Safety of influenza immunization during pregnancy for the fetus and the neonate

doi:10.1016/j.ajog.2012.07.002

American Journal of Obstetrics and Gynecology

Volume 207, Issue 3, Supplement, September 2012, Pages S38-S46

https://doi.org/10.1016/j.ajog.2012.07.002 Get rights and content

Since the 1960s, pregnant women in the United States have been recommended to receive influenza vaccine. A maternal concern about the possibility of adverse fetal and neonatal outcomes after the vaccination of pregnant women has been cited as a reason for low maternal influenza vaccination coverage. Recent research has identified benefits to the fetus and neonate after maternal influenza vaccination that have prompted efforts to increase coverage in pregnant women. There is a long history of research findings that highlight the safety of vaccinating pregnant women. This review summarizes nearly 40 years of research on influenza vaccination of pregnant women and the lack of association with adverse fetal or neonatal outcomes. Future research should focus on vaccinations that are given in the first trimester of pregnancy and on product-specific analyses to account for differences in manufacturing processes.

Section snippets

Time periods relevant to teratogenesis

Safety concerns over influenza vaccination in pregnancy often relate to its potential developmental toxicity and possible teratogenic effects on the fetus. Teratogens are agents that cause permanent changes or disruptions to the anatomy, function, or development of an embryo or fetus.⁶ The effects of teratogens are highly dependent on the nature of the agent, physiologic and biochemical factors of exposed individuals, and the level, timing, and duration of exposure during pregnancy.⁶ Although

Pregnancy-related labeling of vaccines

The US Food and Drug Administration mandates the labeling of all drugs, including vaccines, based on 5 pregnancy categories to describe their safety and effectiveness. These categories are based on existing evidence from both animal and human pregnancy studies and range from category A, which indicates substantial evidence of no risk to the fetus, through category D, which indicates evidence of risk in human studies, although the benefits of the drug may outweigh potential risks (Table 2).

Early studies of influenza immunization in pregnancy (before 2000)

One of the earliest studies to examine fetal effects of maternal influenza vaccination was published in 1973. As part of a larger study to examine factors that were associated with abnormalities that developed in the prenatal and neonatal periods, Heinonen et al¹¹ examined malignancies that arose after exposure to polio or influenza vaccines in utero. Among children of nearly 2300 women who received influenza vaccine during pregnancy, there was only 1 malignancy that was identified within the

Later studies (2000 and later) before H1N1 influenza pandemic

After the 1976 influenza immunization campaign, there was little research that examined the effect and safety of influenza vaccine in pregnant women until the early 2000s. In a large retrospective cohort study that was conducted through a review of automated medical claims records over 5 influenza seasons (1997-2002), Black et al¹⁴ found no maternal deaths or difference in the rate of preterm births between pregnant women who received the influenza vaccine during pregnancy (n = 3719) and

2009 H1N1 pandemic influenza vaccine studies

After the identification of the pandemic 2009 influenza A virus in April 2009, a monovalent vaccine was developed and was ready for distribution by October 2009, in anticipation of the following influenza season. Pregnant women were identified as being at increased risk of severe disease after infection with this influenza strain and were recommended strongly to be vaccinated.³ During the development and testing of these monovalent vaccines, there were a number of clinical trials20, 21, 22 and

Summary and considerations for future evaluations

The available data suggest that influenza vaccination in pregnancy has an overall good safety record for fetal and neonatal outcomes. However, there are several ongoing analyses (for example, within the Vaccine Safety Datalink project) that have focused on the safety of seasonal and pandemic influenza vaccines that are administered during pregnancy. These ongoing analyses might yield new insights into the safety of maternal influenza immunization for fetal and neonatal outcomes.

Future research

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Cited by (73)

