Influenza vaccination during pregnancy: A systematic review of fetal death, spontaneous abortion, and congenital malformation safety outcomes

Vaccine 33 (2015) 2108–2117

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Review

Influenza vaccination during pregnancy: A systematic review of fetal death, spontaneous abortion, and congenital malformation safety outcomes M. McMillan a,∗ , K. Porritt b , D. Kralik c,1 , L. Costi c , H. Marshall d a

School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide 5005, SA, Australia Joanna Briggs Institute, Faculty of Health Sciences, The University of Adelaide, Adelaide 5005, SA, Australia c Women’s and Children’s Hospital, 72 King William Road, North Adelaide 5006, SA, Australia d Vaccinology and Immunology Research Trials Unit (VIRTU), Women’s and Children’s Hospital and School of Pediatrics and Reproductive Health & Robinson Institute, The University of Adelaide, Adelaide 5005, SA, Australia b

a r t i c l e

i n f o

Article history: Received 4 November 2014 Received in revised form 20 January 2015 Accepted 25 February 2015 Available online 8 March 2015

a b s t r a c t Background: Pregnant women are considered the most important risk group for influenza vaccination. Despite this, the potential risk of harm from the vaccine on the fetus is a key factor in low uptake of the vaccine. This systematic review aimed to synthesize the best available evidence on the safety of influenza vaccination during pregnancy on fetal development. Methods and findings: A search of the literature was undertaken from the inception of each database up to March 2014. Both observational and clinical trials were considered. Fetal outcomes were present in 19 observational studies, and 14 of those were primarily investigating the monovalent influenza A (H1N1) 2009 vaccine. There was significant methodological and clinical heterogeneity of the included studies and a narrative summary and tabling of results was performed. Fetal death outcomes for women in later pregnancy ranged from OR 0.34 to 2.95 with 95% confidence intervals crossing or below the null value. Spontaneous abortion less than 24 weeks ranged from HR 0.45 to OR 1.23, with 95% confidence intervals crossing or below the null value. Congenital malformations for women vaccinated during their first trimester ranged from OR 0.67 to 2.18 and imprecise confidence intervals crossed the null value. Included in this review were some high quality studies, although overall the studies have a high risk of selection and confounding bias. Conclusions: Results do not indicate that maternal influenza vaccination is associated with an increased risk of fetal death, spontaneous abortion, or congenital malformations. Statistical imprecision and clinical and methodological heterogeneity of the observational studies mean it is not possible to totally exclude adverse effects. Further studies investigating women vaccinated during their first trimester should be the highest priority to allow for more precise estimates, especially for spontaneous abortion, and congenital abnormality outcomes. © 2015 Elsevier Ltd. All rights reserved.

1. Introduction Worldwide, many health authorities recommend pregnant women receive an influenza vaccination during any trimester of pregnancy [1]. In 2012, the World Health Organization (WHO)

∗ Corresponding author. Tel.: +61 412884028. E-mail addresses: [email protected], [email protected] (M. McMillan), [email protected] (K. Porritt), [email protected] (L. Costi), [email protected] (H. Marshall). 1 Deceased 24 December 2014. http://dx.doi.org/10.1016/j.vaccine.2015.02.068 0264-410X/© 2015 Elsevier Ltd. All rights reserved.

Strategic Advisory Group for Experts on Immunization recommended pregnant women as the most important risk group for inactivated seasonal influenza vaccination [2]. Despite this recommendation, many pregnant women choose not to be vaccinated and many health professionals do not advocate for the vaccine. The potential risk of perceived harm from the vaccine on the unborn child is listed as one of the main reasons [3,4]. Pregnant women are a unique population because of the immunologic and physiologic changes that take place during pregnancy. These immunologic changes may result in altered reactogenicity to influenza vaccines. There is also potential for the unborn fetus to be at risk of harm as the result of vaccination

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during pregnancy. To evaluate the safety of the vaccine on fetal development, outcomes such as spontaneous abortion, fetal death, premature birth, small for gestational age (SGA) infant, congenital malformation, and low birth weight infants are sometimes used. The inflammatory response that may be associated with adverse outcomes for the fetus during influenza infection is also an important consideration for the safety of the influenza vaccine. This is especially so during embryogenesis and the first trimester of pregnancy when the fetus is most at risk [5]. Medications are rarely tested for teratogenicity in controlled clinical trials [5], and the influenza vaccine is no different. Evidence for safety is often derived from epidemiological studies, small single arm descriptive studies, or individual case reporting. This can cause some concerns with the quality of evidence available on which to base recommendations for practice [5]. Due to the large number of new studies investigating the safety of the vaccine in pregnant women, it is important to synthesize the evidence for health professionals, researchers, policy makers, and pregnant women. This article presents the findings from a systematic review that investigated both effectiveness and safety of influenza vaccines for pregnant women, fetus, and infant [6]. In addition, this paper provides a more detailed analysis of critical adverse events including congenital malformation, fetal death, and spontaneous abortion. It also has implications for ongoing research. The protocol for this review was specified in advance and published in PROSPERO International prospective register of systematic reviews CRD42012003235 [7].

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2.3. Assessment of methodological quality Papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments [8]. 2.4. Data synthesis Studies were assessed for clinical and methodological heterogeneity with a view to conduct statistical meta-analysis. The studies were deemed too diverse to provide pooled estimates, and were instead presented in narrative form, including tables, to aid in data presentation. Studies that presented data as frequencies or percentages were converted to odds ratios and 95% confidence interval. Attempts were made to contact authors to provide missing definitions. 3. Results 3.1. Results of search

2. Methods

From the initial database search to March 2014, 7076 articles were identified. After removal of duplicates and evaluation of title and abstract, 6970 records were excluded. Full text articles were retrieved for 106 records, with 86 excluded after review and one study was excluded following critical appraisal. A total of 19 studies were included in this review [9–27]. Fig. 1 describes the identification and selection of studies. Excluded studies and the reason for their exclusion are listed in the supplementary material.

2.1. Search strategy

3.2. Study characteristics

The search strategy aimed to find both published and unpublished studies. A search using keywords and index terms was undertaken across PubMed, Embase, and Scopus from the inception of each database up to March 2014. A search for unpublished studies was conducted using MedNar, ProQuest Dissertation and Theses, and Australian Digital Thesis program. The reference lists of all included articles were searched for additional studies. Only studies published in English were considered for inclusion in this review.

Fetal and infant outcomes were investigated by 19 studies. These included 15 studies that investigated monovalent influenza A (H1N1) 2009 vaccine, or (H1N1) 2009 antigen containing trivalent vaccines [10–18,20–22,26,27]. Outcomes were also reported from one study investigating the monovalent (Hsw1N1) vaccine [9].

