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Ensuring Vaccine Safety in Pregnant Women

Thursday, 25th of May 2017 Print

Also at http://www.nejm.org/doi/full/10.1056/NEJMe1701337

Editorial

Ensuring Vaccine Safety in Pregnant Women

Kathryn M. Edwards, M.D.

N Engl J Med 2017; 376:1280-1282March 30, 2017DOI: 10.1056/NEJMe1701337

In this issue of the Journal, investigators from Denmark present a comprehensive review of the adverse pregnancy outcomes encountered in women who received quadrivalent human papillomavirus (HPV) vaccine during pregnancy, as compared with those who did not.1 The investigators assembled data on all the pregnancies in Denmark that occurred within a 7-year period, and they used nationwide registries to identify the dates of pregnancy, pregnancy outcomes, and maternal characteristics, including receipt of HPV vaccine and dates of vaccine administration. Vaccinated women and unvaccinated women were propensity-score matched in a 1:4 ratio, and pregnancy outcomes were compared. Although a large number of women (1665) were immunized in the first trimester of pregnancy, when organogenesis occurs, their offspring did not have a significantly higher rate of major birth defects than offspring born to unvaccinated women. The numbers of spontaneous abortions, preterm births, infants with low birth weight, infants who were small for gestational age, and stillbirths were not higher in the vaccinated cohorts than in the unvaccinated cohorts, although the number of stillbirths was small. These data are very encouraging and strongly support the safety of HPV vaccines if they are inadvertently given in pregnancy, a finding that complements previous safety reports of HPV vaccine in nonpregnant women.2,3 These data also show that adverse outcomes occur at a baseline rate in pregnancy and that when no control group is included in studies, these outcomes may be inappropriately attributed to the vaccine.

Until recently, pregnant women have been largely excluded from clinical trials because they have been considered to be a vulnerable population. However, over the past few years, there has been a concerted effort to include pregnant women in clinical studies of drugs and vaccines that are used in pregnancy in order to provide pertinent safety and effectiveness data and to not rely solely on data from nonpregnant persons. During pregnancy, the maternal blood volume expands substantially, and there are marked changes in both the hormonal milieu and the physiologic state. Thus, appropriate clinical studies are needed in this population. Fortunately, recent updates to the Common Rule, the ethical framework that guides biomedical research in humans in the United States, have removed the “vulnerable population” classification for pregnant women, and the recently passed 21st Century Cures Act has advocated for the inclusion of pregnant women in clinical trials.4,5 This marked change in attitude about clinical trials involving pregnant women comes at an opportune time since the usefulness of immunizing pregnant women to protect both them and their infants from serious infectious diseases has been clearly shown; several examples are discussed by Omer6 in a review article in this issue of the Journal.

During the H1N1 influenza pandemic, increasing numbers of pregnant women accepted vaccines, given observations that H1N1 infection was associated with higher maternal morbidity and mortality.7 At about the same time, pertussis outbreaks were reported in communities that used acellular pertussis vaccines for routine infant immunization. In pertussis outbreaks in California and the United Kingdom, infant deaths occurred.8,9 To stem the tide of infant deaths, the United Kingdom started a pertussis immunization program targeting pregnant women that proved highly effective in reducing the incidence of infant death and disease.10 Similar data are available from California, where maternal pertussis immunization decreased the risk of infant disease and reduced its severity in infected infants.11 Multiple studies have shown the safety of maternal influenza and pertussis vaccinations in pregnant women and their infants, as outlined in the article by Omer.

Maternal vaccines are also being developed for respiratory syncytial virus (RSV) and group B streptococcus, two pathogens with important consequences in young children. Progress on RSV vaccines was slowed five decades ago after the administration of a formalin-inactivated RSV vaccine to young children resulted in several deaths on subsequent natural RSV infection.12 The effectiveness of monoclonal antibody to RSV in reducing the incidence of disease among premature infants has suggested that delivery of an RSV vaccine to a pregnant mother, with the subsequent transplacental passage of RSV antibody, may be an effective and safer route to protecting infants. Studies of RSV vaccines in pregnant women are ongoing.

Among infants, the rates of early-onset group B streptococcus disease, a leading cause of sepsis and meningitis, have declined since the administration of intrapartum antibiotic agents to pregnant women in developed countries; however, the rates of late-onset meningitis have not changed.13 Intrapartum administration of antibiotics has not been used in developing countries, and the rates of both early-onset and late-onset disease have not declined. Group B streptococcus vaccine is currently being tested in clinical trials involving pregnant women and, if shown to be safe and effective, could be deployed globally.

When vaccines are to be used specifically in pregnant women, it is important that they be carefully studied in prelicensure trials and that their safety be ensured. In the case of HPV vaccine or other vaccines that are not intended for pregnant women but are inadvertently administered to them, postmarketing safety evaluations assume great importance. The carefully conducted postlicensure safety study of HPV vaccine now reported in the Journal is a model for others to emulate.

Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.

Source Information

From the Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville.

References

1

Scheller NM, Pasternak B, Mølgaard-Nielsen D, Svanström H, Hviid A. Quadrivalent HPV vaccination and the risk of adverse pregnancy outcomes. N Engl J Med 2017;376:1223-1233
Full Text

2

Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009;302:750-757 .
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3

Gee J, Naleway A, Shui I, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011;29:8279-8284
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4

Federal Policy for the Protection of Human Subjects (“Common Rule”). Washington, DC: Department of Health and Human Services, Office for Human Research Protections, March 18, 2016 (https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/).

5

H.R.6 — 21st Century Cures Act. July 13, 2015 (https://www.congress.gov/bill/114th-congress/house-bill/6/text).

6

Omer SB.. Maternal immunization. N Engl J Med 2017;376:1256-1267

7

Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303:1517-1525
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8

Infant pertussis cases <3 months of age (based on disease onset), by county — California 2014-2015. Sacramento: California Department of Public Health (https://www.cdph.ca.gov/HealthInfo/discond/Documents/Infant%20pertussis%20cases%20by%20county_2014-2015.pdf).

9

Newborns to be protected against whooping cough. London: Department of Health, September 28, 2012 (https://www.gov.uk/government/news/newborns-to-be-protected-against-whooping-cough).

10

Amirthalingam G, Andrews N, Campbell H, et al. Effectiveness of maternal pertussis vaccination in England: an observational study. Lancet 2014;384:1521-1528
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11

Winter K, Cherry JD, Harriman K. Effectiveness of prenatal tetanus, diphtheria, and acellular pertussis vaccination on pertussis severity in infants. Clin Infect Dis 2017;64:9-14
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Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 1969;89:405-421
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13

Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive group B streptococcal disease in the United States, 1999-2005. JAMA 2008;299:2056-2065
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