Development of MDCK-based quadrivalent split seasonal influenza virus vaccine with high safety and immunoprotection: A preclinical study
2023, Antiviral Research
Vaccination remains the best prevention strategy against influenza. The MDCK-based influenza vaccine prompted the development of innovative cell culture manufacturing processes. In the present study, we report the effects of multiple administrations of a candidate, seasonal, MDCK-based, quadrivalent split influenza virus vaccine MDCK-QIV in Sprague–Dawley (SD) rats. Moreover, the effects of the vaccine were evaluated in terms of fertility and early embryonic development, embryo–fetal development, and perinatal toxicity in the SD rats and immunogenicity in Wistar rats and BALB/c mice. Regarding the safety profile, MDCK-QIV demonstrated tolerance in local stimulation with repeated dose administration and presented no significant effect on the development, growth, behavior, fertility, and reproductive performance of the adult male rats, maternal rats, and their offspring. MDCK-QIV elicited strong hemagglutination inhibition neutralizing antibody response and protection against the influenza virus in the mouse model. Thus, data supported that MDCK-QIV could be further evaluated in human clinical trial, which is currently underway.
Safety and immunogenicity of three seasonal inactivated influenza vaccines among pregnant women and antibody persistence in their infants
2020, Vaccine
Inactivated influenza virus vaccines (IIVs) are recommended for all pregnant women in the United States. We conducted a prospective, randomized, double blind study of three licensed seasonal trivalent IIVs (IIV3s) to assess their safety and immunogenicity in pregnant women and determine the level and persistence of passively transferred maternal antibody in infants.
139 pregnant women ages 18–39 years and 14–33 weeks’ gestation, and 44 non-pregnant women, were randomized 1:1:1 to receive a single intramuscular dose of one of three licensed IIV3s (Agriflu®, Fluzone®, or Fluarix®) prior to the 2010–2011 influenza season. Reactogenicity, adverse events (AEs) and pregnancy outcomes were documented. Serum samples for hemagglutination inhibition (HAI) and neutralization antibody assays were collected prior to and 28 and 180 days after immunization. Maternal sera and cord blood were collected at the time of delivery and sera were obtained from 44 infants at 6 weeks of age.
Pregnant and non-pregnant women experienced similar frequency of injection site (92% and 86%, respectively) and systemic (95% and 87%, respectively) reactions, the majority of which were mild. There were no vaccine-associated maternal or infant serious AEs. Antibody responses to the three vaccine antigens were not different between pregnant and non-pregnant women. The ratios of cord blood (infant) to maternal HAI antibody titers at delivery ranged between 1.1 and 1.7 for each of the vaccine antigens. Influenza antibody concentrations in infants were 70–40% of the birth titer by 6 weeks of age.
The three IIV3s were well tolerated in pregnant women. Antibody responses were comparable in pregnant and non-pregnant women, and after second or third trimester vaccination. Transplacental transfer of maternal antibodies to the infant was efficient. However, antibody titers decline rapidly in the first 6 weeks of life.
Survey of influenza vaccine knowledge, attitudes, and beliefs among pregnant women in the 2016–17 season
2020, Vaccine
Influenza vaccination coverage among pregnant women in the United States is suboptimal. We surveyed women who were pregnant during the 2016–17 influenza season to assess knowledge and attitudes regarding influenza vaccination.
We identified and sampled pregnant women to include approximately equal numbers of vaccinated and unvaccinated women from strata defined by vaccination status and trimester from four integrated health systems in the Vaccine Safety Datalink (VSD). Potential participants were contacted via mail and telephone to complete a standardized survey. Characteristics and responses of women vaccinated and unvaccinated during pregnancy were compared.
The survey was completed by 510 (48%) of 1062 contacted women; 500 were included in the analysis. Vaccine receipt while pregnant was associated with primigravida status (p = 0.02), college degree (p = 0.01), employment in health care (p < 0.01), and history of routine annual influenza vaccination (p < 0.01). Among 330 vaccinated women, the primary reasons for vaccination included protection of self and baby from influenza (n = 233, 71%), and medical professional recommendation (n = 46, 14%). Multiple reasons were given for nonvaccination, but concern about ‘negative effects’ was cited most often (n = 44, 29%). Vaccinated women were significantly more likely to believe that influenza vaccines are safe and effective, and to recognize the potential for harm from influenza infection. Nearly all women reported receiving at least one influenza vaccination recommendation from a healthcare provider.
Vaccinated pregnant women were more likely to receive routine annual influenza vaccine compared to those not vaccinated. Recommendations by obstetric providers should be supplemented with efforts to encourage women of childbearing age to receive annual vaccination.
Neurodevelopmental delay: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data
2019, Vaccine
Citation Excerpt :
Overall, NDD in infants of vaccinated mothers was not reported as an event in this systematic review. The third article was a systematic review of the safety of influenza immunization during pregnancy for the fetus and neonate, which summarized 40 years of research on influenza vaccination in pregnant women, and did not identify infant developmental delay as a concern [114]. Recent clinical studies of influenza, Tdap, RSV and GBS vaccines administered during pregnancy have included neurodevelopmental evaluation of infants for a variable period of time, usually 6 months to the second year of life, using various tools such as the Bayley Scales of Infant and Toddler Development, Third Edition [115].
The fetal origins of mental illness
2019, American Journal of Obstetrics and Gynecology
The impact of infections and inflammation during pregnancy on the developing fetal brain remains incompletely defined, with important clinical and research gaps. Although the classic infectious TORCH pathogens (ie, Toxoplasma gondii, rubella virus, cytomegalovirus [CMV], herpes simplex virus) are known to be directly teratogenic, emerging evidence suggests that these infections represent the most extreme end of a much larger spectrum of injury. We present the accumulating evidence that prenatal exposure to a wide variety of viral and bacterial infections—or simply inflammation—may subtly alter fetal brain development, leading to neuropsychiatric consequences for the child later in life. The link between influenza infections in pregnant women and an increased risk for development of schizophrenia in their children was first described more than 30 years ago. Since then, evidence suggests that a range of infections during pregnancy may also increase risk for autism spectrum disorder and depression in the child. Subsequent studies in animal models demonstrated that both pregnancy infections and inflammation can result in direct injury to neurons and neural progenitor cells or indirect injury through activation of microglia and astrocytes, which can trigger cytokine production and oxidative stress. Infectious exposures can also alter placental serotonin production, which can perturb neurotransmitter signaling in the developing brain. Clinically, detection of these subtle injuries to the fetal brain is difficult. As the neuropsychiatric impact of perinatal infections or inflammation may not be known for decades after birth, our construct for defining teratogenic infections in pregnancy (eg, TORCH) based on congenital anomalies is insufficient to capture the full adverse impact on the child. We discuss the clinical implications of this body of evidence and how we might place greater emphasis on prevention of prenatal infections. For example, increasing uptake of the seasonal influenza vaccine is a key strategy to reduce perinatal infections and the risk for fetal brain injury. An important research gap exists in understanding how antibiotic therapy during pregnancy affects the fetal inflammatory load and how to avoid inflammation-mediated injury to the fetal brain. In summary, we discuss the current evidence and mechanisms linking infections and inflammation with the increased lifelong risk of neuropsychiatric disorders in the child, and how we might improve prenatal care to protect the fetal brain.
Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in 2012–13, 2013–14, and 2014–15
2019, Vaccine
Citation Excerpt :
Early studies of influenza vaccine safety in pregnant women did not report any unexpected or concerning findings. However, between 1997 and 2004 only women in the second and third trimesters were advised to be vaccinated for influenza [9,43,44] resulting in limited information on exposures and outcomes like SAB in the first trimester [7,8,10,11,20,45,46]. More recently, studies and systematic reviews investigating pH1N1-containing vaccines have not identified excess risks of adverse events [3,12,13,15,18,40,47–49].
A recent study reported an association between inactivated influenza vaccine (IIV) and spontaneous abortion (SAB), but only among women who had also been vaccinated in the previous influenza season. We sought to estimate the association between IIV administered in three recent influenza seasons and SAB among women who were and were not vaccinated in the previous influenza season.
We conducted a case-control study over three influenza seasons (2012–13, 2013–14, 2014–15) in the Vaccine Safety Datalink (VSD). Cases (women with SAB) and controls (women with live births) were matched on VSD site, date of last menstrual period, age group, and influenza vaccination status in the previous influenza season. Of 1908 presumptive cases identified from the electronic record, 1236 were included in the main analysis. Administration of IIV was documented in several risk windows, including 1–28, 29–56, and >56 days before the SAB date.
Among 627 matched pairs vaccinated in the previous season, no association was found between vaccination in the 1–28 day risk window and SAB (adjusted odds ratio (aOR) 0.9; 95% confidence interval (CI) 0.6–1.5). The season-specific aOR ranged from 0.5 to 1.7 with all CIs including the null value of 1.0. Similarly, no association was found among women who were not vaccinated in the previous season; the season-specific aOR in the 1–28 day risk window ranged from 0.6 to 0.7 and the 95% CI included 1.0 in each season. There was no association found between SAB and influenza vaccination in the other risk windows, or when vaccine receipt was analyzed relative to date of conception.
During these seasons we found no association between IIV and SAB, including among women vaccinated in the previous season. These findings lend support to current recommendations for influenza vaccination at any time during pregnancy, including the first trimester.