Records identified through database searching (n = 7076) Records excluded after removal of duplicates and examination of title and abstract (n = 6970)

2.2. Inclusion criteria 2.2.1. Types of participants This review focused on pregnant women with or without risk factors for complications from influenza infection, and their fetus. 2.2.2. Types of interventions Inactivated parenteral influenza vaccination Comparator: Unvaccinated pregnant women. Studies that conducted a comparison with a control cohort receiving an alternate vaccine were excluded. This was done to minimize potential confounding with adverse events from the control vaccine.

Full-text studies retrieved for detailed examination (n = 106)

Full text studies excluded with reasons (available in supplementary material) (n = 86) Studies included for critical appraisal by two reviewers (n =20)

2.2.3. Types of studies This review considered both clinical trials and observational epidemiological study designs. Studies reporting on passive surveillance were not included. 2.2.4. Types of outcomes Spontaneous abortion, fetal death, and congenital malformation.

Studies excluded following critical appraisal (available in supplementary material) (n = 1) Studies included in quantitative synthesis (n = 19) Fig. 1. Identification and selection of studies.

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Table 1 Included studies following critical appraisal. Study

Study design

Setting

Participants

Cohort one

Control

Study period

Cantu et al. [20]

Retrospective cohort study

High risk and low risk prenatal care clinics in USA

Women with singleton pregnancies. 52% and 36% had a high-risk clinic visit in each cohort 1st trimester vaccination: Unclear

Unvaccinated (n = 2010)

First 3 months of 2009/10 and 2010/11 seasons.

Chambers et al. [11]

Prospective cohort study

Teratology Information Services, Canada and USA.

Pregnant women < 20 weeks from LMP eligible. Women < 35 years of age (64% vs. 65.4%) 1st trimester vaccination: 42%

Unvaccinated and not exposed to any known teratogen (n = 191)

3 seasons from 2009 to 2012

Deinard et al. [9]

Prospective cohort study

Obstetric clinic in USA

Pregnant women mean 21.97 (SD ± 4.6) 1st trimester vaccination: 23%

Unvaccinated (n = 517)

1976 to 1977

Fell et al. [13]

Retrospective cohort

Ontario residents in Canada

Unvaccinated (n = 32230)

November 2009 to April 2010

Haberg et al. [14]

Retrospective cohort study

Pregnant population of Norway

October to December 2009

Mixed prospective and retrospective cohort study

Unvaccinated (n = 2213)

2009 in the Netherlands and Italy, 2010 in Argentina

Irving et al. [23]

Case control study

Midwife, hospital, and GP settings in Argentina, Italy, Netherlands. USA health care sites linked by a data network

Monovalent influenza A (H1N1) 2009 split-virion with ASO3 adjuvant (n = 25976). 266 women received 2 doses Trade name of vaccine: Pandemrix Monovalent Influenza A (H1N1) 2009, MF59 adjuvanted subunit vaccine. 75% received 2 doses (n = 2295) Trade name of vaccine: Focetria

Unvaccinated (n = 87335)

Heikkinen et al. [12]

All singleton hospital births (20 weeks gestation or more and birth weight equal to or greater than 500 g). Maternal age less than 35 (78%), medical comorbidity 7.4% Trimester vaccinated: Unknown Pregnant women with singleton pregnancies. 80% were aged less than 35 and 11% had a chronic illness 1st trimester vaccination: 9.4% Healthy pregnant women. Overall mean age 31.6 years 1st trimester vaccination: 4%

Monovalent influenza A (H1N1) 2009 vaccine.19.7% also received the seasonal influenza vaccine. (n = 666) 2010/11 Trivalent seasonal vaccine. (n = 428) Trade name of vaccine: Unspecified Monovalent and trivalent influenza A (H1N1) 2009 containing vaccines. Some women (n = 232) in the 2009/10 seasons also had seasonal influenza vaccine that did not contain (H1N1). (n = 1032) Trade name of vaccine: Unspecified Either split or whole virus monovalent influenza A/New Jersey/8/76 virus vaccine Hsw1N1 (n = 176) Trade name of vaccine: Unspecified Monovalent influenza A (H1N1) 2009 vaccine. Adjuvant, type of vaccine and dose not stated (n = 23340) Trade name of vaccine: Unspecified

Pregnancy loss through the first 16 weeks gestation (n = 243).

Randomly matched women with no pregnancy loss through the first 16 weeks gestation (n = 243)

Influenza seasons 2005 to 2007

Kallen, Olausson [15]

Retrospective cohort study

Population cohort from Sweden

Pregnant women who had experienced pregnancy loss, mean age 31.7 (SD ± 6.0). 16.5% with chronic condition Trimester vaccinated: All either before conception or during the 1st trimester Vaccine: Inactivated trivalent vaccine Trade name of vaccine: Unspecified Pregnant women. < 35 years of age (80.2% vs. 77.5%) 1st trimester vaccination: 17.0%

Monovalent influenza A (H1N1) 2009 split virus vaccine AS03adjuvant (n = 18 844) Trade name of vaccine: Pandemrix

October 2009 to December 2010

Launay et al. [24]

Prospective cohort study

Lin et al. [26]

Retrospective cohort study

Three tertiary maternity centers in Paris, France. Medical centers in Taiwan

Pregnant women between 12 and 35 weeks of gestation. 66.5% were < 35 years of age. 1st trimester vaccination: Nil Mean age for both cohorts was 32.4 (SD ± 4.0) and 32.8 (SD ± 3.9) years 1st trimester vaccination: 4.9%

Nonvaccination (n = 138 931) Pre-vaccination (n = 84 484) Unvaccinated (n = 422)

Luoik et al. [22]

Case control Hospitals and study/Retrospective birth registries from USA. cohort study

Mackenzie et al. [27]

Prospective cohort study

Scotland and UK general practices

Pregnant women, < 35 years of age (80.9% vs. 81.7%) 1st trimester vaccination: 137 women in retrospective cohort. Vaccine: Monovalent influenza A (H1N1) 2009 vaccine, or trivalent vaccine Trade name of vaccine: Unspecified Sub population of pregnant women. Characteristics not reported 1st trimester vaccination: 14.7%

Monovalent influenza A (H1N1) 2009 non-adjuvant split virion 15 ␮g, single dose (n = 320) Trade name of vaccine: Panenza Monovalent influenza A (H1N1) 2009, non-adjuvant, split-virus vaccine. Single dose (n = 202) Trade name of vaccine: AdimFlu-S Infants with birth defects (n = 3104).

