American Journal of Obstetrics & Gynecology
Volume 201, Issue 6 , Pages 547-552, December 2009

Safety of influenza vaccination during pregnancy

  • Pranita D. Tamma, MD

      Affiliations

    • Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD
    • Corresponding Author InformationReprints: Pranita D. Tamma, MD, Department of Pediatrics Infectious Diseases, Johns Hopkins University School of Medicine, 200 N. Wolfe St., Room 3095, Baltimore, MD 21287
    • ,
  • Kevin A. Ault, MD

      Affiliations

    • Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA
    • Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA
    • ,
  • Carlos del Rio, MD

      Affiliations

    • Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA
    • Hubert Department of Global Health, Rollins School of Public Health, Emory University School of Medicine, Atlanta, GA
    • Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA
    • ,
  • Mark C. Steinhoff, MD

      Affiliations

    • Global Health Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • ,
  • Neal A. Halsey, MD

      Affiliations

    • Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD
    • Institute for Vaccine Safety, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
    • ,
  • Saad B. Omer, MBBS, MPH, PhD

      Affiliations

    • Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA
    • Hubert Department of Global Health, Rollins School of Public Health, Emory University School of Medicine, Atlanta, GA

Received 4 September 2009; received in revised form 25 September 2009; accepted 29 September 2009. published online 22 October 2009.

Article Outline

The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommends routine influenza vaccination for all women who are or will be pregnant during the influenza season. During seasonal influenza epidemics, during previous pandemics, and with the current influenza A (H1N1) pandemic, pregnancy places otherwise healthy women at increased risk for serious complications from influenza, including death. Inactivated influenza vaccine can be safely and effectively administered during any trimester of pregnancy. No study to date has demonstrated an increased risk of either maternal complications or adverse fetal outcomes associated with inactivated influenza vaccination. Moreover, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received influenza vaccine during pregnancy. In this article, we review the evidentiary basis for the recommendation of vaccination of all women who will be pregnant during the influenza season and safety data of influenza vaccination during pregnancy.

Key words: H1N1, influenza vaccine, pregnancy, safety

 

The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommends routine influenza vaccination for all women who are or will be pregnant during the influenza season. 1 The basis for this unambiguous recommendation is clear. During seasonal influenza epidemics, during previous pandemics, and with the ongoing influenza A (H1N1) pandemic, pregnancy places otherwise healthy women at increased risk for serious complications from influenza. 1, 2, 3, 4 Vaccination continues to be the most effective method for preventing severe influenza illness and its sequelae. 5, 6, 7, 8, 9 Despite robust epidemiologic evidence for increased influenza-related fatality in pregnancy, pregnant women have historically had the lowest vaccine coverage rates of all adults recommended to receive seasonal influenza vaccination. 10 The current pandemic of influenza has once again reminded us that pregnant women are at particularly high risk for morbidity and mortality from influenza and that they are a population that should be vaccinated.

For Editors' Commentary, see Table of Contents

From April 15 through May 18, 2009, 34 confirmed or probable cases of novel influenza A (H1N1) in pregnant women were reported to the CDC; 32% of these women required hospitalization. 4 Pregnant women were >4 times more likely to be hospitalized for novel influenza A (H1N1)-related complications than those infected in the general population, and accounted for 13% of all deaths from pandemic influenza A (H1N1) during this time period. Most of the pregnant women who died as a consequence of pandemic influenza A (H1N1) were healthy prior to their influenza illness. 4 As a result of this and earlier evidence, CDC has placed pregnant women in the highest-priority group to receive vaccination once the novel influenza A (H1N1) vaccine becomes available. 11

Serious influenza-related illnesses in pregnant women will undoubtedly continue to escalate as the influenza A (H1N1) pandemic proceeds. Physicians and other health care providers play a crucial role in the decision-making process with regard to influenza vaccination. They can explore the determinants of vaccine refusal and alleviate fears by addressing real and perceived concerns regarding immunizations during pregnancy. In this article, we review the evidentiary basis for the recommendation of vaccination of all women who will be pregnant during the influenza season and safety data of influenza vaccination during pregnancy.

