Maternal Immunization

Diseases.

Part I

Concepts of maternal immunization

Chapter 1

The history of maternal immunization

Alisa Kachikisa; Linda O. Eckerta,b; Janet A. Englundc    a Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, United States

b Department of Global Health, University of Washington, Seattle, WA, United States

c Department of Pediatrics, Pediatric Infectious Diseases, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States

Abstract

Maternal immunization, or the vaccination of pregnant women for prevention of maternal, fetal and neonatal morbidity and mortality, has emerged as an exciting and rapidly expanding area of vaccine-preventable diseases research and clinical practice. The functionality of the maternal and neonatal immune system, transplacental transfer of antibodies to the fetus and potential inhibition of subsequent active infant immunization have added an additional layer of complexity to vaccine research. Today, vaccines are utilized in pregnant women to protect women and infants against influenza and pertussis, and additional vaccines are in development specifically for use in maternal immunization such as those against respiratory syncytial virus (RSV) and Group B Streptococcus (GBS). The current expanding applications of vaccines administered during pregnancy closely mirrors trends in public policy regarding research in pregnant women. Consideration of past lessons learned, current work in vaccinology, as well as policy regarding inclusion of reproductive age and pregnant women in research may better predict future directions and successes for this approach to the protection of women and infants.

Keywords

Maternal immunization; Vaccination in women; History of vaccines; Pregnancy; Vaccines; Group B Streptococcus; Respiratory syncytial virus; Influenza vaccines; Pertussis vaccines

Acknowledgments

We would like to express our gratitude to Jan Hamanishi for her help in designing Fig. 1 for this article.

Conflict of interest

AK and LOE have no financial conflicts to disclose. JAE has received research support to her institution from GlaxoSmithKline, Gilead, MedImmune, Novavax, and Chimerix. She has served as a consultant for Sanofi Pasteur and Gilead.

Introduction

Maternal immunization, or the vaccination of pregnant women, for prevention of maternal, fetal and neonatal morbidity and mortality, has emerged as an exciting and rapidly expanding area of vaccine-preventable diseases research and clinical practice in the last decades. The intricacies of the maternal and neonatal immune system, the transplacental transfer of antibodies to the fetus and potential inhibition of subsequent active infant immunization have added an additional layer of complexity to vaccine research. Nevertheless, vaccines are currently in development specifically for use in maternal immunization such as those against respiratory syncytial virus (RSV) and Group B Streptococcus (GBS) [1]. While maternal immunization strategies are not a new phenomenon and have a history similar to vaccine strategies overall, their current expanding application more closely mirrors trends in public policy regarding research in pregnancy. Consideration of past lessons learned, current work in vaccinology, as well as policy regarding inclusion of reproductive age and pregnant women in research may better predict future directions and successes for immunization in pregnancy.

The need from a historical perspective: Pregnancy

Improvements in obstetrical care, medical knowledge, access to better nutrition, increases in standard of living, and access to health care have all contributed to improved survival of mothers and their infants in the 21st century. The increased risk for morbidity and mortality during pregnancy, delivery, and post-partum is recorded throughout history. Worldwide, maternal morbidity rates (MMR) per 100,000 deliveries within 42 days of childbirth were between 800 and 1000 per 100,000 live births in the early 1800s and have now fallen to less than 10 deaths per 100,000 live births in high-income countries. Substantial decreases have been also documented in many developing countries, with MMR in 2015 at about 216 deaths per 100,000 live births worldwide [2,3]. Strides are being made in some middle-income countries such as India (MMR 174 per 100,000 in 2015) [3], but less so in certain low-income countries and in those with armed conflict such as the Democratic Republic of Congo (MMR 693 per 100,000 in 2015) [4].