Primarily monovalent influenza A (H1N1) 2009 inactivated AS03-adjuvanted split-virion vaccine. A whole-virion non-adjuvant monovalent influenza A (H1N1) vaccine was also available. (n = 113) Trade name of vaccine: Pandemrix or Celvapan

Unvaccinated (n = 206)

October 12 2009 to February 3 2010 From October 2009 to February 2010

Infants without malformations (n = 1087).

2009/10 and 2010/11.

Unvaccinated (n = 13)

November 2009 to 30 April 2010

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Table 1 (Continued) Study

Study design

Setting

Participants

Cohort one

Control

Study period

Munoz et al. [25]

Retrospective cohort study

Clinic in USA

Healthy pregnant women who had uncomplicated singleton pregnancy. Mean age 30.7 years 1st trimester vaccination: Nil

Unvaccinated (n = 826)

5 influenza seasons from July 1, 1998, to June 30, 2003.

Oppermann et al. [10]

Prospective cohort study

Germany

Median age 33 in vaccinated cohort and 32 in control group 1st trimester vaccination: 6.2% preconception, 17% in the 1st trimester.

Unvaccinated (n = 1329)

April 2009 to June 2010

Pasternak et al. [17]

Retrospective cohort study

Nationwide registry in Denmark

All singleton pregnancies (live births, stillbirths and pregnancies with an abortive outcome) in Denmark. Pregnant women mean age 30 (SD ± 5.2) in the vaccinated cohort and 30.9 (SD ± 4.7) in the unvaccinated 1st trimester vaccination: 7.7%

Seasonal influenza vaccine. Antigenic make up of vaccines not reported Infants and mothers: (n = 225) Trade name of vaccine: unspecified Non-adjuvanted split-virion monovalent influenza A (H1N1) 2009 (n = 216) AS03-adjuvanted split-virion monovalent influenza A (H1N1) 2009 vaccine (n = 90) MF59 adjuvanted subunit monovalent influenza A (H1N1) 2009 vaccine (n = 2). For 15 women the vaccine type could not be ascertained. Total (n = 323) Trade name of vaccine: Pandemrix, CSL (H1N1) Pandemic Influenza Vaccine Monovalent influenza A (H1N1) 2009 inactivated AS03-adjuvanted split-virion vaccine. Fetal death analysis (n = 7062), stillbirth analysis. (n = 7014), spontaneous abortion analysis (n = 2736) Trade name of vaccine: Pandemrix

November 2009 to 30 September 2010 vaccination campaign periods.

Pasternak et al. [16]

Retrospective cohort study

Nationwide registry in Denmark

Rubinstein et al. [21]

Cross sectional study

49 public hospitals in Argentina

Sammon et al. [18]

Retrospective cohort study

UK General Practices

Sheffield et al. [19]

Retrospective cohort study

Hospital system in the USA

Pregnant women with live born singleton infants. Excluded known causes and congenital viral infections possibly associated with birth defects and unspecified congenital viral disease. Pregnant women mean age 30.7 (SD ± 5.2) in the vaccinated cohort and 30.1 (SD ± 5.0) in the unvaccinated 1st trimester vaccination: 345 (analyzed separately) Pregnant women with a live born or stillborn infant of at least 22 weeks gestation or weighing 500 g or more at birth. < 35 years (88.5% vs. 86.9%) 1st trimester vaccination: 39.4% Mean age 29.9 for those who delivered an infant. 5.9% were in another clinical risk group for influenza and 24.6% smoked 1st trimester vaccination: Measured as % of time vaccinated during the 1st trimester. 2.9% vaccinated weeks. Pregnant women, < 35 years of age (89% vs. 91%) 1st trimester vaccination: 5%

Unvaccinated Fetal death analysis (n = 47524). Stillbirth (n = 43663). Spontaneous abortion (n = 32627). Unvaccinated 1st trimester (n = 330) 2nd and 3rd trimester (n = 6642)

The study cohorts were mainly from the USA and Europe, with seven studies undertaken in the USA [9,11,19,20,22,23,25], nine from Europe [10,12,14–17,24] and the UK [18,27], one each from Canada [13], Asia [26], and Argentina [21]. There were five larger retrospective cohort studies with population wide cohorts that sampled the pregnant populations of Norway, Sweden, Denmark, and Ontario [13–17]. Only two studies were performed exclusively on healthy pregnant women [12,25]. Women with comorbidities were represented in the overall sample. Pregnant women vaccinated during their first trimester were under-represented in the study cohorts. There were two studies that were unable to establish the trimester in which vaccination took place [13,20]. Included studies are described further in Table 1.

Monovalent influenza A (H1N1) 2009 inactivated AS03-adjuvanted split-virion vaccine. 1st trimester propensity score matched analysis (n = 330). 2nd and 3rd trimester propensity score matched analysis (n = 6642) Trade name of vaccine: Pandemrix

November 2, 2009 to September 30, 2010 vaccination campaign periods.

Monovalent Influenza A (H1N1) 2009 vaccine MF-59-adjuvanted subunit vaccine. Single dose (n = 7293) Trade name of vaccine: Focteria

Unvaccinated (n = 23195)

September 2010 to May 2011.

Monovalent influenza A (H1N1) 2009 vaccine. Mostly AS03 adjuvanted split-virion vaccine. Number of doses unclear (n = 9445) Trade name of vaccine: Pandemrix

Unvaccinated (n = 26993)

2009/10

Seasonal trivalent influenza vaccine (n = 8864) Trade name of vaccine: unspecified

Unvaccinated (n = 76919)

Five seasons October 2003 to March 2008.

