tdap) vaccines concurrently during pregnancy found a low incidence of adverse events (AEs), providing support for the safety of concurrent vaccine administration during pregnancy^{Footnote 37}. Other studies have similarly reported no significant safety concerns with concurrent administration of these vaccines during pregnancy^{Footnote 38Footnote 39}.

Efficacy and effectiveness

The DSEN SR assessed the effect of seasonal influenza vaccination during pregnancy against influenza-related infection and hospitalization in pregnant persons and/or their infants using findings from 4 randomized controlled trials (RCTs)^{Footnote 40Footnote 41Footnote 42Footnote 43} and 2 observational studies^{Footnote 44Footnote 45}. Additional observational studies (n=6) were identified from the updated literature search reporting data on influenza VE in pregnant persons and/or their infants up to 6 months of age^{Footnote 46Footnote 47Footnote 48Footnote 49Footnote 50Footnote 51}.

Benefits to the pregnant person: Vaccine efficacy/effectiveness outcomes

Summary of study characteristics

Overall, 4 studies reported data on LCI and 3 reported data on hospitalization due to LCI infection during pregnancy or up to 6 months post-partum. Among those, 3 RCTs compared the efficacy of seasonal influenza vaccination during pregnancy to placebo (n=2)^{Footnote 40Footnote 41} or active comparator (n=1; meningococcal quadrivalent vaccine, Menactra^®, Sanofi)^{Footnote 42} against LCI from enrollment to 6 months post-partum. In the 3 RCTs, the occurrence of LCI among 5,089 people receiving IIV was compared to 4,985 people randomized to the placebo or active comparator group. One (1) prospective cohort study identified from the updated literature search evaluated the effectiveness of seasonal IIV4 compared to no influenza vaccination during pregnancy against LCI^{Footnote 46}. One (1) study identified from the DSEN SR that used a test-negative study design evaluated the VE of seasonal influenza vaccination amongst pregnant persons hospitalized for acute respiratory or febrile illness against LCI infection^{Footnote 44}. One (1) prospective cohort study, 1 prospective case-control study and 1 test-negative study design identified from the updated literature search evaluated the effectiveness of seasonal influenza vaccination during pregnancy on LCI hospitalization in pregnant persons^{Footnote 47Footnote 48Footnote 52}.

Summary of vaccine efficacy/effectiveness

A MA of the 3 RCTs suggested that seasonal influenza vaccination during pregnancy reduces the risk of lab-confirmed influenza infection in pregnant persons prior to delivery and up to 6 months post-partum (pooled VE=50%; 95% CI: 22 to 68%, I²=49.22%). The results suggest that the benefit of seasonal influenza vaccination was similar from delivery to 6 months post-partum (pooled VE=57%, 95% CI: 14 to 78%, I²=35.88%) compared to the period between enrollment and delivery (pooled VE=54%, 95% CI: -48 to 86%, I²=72.28%). One (1) prospective cohort study conducted during the 2019-2020 influenza season in Greece also found a protective effect of seasonal IIV4 against LCI infection in pregnant persons (adjusted VE [aVE]=43.5%, 95% CI: 28.4 to 55.6%)^{Footnote 46}.

Figure 1: Text description

Figure 1 depicts a forest plot showing results of a random-effects meta-analysis reporting the risk of maternal lab-confirmed influenza from enrolment to six months post-partum comparing trivalent inactivated seasonal influenza vaccines (TIIV) to a placebo or active comparator. The leftmost column lists the three included studies, each identified by the first author's name and the publication year. Next, to the right, the following information is presented: whether the study period was limited to the influenza season or not, the study's risk of bias, the point estimate of the risk ratio, the lower and upper bounds of the confidence interval (CI), and the number of individuals having the outcome of interest (events) over the sample size of the intervention (TIIV) and over the sample size of the comparison group (placebo/control). The x-axis representing the risk ratio estimates and 95% CI ranges from 0.1 to 10. The vertical line of 'no effect' appears at the value of 1 and separates the outcomes that favour TIIV (on the left) and the placebo/control (on the right). Each horizontal line of the forest plot represents an individual study with the results plotted as a box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The blue diamond shows the pooled result when the individual studies are combined together and averaged. The horizontal points of the diamond are the limit of the 95% CI of the combined point estimate.

The following information is depicted in Figure 1.

Effect estimates from the single studies

Author, year	Only during flu season?	Risk of bias	Risk ratio	Lower bound of the CI	Upper bound of the CI	TIIV events	TIIV sample size	Placebo/control events	Placebo/control sample size	Relative weight
Tapia et al., 2016	No	High	0.30	0.15	0.60	11	2108	40	2085	25.77
Madhi et al., 2014	No	Unclear	0.50	0.29	0.86	19	1062	38	1054	34.24
Steinhoff et al., 2017	Yes	Unclear	0.69	0.44	1.09	31	1847	44	1846	39.99

Pooled result

Statistical model	Risk ratio	Lower bound of the CI	Upper bound of the CI	TIIV events	TIIV sample size	Placebo/control events	Placebo/control sample size	Heterogeneity, I2
Random effect model	0.50	0.32	0.78	61	5089	122	4985	49.22

A MA of 2 test-negative studies suggested that seasonal influenza vaccination during pregnancy reduces the risk of hospitalization due to lab-confirmed influenza in pregnant persons prior to delivery and up to 42 days post-partum (pooled aVE=42%, 95% CI: 19 to 58%, I²=0%)^{Footnote 44Footnote 47}.

Figure 2: Text description

Figure 2 depicts a forest plot showing results of a random-effects meta-analysis of studies using a test-negative study design reporting the risk of maternal lab-confirmed influenza hospitalization during pregnancy or 42 days post-partum among those vaccinated with inactivated influenza vaccines (IIV) compared to unvaccinated individuals during pregnancy. The leftmost column lists the two included studies, each identified by the first author's name and the publication year. Next, to the right, the following information is presented: the log odds ratio (OR), the standard error (SE), the sample size of the intervention (IIV) and the comparison group (unvaccinated), the relative weight of the study, and the odds ratio with its corresponding 95% confidence interval (CI). The x-axis representing the odds ratio estimates and 95% CI ranges from 0.01 to 100. The vertical line of 'no effect' appears at the value of 1 and separates the outcomes that favour IIV (on the left) and no vaccine (on the right). Each horizontal line of the forest plot represents an individual study with the results plotted as a red box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The black diamond shows the pooled result when the individual studies are combined together and averaged. The horizontal points of the diamond are the limit of the 95% CI of the combined point estimate.

The following information is depicted in Figure 2.

Effect estimates from the single studies

Author, year	Log[Odds Ratio]	SE	IIV sample size	Unvaccinated sample size	Weight	OR [95% CI]
Nunes, 2022	-0.633	0.3357	148	253	25.1%	0.53 [0.28, 1.03]
Thompson, 2019	-0.5108	0.1943	169	821	74.9%	0.60 [0.41, 0.88]

Pooled result

Statistical model	TIIV sample size	Placebo sample size	Weight	OR [95% CI]	Heterogeneity, Tau2, Chi2, df (p-value), I2	Test for overall effect, Z (p-value)
Random effect model	317	1074	100.0%	0.58 [0.42, 0,81]	0.00; 0.10; 1 (P=0.75); 0%	3.22 (P=0.001)

One (1) prospective cohort study reported VE of 38% (95% CI: 14 to 55%) against LCI hospitalization during pregnancy or up to 2 days after delivery^{Footnote 48}.

Together, these studies suggest that seasonal influenza vaccination during pregnancy reduces the risk of LCI infection and hospitalization due to LCI during pregnancy and up to 6 months post-partum.

Infant benefits: Vaccine efficacy/effectiveness outcomes

Summary of study characteristics

Overall, 7 studies reported data on LCI infection. Among those, 4 RCTs compared the efficacy of IIV to placebo (n=2)^{Footnote 40Footnote 53} or active comparators (n=2; pneumococcal^{Footnote 43} or meningococcal vaccine^{Footnote 42}) during pregnancy against LCI infection in infants up to 6 months of age. Three (3) cohort studies identified from the updated literature search compared the effectiveness of seasonal influenza vaccination during pregnancy against LCI infection in infants up to 6 months of age^{Footnote 46Footnote 49Footnote 50}.

A total of 5 studies (3 test-negative studies, including 1 identified from the DSEN SR^{Footnote 45Footnote 47Footnote 51}, and 2 cohort studies^{Footnote 49Footnote 50} reported data on the effectiveness of influenza vaccination during pregnancy on hospitalization due to LCI infection in infants up to 6 months of age.

Summary of vaccine efficacy/effectiveness

A MA of the 4 RCTs demonstrated a protective effect of seasonal influenza vaccination during pregnancy against LCI infection in infants up to 6 months of age (pooled VE=37%, 95% CI: 22 to 49%, I²=0.00%). Results from the RCTs suggest that the greatest effect of seasonal influenza vaccination during pregnancy against LCI infection in infants was found from birth up to 2 months of age (pooled VE_{0 to <2 months}=61%, 95% CI: 17 to 81%, I²=39.57%), following which the protective effect of vaccination during pregnancy waned as infant age increased (pooled VE_{2 to <4 months}=42%, 95% CI: -13 to 70%, I²=59.67% and pooled VE_{4 to <6 months}=24%, 95% CI: -3 to 44%, I²=0.00), a biologically plausible finding due to the waning of the effects of passive transfer of antibodies in neonates.

Figure 3: Text description

Figure 3 depicts a forest plot showing results of a random-effects meta-analysis of randomized controlled trials reporting the risk of infant lab-confirmed influenza among infants born to pregnant persons vaccinated against influenza or receiving a placebo or active control during pregnancy. The leftmost column lists the four included studies, which are each identified by the first author's name and the publication year. Next, to the right, the following information is presented: whether the study period was limited to the influenza season or not, the study's risk of bias, the point estimate of the rate ratio, the lower and upper bounds of the confidence interval (CI), and the number of individuals having the outcome of interest (events) over the sample size in person-years of the intervention (TIIV; trivalent inactivated influenza vaccine) and over the sample size in person-years of the comparison group (placebo/control). The x-axis representing the rate ratio estimates and 95% CI ranges from 0.1 to 10. The vertical line of 'no effect' appears at the value of 1 and separates the outcomes that favour TIIV (on the left) and the placebo/control (on the right). Each horizontal line of the forest plot represents an individual study with the results plotted as a box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The blue diamond shows the pooled result when the individual studies are combined together and averaged. The horizontal points of the diamond are the limit of the 95% CI of the combined point estimate.

The following information is depicted in Figure 3.

Effect estimates from the single studies

Author, year	Only during flu season?	Risk of bias	Rate ratio	Lower bound of the CI	Upper bound of the CI	TIIV events	TIIV sample size (person-year)	Placebo/control events	Placebo/control sample size (person-year)	Relative weight
Zaman et al., 2008	Yes	High	0.37	0.14	0.95	6	73	16	73	4.97
Madhi et al., 2014	Yes	Unclear	0.53	0.30	0.92	19	231	36	230	14.17
Tapia et al., 2016	No	High	0.63	0.43	0.91	45	858	71	849	31.39
Steinhoff et al., 2017	Yes	Unclear	0.70	0.52	0.94	74	582	105	579	49.47

Pooled result

Statistical model	Rate ratio	Lower bound of the CI	Upper bound of the CI	TIIV events	TIIV sample size	Placebo/control events	Placebo/control sample size	Heterogeneity, I2
Random effect model	0.63	0.51	0.78	144	1744	228	1730	0.000

A MA of the 3 cohort studies demonstrated a protective effect of seasonal influenza vaccination during pregnancy against LCI infection in infants up to 6 months of age (pooled aVE=41%, 95% CI: 23 to 55%, I²=17%)^{Footnote 46Footnote 49Footnote 50}.

Figure 4: Text description

Figure 4 depicts a forest plot showing results of a random-effects meta-analysis of cohort studies reporting the risk of infant lab-confirmed influenza among infants born to pregnant persons vaccinated and unvaccinated against influenza during pregnancy. The leftmost column lists the three included studies, each identified by the first author's name and the publication year. Next, to the right, the following information is presented: the log odds ratio (OR), the standard error (SE), the relative weight of the study, and the odds ratio with its corresponding 95% confidence interval (CI). The x-axis representing the odds ratio estimates and 95% CI ranges from 0.01 to 100. The vertical line of 'no effect' appears at the value of 1 and separates the outcomes that favour influenza vaccine (on the left) and no vaccine (on the right). Each horizontal line of the forest plot represents an individual study with the results plotted as a red box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The black diamond shows the pooled result when the individual studies are combined together and averaged. The horizontal points of the diamond are the limit of the 95% CI of the combined point estimate.

The following information is depicted in Figure 4.

Effect estimates from the single studies

Author, year	Log[Odds Ratio]	SE	Weight	OR [95% CI]
Foo 2022	-1.1394	0.5004	7.2%	0.32 [0.12, 0.85]
Rowe 2021	-0.594	0.1742	45.9%	0.55 [0.39, 0.78]
Maltezou 2022	-0.3769	0.1717	46.9%	0.69 [0.49, 0.96]

Pooled result

Statistical model	Weight	OR [95% CI]	Heterogeneity, Tau2, Chi2, df (p-value), I2	Test for overall effect, Z (p-value)
Random effect model	100.0%	0.59 [0.45, 0.77]	0.01; 2.41; 2 (P=0.30); 17%	3.88 (P=0.0001)

A MA of the 3 test-negative studies demonstrated a protective effect of seasonal influenza vaccination during pregnancy against hospitalization due to LCI infection in infants up to 6 months of age (pooled aVE=42%, 95% CI: 16 to 59%, I²=71%)^{Footnote 45Footnote 47Footnote 51}. Two (2) cohort studies reported data on hospitalization due to LCI infection in infants up to 6 months of age, but only one demonstrated a significant protective effect of influenza vaccination during pregnancy (aVE, 95% CI: 62%, 9 to 84%^{Footnote 49}, and 21%, 95% CI: -18 to 47%^{Footnote 50}).

