Vaccination in Pregnancy

Background: Vaccination during pregnancy can protect both the expecting mother and the unborn and newborn child from infectious diseases.

Methods: This review is based on publications retrieved by a selective literature search on the immunological particularities of infectious diseases affecting pregnant women, unborn children, and neonates, with particular attention to the guidelines of the German Standing Committee on Vaccinations (Ständige Impfkommission, STIKO) and the pertinent guidelines.

Results: Vaccination during pregnancy protects the expecting mother from a severe course of a number of different infectious diseases. Vaccination with inactivated vaccines against influenza, tetanus, and pertussis is effective, safe, and well tolerated. Women who are pregnant or of child-bearing age should be immunized against tetanus according to the STIKO recommendations. All pregnant women from the second trimester onward should receive an inactivated quadrivalent influenza vaccine. The immunity acquired after vaccination with an acellular pertussis vaccine is present only for a limited time. In a cohort study involving 72,781 pregnant women, pertussis vaccination during pregnancy was found to yield 91% protection against pertussis for their subsequently born children in the first three months of life. Further types of vaccine can also be given during pregnancy if indicated. Additional reasonable measures to protect the health of mother and child include the vaccination of other persons in close contact as well as the closure of relevant vaccination gaps among young adults, particularly women of child-bearing age. Treating physicians play a crucial role in encouraging vaccine acceptance by their patients.

Conclusion: Maternal immunization is a safe and effective strategy for giving neonates passive immune protection against life-threatening infections by the vertical transmission of maternal antibodies until they are able to build up their own adaptive immunity.

Due to specific features of their immune system, pregnant women, fetuses and newborns are particularly susceptible to infectious diseases, including vaccination-preventable diseases which are associated with significant morbidity and mortality. Vaccination in pregnancy can protect pregnant women as well as their unborn and newborn children against infectious diseases. Physicians involved in their care play a key role in the efforts to increase vaccination acceptance.

Key messages

This article discusses the mechanism of action, the evidence related to the expected effects, contraindications, and potential side effects of vaccination in pregnancy. This review is based on pertinent publications retrieved from a selective literature search with special consideration of the current recommendations of the German Standing Committee on Vaccination (STIKO, Ständige Impfkommission).

Special features of the immune system in pregnancy

Immune tolerance to the semiallogeneic fetus by the maternal immune system is a key requirement for a successful pregnancy. The complex adaptive changes needed to create this tolerance increase the risk of a severe course of an infectious disease, for example of influenza, even in immunocompetent pregnant women (1, 2, 3). The fetus is at risk for infection-related diseases acquired in utero or perinatally (4). In general, pregnant women are as capable of mounting an immune response to natural infections and vaccinations as non-pregnant women (5). However, increasing levels of the sex hormones estradiol and progesterone result in changes in the equilibrium of pro-inflammatory and anti-inflammatory reactions which varies over the course of pregnancy (1). As a consequence, more antibodies are formed, while the specific T cell-mediated maternal protection, which is directed against cells infected by a virus, wanes (2, 5, 6).

The placenta is an immunologically active organ capable of interacting with pathogens and modulating the maternal immune response (1). Trophoblast cells are resistant to infection by a variety of viruses and are able to transfer this resistance to other cells via paracrine signaling (7). In addition, a significant transfer of immunoglobulin G (IgG) from the maternal blood to the fetus occurs by means of transcytosis. The active transplacental IgG transfer starts at 13 weeks’ gestation and continues to increase over the course of pregnancy. The largest portion of antibodies is received by the fetus during the last four weeks of pregnancy (8).

The immunological status of newborns and infants

Due to the functional immaturity of the adaptive immune system, the newborn’s immune system characteristically lacks reactivity to multiple (including non-pathogenic) microorganisms in order to prevent excessive inflammatory responses (9). The placental transfer of maternal immunoglobulins to the fetus is a specific adaptation mechanism, compensating to a certain degree for the newborn’s deficits in antibody production during the first months postpartum and providing newborns and infants with temporary passive immunity. In addition, when breastfeeding, secretory IgA antibodies and other immunologically active substances in breast milk are passed to the suckling infant (e1). According to the STIKO immunization schedule, active immunization of infants starts at the age of two months.