3.3. Assessment of methodological quality There were no randomized controlled trials assessing birthing outcomes that had an unvaccinated, or placebo controlled comparison. For the prospective cohort studies attrition bias is the lowest rated criteria. Studies were either unclear as to how many people withdrew, or lost multiple participants to follow up [9–12,27]. The majority of prospective studies were also at risk of selection bias with non-random cohort selection, or limited matching of cohorts [9,11,12,27]. Retrospective cohort studies collected information from medical databases and relied on accurate International Classification of Disease (ICD) coding, or documentation of birthing outcomes using

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Table 2 Adjusted variables. Study

Outcome

Adjusted variables

Chambers et al. [11]

Spontaneous abortion

Adjusted for propensity score comprised of race, previous elective termination, infection and directly adjusted for autoimmune disease Pre-pregnancy body mass index and seasonal vaccine not containing pandemic H1N1 strain Maternal age, family income, education, and maternal smoking Age, parity, marital status, use of nutritional supplements during pregnancy, smoking during pregnancy, history of earlier fetal death, and eight chronic medical conditions Parity, smoking, and maternal age Maternal age, parity, maternal diabetes, and health care utilization Year of birth, maternal age, parity, smoking, BMI, preterm birth, low birth weight, and SGA <2 SD Matched propensity score included maternal age, race, maternal education, family income, marital status, parity, study centre, body mass index (BMI), family history of birth defects, pregnancy intention, peri-conceptional folic acid use, alcohol use, smoking, asthma, diabetes, LMP quarter, infertility treatment, treatment for high blood pressure or toxemia, inter-pregnancy interval, and season of exposure (2009–2010 or 2010–2011) Vaccination time and study entry

Congenital malformation Fell et al. [13] Hårberg et al. [14]

Fetal death Fetal death

Heikkinen et al. [12] Irving Kallen [15]

Fetal death Spontaneous abortion Fetal death, Congenital malformation Congenital malformation

Luoik et al. [22]

Opperman et al. [10] Pasternak et al. [16] Pasternak et al. [17]

Spontaneous abortion, congenital malformation Fetal death, spontaneous abortion, congenital malformation

other regional or national databases. Reliance on medical coding can be susceptible to missing and misclassification of data. To mitigate potential bias, confounding variables were adjusted for using regression modeling or propensity score matching. Maternal age was the most frequently assessed and used in modeling. The risk of residual confounding is inherent in the nature of retrospective observational cohort studies [28]. Overall there is a high risk of confounding bias in the studies in this review. Variables used in adjusted estimates are described in Table 2. The accuracy of gestational age estimations is critical for early pregnancy adverse events and deliberating on the timing of vaccination. It was not described in many studies how this was assessed. Definitions included the last menstrual period (LMP) [18], LMP plus 2 weeks [11,12,22], or ultrasound data with LMP/LMP + 2 weeks as the default when ultrasound data was not available [15–17,23]. Selection bias is also an issue with many studies in this review. The denominator of women vaccinated during the period where an event was being measured i.e. spontaneous abortion <20 weeks was not clear in some studies and these were excluded. There are two studies included in this review in which the funding for the research was primarily, or in part, obtained from the pharmaceutical industry [12,21,26]. The majority of studies were either funded by government, private sources, or self-funded [9–11,13–18,22–25]. Funding sources were unclear in the remainder of studies [19,20,27]. 3.4. Assessment of heterogeneity Studies included in this review have significant clinical and methodological heterogeneity. Clinical heterogeneity is present due to the different vaccine compositions and definitions used. Variable reactogenicity is possible between some of the vaccines in the review. Monovalent or trivalent, whole virion, split-virion, and subunit vaccines are investigated, with ASO3 or MF-59 adjuvanted vaccines further adding to the variability. Clinical heterogeneity is also present with a variety of measures used to classify fetal death, spontaneous abortion, or congenital malformation. Methodologically the multi-directional nature of the observational studies i.e. prospective, retrospective, cross sectional, and case-control studies further reduce the number of studies that are suitable to pool in statistical analysis.

Propensity models included the following variables: Maternal age, county of residence, degree of urbanization, country of birth, parity, history of fetal death in siblings, selected comorbidities, number of hospital admissions and outpatient hospital contacts within three years preceding pregnancy, selected drugs and number of drugs used within six months before pregnancy

3.5. Analysis 3.5.1. Fetal death Fetal death outcomes were reported in 13 studies [9,11–15,17–21,24,26]. Studies that reported fetal death prior to 24 weeks gestation were included in the spontaneous abortion analysis. Monovalent influenza A (H1N1) 2009 vaccines were exclusively investigated in nine studies [12–15,17,18,21,24,26]. In four studies the vaccines contained an ASO3 adjuvant [14,15,17,18]. Three of these consisted of large population wide samples which had point estimates below one and precise confidence intervals [14,15,17], and one had confidence intervals that implied a statistically significant reduction in fetal death [17]. The remaining study conducted in the UK had a point estimate above one with imprecise confidence intervals that crossed the null value [18]. It was calculated using a discrete survival analysis with separate hazard ratios for weeks 9 to 12, weeks 13 to 24, and weeks 25 to 42. Only weeks 25 to 42 were included in the fetal death analysis. The ‘toxicity model’ estimates are tabled as they were designed to identify if there was an association between vaccination and fetal death in the week of vaccination or the three weeks immediately thereafter [18]. Monovalent influenza A (H1N1) 2009 subunit vaccine with MF59 adjuvant was investigated in two studies and one had a point estimate below the null value with precise confidence intervals [21]. The other study with a smaller sample size had a point estimate above one and imprecise confidence intervals that crossed the null value [12]. Both studies that investigated a non-adjuvanted vaccine were statistically imprecise with point estimates below the null value [24,26]. A study investigating an unspecified monovalent influenza A (H1N1) 2009 vaccine used in a population wide sample of Ontario residents in Canada estimated a statistically significant reduction in fetal death following vaccination [13]. Remaining studies with both trivalent and monovalent influenza vaccines consisted of small cohorts with point estimates below or close to the null value with wide imprecise confidence intervals with upper 95% intervals above 9.75 [11,24]. A prospective study investigating the monovalent influenza A (Hsw1N1) vaccine had a point estimate OR of 2.95 with wide imprecise confidence intervals that crossed the null value [9].

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Fig. 2. Forest plot of influenza vaccination versus no vaccination, outcome of fetal death (odds ratio).

Fig. 3. Forest plot of influenza vaccination versus no vaccination, outcome of fetal death (hazard ratio).