Pregnant women have been documented to have increased susceptibility to vaccine-preventable diseases compared to non-pregnant women resulting in increased maternal, fetal, and neonatal morbidity and mortality. Historical records on smallpox infections in the 19th century report increased case fatality rates and adverse outcomes among pregnant women [5,6]. The increased susceptibility of pregnant women and their fetuses to viral illness was again demonstrated in the measles outbreaks in the Faroe Islands in 1846 and in Greenland in 1951 [7–13]. During the influenza pandemics of 1918 and 1957, high rates of mortality were reported among pregnant women. One report of influenza among 1350 pregnant women in 1918 in the United States (US) showed mortality rates of 27%, while another study during the same time period of 86 pregnant women with influenza infection in Chicago reported a 45% mortality rate [11,12]. During the 1957 pandemic, influenza was listed as the leading cause of death for pregnancy-associated deaths in Minnesota; half of the women of reproductive age who died due to influenza were pregnant at the time [13]. Adverse pregnancy outcomes including high rates of miscarriage and preterm birth were reported among pregnant women during the influenza pandemic of 1918 [11,12]. In addition, concern for increase in congenital defects of fetuses in pregnant women affected by the Asian influenza pandemic of 1957 and seasonal influenza have been reported [13–18]. Over several influenza seasons in the 1970s–1990s, pregnant women were significantly more likely to be hospitalized and to present for medical visits than non-pregnant women [19,20]. This finding was reaffirmed during the H1N1 influenza pandemic (2009), when pregnant women and their fetuses had an increased risk for morbidity and mortality compared to women who were not pregnant [21–23].

The need from a historical perspective: Early childhood

Infant mortality rates have also been decreasing worldwide over the past century. In urban settings in the US and Europe in the late 1800s, up to 30% of children died before their first birthday compared with current infant rates in developing countries of 30.5 deaths per 1000 live births [24,25]. Global childhood mortality rates in children less than 5 years of age have fallen from 18.4% in 1960 to 4.3% in 2015. In 2016, 75% of all deaths in children under 5 years still occurred in the first year of life, demonstrating the need for continued improvement. The highest rates of childhood mortality today occur in the neonatal period, or first month of life, due in large part to complications of birth, prematurity, infections, and congenital anomalies [26]. Although infant survival has dramatically improved through improved perinatal care, increased emphasis on the prenatal visits for women, medically-attended deliveries, and infant follow-up is ongoing internationally with support from the World Health Organization (WHO) and other partners. Immunization is playing a significant role in this effort to improve early childhood survival.

History of immunization in pregnant women

Reports of vaccination date back as far as the 17th and 18th century with the use of smallpox inoculation (also known as variolation) to prevent smallpox infection in China, Turkey and the African continent prior to its spread to Europe and America [27,28]. Historic records published in the 19th century demonstrated that compared to women who had not received smallpox vaccine prior to pregnancy, women who had been vaccinated had at least partial protection against smallpox during pregnancy [5]. In 1879, Burckhardt reported his uncontrolled case series on intrauterine vaccination from Basel, Switzerland, in which he showed that infants of women who were re-immunized with smallpox vaccine during pregnancy were refractory to the smallpox vaccine which was administered 4–6 days after birth [29].

In 1904, Polano published his findings on transplacental transfer of tetanus and diphtheria toxoid antibody [30].

In the 20th century, as vaccine research focus shifted to larger scale population-based projects, maternal immunization research also became more population and laboratory-based. Clinical trials on the administration of whole cell pertussis vaccine in pregnancy were conducted in the 1930s and 1940s with variable results. These studies did demonstrate safety in the infant and the potential to transmit protective antibodies to the neonate, but remarkably, did not report on reactogenicity or adverse effects in the pregnant study subjects [31,32]. In the 1940s and 1950s research on the diphtheria vaccine demonstrated diphtheria-specific antibodies in cord blood and the impact of passive immunity in neonates on infant vaccine immune response [33–35]. In the 1950s and 1960s, administration of influenza and polio vaccines during pregnancy became routine given high prevalence of poliomyelitis, known adverse effects of influenza infection in pregnancy, and the benefit of protecting the pregnant woman against both polio and influenza. During that timeframe, safety of live attenuated polio vaccine and inactivated influenza vaccine during pregnancy was demonstrated by long term prospective studies involving 3000 or more women and their infants [36]. Work on vaccines in pregnancy continued globally, with the subsequent publication of an important landmark study in 1961 on tetanus disease in New Guinea. Schofield et al. demonstrated that the risk of neonatal tetanus, an important cause of neonatal mortality globally, was significantly decreased after maternal inoculation with multiple doses of tetanus vaccine during pregnancy [37,38]. Outbreaks of polio in Finland and Israel and meningococcal disease in Brazil were so widespread in the 1970s–1990s that mass immunizations for the entire population of these countries was recommended, which included pregnant women. In the 1970s, 90 million people including pregnant women received the meningococcal A vaccine supplied by Sanofi Pasteur [39]. Follow up studies on the effects of these vaccinations in pregnancy did not demonstrate adverse effects in mother, fetus or infant [40–44]. Nevertheless, by the 1980s, except for certain high-risk groups, maternal immunization in many countries stopped given concerns centered around vaccine safety, efficacy and preparation components for pregnant women. However, this shift in perception of maternal immunization was based on hypothetical potential risk, rather than distinct adverse vaccination outcome data (see Historical perspectives on women’s inclusion in research section).