Goals of vaccination in pregnancy, vaccines and principles of administration

Protection against the effects of vaccination-preventable infectious diseases on female reproductive health and on the health of their offspring requires timely administration of the recommended standard vaccines from birth as well as avoidance of gaps in the vaccination status of women of childbearing potential (10) (Tables 1 and 2). Active immunizations during pregnancy are intended to provide direct individual protection against the corresponding infectious disease and its adverse effects on the course of pregnancy as well as optimum passive immunity for the newborn and young infant.

Table 1

Protection against vaccination-preventable infections

Table 2

Vaccination recommendations for women with regard to vaccination-preventable diseases with impact on pregnancy-associated health of the mother and/or child

Monovalent and multivalent live vaccines and inactivated vaccines are available for immunization. Live vaccines contain attenuated viruses or bacteria which typically do not cause illness in immunocompetent vaccinated persons. Immunization requires multiplication of these pathogens in the vaccinated person. Live attenuated vaccines are contraindicated in pregnancy because the vaccine virus could spread to the unborn child and, theoretically, put the fetus at risk. After vaccination with live vaccine, pregnancy should be avoided for one month. However, accidental vaccination in early pregnancy is not an indication for termination of pregnancy. Based on vaccination-related adverse event data from surveillance programs (11) and a systematic review of epidemiological studies including more than 3500 documented vaccinations with monovalent rubella, measles-rubella and measles-mumps-rubella (MMR) vaccines, no case of rubella embryopathy related to the vaccine virus was identified (e2). As a rule, live vaccines can be administered to breastfeeding women; however, after yellow fever vaccination of nursing mothers, isolated cases of meningoencephalitis have been reported among breastfed infants (e3).

Inactivated vaccines contain inactivated pathogens, immunogenic components of pathogens or detoxified bacterial toxins (toxoids). Some of these vaccines are less immunogenic than live attenuated vaccines and typically require booster vaccinations for lasting immunity. Provided they are not very reactogenic, inactivated vaccines are considered safe for pregnant women and the fetus (12). During the first trimester of pregnancy, only urgently indicated vaccinations should be performed in order to avoid that spontaneous abortions, which commonly occur in this period, are perceived as vaccination-related.

Vaccination in pregnancy: Tetanus

The most extensive experience with maternal immunization has been made with tetanus vaccination. By immunizing pregnant women or women of childbearing potential with at least two doses of tetanus toxoid, neonatal tetanus mortality was reduced by 94% (95% confidence interval [80; 98]) (13). In Germany, less than 15 cases per year have been recorded in the last years, most of which were older adults (e4).

Vaccination in pregnancy: Influenza

Due to the impaired maternal immune defense to viral pathogens and the physiological pregnancy-related changes in the cardiopulmonary system (increase in stroke volume and oxygen consumption, decrease in lung volume), which increase over the course of pregnancy, influenza is associated with an increased risk of pneumonia in pregnant women (2, 3, 6, 14). In a case-control study covering 17 influenza seasons, more than 4300 women of childbearing potential hospitalized for influenza or pneumonia were compared to a control group of almost 22 000 women. The risk of hospitalization was found significantly increased in pregnant women; the odds ratio (OR) increased from 1.44 [0.97; 2.15] in women between 14 and 20 weeks’ gestation to 4.67 [3.42; 6.39] in women between 37 and 42 weeks’ gestation (15).

An analysis of the data of 17 548 022 hospitalized pregnant women from a nationwide US hospital database, covering ten influenza seasons, found that pregnant women with respiratory symptoms were at an increased risk of preterm delivery (adjusted OR [aOR] 3.82 [3.53; 4.14]), cesarean delivery (aOR 3.47 [3.22; 3.74]) and stillbirth (aOR 2.50 [1.97; 3.18]) (16). Furthermore, newborns and infants contracting an influenza infection during the first six months of life have an increased risk of complications such as fever (febrile convulsion), severe generalized disease, and the highest annual incidence of influenza-related deaths in children (17). Influenza vaccines approved in Germany are only to be used in children aged six months and older.

According to STIKO recommendations, all pregnant women should receive an inactivated quadrivalent vaccine with the current antigen combination, as recommended by the World Health Organization (WHO), from the second trimester—in case of increased health risks due to an underlying condition already from the first trimester. Even though some studies found reduced immunogenicity in pregnant women, there is no evidence of reduced clinical efficacy (5).

Studies evaluating maternal and infant endpoints showed that the influenza vaccination is safe, well tolerated and effective (18, 19, 20); here, it should be taken into account that in general the effectiveness of influenza vaccines varies greatly between seasons. According to calculations by the Centers for Disease Control and Prevention (CDC), influenza vaccine efficacy with regard to preventing laboratory-confirmed, influenza-related medical consultations was between 20% and 60% (median 48%) between 2009 and 2019 for all age groups (e5).