The sole study exclusively investigating a trivalent seasonal vaccine reported stillbirths for women vaccinated during the first trimester at OR 2.54 (95% CI, 0.36 to 18.10), and for the second and third trimester OR 1.65 (95% CI, 1.13 to 2.40) [19]. However, this would appear to be incongruent with the raw data presented in the paper and OR estimated from that data which indicates a point estimate below the null value. Attempts to contact the authors were unsuccessful to clarify the results. None of the studies indicated a statistically significant association between the vaccine and fetal death. The highest quality studies conducted analysis using time dependent exposure analysis and estimated hazard ratios [14,17,18]. The studies investigating fetal death are mostly retrospective observational studies and susceptible to selection and confounding bias. Six of the studies reported unadjusted results and have a high risk of bias [9,12,19–21,26]. Results are described in Table 3, and a forest plot of point estimates and 95% confidence intervals is presented in Figs. 2 and 3. 3.5.2. Spontaneous abortion Spontaneous abortion outcomes were reported in 10 studies [9–12,17,18,20,23,24,27]. Three of those studies were excluded from this outcome as they reported crude rates without a clear denominator of the number of women vaccinated or enrolled prior to 20 weeks gestation [9,20,24]. The information was unable to be obtained from the authors. Monovalent influenza A (H1N1) 2009 vaccines were investigated in five studies [10,12,17,18,27]. Pasternak et al. [16], investigated with an abortive outcome between 7 to 22 weeks with monovalent influenza A (H1N1) 2009 AS03-adjuvanted split-virion vaccine. Spontaneous abortion only consisted of pregnant women vaccinated during their first trimester, with an estimate of HR 1.11 (95% CI, 0.71 to 1.74) [17]. Sammon et al. [18] conducted two separate analyses of fetal death following vaccination with monovalent influenza A (H1N1) 2009 AS03 adjuvanted split-virion vaccine. The two periods were between 9 to 12 weeks HR 0.56 (95% CI, 0.43 to 0.73), and 13 to 24 weeks HR 0.45 (95% CI, 0.28 to 0.72) [18]. Both point estimates favored the vaccinated cohort with a confidence interval indicating the results were statistically significant. Despite this, their results also indicated that the vaccine resulted in a reduction in fetal death

at a time when the influenza virus was in limited circulation and no such association should exist. The authors concluded there was residual confounding that was unable to be measured [18]. Opperman et al.’s [10] prospective cohort study investigated monovalent influenza A (H1N1) 2009 AS03 adjuvanted split-virion and non-adjuvanted vaccine. The study contained spontaneous abortion outcomes in 5 of the women in the vaccinated cohort, compared to 105 cases from the 1329 women in the control cohort. Adjusting for vaccination time and study entry they estimated a HR 0.89 (95% CI, 0.36 to 2.19) [10]. It is unclear what week gestation they used to classify spontaneous abortion, however the five abortions all occurred in less than 12 weeks pregnancy. Included in the five spontaneous abortions were three women out of 20 who were vaccinated prior to conception [10]. Heikkinen et al. [12] conducted a mixed prospective and retrospective cohort study in midwife, hospital, and GP settings in Argentina, Italy, and Netherlands on healthy pregnant women. They reported no spontaneous births in the women vaccinated with a monovalent influenza A (H1N1) 2009 MF-59 adjuvanted subunit vaccine and nine in the unvaccinated cohort prior to 22 weeks gestation [12]. The authors were contacted for the denominator of women vaccinated prior to 22 weeks gestation and reported 711 women (31%) were vaccinated during that period. The low number of spontaneous abortions was attributed to the high gestational age (mean 31 weeks) at enrollment [12]. Mackenzie et al.’s [27] prospective study conducted in Scotland and UK general practices contained a sub group of pregnant women in a larger population-wide study. Two types of vaccine were available with the monovalent influenza A (H1N1) 2009 AS03 adjuvanted split-virion vaccine most widely used. There were two spontaneous abortions prior to 24 weeks in the 13 women vaccinated prior to their LMP, and two in the 19 women immunized during their first trimester. Two of these occurred in two different pregnancies in the same woman. None were reported in the 13 women in the unvaccinated cohort [27]. Chambers et al. [11] conducted a prospective cohort study on a combination of trivalent and monovalent influenza vaccines with participants recruited from callers to Teratology Information Services in Canada and the USA. The study ran over three influenza seasons from 2009 to 2012 with spontaneous abortion recorded less than 20 weeks [11]. They estimated a HR of 0.92 (95% CI, 0.31 to

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Table 3 Influenza vaccine versus no vaccine, outcome of fetal death. Study

Design

Composition

Adjuvant

Type

Vaccine group

Control group

Effect estimate subtotals (95% CI)

Definition of fetal death

Hårberg et al. [14] Fell et al. [13] Lin et al. [26] Heikkinen et al. [12] Rubinstein et al. [21] Kallen [15] Pasternak et al. [17] Launay et al. [24] Sammon et al. [18] Deinard [9] Sheffield et al. [19]

Retrospective Retrospective Retrospective Mixed design Cross section Retrospective Retrospective Prospective Retrospective Prospective Retrospective

Mono H1N1 Mono H1N1 Mono H1N1 Mono H1N1 Mono H1N1 Mono H1N1 Mono H1N1 Mono H1N1 Mono H1N1 Mono Hsw1N1 TIV

ASO3 Unspecified Non-adjuvant MF-59 MF-59 ASO3 ASO3 Non-adjuvant ASO3 Unspecified Unspecified

Split-virion Unspecified Split-virion Subunit Subunit Split-virion Split-virion Split-virion Split-virion Split or whole Unspecified

Prospective

TIV+/- Mono H1N1

Unspecified

Unspecified

Cantu et al. [20]

Retrospective

TIV+/- Mono H1N1

Unspecified

Unspecified

87335 32230 206 2213 23195 84 484 47524 422 26993 517 76919 76919 76919 191 191 2010

HR 0.88 (0.66 to 1.17) OR 0.66 (0.47 to 0.91) OR 0.34 (0.01 to 8.39)† OR 1.44 (0.23 to 8.90) OR 0.71 (0.46 to 1.10)† OR 0.81 (0.59 to 1.12) HR 0.44 (0.20 to 0.94) OR 0.58 (0.06 to 5.59)† HR 1.56 (0.73 to 3.34) OR 2.95 (0.18 to 47.39)† OR 0.60 (0.41 to 0.86)† OR 2.54 (0.36 to 18.10)‡ OR 1.65 (1.13 to 2.40) RR 0.23 (0.01 to 3.93) RR 0.57 (0.03 to 9.57)‡ OR 1.10 (0.46 to 2.59)†

>12 weeks >20 weeks >20 weeks* >22 weeks >22 weeks >22 weeks* >22 weeks >22 weeks* >25 weeks >20 weeks >500 g

Chambers et al. [11]

25976 23340 202 2295 7293 18 844 7062 320 9445 176 8864 439 8251 1032 348 979

† ‡ § *

>20 weeks >22 weeks

Crude raw data used to estimate unadjusted odds ratio and 95% confidence interval by review authors. Analysis of women vaccinated during the first trimester. Analysis of women vaccinated during their 2nd and 3rd trimester. Definitions obtained from contact with authors

2.73), which was close to the null value with imprecise statistically non-significant confidence intervals [11]. Irving et al. [23] conducted a case control study in the USA amongst health sites linked by a data network, and this was conducted over two influenza seasons between 2005 and 2007 with an unspecified trivalent vaccine. Pregnancy losses between 5 and 16 weeks were included to capture events in the weeks following vaccine exposure. Controls were randomly selected and matched based on the LMP, as well as having confirmed pregnancy and delivery beyond 20 weeks. The study reported an odds ratio point estimate of 1.23 (95% CI, 0.53 to 2.85) that favored the unvaccinated group in the 28-day exposure window following vaccination [23], although the confidence interval indicates that this result was imprecise and not statistically significant. Studies that used time dependent exposure analysis and casecontrol design account for the actual number of women who were exposed to the vaccine during the time they were susceptible to spontaneous abortion. Due to the retrospective observational design of most studies they remain susceptible to selection and confounding bias, although all studies that estimated HR or OR adjusted for some potential confounding variables.