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Evolution of US immunization recommendations 

The serious consequences of influenza infection during pregnancy have been recognized for almost a century. In a series of 1350 pregnant women reported during the 1918 pandemic, about 50% developed pneumonia, and of these women, more than half died, with a case fatality rate of 27%. 2, 12 The highest mortality was seen in the third trimester. During the pandemic of 1957, nearly half of all women of childbearing age who died were pregnant. 3, 13, 14, 15

Over the years, as data regarding the deleterious effects of influenza on the pregnant female have mounted, and in the absence of evidence linking influenza vaccination during pregnancy to any serious negative consequences for the mother or fetus, the recommendations for influenza vaccination during pregnancy have expanded. Since 2004, ACIP has encouraged pregnant women, regardless of gestational age, to receive routine inactivated influenza vaccination. 1, 16 The American College of Obstetricians and Gynecologists considers the influenza vaccine an “essential element of prenatal care.” 17, 18

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Risks of influenza infection in pregnancy 

Pregnancy is associated with biochemical, mechanical, hemodynamic, as well as immunologic changes in the mother that become most pronounced by the third trimester. These changes include decreased lung capacity and tidal volume, along with increased cardiac output and oxygen consumption. 19, 20, 21 Adaptive humoral immunity remains generally intact with augmentation of the T-helper-type 2 antibody-mediated response. 22 This is in contrast to the selective suppression of T-helper-type 1 cell–mediated immunity that likely protects the developing fetus from maternal cytotoxic-T-lymphocyte activity, but as a consequence, impairs maternal response to infection. 22, 23, 24 Although pregnant women do not have a higher incidence of seasonal influenza than the general population, the combination of impaired cell-mediated immunity as well as physiologic changes that accompany pregnancy leave women increasingly vulnerable to serious influenza-related complications.

Influenza-related hospitalization of healthy pregnant women occurs at a rate of 1-2 per 1000. 25 Schanzer et al 26 determined this risk is 18-fold above that of healthy nonpregnant women. Pregnant women with coexisting medical conditions are at even greater risk of severe influenza-related morbidity. When pregnancy is superimposed on high-risk conditions such as asthma or diabetes mellitus, influenza infection contributes to morbidity that is 3-4 times greater than nonpregnant control subjects with similar high-risk conditions. 27, 28, 29

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Safety of inactivated influenza vaccine for the pregnant woman 

The lack of harmful effects of inactivated influenza vaccination on maternal health during pregnancy has been demonstrated in several studies (Table30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41). Munoz et al32 performed a retrospective analysis of data from 5 influenza seasons using an electronic database of a large multispecialty clinic in the United States. Outcomes of pregnancy were compared between a cohort of 225 healthy women who received influenza vaccine during the second and third trimesters of pregnancy and a control group of 826 healthy unvaccinated women who were matched by age, month of delivery, and type of medical insurance. No serious adverse events occurred within 42 days of vaccination, and there was no difference between the groups in the rates of cesarean section, premature birth, and infant medical conditions from birth to 6 months of age.32