Figure 5: Text description

Figure 5 depicts a forest plot showing results of a fixed-effects meta-analysis of studies using a test-negative study design reporting the risk of lab-confirmed influenza hospitalization in infants up to six months of age born to pregnant persons vaccinated or unvaccinated against influenza during pregnancy. The leftmost column lists the three included studies, each identified by the first author's name and the publication year. Next, to the right, the following information is presented: the log odds ratio (OR), the standard error (SE), the relative weight of the study, and the odds ratio with its corresponding 95% confidence interval (CI). The x-axis representing the odds ratio estimates and 95% CI ranges from 0.01 to 100. The vertical line of 'no effect' appears at the value of 1 and separates the outcomes that favour influenza vaccine (on the left) and no vaccine (on the right). Each horizontal line of the forest plot represents an individual study with the results plotted as a red box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The black diamond shows the pooled result when the individual studies are combined together and averaged. The horizontal points of the diamond are the limit of the 95% CI of the combined point estimate.

The following information is depicted in Figure 5.

Effect estimates from the single studies

Author, year	Log[Odds Ratio]	SE	Weight	OR [95% CI]
Benowitz 2010	-2.4651	0.7644	5.7%	0.09 [0.02, 0.38]
McRae 2022	-0.462	0.2318	61.7%	0.63 [0.40, 0.99]
Nunes 2022	-0.3425	0.3189	32.6%	0.71 [0.38, 1.33]

Pooled result

Statistical model	Weight	OR [95% CI]	Heterogeneity, Chi2, df (p-value), I2	Test for overall effect, Z (p-value)
Fixed effect model	100.0%	0.58 [0.41, 0.84]	6.84; 2 (P=0.03); 71%	2.95 (P=0.003)

Together, these studies suggest that seasonal influenza vaccination during pregnancy reduces the risk of LCI infection and hospitalizations due to LCI infection in infants up to 6 months of age.

Vaccine safety

Summary of study characteristics

The DSEN SR on the safety of influenza vaccination during pregnancy evaluated non-obstetric serious adverse events (SAE) in pregnant persons related to the administration of seasonal influenza vaccination during pregnancy using findings from 3 RCTs and 3 cohort studies. Additionally, the SR included 4 RCTs and 24 observational studies, including 20 cohort and 4 case-control studies, addressing other safety and/or pregnancy/birth related outcomes (i.e., infant death, spontaneous abortion, stillbirth, preterm birth, SGA, low birth weight and congenital anomalies). Outcomes of seasonal influenza vaccination were compared with those for other vaccines (e.g., meningococcal, or pneumococcal vaccines), placebo or no vaccination.

Eleven (11) additional observational studies were identified from the updated literature search evaluating non-obstetric SAEs/AEs and other safety and/or pregnancy/birth outcomes (i.e., spontaneous abortion, stillbirth, preterm birth, SGA, low birth weight and congenital anomalies) related to the administration of influenza vaccine during pregnancy. Of those, 3 were single-arm cohort studies and one was a case series derived from registries of AEs of interest. These study designs were not included in the DSEN SR, but were included in the updated literature search to capture studies reporting data on the safety of administration during pregnancy of more recently licensed influenza vaccines that are based upon new different technologies, including quadrivalent mammalian cell culture-based vaccines (e.g., IIV4c; Flucelvax^® Quad) and RIV (e.g., quadrivalent recombinant influenza vaccines [RIV4]; Supemtek™), given the limited published peer-reviewed evidence on these vaccines.

Summary of vaccine safety

Harms to the pregnant person: Non-obstetric serious adverse events in pregnant people

Serious systemic reactions within 7 days of vaccination

Two (2) RCTs evaluated the risk of severe systemic reactions within 7 days of seasonal influenza vaccination in pregnant people. One (1) RCT conducted in South Africa by Madhi et al. (2014) found 27 of 181 people who received trivalent IIV (IIV3) (14.9%) and 19 of 172 who received a saline placebo (11.0%) experienced at least one severe systemic reaction, which included severe weakness/tiredness, headache, fever, joint pain, and muscle pain, within 7 days of vaccine administration^{Footnote 41}. A larger RCT conducted in Mali by Tapia et al. (2016) found that 2 of 2,105 women who received IIV3 (0.1%) and none of the 2,082 people who received meningococcal vaccine (0.0%) experienced a severe systemic adverse reaction within 7 days of vaccine administration^{Footnote 42}; the 2 severe reactions included febrile sensation and headache, and it was unclear whether those 2 events occurred in the same participant. No significant difference in the frequency of severe systemic reactions within 7 days of seasonal influenza vaccination was observed within each individual study (RR=1.35, 95% CI: 0.78 to 2.34^{Footnote 41}, and RR= 4.95, 95% CI: 0.24 to 102.95^{Footnote 42}); pooled estimates were not calculated given the substantial differences in the risks of SAEs in the intervention groups of the 2 studies and the control groups. There were likely unknown differences in outcomes definitions or other sources of heterogeneity.

Other serious non-obstetric adverse events

Two (2) RCTs, 6 cohort studies and 1 case-series reported data on other non-obstetric SAEs. One (1) RCT conducted by Madhi et al. (2014) found no difference in the occurrence of non-obstetric SAEs that were possibly or probably related to influenza vaccination within 30 days of vaccination administration (1 in 1,062 IIV3 and 0 in 1,054 saline placebo recipients; RR=2.98, 95% CI: 0.12 to 73.01)^{Footnote 41}. Another RCT conducted by Zaman et al. (2008) reported data on peripartum hospitalizations due to non-obstetric causes, with no apparent difference between IIV3 and pneumococcal vaccine recipients (1 event in 159 IIV3 and 2 events in 157 pneumococcal vaccine recipients; RR=0.49, 95% CI: 0.05 to 5.39)^{Footnote 43}.

Five (5) cohort studies reported non-obstetric SAEs either within 42 days of vaccination or within an unknown time period. In an American study, Munoz et al. (2005) found 2 hospitalization events unrelated to pregnancy in 225 vaccinated pregnant persons and 3 in 826 unvaccinated pregnant persons within 42 days of intervention, with none related to vaccination (RR=2.45, 95% CI: 0.41 to 14.56)^{Footnote 54}. The cause of hospitalization included influenza illness with emesis and migraine headache in the vaccinated group, and influenza with emesis, appendicitis, and calculus ureter-stent replacement in the unvaccinated group. Finally, 4 cohort studies did not report any SAEs after the administration of IIV4 (Fluzone^® Quadrivalent)^{Footnote 55}, IIV4-cc (Flucelvax^® Quad)^{Footnote 56} and IIV3 during pregnancy^{Footnote 57Footnote 58}.

Guillain-Barré syndrome

One (1) cohort study and 1 case-series reported data on Guillain-Barré syndrome following seasonal influenza vaccination during pregnancy. Within 42 days of intervention, Nordin et al. (2013) identified no inpatient cases of Guillain-Barré syndrome in 75,906 vaccinated pregnant persons and 1 case in 147,992 unvaccinated pregnant persons in the USA (RR=0.65, 95% CI: 0.03 to 15.95)^{Footnote 59}. One (1) case series identified from the updated literature search reported 1 case (n=239) of Guillain-Barré syndrome that occurred 5 days after IIV4 administration during the third trimester of pregnancy in a 29-year-old woman. The woman gave birth to a healthy baby while recovering and has fully recovered^{Footnote 60}.

These studies suggest that pregnant persons vaccinated with seasonal influenza vaccines during pregnancy appear to experience the same rates of non-obstetric serious AEs as non-pregnant persons vaccinated with seasonal influenza vaccines, pregnant persons vaccinated with pneumococcal or meningococcal vaccines, as well as unvaccinated pregnant persons.

Infant harms: Infant death from 0 to 6 months of age

Four (4) RCTs compared the effect of seasonal influenza vaccination to placebo (n=2)^{Footnote 40Footnote 41} or active comparators (n=2; meningococcal quadrivalent vaccine^{Footnote 42} or 23-valent pneumococcal vaccine^{Footnote 43}) during pregnancy on infant death up to 6 months of age. All RCTs were conducted in low-to-middle-income countries, and the control group infant death risk ranged from 1.1% and 2.8%. A MA of these RCTs did not demonstrate an association between seasonal influenza vaccination during pregnancy and infant death (pooled RR=1.14, 95% CI: 0.86 to 1.50, I²=9.33).

Figure 6: Text description

Figure 6 depicts a forest plot showing results of a random-effects meta-analysis of randomized controlled trials reporting the risk of infant death up to six months of age among infants born to pregnant persons vaccinated or unvaccinated against influenza during pregnancy. The leftmost column lists the four included studies, each identified by the first author's name and the publication year. Next, to the right, the following information is presented: whether the study period was limited to the influenza season or not, the study's risk of bias, the point estimate of the risk ratio, the lower and upper bounds of the confidence interval (CI), and the number of individuals having the outcome of interest (events) over the sample size of the intervention (influenza vaccine) and over the sample size of the comparison group (placebo/control). The x-axis representing the rate ratio estimates and 95% CI ranges from 0.01 to 100. The vertical line of 'no effect' appears at the value of 1 and separates the outcomes that favour influenza vaccine (on the left) and placebo/control (on the right). Each horizontal line of the forest plot represents an individual study with the results plotted as a box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The blue diamond shows the pooled result when the individual studies are combined together and averaged. The horizontal points of the diamond are the limit of the 95% CI of the combined point estimate.

The following information is depicted in Figure 6.

Effect estimates from the single studies

Author, year	Only during flu season?	Risk of bias	Risk ratio	Lower bound of the CI	Upper bound of the CI	IIV events	IIV sample size	Placebo/control events	Placebo/control sample size	Relative weight
Zaman et al., 2008	Yes	High	0.50	0.05	5.49	1	166	2	167	1.32
Madhi et al., 2014	No	Unclear	0.71	0.37	1.37	15	1026	21	1023	16.37
Steinhoff et al., 2017	Yes	Unclear	1.18	0.81	1.70	60	1815	51	1813	45.44
Tapia et al., 2016	No	High	1.39	0.92	2.11	52	2064	37	2041	36.87

Pooled result

Statistical model	Risk ratio	Lower bound of the CI	Upper bound of the CI	IIV events	IIV sample size	Placebo/control events	Placebo/control sample size	Heterogeneity, I2
Random effect model	1.14	0.86	1.50	128	5071	111	5044	9.326

No infant death was reported from a prospective cohort study conducted in Japan among infants diagnosed with fever from 0 to 6 months of age born from vaccinated and unvaccinated pregnant people (0/36 IIV3 and 0/47 unvaccinated)^{Footnote 61}.

These studies suggest that seasonal influenza vaccination during pregnancy is not associated with infant death up to 6 months of age.

Infant harms: Spontaneous abortion

Three (3) cohort studies and 3 observational studies evaluated the effect of IIV during pregnancy on spontaneous abortion (SAB) under 20 and 22 weeks gestational age. Two (2) prospective cohort studies were included in a MA and no association between IIV and SAB was demonstrated (pooled adjusted hazard ratio [aHR]=0.77, 95% CI: 0.31 to 1.89, I²=37.51%)^{Footnote 62Footnote 63}. A third prospective cohort study conducted in Japan found the same risk of SAB under 22 gestational weeks (0.4%) among unvaccinated and vaccinated pregnant people (first-trimester vaccination)^{Footnote 64}.

Figure 7: Text description

Figure 7 depicts a forest plot showing results of a random-effects meta-analysis of cohort studies reporting the risk of spontaneous abortion among pregnant persons vaccinated and unvaccinated against seasonal influenza during pregnancy. The leftmost column lists the two included studies, each identified by the first author's name and the publication year. Next, to the right, the following information is presented: the exposure time, the country where the study was conducted, whether the study period was limited to influenza season or not, the study's risk of bias, the point estimate of the hazard ratio, the lower and upper bounds of the confidence interval (CI), and the number of individuals having the outcome of interest (events) over the sample size of the intervention (TIIV; trivalent inactivated influenza vaccine) and over the sample size of the comparison group (no vaccine). The x-axis representing the risk ratio estimates and 95% confidence interval (CI) ranges from 0.1 to 10. The vertical line of 'no effect' appears at the value of 1 and separates the outcomes that favour TIIV (on the left) and no vaccine (on the right). Each horizontal line of the forest plot represents an individual study with the results plotted as a box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The blue diamond shows the pooled result when the individual studies are combined together and averaged. The horizontal points of the diamond are the limit of the 95% CI of the combined point estimate.

The following information is depicted in Figure 7.

Effect estimates from the single studies

Author, year	Exposure time	Country	Only during flu season?	Risk of bias	Hazard ratio	Lower bound of the CI	Upper bound of the CI	TIIV events	TIIV sample size	No vaccine events	No vaccine sample size	Relative weight
Chambers et al., 2016	Week 1-20	USA	No	7	1.09	0.49	2.41	11	380	15	267	63.18
Mohammed et al., 2020	Week 9-16 up to 20	Australia	No	7	0.42	0.12	1.46	3	603	31	650	36.82

Pooled result

Statistical model	Hazard ratio	Lower bound of the CI	Upper bound of the CI	TIIV events	TIIV sample size	no vaccine events	No vaccine sample size	Heterogeneity, I2
Random effect model	0.77	0.31	1.89	14	983	46	917	37.51

Two (2) retrospective case-control studies conducted by the same set of investigators in the US assessed the association between SAB and vaccination within 28 days prior to SAB. The first study was conducted over 2 consecutive influenza seasons following the 2009 H1N1 pandemic^{Footnote 12}. The authors observed an increased risk of SAB following IIV only in the first post-pandemic season (2010-2011 adjusted odds ratio [aOR] = 3.70, 95% CI: 1.40 to 9.40) but not the second (2011-2012 aOR=1.40, 95% CI: 0.60 to 3.30). Post-hoc analyses of 2010-2011 data found that people who had been previously vaccinated in the 2009-2010 season with the H1N1 pandemic vaccine were at increased risk of SAB following IIV in the 2010-2011 season, which was not observed in those not vaccinated with the H1N1 pandemic vaccine in 2009-2010 but vaccinated with IIV in 2010-2011.