3.5.3. Congenital abnormality Congenital abnormality outcomes were included from 12 studies [9–12,15,16,19,21,22,24,25,27]. Two studies investigated unspecified trivalent seasonal vaccines [19,25], seven monovalent influenza A (H1N1) 2009 vaccines [10,12,15,16,21,24,27], two mixed unspecified trivalent and monovalent influenza A (H1N1) 2009 vaccines, and one (Hsw1N1) 1976 whole or split-virion vaccine [9]. The developing fetus is at most risk during the first trimester [5], so the timing of the vaccination in relation to the date of conception is an important factor. Not all studies included a sub group analysis of women vaccinated during their first trimester, or restricted their results to this population. The definition used for congenital malformation was not standard amongst the studies as some included minor malformations and major malformations, whilst others just counted major malformations. Other than age, the overall assessment of potential confounding variables was inconsistent. Five studies presented crude unadjusted data [9,19,21,24,27]. Congenital malformations due to some chromosomal conditions, genetic disorders, and other known causes such as infection were also managed differently in studies.

Louik et al. [22] conducted a case control study comparing infants with birth defects to non-malformed controls following vaccination with unspecified monovalent influenza A (H1N1) 2009 vaccine, or trivalent seasonal vaccine. Infants with structural defects are identified at study centers in hospitals in the USA. Non-malformed controls were identified randomly at the same study centers. The study adjusted for propensity scores for potential confounding factors based on c-statistic on 41 specific birth defects. This reduced statistical power for the majority of congenital abnormalities and was difficult to interpret. The authors reported no meaningful evidence of specific congenital malformations [22]. Results are not tabled. All malformations in women vaccinated during their first trimester were reported in four studies [10,11,15,27]. All were investigating a monovalent influenza A (H1N1) 2009 vaccine, with three containing a vaccine with AS03 adjuvant [10,15,27]. Three had point estimates close to the null value [10,11,15], and only one had statistically precise confidence intervals [15]. The remaining study by Mackenzie et al. [27] had a point estimate of OR 2.18 with wide imprecise confidence intervals crossing the null value. Major malformations were investigated by three studies that included women vaccinated during their first trimester, Pasternak et al. [16] matched 330 women who were vaccinated with an ASO3 adjuvant monovalent influenza A (H1N1) vaccine in the first trimester with women in the unvaccinated cohort using a propensity score for each participant. Logistic regression was used to estimate prevalence odds ratios. They estimated an OR 1.21 (0.60 to 2.45). The remaining two studies investigating an unspecified trivalent vaccine and monovalent influenza A (H1N1) 2009 vaccine had point estimates below one [10,19], and one had wide confidence intervals with the upper limit at 2.64 [10]. Studies investigating ‘all malformations’ in children born from women vaccinated during any trimester had point estimates below one, except for Heikkinen et al. [12] who estimated OR 1.33 (0.88 to 2.00), and Mackenzie et al. [27] who reported 5 malformations out of 97 vaccinated women, compared to none of the 13 unvaccinated women. Refer to Table 5 for vaccine compositions. Any trimester vaccination ‘major malformations’ were reported in three studies. Two had point estimates above one, with wide confidence intervals crossing the null value [10,24], and the study by Sheffield et al. investigating an unspecified trivalent influenza vaccine had a point estimate near the null value and precise confidence intervals [19].

M. McMillan et al. / Vaccine 33 (2015) 2108–2117

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Table 4 1st trimester influenza vaccination versus no vaccine, outcome of congenital malformation. Subgroup

Design

Composition

Adjuvant

Type

Vaccine group

Control group

Effect estimate subtotals (95% CI)

All malformation Chambers et al. [11] Kallen et al. [15] Mackenzie et al. [27] Opperman et al. [10]

Prospective Retrospective Prospective Prospective

Mono H1N1 ± TIV Mono H1N1 Mono H1N1 Mono H1N1

Unspecified AS03 AS03 Non-adj or AS03

Unspecified Split-virion Split-virion Split-virion

328 3165 19 70

188 84 484 13 1198

RR 0.79 (0.26 to 2.42)‡ OR 1.04 (0.85 to 1.28)$ OR 2.18 (0.82 to 57.98)† OR 0.99 (0.43 to 2.00)

Major malformation Opperman et al. [10] Pasternak et al. [16] Sheffield et al. [19]

Prospective Retrospective Retrospective

Mono H1N1 Mono H1N1 TIV

Non-adj or AS03 AS03 Unspecified

Split-virion Split-virion Unspecified

70 330 439

1198 330 76919

OR 0.79 (0.13 to 2.64) OR 1.21 (0.60 to 2.45) OR 0.67 (0.36 to 1.26)¶

All trimester vaccination studies have a higher risk of bias due to including women who were vaccinated in the later stages of pregnancy and thus less likely to be at risk of a fetus developing congenital malformations post vaccination. The overall quality of the evidence is low with five studies reporting crude unadjusted data [9,19,21,25,27]. Other studies performed adjusted analysis in an attempt to address the risk of confounding. The smaller cohorts in studies investigating first trimester vaccinations resulted in statistically imprecise estimates. Results are described in Tables 4 and 5. 4. Discussion Birth outcomes have been the area of largest growth in evidence over the last four years for influenza vaccination during pregnancy. Most of the research consists of lower-level observational evidence from clinically and methodologically heterogeneous studies. Women vaccinated during the first trimester of pregnancy are under-represented in the studies included in this review and the evidence is more generalizable for women vaccinated in their second or third trimester of pregnancy with the monovalent influenza A (H1N1) 2009 vaccine. The lower number of pregnant women vaccinated during their first trimester means that for spontaneous abortion and congenital abnormalities, many individual studies are statistically imprecise, even though there is no statistically significant evidence of harm. Due to the lack of statistical precision, more evidence is needed to inform this outcome. Both studies by Irving et al. [23] and Pasternak et al. [17] discuss the preliminary nature of their first trimester findings. All cause outcomes of fetal death, spontaneous abortion, and congenital abnormalities limit the findings that can be made [29]. There are numerous confounders that may increase the risk of