In more recent years, early epidemiology reporting increased risks to pregnant women due to pandemic 2009 influenza A/H1N1 infection stimulated research conducted during that influenza pandemic which ultimately demonstrated the beneficial effect of maternal influenza immunization for mothers, fetuses, and infants [21,22]. Maternal pertussis vaccination has also been shown to decrease the morbidity and mortality of pertussis in infants in recent pertussis epidemics by boosting transplacental antibody transfer to the fetus. Another mechanism of infant protection is through the reduction of maternal susceptibility to infection and thereby decreasing the risk of neonatal postnatal exposure [45]. An example of the progression of maternal vaccination is shown in Fig. 1.

Fig. 1 Maternal immunization development and research through history [ 28 , 46 – 77 ].

Examples of recent work in select vaccines

Tetanus toxoid vaccine

Following the demonstration of decreased maternal and neonatal tetanus with tetanus toxoid vaccine administration during pregnancy in the 1960s, several global initiatives have been put in place including the resolution to eliminate neonatal tetanus via maternal immunization set forth by the WHO in 1989. This was endorsed in several subsequent global fora and was broadened in 1999 to include the goal to also eliminate maternal tetanus [50]. Other partners in this effort include the United Nations Children’s Fund (UNICEF), the United Nations Population Fund (UNFPA), the United States Agency for International Development (USAID), the Global Alliance for Vaccines and Immunizations (Gavi), Save the Children, the Bill & Melinda Gates Foundation, Kiwanis International, and other international and national stakeholders [78]. The overall numbers of cases and countries with maternal and neonatal tetanus (MNT) continues to decrease, with MNT successfully eliminated in North and South America and Europe. However, as of January 2018, 15 countries have yet to eliminate MNT (see Fig. 2) [78]. In addition to maternal immunization, strategies that are currently being used or may be increasingly utilized in the future include tetanus toxoid vaccine boosters to females and males both in childhood and adolescence in order to ensure that women are protected before pregnancy and to decrease the tetanus incidence in the general population [79].

Fig. 2 Elimination of maternal and neonatal tetanus (MNT) by 2018. Reprinted with permission World Health Organization. 44 Countries eliminated MNT between 2000 & January 2018: unicef.org; 2018. [Available from: https://www.unicef.org/health/index_43509.html].

Diphtheria vaccine

Research conducted on the diphtheria toxoid vaccine—particularly by Barr et al. in the mid 20th century—explored not only diphtheria vaccine efficacy in neonates but also demonstrated the effect of maternal antibodies on subsequent neonatal immune response to active immunization (see Fig. 3) [33,34]. Maternal immunization with diphtheria vaccine is not currently used for neonatal protection against diphtheria, but since the formulation of tetanus toxoid and acellular pertussis vaccine contains the vaccine against diphtheria as well (i.e., the tetanus, diphtheria and acellular pertussis vaccine [TdaP]), it is routinely administered in pregnancy [47,81]. Completing the primary series of diphtheria vaccine (3 injections) with one booster in neonates, children or adults has been found to incur long-term immune protection against the disease [81].