The second study conducted over 3 consecutive influenza seasons (i.e., 2012-2013, 2013-2014 and 2014-2015) by Donahue, et al. (2019) sought to confirm the association observed between SAB and history of influenza vaccination^{Footnote 65}. No association was found between seasonal influenza vaccination during pregnancy and SAB within 28 days of vaccination (aOR = 0.80, 95% CI: 0.60 to 1.10), including among people vaccinated in the previous season. The authors state that the association of prior season vaccination found in the initial study may have been a spurious result due to residual confounding or random error, or it may have been due to differences in the time periods of the 2 studies. One (1) cohort study identified from the updated literature search conducted in the US over the 2008-2009 to 2013-2014 influenza seasons did not find an association between the history of pandemic H1N1 containing influenza vaccination and spontaneous abortion within 28 days of vaccination (aHR=1.19, 95% CI: 0.97 to 1.46)^{Footnote 66}.

Three (3) additional single-arm cohort studies and 1 case series identified from the updated literature search reported data on SAB in persons vaccinated with IIV during pregnancy. The 1 case-series study described SABs after vaccine exposure that were reported from several countries to the Fluzone^® Quadrivalent (IIV4, Sanofi) Pregnancy Registry from 2013 to 2019. Four (4) SABs were captured by the pregnancy registry; however, the frequency of neonatal adverse outcomes presented in the study are consistent across the literature and do not exceed the expected rates in the general population. One (1) cohort study described SABs identified among IIV-exposed pregnancies that were reported to the US registry or through GSK worldwide safety database. From the US registries, 3 spontaneous abortions were reported from 115 pregnancies. From the 3 SABs reported, there were 2 SABs in which exposure occurred during the first trimester, and 1 for which the date of exposure was unknown. From the worldwide database, 26 out of 676 reports of influenza vaccine exposure during pregnancy resulted in SABs; however, there was no information on exposure timing. SABs originate during the first and second trimesters of pregnancy (i.e., at risk periods), therefore, exposures occurring in the third trimester are not likely to be causally associated. Two (2) prospective cohort studies that were conducted to fulfill a post-marketing commitment to the US Food and Drug Administration (FDA) evaluated the safety of IIV4 (Afluria^® Quadrivalent) and IIV4-cc (Flucelvax^® Quadrivalent) administrated during pregnancy. The studies reported 2.5 and 1.9% SABs after administration of IIV4 and IIV4-cc during the first trimester of pregnancy, respectively, which was not increased when compared to the rate in the general US population. Overall, from the 3 single-arm cohort studies and the case series study, no safety signals were identified among pregnant persons exposed to IIV.

One cohort study did not observe a significant association between immunization with a pandemic H1N1-containing influenza vaccine prior to 21 6/7 weeks' gestation and spontaneous abortion, regardless of the vaccine received in the prior influenza season (i.e., pandemic H1N1-containing influenza vaccine or non-pandemic-H1N1-containing influenza vaccine)^{Footnote 66}.

Together, these studies suggest that seasonal influenza vaccination during pregnancy does not appear to be associated with an increased risk of spontaneous abortion.

Infant harms: Other birth outcomes

No safety issues were identified regarding the administration of seasonal influenza vaccines during pregnancy, with respect to other adverse birth outcomes including stillbirth (≥18-22 gestational weeks or ≥500g); preterm birth; SGA; low birth weight; and congenital anomalies identified at birth or up to 6 months of age. Evidence was derived from both RCTs and observational studies, including case-control studies and cohort studies. Limited published peer-reviewed evidence regarding the safety of administration during pregnancy of more recently licensed influenza vaccines that are based upon new different technologies, including mammalian IIV-cc (e.g., IIV4-cc; Flucelvax^® Quad) and RIV (e.g., RIV4; Supemtek™) was identified. Details on other adverse birth outcomes are available in Table 1. Summary of evidence.

Ethics, equity, feasibility and acceptability considerations

Ethics considerations

NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm; maintaining trust; respect for persons and fostering autonomy; and promoting justice and equity. NACI also identified the ethical imperative to protect the public's health and the health of the most vulnerable. NACI addressed the identified ethical considerations throughout the vaccine guidance development process and these considerations have been incorporated into the recommendations.

Equity considerations

No distinct inequities that may arise because of the recommendations were identified. However, the following intersectional factors described in NACI's EEFA framework were considered: pre-existing conditions; social factors; place of residence; and access to healthcare.

Pregnant individuals and individuals with chronic health conditions are identified among the groups at greater risk of influenza-related complications or hospitalization^{Footnote 1}. Racialized people and Indigenous people may also be at increased risk for severe influenza disease due to a variety of intersecting factors, including underlying medical conditions and potentially decreased access to healthcare resources. Canadians with low household incomes, unstable or crowded housing, and individuals living in remote or rural areas may face increased exposure to influenza and challenges accessing healthcare^{Footnote 36}. Gender-diverse pregnant people are more likely to face discrimination or poor treatment in medical settings and may be more reluctant to seek healthcare. Individuals such as international students and newcomers to Canada may face language barriers in accessing healthcare.

Feasibility considerations

Based on the feasibility matrix NACI completed as part of its EEFA analysis, there were no distinct, significant issues identified for feasibility with respect to resource and integration implications that could impact decision making for this recommendation since this is an existing immunization program. Recommendations that allow vaccination at all gestational stages of pregnancy would reduce feasibility barriers in vaccination programs.

Acceptability considerations

NACI evaluated the following acceptability considerations when making its recommendations: individual beliefs; values and knowledge; socio-demographic factors; and systemic factors. Refusing vaccination during pregnancy is common globally, resulting in a low vaccine coverage rate^{Footnote 70}. Low vaccine uptake in pregnant individuals has been partly attributed to vaccine hesitancy, which is complex and multidimensional and can be influenced by individual, logistical, cultural, and sociologic factors.

A pregnant individual's beliefs, values, and knowledge about seasonal influenza and vaccination affect the acceptance of vaccination during pregnancy^{Footnote 70Footnote 71}. Individuals who believe the vaccines to be safe and effective and individuals who perceive themselves to be at risk of seasonal influenza and have the desire to protect others against the virus are more likely to pursue vaccination^{Footnote 70Footnote 71Footnote 72Footnote 73}. Conversely, pregnant individuals are less likely to pursue vaccination if they have anti-vaccination beliefs and concerns regarding the effects of vaccination on the health of the individual and fetus, and limited knowledge regarding the risks of influenza and the benefits of vaccination during pregnancy^{Footnote 70Footnote 71Footnote 73}. In the 2021 Canadian Survey on Vaccination During Pregnancy Study (SVP), 51% of participants responded that their reason for not getting the influenza vaccine during pregnancy was "not wanting to be vaccinated during pregnancy"^{Footnote 36}. Furthermore, evidence from Okoli et al. (2021) suggests a potential vulnerability of multiparous women with respect to the uptake of preventive care^{Footnote 74}, as they may assume that their current pregnancy will be uneventful because previous pregnancies were uneventful and may become complacent about vaccination. These data suggest that programs designed to enhance pregnant individuals' information and vaccine literacy may promote greater seasonal influenza vaccine acceptance during pregnancy^{Footnote 74}. Additionally, it is important to note that in 2021, the SVP reported a significant increase (53%) in influenza vaccination among pregnant individuals since the 2019 survey (45%)^{Footnote 36}.

Systemic factors contribute to the acceptability of seasonal influenza vaccination among pregnant individuals. Systems and policies or delivery models that promote universal access to vaccines are most effective at improving uptake and coverage in the Canadian context^{Footnote 72}. Healthcare providers also play an important role in offering the influenza vaccine and positively influencing pregnant individuals' perceptions of seasonal influenza vaccination^{Footnote 70Footnote 71Footnote 73Footnote 75Footnote 76}. Increased access to trusted healthcare providers who inform pregnant individuals of the benefits and recommendations of seasonal influenza vaccination during pregnancy is associated with increased acceptability^{Footnote 77}. Qiu et al. (2021)'s internationally sourced SR findings suggest that a healthcare provider's recommendation was a main facilitator of vaccine acceptability among pregnant individuals, and its absence was the main barrier reported among unvaccinated women^{Footnote 78}. Blanchard-Rohner et al. (2012) found in their Switzerland based study that most past-partum people neither recalled being recommended vaccination nor informed about the risks of influenza during pregnancy^{Footnote 79}. Evidence from the SVP study (2021) supports these conclusions in the Canadian context with the proportion of women vaccinated against influenza during pregnancy being substantially higher among women who received a recommendation to be vaccinated (70%), compared to those who did not receive a recommendation to be vaccinated (14%)^{Footnote 36}. Providers' knowledge and beliefs about the influenza vaccine, their experiences supporting pregnant individuals, as well as their workload and time constraints, affect their practices in advocating for the influenza vaccine during pregnancy^{Footnote 80}. These findings suggest that improved access to healthcare providers who are well informed and can communicate the importance of seasonal influenza during pregnancy is the most likely way to increase vaccine acceptability.

Impact of COVID-19 pandemic on vaccination during pregnancy

The COVID-19 pandemic has affected the acceptability of vaccination and seasonal influenza vaccination. The Childhood National Immunization Coverage Survey (CNICS) collects information on national immunization coverage for vaccines administered to children and pregnant individuals. Data from the CNICS released in December 2022 showed the proportion of pregnant people who were more inclined to get vaccinated as a result of the pandemic varied across provinces and territories, from a low of 9% (Quebec) to a high of 32% (Yukon). Survey results also showed that the pandemic increased intent to receive vaccination among racialized groups; for example, a significantly higher proportion of Filipino Canadians (39%) and South Asian Canadians (26%) were more inclined to get vaccinated as a result of the pandemic relative to non-Indigenous and non-racialized people (14%)^{Footnote 81}.

Furthermore, the SVP study (2021) identified systematic barriers to receiving vaccinations in Canada in the context of the COVID-19 pandemic. This survey (2021) found that 11% of the pregnant individuals surveyed reported that they encountered an obstacle or delayed vaccination during the COVID-19 pandemic. Of those, 73% reported limited appointment availability, 40% were concerned about being exposed to COVID-19, 25% reported a lack of walk-in options, and 12% received recommendations from a doctor or local public health authority to delay vaccination^{Footnote 36}.

Discussion

The present SR and MA examined current literature on the use of influenza vaccines during pregnancy. Findings from this review suggest that influenza vaccination during pregnancy is effective in reducing the risk of LCI infection and hospitalization in both pregnant individuals and their infants up to 6 months post-partum. Overall, the evidence from this review indicates that seasonal influenza vaccine efficacy and effectiveness in pregnant individuals appear to be comparable to the general population of healthy adults and consistent with VE point estimates reported in a previous MA by Osterholm, et al. (2012)^{Footnote 82}.

The evidence also suggests that influenza vaccination during pregnancy does not increase the risk of non-obstetric SAEs in pregnant persons; infant death; spontaneous abortion; stillbirth; pre-term birth; small for gestational age; low birth weight; and congenital anomalies. In fact, some studies suggested a protective effect of influenza vaccination for stillbirth^{Footnote 83Footnote 84Footnote 85} and low birth weight^{Footnote 63Footnote 86Footnote 87Footnote 88Footnote 89}.

The SR and MA findings are in accordance with other reviews that have been undertaken to evaluate the efficacy/effectiveness of influenza vaccination during pregnancy^{Footnote 15Footnote 16Footnote 90}. By comparison, the SR and MA by Quach et al. (2020) reported similar protective effects of seasonal influenza vaccine against LCI in pregnant persons (RR=0.15, 95% CI: 0.06 to 0.36 and OR=0.37, 95% CI: 0.23 to 0.61)^{Footnote 16}. Moreover, Nunes et al. (2017) and Jarvis et al. (2020) consistently reported similar protective effects, with meta-analyses demonstrating a reduction in the risk of LCI in infants born to the vaccinated parent (RR=0.52, 95% CI: 0.41 to 0.67^{Footnote 90} and RR=0.66, 95% CI: 0.50 to 0.85^{Footnote 15}). Minor differences in the pooled results from the findings of the present review may be attributed to variations in the study inclusion criteria, MA methods and other factors.

The findings of this SR are also consistent with previous reviews that investigated the safety of influenza vaccines administered during pregnancy and found no significant association with increased safety risk^{Footnote 13Footnote 14Footnote 15Footnote 16Footnote 90Footnote 91}. Particularly, Minozzi et al. (2022) and Hansen et al. (2021) reported pooled estimates that support the present review's findings, demonstrating a lack of association between the influenza vaccine and infant death (RR=1.24, 95% CI: 0.96 to 1.60^{Footnote 13} and RR=1.11, 95% CI: 0.87 to 1.41)^{Footnote 14}. Furthermore, current evidence suggests that there are no adverse early childhood health outcomes associated with influenza immunization during pregnancy^{Footnote 92Footnote 93Footnote 94}.

Despite similarities in the estimates of efficacy and effectiveness of influenza vaccines during pregnancy, limitations in the included studies in this review should be noted. Firstly, adjustment for confounding was not consistently conducted in the observational studies, nor was accounting for immortal time bias for time-dependent outcomes. With respect to study design, there was high variability in the outcome definitions and the time points for some outcomes. Furthermore, it was unclear if some RCT outcomes could be generalized to the Canadian context. Finally, assumptions were made regarding equivalence of effect estimates and for VE estimates, as the concordance of influenza vaccine strains with circulating strains was not considered.

Beyond the scope of this review, a wide range of additional influenza vaccine efficacy/effectiveness and safety outcomes regarding influenza vaccination during pregnancy have been systematically explored in the literature. For example, Jarvis et al. (2020) and Quach et al. (2020) assessed influenza vaccine efficacy/effectiveness during pregnancy by investigating the incidence of influenza-like illness (ILI) and other respiratory illnesses^{Footnote 15Footnote 16}. Conversely, Hansen et al. (2021) assessed seasonal influenza vaccine safety by reporting on non-influenza infectious AEs, all-cause mortality, and mortality from presumed infectious causes^{Footnote 14}, whereas Jarvis et al. (2020) reported long-term respiratory conditions (asthma)^{Footnote 15}.