fetal death including maternal age, smoking, past history of preterm birth, short cervical length, low socio-economic status, African ancestry, alcohol or drug use, and chronic disease such as hypertension, renal insufficiency, or diabetes [30]. Potential confounders such as prior preterm birth, inter-pregnancy interval, gestational diabetes, and folic acid use during organogenesis were infrequently assessed or adjusted for in modeling in the studies in this review. Causality and purported risk factors for fetal death have been difficult to prove, with some risks requiring cofactors to exert their effect. Between 25 and 60 percent of all fetal deaths occur without any identifiable fetal, placental, maternal, or obstetrical aetiology [30]. This further complicates assessing associations between interventions on both safety and potential protective effects. Selection bias is also an issue with many studies in this review. This is especially true for studies investigating spontaneous abortion and congenital malformation where the timing of vaccination is important to establish accurate denominators and evaluate critical periods of risk. Early in 2014, a Cochrane systematic review was updated to include safety outcomes for pregnant women and their fetus [31]. The Cochrane review provides a broad analysis of effectiveness and safety of the vaccine. The systematic review reports that influenza vaccination with the monovalent influenza A (H1N1) 2009 vaccine during pregnancy is not associated with a higher risk of abortion, congenital malformation, or neonatal death. It contained pooled estimates for fetal death and congenital malformation. In this review it was decided that the clinical and methodological heterogeneity of studies discouraged statistical pooling of results in meta-analysis. Meta-analysis of observational studies carries a risk of overestimation or underestimation due to combining errors in measurement of the exposure variables, confounding, and biases,

Table 5 Any trimester influenza vaccination versus no vaccine, outcome of congenital malformation. Study

Design

Composition

Adjuvant

Type

Vaccine group

Control group

Effect estimate subtotals (95% CI)

All malformation Opperman et al. [10] Heikkinen et al. [12] Mackenzie et al. [27] Rubinstein et al. [21] Deinard [9] Munoz et al. [25]

Prospective Mixed Prospective Cross section Prospective Retrospective

Mono H1N1 Mono H1N1 Mono H1N1 Mono H1N1 Mono Hsw1N1 TIV

Non-adj or AS03 MF-59 AS03 MF-59 Unspecified Unspecified

Split-virion Subunit Split-virion Subunit Split or whole Unspecified

321 2295 97 7293 176 225

1198 2213 13 23195 517 825

OR 0.92 (0.58 to 1.46) OR 1.33 (0.88 to 2.00) OR 1.60 (0.08 to 30.70)† OR 0.81 (0.55 to 1.19) † OR 0.58 (0.32 to 1.06) † OR 0.12 (0.01 to 1.95) †

Major malformation Opperman et al. [10] Launay et al. [24] Sheffield et al. [19]

Prospective Prospective Retrospective

Mono H1N1 Mono H1N1 TIV

Non-adj or AS03 Non-adjuvant Unspecified

Split-virion Split-virion Unspecified

321 320 8425

1198 557 76919

OR 1.11 (0.51 to 2.42) OR 2.34 (0.52 to 10.51)† OR 1.01 (0.84 to 1.22)¶¥

† Crude raw data used to estimate unadjusted odds ratio and 95% confidence interval by review authors. 2nd and 3rd trimester vaccination only. Definitions: ‡ Metropolitan Atlanta Congenital Defects Program coding, EUROCAT definitions, $ Swedish Medical Birth Register definitions, ¶ Major malformations, significant functional or cosmetic impairment, or those that were life limiting, Alterations in anatomical development diagnosed during gestation or physical examination, Major and minor malformations from discharge summaries. ¥

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that do not usually occur in randomized controlled trials [28]. This is especially so with clinical and methodological differences in studies [32]. It is likely that with consistent methods of manufacture the safety profile of influenza vaccines will be similar. However, different vaccine compositions may have different reactogenicity and also need to be assessed separately when considering safety. Studies by Chambers et al., Rubinstein et al., Cantu et al., Lin et al., and Sammon et al. that were published after the Cochrane study search period were additional studies in this review. None of the additional studies indicated a statistically significant increase in fetal death. This review also differentiates between fetal death earlier in pregnancy and later in pregnancy and proposes that separate analysis should be conducted in future reviews. An analysis of congenital malformation was also performed in the Cochrane review with similar studies included in this review. Only Chambers et al. and Louik et al. were additions to this review. However, an important consideration in the assessment of congenital malformations is the timing of vaccination. Our findings suggests that future research should differentiate pregnant women vaccinated near conception, or during their first trimester, for congenital malformation outcomes, rather than combined all trimester findings. As well as the Cochrane review, a systematic review on fetal death and premature birth has recently been published [33]. The authors performed analysis on early and late fetal death similar to this review. Findings presented in the review by Fell et al. on fetal death are in parallel to the findings in this review, particularly the need for future studies to include information on first trimester vaccinations. This has also been a conclusion from earlier literature reviews [34,35]. Other fetal outcomes such as premature birth, small for gestational age infant, and low birth weight infant are described in other systematic reviews [6,31,33,36]. Whilst every effort has been made to remain objective and transparent, not conducting meta-analysis means that findings are open to subjective assessment and potential bias from the authors. By adhering to PRISMA guidelines every effort has been made to minimize this bias. Due to the observational nature of the studies, and especially the large number of retrospective studies, there is a risk of selection bias and residual confounding that is inherent in observational studies [29]. Several studies contained in this review do not contain product specific information about the type of vaccine i.e. sub-unit, split-virion and adjuvant used and this is a limitation of this review. Even though the review aimed to be as inclusive as possible, evidence derived purely from national or regional passive vaccination surveillance was excluded from this review for two main reasons. The task of locating and collating studies and grey literature that contained passive surveillance information from around the world would have been a monumental task. Even though surveillance provides an important indicator for clusters of events, changing trends, or severe adverse events, it is prone to under reporting [37]. From a systematic review perspective it was thought that the level of evidence quality was not suitable or practical for this review. Research on influenza vaccination in pregnancy is a rapidly moving field. It is difficult to remain up-to-date with the most current information. Observational research rather than randomized controlled trials (RCT) have been the mainstay of evidence available for women vaccinated during pregnancy, due to the comparative cost and ethical considerations since the vaccine is already recommended in most countries [29]. Even though observational research will likely remain the mainstay in high income countries, it is worth noting that RCTs are currently underway [38], and one has recently been published that is not included in this review [39]. RCTs provide the highest quality evidence regarding the effectiveness and safety of vaccines. Despite this, large studies using data from medical coding and national datasets will continue to