View all citing articles on Scopus

: S.B.O. was awarded the Maurice R. Hilleman Early-stage Career Investigator Award by the National Foundation for Infectious Diseases. The award was funded by an unrestricted educational grant to the National Foundation for Infectious Diseases from Merck and Co, Inc. However, S.B.O. had no direct interaction with Merck. The other authors report no conflict of interest.

: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Vaccine Program Office, the Centers for Disease Control and Prevention, or the Food and Drug Administration.

: Reprints not available from the authors.

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SupplementSafety of influenza immunization during pregnancy for the fetus and the neonate

Section snippets

Time periods relevant to teratogenesis

Pregnancy-related labeling of vaccines

Early studies of influenza immunization in pregnancy (before 2000)

Later studies (2000 and later) before H1N1 influenza pandemic

2009 H1N1 pandemic influenza vaccine studies

Summary and considerations for future evaluations

Influenza immunization: statement

Public Health Rep

Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP)

MMWR Recomm Rep

Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009

MMWR Recomm Rep

Benefits to mother and child of influenza vaccination during pregnancy

Hum Vaccin Immunother

Influenza vaccination coverage among pregnant women: United States, 2010-11 influenza season

MMWR Morb Mortal Wkly Rep

Medications in pregnancy and lactation: part 1, teratology

Obstet Gynecol

Variability in human embryonic development and its implications for the susceptibility to environmental teratogenesis

Birth Defects Res A Clin Mol Teratol

Early human development

Clin Obstet Gynecol

Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011

MMWR Morb Mortal Wkly Rep

Influenza immunization during pregnancy: US regulatory perspective

Am J Obstet Gynecol

Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy

Int J Epidemiol

A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome

Am J Obstet Gynecol

Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant

J Infect Dis

Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants

Am J Perinatol

Safety of influenza vaccination during pregnancy

Am J Obstet Gynecol

Supplement
Safety of influenza immunization during pregnancy for the fetus and the neonate