Studies considering the impact of timing of influenza vaccination on protection of the pregnant individual and fetus/newborn are limited. A 2019 SR and MA on optimal timing on influenza vaccination during pregnancy found that individuals vaccinated later during pregnancy had a greater immune response to vaccination and increased antibody transfer to the fetus^{Footnote 95}. However, prioritizing vaccination during a later gestational age could leave the pregnant person vulnerable to influenza infection for a significant proportion of the pregnancy and may be challenging to implement programmatically.

NACI will continue to monitor the evidence base and will update its guidance as needed.

Recommendations

Following the review of available evidence summarized above, as well as the assessment of EFFA considerations with the EEFA Framework, the following section outlines the evidence-informed recommendations made by NACI regarding influenza vaccination in pregnancy. NACI will continue to carefully monitor the scientific developments related to influenza vaccines, as well as ongoing vaccine pharmacovigilance, and will update its recommendations as required. Additional information on the strength of NACI recommendations is available in Table 4.

The following recommendation for influenza vaccination in pregnancy supplements NACI's overarching recommendations for influenza vaccination, which are available in the NACI seasonal influenza vaccine statement. The overarching NACI recommendation for influenza vaccination is that an age-appropriate influenza vaccine should be offered annually to anyone 6 months of age and older (Strong NACI Recommendation), noting product-specific contraindications.

1. NACI recommends that influenza vaccine should be offered to pregnant individuals. Recommended products include: IIV-SD, IIV-cc, and RIV. (Strong NACI Recommendation)

• There has been no identified safety signal regarding the use of RIV during pregnancy although published clinical data are limited.
• There has been no identified safety signal regarding the use of LAIV in pregnancy, although there are more data on the safety of other influenza vaccine products in pregnancy. There is also evidence that IIV has higher efficacy than LAIV in healthy adults. Note that vaccination with LAIV during pregnancy should not be considered a reason to terminate pregnancy.
• The only adjuvanted vaccine in Canada for the 2023/2024 influenza season is the adjuvanted inactivated trivalent influenza vaccine (IIV3-Adj), which is authorized for infants 6 to 23 months (Fluad Pediatric^®) and adults 65 years and older (Fluad^®). There has been no identified safety signal regarding adjuvanted influenza vaccines in pregnancy; however, IIV3-Adj is not authorized for people of reproductive age.
• The only high-dose vaccine in Canada for the 2023/2024 influenza season is the high-dose inactivated quadrivalent influenza vaccine IIV4-HD (Fluzone^® High-Dose Quadrivalent) which is authorized for adults 65 years and older. There has been no identified safety signal regarding high-dose influenza vaccines in pregnancy, however, IIV4-HD is not authorized for people of reproductive age.

Summary of evidence and rationale:

• The safety of influenza vaccination during pregnancy is consistently supported by numerous studies, including clinical trials and observational studies, and routine pharmacovigilance data from safety reporting systems.
• Published data, including currently available studies of fetal death, spontaneous abortion, and congenital malformations, do not report unexpected or concerning patterns. The evidence reaffirms that seasonal influenza vaccination during pregnancy does not appear to be associated with significant safety issues with respect to adverse birth outcomes or maternal non-obstetric SAEs.
• Published data continue to demonstrate the efficacy/effectiveness of influenza vaccination during pregnancy for protection against LCI infection and to help mitigate the severity of influenza infection.
• The efficacy/effectiveness of seasonal influenza vaccination in pregnant individuals is comparable to the general adult population.
• Studies have demonstrated that infants receive protection from maternal antibodies as a result of influenza vaccination during pregnancy, and their results suggest that seasonal vaccination during pregnancy reduces the risk of LCI infections and LCI hospitalizations in infants up to 6 months of age.

2. NACI recommends that influenza vaccination should be offered at any stage of pregnancy (i.e., in any trimester). (Strong NACI recommendation)

• If an individual's pregnancy extends over 2 influenza seasons, that person may receive 2 doses of influenza vaccine (i.e., one dose in each season, during the course of the pregnancy).

Summary of evidence and rationale:

• There is insufficient evidence to establish the optimal timing of influenza vaccination for maternal or fetal/newborn outcomes.
• Prioritizing vaccination during a specific gestational stage may lead to programmatic challenges and missed vaccination opportunities.

3. NACI recommends the inclusion of all pregnant individuals, at any stage of pregnancy, among those who are particularly recommended to receive influenza vaccination. (Strong NACI recommendation)

Summary of evidence and rationale:

• The evidence consistently shows an association between pregnancy and increased disease severity with influenza infection. This includes hospitalization, admission to the ICU, invasive mechanical ventilation, and maternal mortality.
• There is also a higher risk of adverse neonatal outcomes (e.g., premature delivery, low birth weight, NICU admission) with influenza infection during pregnancy.
  • The risks for preterm delivery, low birth weight and admission to the NICU increase with disease severity in the pregnant person.
• Infants under 6 months are at increased risk of hospitalization due to influenza infection compared to children from other ages. However, influenza vaccine is not effective in infants under 6 months; therefore, passive immunization of fetuses through transplacentally transmitted anti-influenza antibodies is currently the best available prevention strategy.
• Despite the increased risks of severe disease there is a suboptimal uptake of influenza vaccination during pregnancy in Canada, with only approximately 53% of pregnant individuals receiving the vaccine in 2021.
  • Among pregnant people, there is a disproportionate burden of disease and low vaccine uptake among those who are racialized, Indigenous, younger, low-income, and/or living in rural settings.

4. NACI reiterates its recommendation that influenza vaccination may be given at the same time as, or at any time before or after administration of another vaccine, including COVID-19 or pertussis vaccine. (Strong NACI recommendation)

• Every appropriate opportunity to immunize during pregnancy, with any immunization for which the pregnant person is eligible, should be taken.

Summary of evidence and rationale:

• No known safety signal for concurrent administration of influenza with another vaccine during pregnancy has been identified.
• Administration of multiple vaccines at the same visit is a strategy for increasing immunization uptake.

Research priorities

• Study the longer-term outcomes of infants and children exposed to influenza infection in-utero.
• Research on seasonal influenza illness and vaccination rates among pregnant individuals and infants outside of a 2009 H1N1 pandemic context, particularly during/following the COVID-19-pandemic.
• Collect national-level influenza surveillance data for pregnant individuals and infants under 6 months of age in Canada will help to better define the burden of disease for pregnant people and infants.
• Study the longer-term outcomes for children born to individuals vaccinated during pregnancy.
• Collect additional safety data for newer vaccine technologies, including cell culture and RIV.
• Study the timing of influenza immunization in pregnant individuals with respect to duration or waning of protection against infection and severe disease.
• Examine vaccine confidence and acceptability among pregnant individuals in Canada, especially among racialized groups.
• Investigate range and complex interplay of factors that influence acceptability of influenza immunization in general and for high-risk groups (including pregnant individuals).
• Study the COVID-19 pandemic's potential ongoing impact on vaccine hesitancy and maternal vaccine uptake.
• Learn more about patient, provider, and system-level barriers to vaccination in pregnancy in Canada, including:
  • Policy and structural factors;
  • Patients' knowledge, understanding and beliefs about influenza vaccination during pregnancy, especially given the heterogeneity of Canada's population (i.e., differences in socioeconomic and cultural backgrounds and differences in trust in the medical system).

Surveillance priorities

Ongoing and systematic data collection, analysis, interpretation, and timely dissemination is fundamental to planning, implementation, evaluation, and evidence-based decision-making. To support such efforts, NACI encourages ongoing surveillance and continued expansion of surveillance details in the epidemiology of influenza in Canada.

Overall, there is a gap in knowledge on the impact of seasonal influenza among pregnant persons and perinatal/postnatal outcomes in Canada and worldwide. To date, most epidemiological studies have focused on the 2009 H1N1 pandemic in certain high-income countries (e.g., US) and report inconsistent findings on the association between influenza illness and adverse perinatal outcomes. There is also a shortage of studies conducted after the COVID-19 pandemic, beginning in late 2019/early 2020. Therefore, more updated surveillance on seasonal influenza among pregnant persons and young infants in low, medium, and high-income countries, including Canada, is needed to better understand the burden of disease and develop targeted vaccine campaigns for these high-risk groups.

In Canada, FluWatch, the national surveillance system, monitors the spread of influenza and ILI by province/territory and age group, but does not specify pregnancy status. Therefore, initiatives are needed to collect influenza information (e.g., ILI incidence, viral strain, hospitalization) from pregnant persons to inform appropriate public health efforts such as targeted vaccination campaigns and education.