be important in the ongoing assessment of the safety of influenza vaccines for the fetus. Studies that have access to population wide data have the advantage of capturing and providing findings from one influenza season, at low cost, and with good statistical power. Ideally these types of studies need to identify the precise timing of vaccination in relation to the gestational age of the fetus, adjust for potential confounding variables, and include time-dependent analysis from time of exposure to event in order to minimize bias. This is an issue for vaccines that are not used in regions where researchers have access to population wide data. This review is specifically focused on the safety of the vaccine during pregnancy. It is not appropriately designed to assess potential protective effects of the vaccine. It is possible that the vaccine provides protection either through a reduction in influenza illness, or severity of illness, or due to non-specific effects of influenza vaccination. In two studies a statistically significant association was estimated with a reduction for fetal death following vaccination [13,16]. To have more confidence in the potential protective effects of vaccines on fetal development, studies should be cognizant of the timing of the peak influenza period and ideally have laboratory confirmed end points, or identification of influenza-like illness. To provide strong evidence of protection future studies should be designed as studies of effectiveness, taking in recommendations from Simonsen et al. about lessons learnt in other populations and use of ‘all cause’ outcomes [29]. Large prospective studies are likely to be the studies best designed to assess effectiveness. They also will allow for more accurate measurement of gestational age, vaccination timing, event information, and collection of relevant potential confounding variables. A number of studies investigated the effects of the influenza vaccine on spontaneous abortion, fetal death, and congenital malformation. The results do not indicate that maternal influenza vaccination is associated with an increased risk of fetal death, spontaneous abortion, or congenital malformations. However, statistical imprecision, observational design, and clinical and methodological heterogeneity mean it is not possible to totally exclude harm. Further studies investigating women vaccinated during their first trimester should be the highest priority to allow for more precise estimates, especially for spontaneous abortion, and congenital abnormality outcomes. Contributions MM was the lead for the systematic review. MM performed the search, screening, appraisal, data extraction, analysis, and manuscript writing. LC was involved in article screening and critical appraisal. HM, DK, KP were involved in protocol development and oversight during each stage of the review. All authors were involved in revising the manuscript. DK did not review changes to the manuscript following peer review or the final proof. Funding No funding was received to conduct this review. Conflict of interest statement Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi disclosure.pdf and declare: (1) No financial support was received for the submitted work. (2) LC, DK, KP have no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work. HM is supported by an NHMRC Career Development Fellowship

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(1016272). HM’s institution has received research grants from vaccine manufacturers GSK, Pfizer, Novartis and Sanofi Pasteur for investigator-led research. HM has been an investigator for studies funded by pharmaceutical companies including Pfizer, GSK Sanofi-Pasteur, Novartis. Travel support has been provided to her institutions by GSK and/or Sanofi-Pasteur for HM to present scientific data at international meetings. MM has received travel support by GSK to present at a national immunization conference. There are no other potential conflicts of interest. Transparency declaration The lead author (the manuscripts guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Data sharing Details of how to obtain additional data from the study can be obtained from MM ([email protected]). Acknowledgements Joanna Briggs Institute and Australian Commonwealth Government for MM’s funded candidature in Master of Clinical Science: Evidence Based Healthcare. Dedicated to the memory of Professor Debbie Kralik, an exemplary clinician, leader, innovator, teacher, and researcher. References [1] Rasmussen SA, Watson AK, Kennedy ED, Broder KR, Jamieson DJ. Vaccines and pregnancy. Past, present, and future. Semin Fetal Neonatal Med 2014;19:161–9, http://dx.doi.org/10.1016/j.siny.2013.11.014. [2] Organization WH, editor. The weekly epidemiological record (WER). Geneva: World Health Organization; 2012. p. 201–16. [3] Drees M, Johnson O, Wong E, Stewart A, Ferisin S, Silverman PR, et al. Acceptance of 2009 H1N1 influenza vaccine among pregnant women in Delaware. Am J Perinatol 2012;29:289–94, http://dx.doi.org/10.1055/s-0031-1295660. [4] McCarthy EA, Pollock WE, Nolan T, Hay S, McDonald S. Improving influenza vaccination coverage in pregnancy in Melbourne 2010–2011. Aust NZ J Obstet Gynaecol 2012;52:334–41, http://dx.doi.org/10.1111/j.1479828X.2012.01428.x. [5] Ruedy J. Teratogenic risk of drugs used in early pregnancy. Can Fam Phys Med Famille Can 1984;30:2133–6. [6] McMillan M, Kralik D, Porritt K, Marshall H. Influenza vaccination during pregnancy: a systematic review of effectiveness and adverse events. JBI Database Syst Rev Implementation Rep 2014;12:251, http://dx.doi.org/10.11124/jbisrir2014-1269. [7] McMillan M, Kralik D, Porritt K, Marshall H. Influenza vaccination during pregnancy: a systematic review of effectiveness and adverse effects. In: PROSPERO 2012:CRD42012003235. PROSPERO: International Prospective Register of Systematic Reviews; 2012. [8] The Joanna Briggs Institute. Joanna Briggs Institute Reviewers’ Manual: 2014 edition. The Joanna Briggs Institute; 2014. [9] Deinard AS, Ogburn P. A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome. Am J Obstet Gynecol 1981;140:240–5. [10] Oppermann M, Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B, Allignol A, Meister R, et al. A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. Vaccine 2012;30:4445–52, http://dx.doi.org/10.1016/j.vaccine.2012.04.081. [11] Chambers CD, Johnson DL, Xu R, Luo Y, Louik C, Mitchell AA, et al. Risks and safety of pandemic H1N1 vaccine in pregnancy: birth defects, spontaneous abortion, preterm birth, and small for gestational age infants. Pharmacoepidemiol Drug Saf 2013;22:14–5, http://dx.doi.org/10.1016/ j.vaccine.2013.08.097. [12] Heikkinen T, Young J, van Beek E, Franke H, Verstraeten T, Weil JG, et al. Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. Am J Obstet Gynecol 2012;207:177e1–8, http://dx.doi.org/10.1016/j.ajog.2012.07.007. [13] Fell DB, Sprague AE, Liu N, Yasseen 3rd AS, Wen SW, Smith G, et al. H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. Am J Public Health 2012;102:e33–40, http://dx.doi.org/10.2105/AJPH.2011.300606.

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