TABLE. Summary of data on safety outcomes of studies of influenza immunization during pregnancy
StudyDesignStudy groupControl groupFollow-up periodMaternal outcomesInfant outcomes
Zaman et al,30 2008Prospective, randomized, double-blind controlled trial172 pregnant women in third trimester168 pregnant women who received 23-valent pneumococcal polysaccharide vaccine7 d postvaccination; mother-infant pairs followed up to 24 wk of lifeNo serious adverse events or differences in pregnancy outcomesNo differences in gestational age, proportion with cesarean delivery, birthweight, or APGAR score
France et al,31 2006Retrospective, matched cohort3160 infants born to vaccinated mothers37,969 infants born to nonvaccinated mothersEnd of influenza seasonNot assessedNo difference with regard to birthweight, gestational age, or length of stay for birth hospitalization
Munoz et al,32 2005Retrospective, matched cohort225 pregnant women in second and third trimesters826 nonimmunized pregnant women42 d after immunization; birth to 6 mo of ageNo serious adverse events or differences in pregnancy outcomesNo differences in outcomes of pregnancy (cesarean delivery and premature delivery) and infant medical conditions
Black et al,33 2004Retrospective cohort3719 pregnant women immunized45,866 womenUntil deliveryNo difference in cesarean sectionNo difference in cesarean section or preterm delivery
Yeager et al,34 1999Prospective cohort319 pregnant women immunized in second and third trimestersNoneNext prenatal visitNo preterm labor or other serious eventsNot assessed
Englund et al,35 1993Randomized, controlled trial13 pregnant women in third trimester13 pregnant women who received tetanus toxoid vaccineNot specifiedNo significant adverse reactions, including fever, moderate or severe pain, or need to visit a physician noted in either groupSimilar gestational ages in both groups; no health concerns in infants examined between 1-3 mo of age
Deinard and Ogburn,36 1981Prospective cohort189 pregnant women (13 prior to conception; 41, 58, and 77 in first, second, and third trimesters, respectively)517 nonvaccinated pregnant women48 h after immunization; pregnancy outcome to 8 wk of lifeNo differences in maternal health, pregnancy outcome, or postpartum courseNo significant differences in adverse pregnancy outcomes (congenital anomalies, neonatal mortality)
Sumaya and Gibbs,37 1979Retrospective, matched cohort56 women in second and third trimesters40 nonvaccinated pregnant women24 h after immunizationNo significant immediate reactions or differences in pregnancy courseNo increased fetal complications associated with vaccine
Murray et al,38 1979Prospective, matched cohort59 pregnant immunized women (5, 22, and 32 in first, second, and third trimesters, respectively)27 nonpregnant vaccinated womenNot specifiedNo significant side effects after immunization in any womenNot assessed
Heinonen et al, 1973,39 and 197740Prospective cohort2291 pregnant immunized women; up to 650 in first trimesterNoneUp to 7 y of age No suggestive associations for congenital malformations, malignancies, or neurocognitive disabilities
Hulka,41 1964Retrospective and prospective cohort225 pregnant immunized women (19 in first trimester)44 nonpregnant influenza immunized; 104 pregnant and 25 nonpregnant immunized with placeboUp to 3 d after vaccination and at deliveryLocal pain at injection site and some systemic symptoms greater in women immunized with influenza vaccineNo association with fetal anomalies or miscarriage

Tamma. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2009.

During the 1976-1977 influenza season, 56 women who received the inactivated influenza vaccine during the second and third trimesters of pregnancy were evaluated. No notable immediate reactions were observed, nor were there any differences between the course or outcome of pregnancies between the vaccinated women and control group of 40 nonvaccinated pregnant women.37 No significant adverse reactions, including fever, moderate or severe pain, or need to visit a physician, were observed in another study in which 26 women were randomized to receive the inactivated influenza vaccine or tetanus toxoid vaccine in the third trimester of pregnancy.35 Deinard and Ogburn36 evaluated 189 women immunized with the trivalent inactivated influenza vaccine during the 3 trimesters of pregnancy and noted no differences in maternal health or pregnancy outcome compared to the control group of 517 pregnant women who did not receive the vaccine. The few serological studies on pregnant women suggest that antibody response to influenza vaccine is comparable to age-matched, nonpregnant control subjects.35, 36, 37

The Vaccine Adverse Event Reporting System contains a database for reports regarding influenza vaccination during pregnancy. It is a postmarketing surveillance system with strengths and weaknesses inherent to passive surveillance systems.42 Of 26 reports related to influenza vaccine in pregnant women from 2000 through 2003, 6 concerned misadministration of the influenza vaccine without negative consequences, 9 described self-limited injection site reactions, 8 were related to systemic symptoms that regressed with time, and 3 reported miscarriages.43 During this time period, an estimated 2 million pregnant women received influenza vaccination.44 These data suggest a low rate of adverse events associated with administration of the inactivated influenza vaccine during pregnancy.43 Licensed 2009 H1N1 monovalent vaccines will be produced using the same manufacturing process as seasonal influenza vaccines, thus it is anticipated that they will have a similar safety profile with serious adverse events after vaccination uncommon.1, 11