Tables

Table 1. Summary of evidence

Study	Outcome	Vaccine	Study design	Participants (n/N)	Summary of key findings	Summary
						Level of evidence	Quality
Vaccine efficacy
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the Canadian Institutes of Health Research (CIHR) and the Drug Safety and Effectiveness Network (DSEN)	Lab-confirmed influenza (LCI) assessed by RT-PCR during pregnancy and up to 6 months post-partum	IIV3 (Vaxigrip®, Sanofi) Placebo Active control: Meningococcal quadrivalent vaccine (Menactra®, Sanofi Pasteur)	RCTsFootnote 40Footnote 41Footnote 42 Countries: Nepal (n=1) Mali (n=1) South Africa (n=1) Follow-up: Not restricted to influenza season between 2011 and 2014 (n=2) One RCT was restricted to the 2011-2012 and 2012-2013 influenza seasonsFootnote 40 Funding: Non-industry (n=3)	Pregnant persons (n=10,074) IIV3: n=5,089 (50.5%) Placebo or active control: n=4,985 (49.5%)	The MA included 3 RCTs The pooled vaccine efficacy was 50% (95% CI: 22 to 68%), I2=49.22%	Level I	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Laboratory-confirmed influenza (LCI) assessed by RT-PCR in infant up to 6 months of age	IIV3 (Vaxigrip®, Sanofi and Fluarix, GSK) Placebo Active control: Meningococcal quadrivalent vaccine (Menactra®, Sanofi Pasteur) and Pneumococcal vaccine, 23-valent (Pneumovax® 23, Merck)	RCTsFootnote 40Footnote 41Footnote 42Footnote 43 Countries: Bangladesh (n=1) South Africa (n=1) Mali (n=1) Nepal (n=1) Follow up: Not restricted to influenza season between 2004 and 2014 (n=3) One RCT was restricted to the 2011-2012 and 2012-2013 influenza seasonsFootnote 40 Funding: Non-industry (n=3) and mixed funding (n=1)	Infants up to 6 months of age (n=3,474) IIV3: n=1,744 (50.2%) Placebo or active control: n=1,730 (49.8%)	The MA included 4 RCTS The pooled vaccine efficacy was 37% (95% CI: 22 to 49%), I2=0.00%	Level I	Fair
Vaccine effectiveness
Maltezou HC, Stavros S, Asimakopoulos G et al. Effectiveness of maternal vaccination with quadrivalent inactivated influenza vaccine in pregnant women and their infants in 2019-2020. 2022Footnote 46 Funded by Sanofi	Lab-confirmed influenza assessed by RT-PCR during pregnancy	IIV4 (VaxigripTetra®, Sanofi)	Prospective cohort study Country: Greece Follow up: 2019-2020 influenza season Funding: Industry	Pregnant persons 18 to 45 years of age (n=636) IIV4: n=406 (63.8%) Unvaccinated: n=230 (36.2%)	The aVE was 43.5% (95% CI: 28.4 to 55.6%)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN And study identified from the update literature search: Nunes MC, Walaza S, Meiring S, et al. Effectiveness of influenza vaccination of pregnant women for prevention of maternal and early infant influenza-associated hospitalizations in South Africa: A prospective test-negative study. 2022Footnote 47 Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service; the US Centers for Disease Control and Prevention; and the Bill and Melinda Gates Foundation	Hospitalization due to LCI assessed by RT-PCR during pregnancy or up to 42 days post-partum	IIV (Seasonal influenza vaccine)	TND studies (Thompson 2019 and Nunes 2022)Footnote 44Footnote 47 Countries: Australia (n=1) Canada (n=1) United States (n=1) Israel (n=1) South Africa (n=1) Follow up: 7 influenza seasons between 2010 and 2018 Funding: Non-industry (n=2)	Pregnant persons (n=1,391) IIV: n=317 (22.8%) Unvaccinated: n=1,074 (77.2%)	The MA included 2 TND studies The pooled aVE was 42% (95% CI: 19 to 59%), I2=0.00%	Level II-2	Good
Vousden N, Bunch K, Knight M et al. Incidence, risk factors and impact of seasonal influenza in pregnancy: A national cohort study. 2021Footnote 48 Funded by the National Institute for Health Research (NIHR)	Hospitalization due to LCI assessed by virological testing at any stage of pregnancy or up to 2 days after delivery	IIV (Seasonal influenza vaccine)	Prospective cohort study Country: United Kingdom Follow up: Not restricted to the influenza season between 2016/11/01 to 2018/10/30 Funding: Non-industry	Individuals hospitalized at any stage of pregnancy or up to 2 days after delivery (n=1,099) IIV: n=320 (29.1%) Unvaccinated: n=466 (42.4%) Unknown/missing: n=313 (28.5%)	The VE was 38% (95% CI: 14 to 55%)	Level II-2	Fair
Studies identified from the update literature search: Maltezou HC, Stavros S, Asimakopoulos G et al. Effectiveness of maternal vaccination with quadrivalent inactivated influenza vaccine in pregnant women and their infants in 2019-2020. 2022Footnote 46 Funded by Sanofi Foo D, Sarna M, Pereira G et al. Longitudinal, population-based cohort study of prenatal influenza vaccination and influenza infection in childhood. 2022Footnote 49 Funded by the National Health and Medical Research Council, Curtin University Graduate Research School, Wesfarmers Centre of Vaccines and Infectious Disease Rowe SL, Leder K, Perrett KP, et al. Maternal Vaccination and Infant Influenza and Pertussis. 2021Footnote 50 Funded by the Victoria State Government Department of Health in Australia as part of routine vaccine program evaluation	LCI in infants up to 6 months of age	IIV (Seasonal influenza vaccine)	Cohort studiesFootnote 46Footnote 49Footnote 50 Countries: Greece Australia Follow up: 2019-2020 influenza season (n=1) Not restricted to influenza season (n=2) between 2012 and 2017 Funding: Non-industry (n=2) and industry (n=1)	Infants up to 6 months of age (n=296,611) Infants born to vaccinated gestational parent: n=100,042 (33.7%) Infants born to unvaccinated gestational parent: n=196,569 (66.3%)	The MA included 3 cohort studies The pooled VE was 41% (95% CI: 23 to 55), I2=17%	Level II-2	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN And studies identified from the update literature search: Nunes MC, Walaza S, Meiring S, et al. Effectiveness of influenza vaccination of pregnant women for prevention of maternal and early infant influenza-associated hospitalizations in South Africa: A prospective test-negative study. 2022Footnote 47 Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service; the US Centers for Disease Control and Prevention; and the Bill and Melinda Gates Foundation McRae J, Blyth CC, Cheng AC et al. Preventing severe influenza in Australian infants: Maternal influenza vaccine effectiveness in the PAEDS-FluCAN networks using the test-negative design. 2022Footnote 51 Funded by the National Health and Medical Research Council, Australian Government Department of Health, and Departments of Health in NSW, Victoria, Queensland, South Australia, Western Australia, and the Northern Territory	Hospitalization due to LCI infection in infants up to 6 months of age	IIV (Seasonal influenza vaccine)	TND studies (Benowitz 2010, McRae 2022, and Nunes 2022)Footnote 45Footnote 47Footnote 51 Countries: Australia (n=1) South Africa (n=1) United States (n=1) Follow up: 5 influenza seasons between 2015 to 2019 (n=2) Not restricted to influenza season (n=1) between 2000/10 and 2009/04 Funding: Non-industry (n=3)	Infants up to 6 months of age (n=1,702) Infants born to vaccinated gestational parent: n=612 (36.0%) Infants born to unvaccinated gestational parent: n=1,090 (64.0%)	The MA included 3 TND studies The pooled aVE was 42% (95% CI: 16 to 59%), I2=71%	Level II-2	Fair
Foo D, Sarna M, Pereira G et al. Longitudinal, population-based cohort study of prenatal influenza vaccination and influenza infection in childhood. 2022Footnote 49 Funded by the National Health and Medical Research Council, Curtin University Graduate Research School, Wesfarmers Centre of Vaccines and Infectious Disease	Hospitalization due to LCI in infants up to 6 months of age	IIV (Seasonal influenza vaccine)	Retrospective, population-based cohort study Country: Australia Follow up: Not restricted to influenza seasons between 2012/04/01 and 2017/07/01 Funding: Non-industry	Singleton, live-born infants (n=124,760) Infants born to vaccinated gestational parent: n=14,396 (11.5%) Infants born to unvaccinated gestational parent: n=110,364 (88.5%)	The aVE was 62% (95% CI: 9 to 84%)	Level II-2	Good
Rowe SL, Leder K, Perrett KP, et al. Maternal Vaccination and Infant Influenza and Pertussis. 2021Footnote 50 Funded by the Victoria State Government Department of Health in Australia as part of routine vaccine program evaluation	Hospitalization due to LCI in infants up to 6 months of age	IIV (Seasonal influenza vaccine)	Retrospective cohort study Country: Australia Follow up: Not restricted to influenza seasons between 2015/09/01 and 2017/12/31 Funding: Non-industry	Infants up to 6 months of age (n=185,404) Infants born to vaccinated gestational parent: n=85,365 (46.0%) Infants born to unvaccinated gestational parent: n=86,012 (46.4%) Infants born to gestational parents with missing/unknown vaccination status: n=14,027 (7.6%)	The aVE was 20.85% (95% CI: -17.74 to 46.79%) in infant under 6 months of age The aVE was 34.37% (95% CI: -14.83 to 62.49%) in infant under 2 months of age, and the aVE was 4.00% (95% CI: -66.75 to 44.73%) in infants 2 months to under 6 months of age	Level II-2	Fair
Safety
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Non-obstetric SAEs in pregnant persons: severe systemic reactions within 7 days of intervention	IIV3 (Vaxigrip®, Sanofi) Placebo Active control: Meningococcal quadrivalent vaccine (Menactra®, Sanofi)	2 RCTsFootnote 41Footnote 42 Countries: Mali (n=1) South Africa (n=1) Follow up: Not restricted to influenza season (n=2) between 2011 and 2014 Funding: Non-industry (n=2)	Pregnant individuals (n=4,540) IIV3: n=2,286 (50.3%) Placebo: n=172 (3.8%) Active control: n=2,082 (45.9%)	No discernible difference between groups in either included RCT Tapia et al., 2016: 2 of 2,105 vaccinated and 0 of 2,082 controlFootnote 42 Madhi et al., 2014: 27 of 181 vaccinated and 19 of 172 control (p=0.36)Footnote 41	Level I	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Non-obstetric SAEs in pregnant persons: peripartum hospitalization	IIV3 (Fluarix, GSK) Active control: Pneumococcal vaccine, 23-valent (Pneumovax® 23, Merck)	RCTFootnote 43 Country: Bangladesh Follow up: Not restricted to influenza season between 2004/08 and 2005/11 Funding: Mixed funding	Pregnant individuals (n=316) IIV3: n=159 (50.3%) Active control: n=157 (49.7%)	Single RCT found no apparent difference in risk between IIV3 (1 event/159) and active control (2 events/157)	Level I	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Non-obstetric SAEs in pregnant persons: events possibly or probably related to vaccination within 30 days of intervention	IIV3 (Vaxigrip®, Sanofi) Placebo	RCTFootnote 41 Country: South Africa Follow up: Enrolled before the 2011-2012 and 2012-2013 influenza seasons Funding: Non-industry	Pregnant individuals (n=2,116) IIV3: n=1,062 (50.2%) Placebo: n=1,054 (49.8%)	Single RCT found no apparent difference in risk between IIV3 (1/1,062) and placebo (0/1,054) groups	Level I	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Non-obstetric SAEs in pregnant persons: events unrelated to pregnancy causing hospitalization within 42 days of vaccine administration	IIV3 (Seasonal influenza vaccine)	Retrospective cohort studyFootnote 54 Country: United States Follow up: 6 influenza seasons between 1998 and 2003 Funding: Non-industry	Pregnant persons in the second or third trimester of gestation (n=1,051) IIV3: n=225 (21.4%) Unvaccinated: n=826 (78.6%)	A single cohort study found no apparent difference in risk between IIV3 (2/225) and unvaccinated pregnant individuals (3/826)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Non-obstetric SAEs in pregnant persons: inpatient Guillain-Barré syndrome within 42 days	IIV3 (Seasonal influenza vaccine)	Retrospective cohort studyFootnote 59 Country: United States Follow up: Not restricted to influenza season between 2002/06/01 and 2009/07/31 Funding: Non-industry and insurance	Pregnant persons in the first trimester of gestation (n=223,898) IIV3: n=75,906 (33.9%) Unvaccinated: n=147,992 (66.1%)	A single cohort study found no significant difference between IIV3 vaccinated (0/75,906) and unvaccinated (1/147,992) pregnant persons (p=0.34)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Non-obstetric SAEs in pregnant persons: no defined and time of follow-up not reported	IIV3 (Seasonal influenza vaccine)	Retrospective cohort studyFootnote 58 Country: India Follow up: Not restricted to influenza season between 2016/01 and 2018/03 Funding: Not reported	Pregnant persons (n=346) IIV3: n=288 (83.2%) Unvaccinated: n=58 (16.8%)	No events found in a single cohort study of 288 IIV3 vaccinated and 58 unvaccinated pregnant persons	Level II-2	Fair
Ledlie S, Gandhi-Banga S, Shrestha et al. Exposure to quadrivalent influenza vaccine during pregnancy: Results from a global pregnancy registry. 2022Footnote 60 Funded by Sanofi	Non-obstetric AEs in pregnant persons: Guillain-Barré syndrome	IIV4 (Fluzone® Quadrivalent; Sanofi)	Retrospective and prospective case series, multicenters Countries: United States Canada Australia Brazil Mexico New Zealand Thailand Costa Rica India Follow up: Between 2013/08 and 2019/09 Funding: Industry	Individuals of reproductive age who were exposed to IIV4 during pregnancy or within 30 days of their last menstrual period (n=239) Trimester of exposure, n (%): First: 42 (17.6%) Second: 82 (34.3%) Third: 58 (24.3%) Unknown: 57 (23.9%)	One (0.4%) case of Guillain-Barré syndrome occurred within 5 days of vaccination in a 29-year-old female who recovered and gave birth to a healthy baby while recovering	Level III	Poor Reporting bias High rate of loss to follow up (80%)
Carreras JJ, Lluch JA, Taboada JA, et al. Adverse events in pregnant women with the tetravalent influenza vaccine obtained from cell cultures. 2022Footnote 56 Funded by Seqirus	Non-obstetric AEs in pregnant persons at any time after vaccine administration	IIV4-cc (Flucelvax® Quad, Seqirus)	Retrospective cohort study, multicenter Country: Spain Follow up: 2019-2020 influenza season Funding: Industry	Individuals 18 to 64 years old vaccinated with IIV4-cc (n=244,731) Pregnant individuals: N=24,870 (10.2%) Non-pregnant individuals: N=219,861 (89.8%)	The rate of AEs per 100,000 doses administered was 4.0 and 5.9 in pregnant and non-pregnant individuals, respectively No serious AE were reported among pregnant individuals	Level II-2	Poor Reporting bias Inconsistency in the quality of data Limited data provided on AE and timing following vaccine administration
Betancourt-Cravioto M, Cervantes-Powell P, Tapia-Conyer R et al. Improved post-marketing safety surveillance of quadrivalent inactivated influenza vaccine in Mexico using a computerized, SMS-based follow-up system. 2022Footnote 55 Funded by Sanofi	Non-obstetric AEs in pregnant persons within 42 days of vaccine administration	IIV4 (Fluzone® Quadrivalent; Sanofi)	Prospective cohort study, multicenter Country: Mexico Follow up: 3 influenza seasons between 2015-2016 and 2017-2018 Funding: Industry	Individuals 6 months and older who received a routine influenza vaccine at study centers (n=2,013) Pregnant individuals: n=18 (0.9%)	One (5.6%) pregnant individual reported a non-serious AE (i.e., AE did not require a medical visit)	Level II-2	Poor Small sample size Reporting bias No information on AE reported, including severity and duration