A randomized, double-blind, placebo-controlled study from 2011 and 2012 showed a vaccine efficacy against laboratory-confirmed influenza of 50.4% [14.5; 71.2] for HIV-negative pregnant women and of 48.8% [11.6; 70.4] for their infants up to an age of 24 weeks; vaccine efficacy in HIV-positive pregnant women was 57.7% [0.2; 82,1] (18).

In a retrospective cohort study, the number of preterm births among pregnant women vaccinated in the influenza season was significantly reduced (aOR  0.60 [0.38; 0.94]) (19). A large cohort study found 70% fewer cases of influenza-like illness (relative risk [RR] 0.30 [0.19; 0.46]) and 81% fewer hospitalizations (RR 0.19 [0.06; 0.60]) among infants aged six months or under of vaccinated mothers (20).

Vaccination in pregnancy: Pertussis

The gram-negative rod bacterium Bordetella pertussis is responsible for causing whooping cough. It is transmitted by airborne droplets and highly contagious. With an annual incidence between 10 and 40 cases per 100 000 population, pertussis is a common infectious disease, typically taking several weeks to months to clear (21). Pertussis primarily affects children and adolescents, but is often diagnosed in adults too.

The immunity achieved with acellular pertussis vaccine is only temporary; however, even pertussis infection does not leave lifelong immunity. Frequently, long-lasting mild cough is the only symptom observed in infected adolescents and adults. They are the most common source for the transmission of Bordetella pertussis to unvaccinated infants. Between 2014 and 2018, the adjusted mean incidences of pertussis and pertussis-related hospitalization during the first three months of life were 111.3 and 70.1 of 100 000 infants, respectively (22). Of the hospitalized infants, up to 61% can experience apnea, 23% pneumonia, about 1% seizures, and 0.3% encephalopathy (23).

In March 2020, the STIKO decided to recommend pertussis vaccination for every pregnancy. The safety evaluation was based on three randomized controlled trials and eleven non-randomized studies with a total study population of 1.4 million pregnant women. The efficacy was determined based on four cohort studies and four case-control studies with a total study population of 855 546 mother-child pairs. The assessed safety endpoints were fever ≥ 38 °C, preeclampsia, chorioamnionitis, preterm birth, and stillbirth, low birth weight, congenital malformations, as well as intensive care treatment, sepsis and death of newborns within seven and 28 days postpartum, respectively.

The vaccination is generally well tolerated. Six additional cases of fever after vaccination per 100 000 vaccinated women are to be expected. According to the results of a UK cohort study with 72 781 pregnant women, pertussis vaccination in pregnancy protects infants aged three months or under against pertussis in 91% of cases (24). A case-control study with 6252 pregnant women found a vaccine efficacy against pertussis-related hospitalization in infants aged two months or under of 91% (25) (Table 3).

Table 3

Pertussis vaccines are not monovalent but only available as combination vaccines (together with tetanus toxoid [T] and reduced diphtheria toxoid [d] as the Tdap vaccine or with additional inactivated polio vaccine (IPV) component as the Tdap-IPV vaccine). According to the STIKO recommendation, every pregnant women should be vaccinated against pertussis using the Tdap(-IPV) vaccine during the gestational weeks 28 to 32—those at an increased risk of preterm birth should already be vaccinated in the second trimester. If a mother did not receive the vaccination in pregnancy, she should preferentially be vaccinated in the first days after giving birth. The incidence of vaccination-related side effects did not increase if the Tdap vaccine was repeated when a minimum interval of four weeks to the previous Td vaccination was observed (26, 27). Likewise, the co-administration of influenza vaccine, which is also recommended in pregnancy, is not associated with an increased risk of side effects (28).

According to the STIKO recommendations, close household contacts of the newborn should also receive a dose of pertussis vaccine, ideally up to four weeks prior to the birth of the child, if they have not been vaccinated against pertussis in the last ten years.

In most women vaccinated prior to pregnancy, antibody titers are too low to afford optimum protection of the newborn by placental transmission of antibodies (29, 30). By contrast, vaccination of pregnant women with an ap-containing vaccine resulted in high levels of antibodies in the blood of the expectant mothers and the newborns (31).