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Benefits of influenza vaccination for the neonate 

Studies from the United States and Hong Kong demonstrate high rates of hospitalization among infants with influenza, especially in the age group <6 months.45, 46, 47 A review of the US influenza mortality during the 2003-2004 influenza season revealed that childhood deaths associated with influenza were most frequent in infants aged <6 months. 48 Because of limited immunogenicity in this age group, inactivated influenza vaccine is not currently licensed for infants <6 months of age.1

Transplacental influenza antibody has been postulated to provide indirect protection in newborns, a period of increased vulnerability to influenza and its complications. Zaman et al30 conducted a prospective, controlled, blinded trial that assessed the clinical effectiveness of maternal influenza vaccine in their infants. Among infants of the 172 mothers who received influenza vaccination, there were fewer cases of laboratory-confirmed influenza than among infants in the control group, with a vaccine effectiveness of 63% until at least 6 months of age. There was a 29% and 36% reduction in the rates of febrile respiratory illnesses in infants and mothers, respectively.

The advantage of endowing the fetus with maternal antibody prior to birth was also demonstrated during the influenza H1N1 epidemic of 1979. Infants born to mothers with natural serum antibody to influenza A had higher H1-specific passive antibody titers than control subjects. They also had influenza symptoms that were delayed in onset and of shorter mean duration as compared with infants of nonimmune mothers.49, 50 Immunization of pregnant women with influenza virus antigens evokes an antibody response that could result in the passive transfer of sufficient antibody to protect the very young infant for the duration of the influenza season.37, 38

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Safety of maternal influenza vaccination for the fetus 

Many pregnant women struggle with the concept of vaccination during pregnancy because of theoretical concerns regarding harm to the fetus. In the longitudinal, population-based Collaborative Perinatal Project that was conducted between 1959-1965, >2000 pregnant women received influenza vaccination, almost a third during the first trimester. The children of these women were followed up for the first 7 years of life, and maternal influenza immunization did not increase the number of stillbirths, congenital malformations, malignancies, or neurocognitive disabilities. 39, 40

In another longitudinal, prospective study, Deinard and Ogburn 36 detected no association between maternal influenza immunization and maternal, perinatal, or infant complications. No teratogenicity was documented, and the infants of vaccinated mothers did not differ from nonvaccinated offspring in physical or neurological assessments at birth and 8 weeks of life.

Similarly, a large retrospective, matched cohort study, which included 3160 infants born to influenza-vaccinated mothers and 37,969 infants born to nonvaccinated mothers, revealed no differences with regard to birthweight, gestational age, or length of stay for birth hospitalization. 31 The safety of the inactivated influenza vaccine was assessed in 7 other trials in which >4500 pregnant women were vaccinated and no significant adverse effects to the fetus were identified 30, 32, 33, 35, 37, 41 (Table).

It is always beneficial to have an active surveillance system in place to provide feedback of the adequacy, strengths, and weaknesses of the vaccine in question. This will be no different for the novel influenza A (H1N1) vaccine. The CDC and the Food and Drug Administration will be closely monitoring any adverse effects of the influenza A (H1N1) 2009 monovalent vaccine through the Vaccine Adverse Event Reporting System and Vaccine Safety Datalink. 51 The Vaccine Safety Datalink uses rapid cycle analysis to monitor specified adverse events in near real time, with appropriate comparison groups. Moreover, large-scale safety monitoring studies, led by academic researchers, are being established. Ongoing proactive safety monitoring will maintain confidence in the immunization efforts related to maternal influenza vaccination and encourage continued improvements to the vaccine.

