Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron Variant

Background

Vaccination against infectious diseases is a key component of public health programs around the world [1,2]. Their implementation requires appropriate awareness and acceptance of vaccines by parents of children, adolescents, and adults [3,4].

Women of childbearing age belong to the group of people with specific indications for vaccination [5]. Thanks to this, they are better prepared for pregnancy and the birth of a healthy baby [4]. Recommendations for vaccination of adolescents and people of childbearing age always require an individual approach depending on the history of vaccinations performed so far, documented in the immunization card, and the age of the woman who plans to become pregnant [6–8]. The immunization needs of women in different years of life are different [9,10]. The decision to vaccinate may also be preceded by serological tests of vaccine antibody titers [6–8]. This applies primarily to vaccination against rubella and chickenpox [11,12]. If an adult has not received all doses of vaccines, as recommended by national vaccination programs, they can be supplemented at any age [9,13,14].

This article aims to review current global recommendations for the vaccination of pregnant and breastfeeding women, including against the Omicron variants of SARS-CoV-2.

This literature review covers currently recommended vaccinations for women and men during the reproductive period (ie, against chickenpox, mumps, rubella, measles, hepatitis A and B, influenza, human papillomavirus, diphtheria, pertussis, tetanus, and meningococci), and for pregnant women and breastfeeding mothers (ie, against diphtheria, pertussis, tetanus, and influenza), including vaccines against COVID-19 in the context of the dominance of the Omicron variant. The implementation of these vaccinations is important due to the Polish Immunization Program [9], which includes most vaccinations in early childhood. Cultural changes affecting the planning of the first pregnancy after the age of 30 require the administration of booster doses for some inactivated vaccines administered in childhood or supplementation of mandatory and recommended vaccinations not administered during this period.

Functioning of the Immune System During Pregnancy

The gestation period is associated with increased susceptibility to infections and often their severe course, as well as adverse effects on the fetus resulting from infection with specific pathogens [15,16]. Pregnancy causes a decrease in the number of B1 cells, which influences on deficiency of IgM antibodies and a decrease in the functionality of B cells [3]. These changes weaken the innate immunity of the pregnant woman and increase her susceptibility to infections [17–19]. During pregnancy, the activity of the complement system also increases, causing an increase in the immune response to some antibodies (eg, against influenza), leading to various obstetric complications (eg, preeclampsia) [15]. At the same time, adaptation in the mother’s immune system is the site of many physiological changes that protect her and the fetus from pathogens [5,16,17]. The mother’s increased immune reactivity, while providing her protection, finds a balance to maintain a healthy pregnancy and avoid a harmful immune response against the allogeneic fetus. Although the mechanism of this phenomenon is not precisely understood, studies confirm a dynamic interaction between the immune systems of the mother and fetus, despite suppression of immunity in the mother [5,20–23].

At the same time, a state of increased innate immune response and reduced cellular response is observed during pregnancy, which is maintained through the transformation of the cytokine phenotype (ie, the transition from the dominance of Th1 lymphocytes to Th2). Reducing cellular immunity increases the likelihood of infection [15]. It is assumed that proinflammatory cytokines trigger an immune response and cause tissue damage. Typically, a viral infection, such as rubella or chickenpox, occurs as a result of an acute, primary infection during pregnancy, although pre-pregnancy infections may also reactivate [16]. Their incidence increases with gestational age, due to changes in the factors determining the mother’s immunity and the decreasing anatomical thickness of the placenta. In contrast, the clinical manifestations of infection and the risk of complications are more severe when the infection occurs in the early stages of pregnancy and is associated with maternal comorbidities [17,24].

Immune changes associated with pregnancy also affect the pathogenesis of autoimmune diseases, which can change the profile of symptoms in pregnant patients [17]. Changing the cytokine profile from a Th1-mediated phenotype to a Th2-engaging phenotype alleviates inflammatory autoimmune disease while exacerbating humoral autoimmune disease [18,24].

COVID-19 During Pregnancy and Breastfeeding

Due to altered maternal immunity, as well as adaptive changes in the respiratory, cardiovascular, and hematological systems, there is a risk of potential susceptibility of pregnant women to COVID-19 infection [14]. There is little evidence on various pregnancy disorders, including fetal growth limitations, preterm birth, and maternal mortality caused by COVID-19 infection per patient in the first trimester of pregnancy, but seasonal flu is known to be associated with higher rates of early miscarriages. Nevertheless, most studies did not observe a significant risk of severe COVID-19 infection among pregnant women than in the general population [8,25].

COVID-19 infection reduces the expression of angiotensin-converting enzyme-2 (ACE2), leading to increased angiotensin II activity followed by an increased immune response seen in COVID-19 patients [22]. The binding of the virus to ACE2 receptors reduces their dynamics on alveolar epithelial cells and activates the host’s adaptive immune response. Many inflammatory markers (mainly interleukin IL-1β, IL-4, IL-10, and interferon γ) are released, which disrupt the integrity of endothelial cells and thus hinder the vesicular-capillary barrier, often causing severe hypoxemia [7,26]. It seems that immune system adaptations during pregnancy may affect the response profile after vaccination against COVID-19. Although studies have shown the effectiveness of these vaccines in pregnant women, the small number of vaccinated expectant mothers makes it difficult to fully investigate this issue [27].

Undoubtedly, the gestation period is associated with a higher susceptibility to diseases that can be prevented by vaccination. Due to fluctuations in the hormonal balance of the body and modifications in the immune system, exposure to complications of various diseases, including infectious ones, is much higher in pregnant women than in the general population. Hence, vaccination of expectant mothers is a comprehensive element of antenatal care aimed at improving the health of both mother and child [4,5].