Vanni T, Thomé BdC, Oliveira MMM, et al. Active pharmacovigilance of the seasonal trivalent influenza vaccine produced by Instituto Butantan: A prospective cohort study of five target groups. 2021Footnote 57 Funded by the Butantan Foundation	Non-obstetric AEs in pregnant persons within 42 days of vaccine administration	IIV3 (Seasonal influenza vaccine)	Prospective cohort study, multicenter Country: Brazil Follow up: 2 influenza seasons between 2017 and 2018 Funding: Non-industry	Individuals 6 months of age and older who received a routine influenza vaccine at study centers (n=942) Pregnant individuals: n=108 (11.5%)	82 (75.9%) pregnant individuals had an AE 78 (72.2%) pregnant individuals had an adverse reaction (i.e., any AE with a reasonable causal relationship with the vaccine, according to "Uppsala Monitoring Centre" of the World Health Organization UMC-WHO) No SAE was reporting in pregnant	Level II-2	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Infant death up to 6 months of age	IIV3 (Seasonal influenza vaccine: Vaxigrip®, Sanofi; n=3, Fluarix, GSK; n=1) Placebo (n=2) Active control: Meningococcal quadrivalent vaccine (n=1, Menactra®, Sanofi) or Pneumococcal vaccine, 23-valent (n=1, Pneumovax® 23, Merck)	4 RCTs (Zaman 2006, Madhi 2014, Tapia 2016, Steinhoff 2017)Footnote 40Footnote 41Footnote 42Footnote 43 Countries: Bangladesh (n=1) South Africa (n=1) Mali (n=1) Nepal (n=1) Follow up: Not restricted to influenza season between 2004 and 2014 (n=4) Funding: Non-industry (n=3) and mixed funding (n=1)	Infants up to 6 months of age (n=10,115) IIV3: n=5,071 (50.1%) Placebo or active control: n=5,044 (49.9%)	The MA included 4 RCTs The pooled risk ratio was 1.14 (95% CI: 0.86 to 1.50), I2=9.33%	Level I	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Infant death up to 6 months of age	IIV3 (Seasonal influenza vaccine)	Prospective cohort studyFootnote 61 Country: Japan Follow up: Not restricted to influenza season between 2010/11 and 2011/04 Funding: Not reported	Infants diagnosed with fever (n=83) Infants born to vaccinated gestational parent: n=36 (43.4%) Infants born to unvaccinated gestational parent: n=47 (56.6%)	No Infant death was reported among infants born to vaccinated and unvaccinated gestational parent	Level II-2	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Spontaneous abortion (<20 gestational weeks)	IIV (Seasonal influenza vaccine)	2 cohort studiesFootnote 62Footnote 63 Countries: Australia (n=1) Canada (n=1) United States (n=1) Follow up: Not restricted to influenza season between 2010 and 2017 Funding: No funding (n=1) and mixed funding (n=1)	Pregnant persons (n=1,900) II V: n=983 (51.7%) Unvaccinated: n=917 (48.3%)	The MA included 2 cohort studies The pooled aHR was 0.77 (95% CI: 0.31 to 1.89), I2=37.51%	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Spontaneous abortion (<22 gestational weeks)	IIV3 (Seasonal influenza vaccine)	Prospective cohort studyFootnote 64 Country: Japan Follow up: Not restricted to the influenza season between 2013/10 and 2013/12 Funding: Non-industry	Individuals in their first trimester of pregnancy (n=2,826) IIV3: n=1,121 (39.7%) Unvaccinated: n=1,705 (60.3%)	A single cohort study reported raw data with the same risk in both exposed and unexposed groups (0.4% and 0.4%, respectively)	Level II-2	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Spontaneous abortion (<20 gestational weeks) within 28 days of vaccine administration	IIV3 (Seasonal influenza vaccine)	Retrospective case-control study)Footnote 65 Country: United States Follow up: 2 influenza seasons between 2010/2011 and 2011/2012 Funding: Non-industry	Pregnant individuals between 18- and 44-year-old vaccinated against influenza (n=970)	The aOR was 3.70 (95% CI: 1.40 to 9.40) in 2010/2011 and 1.40 (95% CI: 0.60 to 3.30) in 2011/2012 Post-hoc analyses of 2010/2011 data: Among individuals previously vaccinated with pH1N1-containing vaccine the aOR was 7.7 (95% CI: 2.2 to 27.3). Among individuals not vaccinated in the previous season the aOR was 1.3 (95% CI: 0.7 to 2.7)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Spontaneous abortion (<20 gestational weeks) within 28 days of vaccine administration	IIV3 (Seasonal influenza vaccine)	Retrospective case-control studyFootnote 65 Country: United States Follow up: 3 influenza seasons between 2012/2013 and 2014/2015 Funding: Non-industry	Pregnant individuals between 18- and 44-year-old (n=2,472) Vaccinated in the previous season: n=1,254 (50.3%) Not vaccinated in the previous season: n=1,218 (49.3%)	Overall, the aOR was 0.80 (95% CI: 0.60 to 1.10) The aOR was 0.9 (95% CI: 0.6 to 1.5) in those vaccinated in the previous season and 0.7 (95% CI: 0.4 to 1.1) in those not vaccinated in the previous season	Level II-2	Good
Romano CJ, Hall C, Khodr ZG, et al. History of pandemic H1N1-containing influenza vaccination and risk of spontaneous abortion and birth defects. 2021Footnote 66 Funded by the Defense Health Agency Immunization Healthcare Division and the U.S. Navy Bureau of Medicine and Surgery	Spontaneous abortion (<22 gestational weeks) within 28 days of vaccine administration	IIV3 (Seasonal influenza vaccine)	Retrospective cohort study Country: United States Follow up: 6 influenza seasons between 2008/2009 and 2013/2014 Funding: Non-industry	Pregnant individuals 17 years and older (n=26,264) Exposed to a pH1N1-containing vaccine in the season prior to pregnancy: n=21,736 (82.8%) Exposed to non-pH1N1-containing vaccine in the season prior to pregnancy: n=4,528 (17.2%)	The aHR was 1.19 (95% CI: 0.97 to 1.46)	Level II-2	Good
Robinson C, Oberye J, Van Boxmeer J et al. A prospective cohort study on pregnancy outcomes of persons immunized with a seasonal quadrivalent inactivated influenza vaccine during pregnancy. 2022Footnote 68 Funded by Seqirus Inc	Spontaneous abortion (<20 gestational weeks)	IIV4 (Afluria® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4 at any time during pregnancy (n=483) Trimester of exposure: First: n=171 (35.4%) second: n=201 (41.6%) third: n=111 (23.0%) Vaccinated <20 gestational weeks: n=160 (33.1%)	4 events (2.5%, 95% CI: 0.7 to 6.3%) were reported among those vaccinated at under 20 gestational weeks (n=160)	Level III	Fair
Robinson C, Van Boxmeer J, Tilson H, et al. Outcomes in pregnant persons immunized with a cell-based quadrivalent inactivated influenza vaccine: A prospective observational cohort study. 2022Footnote 69 Funded by Seqirus Inc	Spontaneous abortion (<20 gestational weeks)	IIV4-cc (Flucelvax® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4-cc at any time during pregnancy (n=665) Trimester of exposure: First: n=178 (26.8%) Second: n=277 (41.6%) Third: n=210 (31.6%) Vaccinated <20 gestational weeks: n=211 (31.7%)	4 events (1.9%, 95% CI: 0.5 to 4.8%) were reported among those vaccinated at under 20 gestational weeks (n=211)	Level III	Fair
Ledlie S, Gandhi-Banga S, Shrestha et al. Exposure to quadrivalent influenza vaccine during pregnancy: Results from a global pregnancy registry. 2022Footnote 60 Funded by Sanofi	Spontaneous abortion	IIV4 (Fluzone® Quadrivalent; Sanofi)	Retrospective and prospective case series, multicenters Countries: United States Canada Australia Brazil Mexico New Zealand Thailand Costa Rica India Follow up: Between 2013/08 and 2019/09 Funding: Industry	Individuals of reproductive age who were exposed to IIV4 during pregnancy or within 30 days of their last menstrual period (n=239) Trimester of exposure, n (%): First: 42 (17.6%) Second: 82 (34.3%) Third: 58 (24.3%) Unknown: 57 (23.9%)	4 events (6.4%, 95% CI: 2.08 to 15.90%) were reported	Level III	Poor Reporting bias High rate of loss to follow up (80%)
Nwoji U. Seasonal influenza vaccine exposure in pregnancy: 5-year results from a pregnancy registry. 2022Footnote 67 Funded by GlaxoSmithKline Biologicals SA	Spontaneous abortion (<22 gestational weeks)	IIV3 (Fluarix and FluLaval, GSK) or IIV4 (Fluarix Quadrivalent and FluLaval Quadrivalent, GSK)	Prospective cohort study Country: United States Follow up: Not restricted to influenza seasons between 2014/06/01 to 2019/05/31 Funding: Industry	Individuals vaccinated during pregnancy or within 28 days preceding conception (n=507) Trimester of exposure, n (%): First: n=84 (16.6%) Second: n=113 (22.3%) Third: n=91 (17.9%) Unknown: n=219 (43.2%) Lost to follow up: n=359 (70.8%)	3 events (2.6%) were reported 2 occurred among those vaccinated during the first trimester of pregnancy and one had unknown trimester of exposure	Level III	Poor Reporting bias High rate of loss to follow up (70.8%)
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Stillbirth (≥18-22 gestational weeks or ≥500g)	IIV3 (Seasonal influenza vaccine)	Retrospective cohort studyFootnote 83 Country: Australia Follow up: Not restricted to influenza season between 2012/04/01 and 2013/12/31 Funding: Non-industry	Pregnant individuals (n=58,008) IIV3: n= 5,076 (8.8%) Unvaccinated: n= 52,932 (91.2%)	The aHR was 0.49 (95% CI: 0.29 to 0.83)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Stillbirth (≥18-22 gestational weeks or ≥500g)	IIV (Seasonal influenza vaccine)	Retrospective case-control studyFootnote 96 Country: United States Follow up: Not restricted to influenza season between 2012/01/01 and 2015/09/30 Founding: Non-industry	Pregnant persons (n=12,109) II V: n=1,736 (14.3%) Unvaccinated: n=10,373 (85.7%)	The aOR was 0.95 (95% CI: 0.79 to 1.14)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Stillbirth (≥18-22 gestational weeks or ≥500g)	IIV (Seasonal influenza vaccine)	Retrospective cohort studyFootnote 97 Country: Australia Follow up: Between December and July, from 2012/04 and 2015/07 Funding: Non-industry	Individuals in their first trimester of pregnancy (n=11,955) IIV: n=2,391 (20.0%) Unvaccinated: n=9,564 (80.0%)	The adjusted risk ratio (aRR) was 1.18 (95% CI: 0.64 to 2.18)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Stillbirth (≥18-22 gestational weeks or ≥500g)	IIV (Seasonal influenza vaccine)	Prospective cohort studyFootnote 62 Countries: Canada United States Follow up: Not restricted to influenza season between 2010 and 2014 Funding: Mixed funding	Pregnant individuals (n=1,707) IIV: n=1,240 (72.6%) First trimester: n=477 (27.9%) Unvaccinated: n=467 (27.4%) First trimester: n=467 (27.4%)	The risk ratio was 0.38 (95% CI: 0.05 to 2.92) In analysis restricting to vaccination during the first trimester of pregnancy, the risk ratio was 0.98 (95% CI: 0.13 to 7.50)	Level II-2	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Stillbirth (≥18-22 gestational weeks or ≥500g)	IIV3 (Seasonal influenza vaccine)	Prospective cohort studyFootnote 84 Country: United States Follow up: Between October and March from 2003 to 2008 Funding: Not reported	Pregnant persons (n=85,783) IIV3: n=8,864 (10.3%) First trimester: n=447 (0.5%) Unvaccinated: n=76,919 (89.7%) First trimester: n=76,919 (89.7%)	The risk ratio was 0.60 (95% CI: 0.41 to 86) In analysis restricting to vaccination during the first trimester of pregnancy, the risk ratio was 2.54 (95% CI: 0.36 to 18.01)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Stillbirth (≥18-22 gestational weeks or ≥500g)	IIV3 (Seasonal influenza vaccine)	Prospective cohort studyFootnote 64 Country: Japan Follow up: Between September and December 2013 Funding: Non-industry	Pregnant individuals (n=10,330) IIV3: n=3,943 (38.2%) First trimester: n=1,121 (10.9%) Unvaccinated: n=6,387 (61.8%) First trimester: n=1,705 (16.5%)	The risk ratio was 0.44 (95% CI: 0.12 to 1.58) In analysis restricting to the first trimester of pregnancy, the risk ratio was 0.30 (95% CI: 0.01 to 6.33)	Level II-2	Fair
Giles ML, Davey MA, Wallace EM. Associations Between Maternal Immunisation and Reduced Rates of Preterm Birth and Stillbirth: A Population Based Retrospective Cohort Study. Frontiers in Immunology. 2021Footnote 85 Funding: Not reported	Stillbirth	IIV (Seasonal influenza vaccine)	Retrospective cohort study Country: Australia Follow up: Not restricted to influenza season between 2015/07 and 2018/12 Funding: Not reported	Pregnant persons with singleton pregnancies >28 gestational weeks (n=269,493) IIV: n=138,698 (51.5%) Unvaccinated: n=112,155 (41.6%) Not reported/unknown: n=18,640 (6.9%)	The aRR was 0.25 (95% CI: 0.20 to 0.31)	Level II-2	Fair
Robinson C, Oberye J, van Boxmeer J, et al. A Prospective Cohort Study on Pregnancy Outcomes of Persons Immunized with a Seasonal Quadrivalent Inactivated Influenza Vaccine during Pregnancy. Vaccines. 2022Footnote 68 Funded by Seqirus Inc	Stillbirth (≥20 gestational weeks or ≥500g)	IIV4 (Afluria® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4 at any time during pregnancy (n=483) Trimester of exposure: First: n=171 (35.4%) Second: n=201 (41.6%) Third: n=111 (23.0%)	2 (0.4%, 95% CI: 0.1 to 1.5%) events were reported One occurred in an individual vaccinated during the first trimester and one in an individual vaccinated during the second trimester of pregnancy	Level III	Fair
Robinson C, Van Boxmeer J, Tilson H, et al. Outcomes in Pregnant Persons Immunized with a Cell-Based Quadrivalent Inactivated Influenza Vaccine: A Prospective Observational Cohort Study. Vaccines. 2022Footnote 69 Funded by Seqirus Inc	Stillbirth (≥20 gestational weeks or ≥500g)	IIV4-cc (Flucelvax® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4-cc at any time during pregnancy (n=665) Trimester of exposure: First: n=178 (26.8%) Second: n=277 (41.6%) Third: n=210 (31.6%)	No event was reported	Level III	Fair
Nwoji U. Seasonal influenza vaccine exposure in pregnancy: 5-year results from a pregnancy registry. Hum Vaccin Immunother. 2022Footnote 67 Funded by GlaxoSmithKline Biologicals SA	Stillbirth (≥18-22 gestational weeks or ≥500g)	IIV3 (Fluarix and FluLaval, GSK) or IIV4 (Fluarix Quadrivalent and FluLaval Quadrivalent, GSK)	Prospective cohort study Country: United States Follow up: Not restricted to influenza seasons between 2014/06/01 to 2019/05/31 Funding: Industry	Individuals vaccinated during pregnancy or within 28 days preceding conception (n=507) Trimester of exposure, n (%): First: n=84 (16.6%) Second: n=113 (22.3%) Third: n=91 (17.9%) Unknown: n=219 (43.2%) Lost to follow up: n=359 (70.8%)	One (0.9%) event was reported among an individual vaccinated during the first trimester of pregnancy Causal association with vaccination was ruled out	Level III	Poor Reporting bias High rate of loss to follow up (70.8%)
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Pre-term birth (<37 completed gestational weeks)	IIV3 (Seasonal influenza vaccine)	Fifteen cohort studies Countries: Australia (n=2) Canada (n=4) Laos (n=1) Nicaragua (n=1) United States (n=8) Follow up: 6 studies were restricted to influenza seasons between 2004 and 2015 9 studies were not restricted to influenza seasons between 2002 and 2018 Funding: Non-industry (n=10), non-industry and insurance (n=2), mixed (n=1), no funding (n=1), and not reported (n=1)	Studies that accounted for immortal time bias (n=152,476) IIV3: n=66,749 (43.8%) Unvaccinated: n=85,727 (56.2%) Studies that did not account for immortal time bias (n=151,032) IIV3: n=67,558 (44.7%) Unvaccinated: n=83,474 (55.3%) When influenza vaccination during the first trimester of pregnancy was considered (n=47,211) IIV3: n=19,135 (40.5%) Unvaccinated: n=28,076 (59.5%)	The MA included 6 cohort studies that accounted for immortal time bias The pooled aHR was 1.09 (95% CI: 0.89 to 1.33), I2=28.18% for studies that accounted for immortal time bias The MA included ten cohort studies that did not account for immortal time bias The pooled aRR was 0.86 (95% CI: 0.76 to 0.97), I2=71.15% for studies that did not account for immortal time bias A MA included six cohort studies restricted to vaccination during the first trimester of pregnancy The pooled aHR was 1.05 (95% CI: 0.92 to 1.20), I2=30.46% for studies restricted to vaccination during the first trimester of pregnancy	Level II-2	Good