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Influenza vaccination and thimerosal 

Thimerosal, a mercury-containing compound, is a preservative that has been used in some vaccines, including multivial inactivated influenza vaccines, to reduce the likelihood of microbial growth. Concerns came to public attention in 1999 because of uncertainty regarding the applicability of guidelines for long-term exposure to methylmercury, primarily from fish consumption, to intermittent exposure to ethylmercury, a breakdown product of thimerosal. Subsequent studies have shown that ethylmercury does not accumulate and cause harm to the fetal brain like methylmercury, and mounting evidence suggests no increased risk for neurodevelopmental disorders from exposure to thimerosal-containing vaccines. 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 In 2004, the US Institute of Medicine reviewed cumulative pediatric exposure to thimerosal-containing vaccines, which led them to reject the hypothesis of a causal link between infants exposed to thimerosal-containing vaccines and autism. 62 The US Public Health Service and other organizations have recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines as part of a strategy to reduce mercury exposures from all sources. 63

Thimerosal-free versions of the trivalent-inactivated vaccine are increasingly available and a thimerosal-free version of the novel influenza A (H1N1) vaccine will be available in the fall. Limitations in the availability of thimerosal-free influenza vaccines should not preclude administration of inactivated influenza vaccines in pregnant women. 1

After reviewing the existing body of evidence with regard to thimerosal and the concerns for the developing fetus, the ACIP concludes: “The benefits of influenza vaccination for all recommended groups, including pregnant women and young children, outweigh concerns on the basis of a theoretical risk from thimerosal exposure through vaccination. The risks for severe illness from influenza virus infection are elevated among both young children and pregnant women, and vaccination has been demonstrated to reduce the risk for severe influenza illness and subsequent medical complications. In contrast, no scientifically conclusive evidence has demonstrated harm from exposure to vaccine containing thimerosal preservative. For these reasons, persons recommended to receive TIV [trivalent inactivated influenza vaccine] may receive any age- and risk factor-appropriate vaccine preparation, depending on availability.” 1

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Conclusion 

Inactivated influenza vaccine can be safely and effectively administered during any trimester of pregnancy. No study to date has demonstrated an increased risk of either maternal complications or untoward fetal outcomes associated with inactivated influenza vaccination. In addition, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received influenza vaccine during pregnancy. Immunization of the mother reduces 1 potential source of viral exposure to the infant, and immunization of other family members will decrease other potential sources. Health care workers caring for pregnant females can play a pivotal role in helping to protect women and newborns from this vaccine-preventable disease and should anticipate questions that expecting mothers may have regarding vaccine safety.

Over the next several months, we will likely witness a surge of infections caused by the novel influenza A (H1N1) virus. As health care workers it is essential that we encourage the vaccination of pregnant women against both the pandemic influenza A (H1N1) virus, as well as seasonal influenza. If pregnancy-related mortality data from prior influenza pandemics are a predictor of what we are to expect in the upcoming months, a significant number of deaths can be averted with influenza vaccination.

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 Dr Tamma is supported by a National Institutes of Health (NIH) fellowship training Grant. Dr del Rio is supported by Grants from NIH (HIV vaccine trials network and vaccine treatment and evaluation units), Centers for Disease Control and Prevention (CDC), Emory Global Health Institute, Merck and Co., Inc. (West Point, PA), and Sanofi Pasteur. Dr Steinhoff is supported by the Bill and Melinda Gates Foundation, NIH, and Wyeth Vaccines. Dr Halsey is supported by Berna, Intercel, Merck (North Wales, PA), Novartis, CDC, and NIH. Dr Omer is supported by the Bill and Melinda Gates Foundation, CDC, Merck (North Wales, PA), and Emory Global Health Institute.

 Dr Omer was awarded the Maurice R. Hilleman Early-stage Career Investigator Award by the National Foundation for Infectious Diseases, funded by an unrestricted educational Grant to the National Foundation for Infectious Diseases from Merck and Co., Inc. However, Dr Omer had no direct interaction with Merck and Co., Inc. related to this award.

PII: S0002-9378(09)01108-9

doi:10.1016/j.ajog.2009.09.034

American Journal of Obstetrics & Gynecology
Volume 201, Issue 6 , Pages 547-552, December 2009

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