Fig. 3 Diphtheria is deadly—Immunisation is the safeguard. UK Ministry of Health advertisement for diphtheria toxoid vaccine from the 1960s [80].

Influenza vaccine

Following the 2009 A/H1N1 influenza pandemic and research demonstrating decreased morbidity and mortality of pregnant women and neonates following immunization, the WHO designated pregnant women as a priority group for influenza vaccination in 2012. Seasonal influenza vaccine is now recommended by the WHO and other national health authorities (see Fig. 4) [83–85]. The development of maternal influenza vaccination platforms is further discussed in the Influenza chapter.

Fig. 4 Flu. I’m ready for you. National Health Service (NHS) Scotland advertisement for influenza vaccine in pregnancy [82].

Pertussis vaccine

Based on recent research demonstrating decreased morbidity and mortality in neonates following maternal immunization with acellular pertussis, the United States Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) recommended a single dose of acellular pertussis vaccine combined with tetanus and diphtheria toxoid (TdaP) for all pregnant women in 2011. The Joint Committee on Vaccination and Immunization in the United Kingdom (UK) introduced routine administration during pregnancy in 2012, although the vaccine utilized in the UK is the multivalent vaccine dTaP-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis and inactivated polio antigen) [86]. That same year, the US ACIP changed their single dose recommendation to one recommending maternal acellular pertussis immunization during each pregnancy [87]. The WHO added pertussis vaccination during pregnancy to its pertussis vaccine position paper in 2015 [88]. Pertussis vaccine during each pregnancy is currently recommended by multiple international and national health authorities (see Pertussis chapter).

Current work

Routine vaccination during pregnancy as endorsed by the WHO and health authorities in the UK, the US and an increasing number of countries include tetanus toxoid and acellular pertussis-containing vaccines as well as inactivated influenza vaccine (see Table 1) [46,94–97]. Other vaccinations that may be recommended during pregnancy under certain circumstances, particularly in pregnant women who are unimmunized and at risk for endemic or epidemic exposure, include meningococcal conjugate vaccine, polio vaccine, yellow fever vaccine, and hepatitis A and B vaccines [47]. MenAfriVac, a meningococcus capsular group A vaccine that is conjugated with the tetanus toxoid vaccine, is currently administered to all demographic groups in sub-Saharan Africa including pregnant and lactating women and no adverse effects have been reported [89,90,98]. Given theoretical risks of primary viral infection to mother and fetus, live vaccines such as those for measles, mumps and rubella as well as influenza, varicella and zoster, are not recommended in pregnancy [47]. In cases of less commonly used vaccines, the benefit of administration of the vaccine is weighed against the risk of exposure to mother and fetus [99].

Table 1

Abbreviations: CMV, cytomegalovirus; EBOV, Ebola virus; GBS, group B Streptococcus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; WHO, World Health Organization; ZiV, Zika virus.

a The WHO recommendation for elimination of both maternal and neonatal tetanus occurred in 1999. The first WHO position paper on tetanus vaccine in pregnancy was published in 2006.

The impact of maternal vaccination on subsequent active vaccination in the infant has been conducted following maternal immunization with pertussis, Haemophilus influenzae type b, and influenza vaccines [100–102]. Further evaluation is needed, particularly when maternal immunization with vaccines utilized in primary infant immunization such as DTP (Diphtheria, tetanus and acellular pertussis) are used following maternal immunization with one or multiple similar or identical antigens (e.g., Tdap). This may become increasingly important if the WHO schedule of Expanded Programme on Immunization (EPI) is used in early infancy, as the EPI schedule begins immunization at 6 weeks of age and re-immunizes infants at 10 and 14 weeks of age. The first months of life represent a time period when maternal antibodies are likely to be at higher concentrations than later in infancy, such as in current schedules commonly utilized by countries not using EPI vaccine schedules (e.g., primary infant immunization given at 2, 4, 6 and 12 months in US or 3, 5, 12 months in Sweden or 2, 3, 4, and 12 months in the UK) [85,103,104].