Duque J, Howe AS, Azziz-Baumgartner et al. Multi-decade national cohort identifies adverse pregnancy and birth outcomes associated with acute respiratory illness hospitalisations during the influenza season. 2022Footnote 87 Funding: not reported	Preterm birth (<37 weeks of gestation)	IIV (Seasonal influenza vaccine)	Retrospective cohort Country: New Zealand Follow up: Sixteen influenza seasons between 2003 and 2018 Funding: Not reported	Individuals between 15 and 49 years of age who were pregnant (n=822,391) Vaccinated pregnant persons with preterm birth between 2010 and 2018: n=3,895 (6.1%) Unvaccinated pregnant persons with preterm birth between 2010 and 2018: n=29,825 (8.0%)	The aHR was 0.79 (95% CI: 0.77 to 0.82)	Level II-2	Good
Giles ML, Davey M and Wallace EM. Associations between maternal immunisation and reduced rates of preterm birth and stillbirth: A population based retrospective cohort study. 2021Footnote 85 Funding not reported	Preterm birth (<37 weeks of gestation)	IIV (Seasonal influenza vaccine)	Retrospective cohort study Country: Australia Follow up: Not restricted to influenza season between 2015/07 and 2018/12 Funding: Not reported	Pregnant persons with singleton pregnancies >28 gestational weeks (n=269,493) IIV: n=138,698 (51.5%) Unvaccinated: n=112,155 (41.6%) Not reported/unknown: n=18,640 (6.9%)	The aRR was 0.69 (95% CI: 0.66 to 0.72)	Level II-2	Fair
Robinson C, Oberye J, van Boxmeer J, et al. A Prospective Cohort Study on Pregnancy Outcomes of Persons Immunized with a Seasonal Quadrivalent Inactivated Influenza Vaccine during Pregnancy. Vaccines. 2022Footnote 68 Funded by Seqirus Inc	Preterm birth (<37 weeks of gestation)	IIV4 (Afluria® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4 at any time during pregnancy (n=483) Trimester of exposure: First: n=171 (35.4%) Second: n=201 (41.6%) Third: n=111 (23.0%)	Overall, 31 (7.2%) events were reported Events by trimester of exposure, n (%): First: n=10 (6.6%) Second: n=17 (8.9%) Third: n=4 (4.7%)	Level III	Fair
Robinson C, Van Boxmeer J, Tilson H, et al. Outcomes in Pregnant Persons Immunized with a Cell-Based Quadrivalent Inactivated Influenza Vaccine: A Prospective Observational Cohort Study. Vaccines. 2022Footnote 69 Funded by Seqirus Inc	Preterm birth (<37 weeks of gestation)	IIV4-cc (Flucelvax® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4-cc at any time during pregnancy (n=665) Trimester of exposure: First: n=178 (26.8%) Second: n=277 (41.6%) Third: n=210 (31.6%)	Overall, 52 (9.2%) events were reported Events by trimester of exposure, n (%): First: n=17 (10.3%) Second: n=27 (10.8%) Third: n=8 (5.4%)	Level III	Fair
Ledlie S, Gandhi-Banga S, Shrestha et al. Exposure to quadrivalent influenza vaccine during pregnancy: Results from a global pregnancy registry. 2022Footnote 60 Funded by Sanofi	Preterm birth (<37 weeks of gestation)	IIV4 (Fluzone® Quadrivalent; Sanofi)	Retrospective and prospective case series, multicenters Countries: United States Canada Australia Brazil Mexico New Zealand Thailand Costa Rica India Follow up: Between 2013/08 and 2019/09 Funding: Industry	Individuals of reproductive age who were exposed to IIV4 during pregnancy or within 30 days of their last menstrual period (n=239) Trimester of exposure, n (%): First: 42 (17.6%) Second: 82 (34.3%) Third: 58 (24.3%) Unknown: 57 (23.9%)	One (6.67%) event was reported among reports with known neonatal outcomes (n=15)	Level III	Poor Reporting bias High rate of loss to follow up (80%)
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN And study identified in update literature search: Giles ML, Davey M and Wallace EM. Associations between maternal immunisation and reduced rates of preterm birth and stillbirth: A population based retrospective cohort study. 2021Footnote 85 Funding not reported	Small-for-gestational-age birth	IIV (Seasonal influenza vaccine)	12 cohort studies Countries: Canada (n=2) United States (n=6) Australia (n=2) Nicaragua (n=1) Laos (n=1) Follow up: Restricted to influenza season between 2014 and 2015 (n=2) Not restricted to influenza season between 2004 and 2017 (n=10) Funding: Non-industry (n=6), non-industry and insurance (n=2), mixed funding (n=1), not reported (n=2), and no funding (n=1)	Pregnant persons (n=548,277) IIV: n=271,045 (n=49.4%) Unvaccinated: n=277,232 (50.6%)	The MA included 12 cohort studies The pooled aRR was 0.97 (95% CI: 0.90 to 1.04), I2=71%	Level II-2	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN And study identified in update literature search: Duque J, Howe AS, Azziz-Baumgartner et al. Multi-decade national cohort identifies adverse pregnancy and birth outcomes associated with acute respiratory illness hospitalisations during the influenza season. 2022Footnote 87 Funding not reported	Low birth weight (<2,500 g)	IIV (Seasonal influenza vaccine)	3 cohort studiesFootnote 63Footnote 86Footnote 87 Countries: New Zealand (n=1) Australia (n=1) United States (n=1) Follow up: Sixteen influenza seasons between 2003 and 2018 (n=1) Not restricted to influenza season between 2010 and 2015 (n=2) Funding: Non-industry (n=1), no funding (n=1), and not reported (n=1)	Pregnant persons (n=168,633) IIV: n=68,039 (40.3%) Unvaccinated: n=100,594 (59.7%)	The MA included 3 cohort studies The pooled aHR was 0.89 (95% CI: 0.83 to 0.96), I2=37%	Level II-2	Good
Robinson C, Oberye J, van Boxmeer J, et al. A Prospective Cohort Study on Pregnancy Outcomes of Persons Immunized with a Seasonal Quadrivalent Inactivated Influenza Vaccine during Pregnancy. Vaccines. 2022Footnote 68 Funded by Seqirus Inc	Low birth weight (<2,500 g)	IIV4 (Afluria® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4 at any time during pregnancy (n=483) Trimester of exposure: First: n=171 (35.4%) Second: n=201 (41.6%) Third: n=111 (23.0%)	Overall, 25 (5.4%) events occurred Events by trimester of exposure, n (%): First: n=7 (4.4%) Second: n=13 (6.7%) Third: n=5 (4.5%)	Level III	Fair
Robinson C, Van Boxmeer J, Tilson H, et al. Outcomes in Pregnant Persons Immunized with a Cell-Based Quadrivalent Inactivated Influenza Vaccine: A Prospective Observational Cohort Study. Vaccines. 2022Footnote 69 Funded by Seqirus Inc	Low birth weight (<2,500 g)	IIV4-cc (Flucelvax® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4-cc at any time during pregnancy (n=665) Trimester of exposure: First: n=178 (26.8%) Second: n=277 (41.6%) Third: n=210 (31.6%)	Overall, 37 (5.8%) events occurred Events by trimester of exposure, n (%): First: n=14 (8.3%) Second: n=15 (5.7%) Third: n=8 (3.9%)	Level III	Fair
Ledlie S, Gandhi-Banga S, Shrestha et al. Exposure to quadrivalent influenza vaccine during pregnancy: Results from a global pregnancy registry. 2022Footnote 60 Funded by Sanofi	Low birth weight (<2,500 g)	IIV4 (Fluzone® Quadrivalent; Sanofi)	Retrospective and prospective case series, multicenters Countries: United States Canada Australia Brazil Mexico New Zealand Thailand Costa Rica India Follow up: Not restricted to influenza seasons between 2013/08 and 2019/09 Funding: Industry	Individuals of reproductive age who were exposed to IIV4 during pregnancy or within 30 days of their last menstrual period (n=239) Trimester of exposure, n (%): First: 42 (17.6%) Second: 82 (34.3%) Third: 58 (24.3%) Unknown: 57 (23.9%)	2 (10.0%) events were reported among reports with known neonatal outcomes (n=30)	Level III	Poor Reporting bias High rate of loss to follow up (80%)
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Congenital anomalies identified at birth	IIV3 (Seasonal influenza vaccine)	Prospective cohort studyFootnote 63 Country: Australia Follow up: Not restricted to influenza season between 2015/03 and 2017/12 Funding: No funding	Pregnant persons (n=1,207) IIV3 during the first trimester of pregnancy: n=141 (11.7%) Unvaccinated: n=1,066 (88.3%)	The aRR was 0.33 (95% CI: 0.04 to 2.73)	Level II-2	Good
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Congenital anomalies identified at birth	IIV3 (Seasonal influenza vaccine)	Prospective cohort studyFootnote 84 Country: United States Follow up: Not restricted to influenza season between October to March from 2003 to 2008 Funding: Not reported	Pregnant persons (n=77,366) IIV3 during the first trimester of pregnancy: n=447 (0.6%) Unvaccinated during the first trimester of pregnancy: n=76,919 (99.4)	The OR was 0.67 (95% CI: 0.36 to 1.25)	Level II-2	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Congenital anomalies identified at birth	IIV3 (Seasonal influenza vaccine)	Prospective cohort studyFootnote 64 Country: Japan Follow up: Not restricted to influenza season between September and December 2013 Funding: Non-industry	Pregnant persons (n=2,826) IIV3 during the first trimester of pregnancy: n=1,121 (39.7%) Unvaccinated: n=1,705 (60.3%)	Single cohort study reported no significant difference between infants born to gestational parent vaccinated with IIV3 in the first trimester (33/1,121) and unvaccinated gestational parents (55/1,705); p=0.67	Level II-2	Fair
Robinson C, Oberye J, van Boxmeer J, et al. A Prospective Cohort Study on Pregnancy Outcomes of Persons Immunized with a Seasonal Quadrivalent Inactivated Influenza Vaccine during Pregnancy. Vaccines. 2022Footnote 68 Funded by Seqirus Inc	Congenital anomalies identified at birth	IIV4 (Afluria® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4 at any time during pregnancy (n=483) Trimester of exposure: First: n=171 (35.4%) second: n=201 (41.6%) third: n=111 (23.0%)	2 (1.2%) cases of major congenital malformation were identified among infant born to parent that received IIV4 vaccine during the first trimester of pregnancy	Level III	Fair
Robinson C, Van Boxmeer J, Tilson H, et al. Outcomes in Pregnant Persons Immunized with a Cell-Based Quadrivalent Inactivated Influenza Vaccine: A Prospective Observational Cohort Study. Vaccines. 2022Footnote 18 Funded by Seqirus Inc	Congenital anomalies identified at birth	IIV4-cc (Flucelvax® Quadrivalent, Seqirus)	Single-arm prospective cohort study Country: United States Follow up: 4 influenza seasons between 2017/2018 and 2020/2021 Funding: Industry	Individuals vaccinated with IIV4-cc at any time during pregnancy (n=665) Trimester of exposure: First: n=178 (26.8%) Second: n=277 (41.6%) Third: n=210 (31.6%)	One live-born infant (0.6%) with major congenital malformation was born to an individual that received IIV4-cc during the first trimester of pregnancy and the reported birth defect had a known cause other than exposure to the study vaccine	Level III	Fair
Wolfe D, Garritty C, Hamel C, et al. Safety and effectiveness of influenza vaccine during pregnancy – a systematic review. 2022Footnote 18 Funded by the CIHR and the DSEN	Congenital anomalies identified from birth up to 6 months of age	IIV (Seasonal influenza vaccine)	Retrospective case-control studyFootnote 98 Country: United States Follow up: 3 influenza seasons from 2011/2012 to 2013/2014 Funding: Mixed funding	Pregnant persons (n=4,277) IIV during the first trimester of pregnancy: n=711 (16.6%) Unvaccinated: n=3,566 (83.4%)	The aOR was 1.01 (95% CI: 0.85 to 1.21)	Level II-2	Fair
Romano CJ, Hall C, Khodr ZG, et al. History of pandemic H1N1-containing influenza vaccination and risk of spontaneous abortion and birth defects. 2021Footnote 66 Funding: Defense Health Agency Immunization Healthcare Division and the U.S. Navy Bureau of Medicine and Surgery	Congenital anomalies identified from birth up to 6 months of age	IIV3 (Seasonal influenza vaccine)	Retrospective cohort study Country: United States Follow up: 6 influenza seasons between 2008/2009 and 2013/2014 Funding: Non-industry	Pregnant individuals 17 years and older (n=26,264) Exposed to a pH1N1-containing vaccine in the season prior to pregnancy: n=21,736 (82.8%) Exposed to non-pH1N1-containing vaccine in the season prior to pregnancy: n=4,528 (17.2%)	The aHR was 1.05 (95% CI: 0.83 to 1.34)	Level II-2	Good
Sarna M, Pereira GF, Foo D et al. The risk of major structural birth defects associated with seasonal influenza vaccination during pregnancy: a population-based cohort studyFootnote 99 Funded by Curtin University of Technology; National Health and Medical Research Council; Norges Forskningsrad; Telethon Kids Institute, Department of Health	Congenital anomalies identified from birth up to 6 months of age	IIV (Seasonal influenza vaccine)	Retrospective cohort study Country: Australia Follow up: Not restricted to influenza season between 2012/04/01 and 2016/04/12 Funding: Non-industry	Pregnant persons (113,936) IIV during the first trimester of pregnancy: n=2,811 (2.5%) Unvaccinated: n=111,125 (97.5%)	Weighted prevalence ratio up to one month of birth was 0.98 (95% CI: 0.68 to 1.43)	Level II-2	Good
Nwoji U. Seasonal influenza vaccine exposure in pregnancy: 5-year results from a pregnancy registry. Hum Vaccin Immunother. 2022Footnote 67 Funded by GlaxoSmithKline Biologicals SA	Congenital anomalies identified from birth up to 6 months of age	IIV3 (Fluarix and FluLaval, GSK) or IIV4 (Fluarix Quadrivalent and FluLaval Quadrivalent, GSK)	Prospective cohort study Country: United States Follow up: Not restricted to influenza seasons between 2014/06/01 to 2019/05/31 Funding: Industry	Individuals vaccinated during pregnancy or within 28 days preceding conception (n=507) Trimester of exposure, n (%): First: n=84 (16.6%) Second: n=113 (22.3%) Third: n=91 (17.9%) Unknown: n=219 (43.2%) Lost to follow up: n=359 (70.8%)	Among those with known pregnancy outcome (n=115), 3 (2.6%) events were deemed unlikely to be causally associated with IIV and one (0.9%) event had insufficient information to assess causality	Level III	Poor Reporting bias High rate of loss to follow up (70.8%)
Ledlie S, Gandhi-Banga S, Shrestha et al. Exposure to quadrivalent influenza vaccine during pregnancy: Results from a global pregnancy registry. 2022Footnote 60 Funded by Sanofi	Congenital anomalies identified from birth up to 6 months of age	IIV4 (Fluzone® Quadrivalent; Sanofi)	Retrospective and prospective case series, multicenters Countries: United States Canada Australia Brazil Mexico New Zealand Thailand Costa Rica India Follow up: Between 2013/08 and 2019/09 Funding: Industry	Individuals of reproductive age who were exposed to IIV4 during pregnancy or within 30 days of their last menstrual period (n=239) Trimester of exposure, n (%): First: 42 (17.6%) Second: 82 (34.3%) Third: 58 (24.3%) Unknown: 57 (23.9%)	One event was reported among those vaccinated during the first trimester of pregnancy with known neonatal outcomes	Level III	Poor Reporting bias High rate of loss to follow up (80%)
Abbreviation: AE; adverse event, aHR; adjusted hazard ratio, aOR; adjusted odds ratio, aRR; adjusted risk ratio, aVE; adjusted vaccine effectiveness, CI; confidence interval, CIHR; Canadian Institutes of Health Research, DSEN; Drug Safety and Effectiveness Network, GSK; GlaxoSmithKline; IIV; inactivated influenza vaccine, IIV3; trivalent inactivated influenza vaccine, IIV4; quadrivalent inactivated influenza vaccine, IIV4-cc; Cell-culture based quadrivalent inactivated influenza vaccine, MA; meta-analysis, pH1N1; pandemic A(H1N1) strain, RCT; randomized controlled trial, RT-PCR; reverse transcription polymerase chain reaction, TND; test-negative design, VE; vaccine effectiveness; GSK: GlaxoSmithKline; NA: not applicable.