Since after maternal immunization the desired, passively transferred maternal antibodies against pertussis are present at the time of the first pertussis vaccination of infants, these could temporarily affect the serologically detectable immune response of the vaccinated infants. After the fourth dose of a DTaP-containing vaccine, however, most studies found no significant differences between the antibody levels measured in children of vaccinated compared to unvaccinated mothers (23).

Vaccination in pregnancy: Hepatitis B

Globally, hepatitis B (HB) is one of the most common viral diseases. In Germany, altogether 4507 cases of hepatitis B were reported in 2018, including five infections among children aged one year or under (e6). Vertical transmission from the typically chronically infected mother to the child is the primary cause of viral hepatitis B in infected children (32); if the virus is contracted perinatally, the infection takes a chronic course in about 90% of the affected children (e7). Of the patients with chronic HBV infection, 20 to 30% later develop liver cirrhosis and/or liver cancer (33).

In order to reduce the risk of perinatal transmission, screening for HBsAg should be performed after 32 weeks’ gestation according to the maternity guideline of the German Federal Joint Committee (G-BA, Gemeinsamer Bundesausschuss). In case of a positive screening result, simultaneous active and passive immunization of the newborn is initiated within twelve hours after delivery. With this approach, vertical HBV transmission can almost always be prevented in newborns of mothers with low-level viremia in pregnancy, while in mothers with high-level viremia the transmission rate can be reduced significantly (34).

Measures to improve vaccination acceptance

Despite the evidence in support of the benefits for mother and child as well as the safety and efficacy of vaccination in pregnancy, the currently data available show a rather low acceptance of vaccination in pregnancy. The seasonal influenza vaccination rates in pregnancy were at just above 10%, based on nationwide outpatient claims data of statutory health insurance physicians for the years 2009 to 2015 (35). In a survey by the Robert Koch Institute (RKI), however, 41% of the surveyed pregnant women stated that they would get vaccinated in pregnancy against pertussis, if this vaccination was recommended by STIKO (36).

Physicians play a key role in the communication of vaccination-related information. In a survey of women after delivery, personal recommendation of vaccination against seasonal influenza by a gynecologist/obstetrician was stated as the most important reason for making the decision to get this vaccination (37). Vilca and Esposito (38) also highlight the critical role of gynecologists/obstetricians especially with regard to vaccination in pregnancy and recommend to routinely integrate maternal immunization in prenatal care.

In a study conducted by the Robert Koch Institute (39), 87% of the surveyed community-based gynecologists stated that they would want to vaccinate their patients during pregnancy if this is recommended by the STIKO. 95.2% of the gynecologists regarded the inclusion of the STIKO-recommended vaccinations for pregnant women in the maternity guideline and the documentation in the German maternity record (“Mutterpass”) for a suitable measure to improve vaccination rates in pregnancy.

Vaccinations before and during pregnancy will continue to gain importance in the future. Currently, new vaccines to protect unborn and newborn children from infection with respiratory syncytial virus, group B streptococcus, herpes simplex virus, and cytomegalovirus are being developed (e8).

Maternal immunization is a safe and effective strategy to provide young infants with passive immunoprotection against life-threatening infections by means of vertical transmission of maternal antibodies until they have established adaptive immunity of their own. Further useful measures to protect the health of mother and child include timely administration of the recommended standard vaccinations starting from birth, the vaccination of close contacts (cocoon strategy) as well as closing relevant immunization gaps in young adults, especially in women of childbearing potential.

Conflict of interest statement
Dr. Wojcinski received consultancy fees from GSK, MSD and Sanofi. He received reimbursement of travel and accommodation expenses from GSK, MSD, Sanofi, and Pfizer. He received fees for the preparation of scientific meetings from GSK, MSD and Sanofi Pasteur.

Prof. Liese received consultancy fees from GSK, Pfizer, Sanofi-Pasteur, and MSD. He received honoraria for conducting contract clinical trials for GSK and Pfizer.

The remaining authors declare not to have any conflicts of interest.

Manuscript received on: 24 June 2020; revised version accepted on 2 November 2020

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Dr. med. Marianne Röbl-Mathieu
Connollystr. 4, 80809 München, Germany

Cite this as:
Röbl-Mathieu M, Kunstein A, Liese J, Mertens T, Wojcinski M: Vaccination in pregnancy. Dtsch Arztebl Int 2021; 118: 262–8. DOI: 10.3238/arztebl.m2021.0020

►Supplementary material

eReferences:
www.aerzteblatt-international.de/m2021.0020

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