Future work

Given the potential of far-reaching protective effect of maternal immunization, from mother to fetus to neonate, several new vaccines are currently in development for use in pregnancy (see Table 1). The RSV F nanoparticle vaccine by Novavax (Gaithersburg, MD) in phase III clinical trials in pregnant women (ClinicalTrials.gov NCT02624947) and smaller studies of other RSV vaccines such as the RSV-PFP2 (purified F protein) have shown immunogenicity and lack of reactogenicity in pregnant women, efficient transplacental antibody transfer, and potential protective effects in the infant [105–108]. Other vaccine candidates for RSV are also under development. Group B Streptococcus (GBS) is also a desirable target for vaccine production given its pathogenicity in pregnancy and the neonatal period. Novartis has recently conducted a clinical trial in South Africa with its multivalent conjugate GBS vaccine (ClinicalTrials.gov, NCT01412804). Other future targets for maternal immunization that are currently in the research pipeline and development stages are vaccines against cytomegalovirus (CMV) and herpes simplex virus (HSV). A vaccine against Zika virus is also currently in the research stages [91], refer to relevant chapter. In recent years a vaccine against Ebola infection has been developed and administered for the purposes of disease containment, however it is investigational and safety data for pregnant and lactating women is still pending [92].

Historical perspective on women’s inclusion in research

Important factors in the development of maternal immunizations have been the changing perspectives and trends in women’s involvement in research. Pharmaceutical development as well as medical research became more regulated in the early 1900s. Particularly tonics advertised for women that were found to be addictive played a role in introducing the Food and Drugs Act in 1906 in the US which helped establish the governmental regulatory agency, the Food and Drug Administration (FDA) [54]. The movement toward protection of the rights of human research subjects gained more traction during the Nuremburg trials in 1946 when Nazi physicians were convicted of crimes against humanity after the end of World War II and ultimately led to the Universal Declaration of Human Rights [55].

In the 1960s and 1970s, several incidents occurred which shaped protectionist policy regarding participation of women in clinical research and use of pharmaceuticals in pregnancy for much of the next three to four decades. In 1961–1962, thalidomide, a drug specifically marketed to pregnant women for treatment of morning sickness and in widespread use in Europe, was found to be teratogenic resulting in severe abnormalities of fetal limb development and other organ systems [56]. In 1971 and 1974, severe adverse health effects were announced in female offspring of pregnant women who used diethylstilbestrol (DES) and the Dalkon Shield as a contraceptive device [57,58]. In addition, research studies conducted on reproductive age women in New Zealand and in the US raised serious ethical concerns [55,109,110]. In response to the increase in pharmaceutical and research scandals and activist outcry, in 1975, the US Department of Health and Human Services (DHHS) designated pregnant women as a vulnerable population in which research should only be conducted under special circumstances [55,59]. In 1977, due to concerns about liability, the FDA issued a policy to prohibit reproductive age women and pregnant women from participating in early phases of clinical trials on pharmaceuticals [54]. This policy was commonly interpreted to apply to all clinical phases for drug trials and effectively, within a short period of time, reproductive age women and pregnant women were essentially excluded from participation in clinical research [111].

The US Public Health Service Task Force’s report on Women’s health Issues in 1985 outlined lack of data specific to women’s health and started the movement of policy regarding inclusion of women in research away from the protectionist and more toward an inclusionist approach [60,61]. In 1986, the US National Institutes of Health (NIH) introduced a policy that encouraged but did not mandate the inclusion of women in research trials [59]. Despite these changes, women were not represented in clinical trials at appropriate rates [61]. Following a public outcry, in 1990, the US Congress passed the Women’s Health Equity Act that mandated research in areas of women’s health and established an office for women’s health at the NIH [62,63]. Nonetheless, in 1991 the Federal Policy for the Protection of Human Subjects, also known as the Common Rule was published by the US DHHS that contained additional protections for pregnant women, human fetuses, and neonates [76]. Under this Common Rule, if research involving pregnant women is thought to benefit only the fetus, consent of not only the woman but also that of the biological father is required unless he is unavailable or incompetent or if the pregnancy was a result of rape [112].