Table 2. Ranking individual studies: Levels of evidence based on research design

Level	Description
I	A randomized controlled trial.
II-1	A controlled trial without randomization.
II-2	A cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
II-3	A multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III	Clinical experience, descriptive study or case report, or report of expert committees.

Table 3. Ranking individual studies: Quality (internal validity) rating of evidence

Quality rating	Description
Good	A study (including meta-analyses or systematic reviews) that meets all design- specific criteriaTable 3 Footnote a well.
Fair	A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known "fatal flaw".
Poor	A study (including meta-analyses or systematic reviews) that has at least one design-specificTable 3 Footnote a "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
Table 3 - Footnote a General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:21-35. Return to Table 3 Footnote a referrer

Table 4. NACI recommendations: Strength of recommendation

	Strong	Discretionary
Wording	"should/should not be offered"	"may/may not be offered"
Rationale	Known/anticipated advantages outweigh known/anticipated disadvantages ("should"), or Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")	Known/anticipated advantages are closely balanced with known/anticipated disadvantages, or uncertainty in the evidence of advantages and disadvantages exists
Implications	A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.	A discretionary recommendation may be offered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.

List of abbreviations

AE

Adverse event

aHR

Adjusted hazard ratio

aOR

Adjusted odds ratio

aRR

Adjusted risk ratio

aVE

Adjusted vaccine effectiveness

CI

Confidence interval

CIG

Canadian Immunization Guide

CIHR

Canadian Institutes of Health Research

CNICS

Childhood National Immunization Coverage Survey

DSEN

Drug Safety and Effectiveness Network

EEFA

Ethics, equity, feasibility, and acceptability

FDA

Food and Drug Administration (United States)

GRADE

Grading of Recommendations, Assessment, Development, and Evaluation

HA

Hemagglutinin

HI

Hemagglutination inhibition

HR

Hazard ratio

ICU

Intensive care unit

IIV

Inactivated influenza vaccine

IIV3

Trivalent inactivated influenza vaccine

IIV4

Quadrivalent inactivated influenza vaccine

IIV4-cc

Cell-culture based quadrivalent inactivated influenza vaccine

IIV4-SD

Standard-dose quadrivalent inactivated influenza vaccine

IIV-Adj

Adjuvanted inactivated influenza vaccine

IIV-HD

High-dose inactivated influenza vaccine

IIV-SD

Standard-dose inactivated influenza vaccine

ILI

Influenza-like illness

IM

Intramuscular

IRR

Incidence rate ratio

IWG

Influenza Working Group

LAIV

Live attenuated influenza vaccine (egg based)

LBW

Low birthweight

LCI

Laboratory-confirmed influenza

MA

Meta-analysis

NA

Neuraminidase

NACI

National Advisory Committee on Immunization

NOC

Notice of Compliance

NOS

Newcastle Ottawa Scale

OR

Odds ratio

PHAC

Public Health Agency of Canada

RCT

Randomized controlled trial

RIV

Recombinant influenza vaccine

RIV4

Quadrivalent recombinant influenza vaccine

RoB

Risk of bias

RR

Risk ratio

RT-PCR

Reverse transcription polymerase chain reaction

rVE

Relative vaccine efficacy

SAB

Spontaneous abortion

SAE

Serious Adverse Event

SGA

Small for Gestational Age

SR

Systematic Review

SVP

Canadian Survey on Vaccination During Pregnancy Study

Tdap

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis

US

United States

VAERS

Vaccine Adverse Event Reporting System (US)

VE

Vaccine effectiveness

WHO

World Health Organization

Acknowledgements

This statement was prepared by: P Doyon-Plourde, A Sinilaite, W Siu and J Papenburg, on behalf of the NACI Influenza Working Group and was approved by NACI.

NACI gratefully acknowledges the contribution of: F Crane, R Garno, A Gil, K Gusic, SH Lim, B Pe Benito, S Pierre, C Tremblay, R Yorke, M Tunis, C Williams, and M Xi.

NACI Influenza Working Group

Members: J Papenburg (Chair), P De Wals, D Fell, I Gemmill, R Harrison, J Langley, A McGeer, and D Moore.

Former members: D Fell

Liaison representatives: L Grohskopf (Centers for Disease Control and Prevention [CDC], United States).

Ex-officio representatives: L Lee (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), K Daly (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), B Warshawsky (Vice President's Office, Infectious Disease Prevention and Control Branch [IDPCB]), and M Russell (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]).

External experts (topic of pregnancy and breastfeeding): T Bogler, I Boucoiran, K Campbell, E Castillo, and D Money.

NACI

S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O'Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.

Liaison Representatives: L Bill/M Nowgesic (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), S Buchan (Canadian Association for Immunization Research and Evaluation), E Castillo (Society of Obstetricians and Gynaecologists of Canada), J Comeau (Association of Medical Microbiology and Infectious Disease Canada), M Lavoie (Council of Chief Medical Officers of Health), J MacNeil (Centers for Disease Control and Prevention, United States), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), M Osmack (Indigenous Physicians Association of Canada), J Potter (College of Family Physicians of Canada), and A Ung (Canadian Pharmacists Association).

Former Liaison Representatives: N Dayneka, and J Emili

Ex-Officio Representatives: V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases [CIRID], Public Health Agency of Canada [PHAC]), M Lacroix (Public Health Ethics Consultative Group, PHAC), P Fandja (Marketed Health Products Directorate, Health Canada), M Su (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), C Pham (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), M Routledge (National Microbiology Laboratory, PHAC) and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).

Appendix A: Review update methods

The methods related to the review update completed by the NACI Secretariat were generally aligned with those used by Wolfe et al. (2020)^{Footnote 18}.

Review questions

The following research questions were addressed:

Research question 1: Are influenza vaccines safe for pregnant persons and their newborn infants if received any time during pregnancy?

Research question 2: Are influenza vaccines effective for preventing influenza and its complications for pregnant persons and their newborn infants if received at any time during pregnancy?

Study eligibility criteria

Eligibility criteria defining studies for inclusions were the same as those used by Wolfe et al. (2020) apart from the inclusion of single-arm cohort studies and studies based on databases of voluntary reporting or surveillance of AEs (Table 5)^{Footnote 18}. These studies were included in the review update completed by the NACI Secretariat to capture evidence on more recently licensed influenza vaccines that are based upon new different technologies, including quadrivalent mammalian cell culture-based vaccines and RIV.

Table 5. Study eligibility criteria

	Inclusion criteria	Exclusion criteria
Population	Pregnant women and their unborn and newborn infants under 6 months of age	Women vaccinated preconception or post-partum
Interventions	Seasonal and pandemic influenza vaccines of any valency that were indicated for adults	Vaccines contraindicated during pregnancy (e.g., live-attenuated vaccines)
Comparators	Placebo, no influenza vaccine, active comparators (e.g., other influenza vaccine, meningococcal or pneumococcal vaccines)	No comparator or vaccines contraindicated during pregnancy
Outcomes	Dichotomous measures of the following outcomes: Maternal Vaccine effectiveness against lab-confirmed influenza (LCI) LCI hospitalization Influenza-like illness (ILI) and other influenza-associated outcomes Serious non-obstetric adverse events (SAEs) Infant Vaccine effectiveness against lab-confirmed influenza (LCI) LCI hospitalization Influenza-like illness (ILI) and other influenza-associated outcomes Early neonatal death within 7 days of birth Death within 6 months of birth Birth outcomes Spontaneous abortion (SAB) Stillbirth Preterm birth (PTB) Small-for-gestational-age birth (SGA) Low birth weight (LBW) Congenital anomalies	Immunogenicity outcomes Outcomes with continuous measures
Study designs	RCTs, prospective and retrospective cohort studies, case-control and test-negative studies, nested designs, single-arm cohort studies, studies based on databases of voluntary reporting or surveillance of adverse events	Systematic reviews, narrative reviews, case reports, abstracts
Language	English and French language publications only	Other languages

Literature search

The updated search strategy was developed in collaboration with librarian from the Health Library of Health Canada and PHAC (search strategy available upon request). Separate strategies were performed for RCTs and observational studies. The RCT search was performed in Ovid MEDLINE^® ALL, Embase, and the Cochrane Central Register of Controlled Trials. The observational studies were identified using Ovid MEDLINE^® ALL and Embase. All searches were performed on January 13, 2023. Searches were restricted to articles published in English and French. Articles retrieved in the Health Library of Health Canada and PHAC literature searches were loaded into RefWorks (ProQuest LLC, Ann Arbor, MI), and uploaded to DistillerSR (Evidence Partners, Ottawa, Canada).

Study selection process

Two (2) reviewers independently screened titles and abstracts for study eligibility. The full texts of studies identified in the first phase of screening were assessed independently by 2 reviewers for inclusion in the SR. Screening conflicts were resolved by discussion or arbitration by a third reviewer.

Data extraction

A data extraction form was developed for this SR. The extraction process was piloted independently by 2 reviewers to assess quality and consistency of data collection. Data were extracted by one reviewer and verified by a second. Study authors were contacted by email to obtain additional data or confirm data when necessary.

The following data were extracted from each report: study design, population characteristics definition of intervention and comparator, outcome definition, statistical analyses, and key findings.

Risk of bias assessment

Following data extraction, 2 reviewers independently assessed the risk of bias (RoB) at the outcome level using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0) or adaptations of the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies as described by Wolfe et al. (2020)^{Footnote 18}. Disagreements were resolved by discussion or arbitration by a third reviewer.

Synthesis and statistical methods

Data were combined with Wolfe et al. (2020) findings by outcome to evaluate the availability of quantitative evidence, as well as the feasibility and appropriateness of meta-analysis^{Footnote 18}.

Meta-analyses were conducted when 2 or more study reported evidence that was not clinically heterogenous as described by Wolfe et al. (2020)^{Footnote 18}. Briefly, random effect models were used, and statistical heterogeneity was assessed using the I² statistic, with a threshold of 50% or higher suggesting potentially important heterogeneity. Forest plots were used to present meta-analyses. Evidence was summarized narratively when meta-analysis was deemed inappropriate. All analyses were conducted using the Review Manager software (Version 5.4)^{Footnote 100}.

Appendix B: Prisma flow diagram for review update

Appendix B: Text description

The PRISMA flow diagram describes the process by which studies or records were identified and selected via databases and registers. The process is broken down into three stages: Identification, Screening and Included.

Stage 1: Identification

• There were 1,494 records identified through database and register searching, 351 duplicate records were removed before screening.

Stage 2: Screening

• 1,143 records were screened. Of these 999 records were excluded, with a remainder of 144 full texts. One full text was not retrieved and was excluded.
• A total of 143 full texts were assessed for eligibility. Of these, 126 articles were excluded. The reasons for their exclusion are as follows: 38 articles did not focus on the relevant population of interest, 18 articles did not report outcomes of interest, 30 articles did not involve relevant interventions, 18 articles were not conducted with the desired study design, 4 articles were in languages that were not accessible for review, and 4 articles were excluded for various other reasons.

Stage 3: Included

• 17 articles were included in the review. Of those, 13 were comparative studies, and 4 were descriptive studies.