In 1993, the Council for International Organizations of Medical Sciences (CIOMS) characterized the exclusion of pregnant women from research as a whole as unjust [64,65]. This was supported by the FDA and the European Medicines Agency, the agency of the European Union responsible for evaluation, regulation and monitoring of medicines which was established in 1995 [66–68]. In the same year, following the US General Accounting Office’s report on the FDA’s policy toward women titled, Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing, the FDA issued their Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs which outlined expectations that both men and women be involved in clinical drug trials [68,69]. The NIH also released its Revitalization Act of 1993 (P.L. 103-43) which encouraged the inclusion of women and minorities in research and clinical trials, and was followed by specific guidelines to this effect in 1994 [70,71]. In 2016, the US Congress’ 21st Century Cures Act in the established the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) to advise the US DHHS on priorities for research and therapies for pregnant and lactating women [75,113]. Revisions of the Common Rule are projected to occur in early 2019 which may remove the requirement for paternal consent and the designation of pregnant women as a vulnerable population [113].

An example of inclusionist policy toward pregnant women in research is that of MenAfriVac mass immunization campaigns. In 2010, preparations were being made for mass immunizations in West Africa against endemic meningococcal disease. The discussion at the time was whether pregnant women should be excluded from this campaign given lack of long-term safety data [72]. The WHO’s Global Advisory Committee on Vaccine Safety concluded that MenAfriVac should be offered to all women including pregnant women based on (1) clear benefit from immunization for pregnant women, (2) no alternative way to protect against meningococcal disease, (3) clear risk for disease in this geographical area and (4) lack of adverse safety data. At the same time, the committee also emphasized that data should be collected regarding safety and adverse events especially in pregnant and lactating women [72].

Despite advances, the discussion regarding representation of pregnant women in research continues. This was especially important during the Ebola treatment trials in West Africa in the outbreak in 2013–2016. Given extremely high maternal mortality and fetal and neonatal mortality nearing 100% with Ebola infection in pregnancy, the WHO Research Ethics Review Committee (WHO-ERC) emphasized inclusion of pregnant women and children in research protocols [73,114]. Nonetheless, most pregnant women were excluded from drug and vaccine trials during the Ebola outbreak [115]. Pregnant and lactating women were also excluded from receiving an investigational vaccine against Ebola during an outbreak in the Democratic Republic of Congo in 2018 due to lack of safety data [92]. In regards to other emerging diseases, in 2017 a WHO scoping meeting on vector-borne diseases encouraged inclusion of pregnant women and reproductive-age women in future vaccine trials against the Zika virus with ethical oversight [74]. In the 21st century, progress has been made due to policy changes by international and national regulatory and research agencies. However, more work is still needed [61,65].

Current challenges

Maternal immunizations continue to face several challenges including regulatory and legal issues, medical-legal liability and risk for vaccine manufacturers in the research and development of vaccines for use in pregnancy. Currently, none of the vaccines recommended for use in pregnancy has actually been licensed by regulatory authorities for use during pregnancy. In 2018 a proposal was submitted by the US Department of Health and Human Services to add the category of vaccines recommended for pregnant women to the Vaccine Injury Table within the National Vaccine Injury Compensation Program [116], a major potential advance for immunization during pregnancy. While there has been a paradigm shift in recent years from protection pregnant women from research to protecting them through research, there is still room for improvement [117].

Conclusion

Maternal immunization research and clinical application has a rich history and an even brighter future. Pregnancy and the neonatal period continue to come into focus as areas of medicine that necessitate more rigorous research and investment. The history of women’s involvement in research is a cautionary tale of the need to avoid protecting women from research, while also recognizing the complex nature of pregnancy and emphasizing the need for research as a vehicle to making pregnancy and the postpartum period safer. It is also important to study and highlight maternal benefit from vaccines in pregnancy as an end in itself beyond emphasizing the woman serving solely as a vehicle for fetal and neonatal disease prevention. Maternal immunization is a complex field that must take into account multiple factors: maternal immunogenicity, transplacental antibody transfer, the immune system of the neonatal and subsequent neonatal immunogenicity, as well as potential adverse effects in mother and infant. The continued study of established vaccines as well as the development of new vaccines will continue to challenge and inspire efforts to improve maternal and neonatal health globally in the future.

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