Recommendations for Vaccination of Adolescents and Adults in the Reproductive Period

To protect against bacterial and viral infections dangerous to both the pregnant, fetus, and newborn, vaccination against rubella, measles, mumps, chickenpox, pertussis, hepatitis A and B, meningococcus, HPV and influenza in adolescents and adults in the reproductive period should be considered. Table 1 presents recommendations for these vaccinations, taking into account local arrangements [6,7,9].

In many countries, it is recommended to vaccinate adults susceptible to VZV infection, and in Germany and the United States, serological tests are recommended for women of childbearing potential. If a negative result is obtained, it is recommended to carry out vaccination by the manufacturer’s recommendations [28].

The persistence of seroprotection in the case of rubella is estimated at >15 years. Therefore, it is recommended that the MMR vaccine be considered for the prevention of congenital rubella as well as measles and mumps in young women working in pediatric environments if >10 years have passed since the last MMR vaccination. Non-pregnant women who have received live vaccines (MMR, VZV) should be advised to avoid pregnancy for at least 4 weeks [29–33].

If vaccination against hepatitis B is required in adolescents and adults, a combined vaccine against hepatitis A and B is available in a 3-dose schedule for subjects >16 years of age [6,9].

The most effective method of preventing influenza is vaccination against this disease. Annual vaccination against influenza is recommended for all people over 6 months of age who have no contraindications to vaccination. Current strains for the production of influenza vaccines are recommended each year by the World Health Organization (WHO). Their validity period is one flu season. Inactivated and attenuated influenza vaccines are available. Both types of vaccines provide active immunization against 4 strains of influenza virus (2 subtypes A and 2 subtypes B) and are referred to as 4-valent vaccines [7]. The inactivated 4-valent influenza vaccine can be used in all people who do not have any special contraindications, while the attenuated vaccine can be used in healthy, non-pregnant women. In Poland, only 1 “live” intranasal influenza vaccine is used, recommended for children and adolescents from 6 months of age to 18 years of age [7,8,34].

Human papillomavirus (HPV) is a pathogen that can cause many different diseases, depending on its subtype. Among the 200 types of human papillomaviruses, about 40 are responsible for urogenital infections in women and men [6,35]. In Europe, 8 types are important (16, 18, 31, 33, 35, 45, 56, and 58). Among them, those numbered 16 and 18 are responsible for more than 70% of cervical cancer cases. Infection with the pathogen of various types of human papillomaviruses can cause cancer not only in cervical cancer but also in the anus, penis, vulva, vagina, mouth, pharynx, larynx, and paranasal sinuses [36,37]. In the United States, as in Poland, a 2-valent vaccine against oncogenic types of virus 16 and 18, a 4-valent vaccine against types 6, 11, 16, and 18, and a 9-valent vaccine against types 6, 11, 16, 18, 31, 33, 45, 52, and 58 are registered. Available vaccines protect against precancerous lesions of the genital organs (cervix, vulva, vagina) and cervical cancer. The 2-valent vaccine is reimbursed in Poland from November 1, 2021, for people over 9 years of age, and from June 1, 2023, it is free. A universal HPV vaccination program is aimed at girls and boys aged 12 and 13 years [38,39].

If a woman during the reproductive period has not had vaccinations against diphtheria, tetanus, and pertussis, then at any age they should be supplemented [40,41]. The vaccination schedule includes the administration of one dose of dTpa. After a period of 1–2 months, the Td vaccine should be administered, and after 6–12 months, another dose of Td (a total of 3 doses of primary vaccination). Booster doses of dTpa vaccine are recommended to be administered every 10 years [42,43].

All people, regardless of gender and age, are exposed to meningococcal infection. Many cases of the disease occur in adolescents and young adults. The most dangerous is invasive meningococcal disease (IMD), which involves meningitis or sepsis [44]. Clinically, it develops very quickly and is fraught with high mortality and often permanent complications. Most cases of IMD are caused by meningococcal serogroups B and C. Recently, the participation of meningococcal serogroup W is also important. Vaccination against meningococcal group B includes the administration of 2 doses of vaccine and in the case of meningococcal vaccination of groups A, C, Y, and W one dose of vaccine [3,4,6].

Recommendations for Vaccination of Pregnant Women – Priorities and Prospects

Based on the available research results, and opinions of scientific societies and pro-health organizations, vaccination of pregnant women is safe for them and developing fetuses with selected inactivated vaccines, as well as administered in particularly justified situations of exposure to infection with other vaccines (eg, vaccination against COVID-19). Pregnant women are not given “live” vaccines [8,45]. Table 2 presents vaccinations recommended for pregnant and breastfeeding women, taking into account local recommendations [8,9,10,26].

If there is a possibility of exposure to an infectious disease that threatens the health of the mother or newborn, the benefits of vaccinating the pregnant woman are greater than the theoretical risks associated with them. Toxoids and inactivated antibacterial and antiviral vaccines are safe in pregnancy. They do not cause complications in either the mother or the fetus. In addition, according to available knowledge, the use of immunoglobulin preparations during pregnancy does not cause complications in the development of the fetus. In contrast, attenuated (“live”) antiviral or antibacterial vaccines are contraindicated during pregnancy, since there is theoretically a risk of causing infection in the fetus. So far, no data are available to suggest that giving a pregnant woman a vaccine containing ‘live’ viruses may be associated with fetal harm [46,47]. Pregnant women are recommended to be vaccinated against influenza tetanus and pertussis with a combined vaccine containing tetanus toxoid and reduced doses of diphtheria toxoid and acellular pertussis antigens (dTpa) [48]. Pregnant women planning to travel abroad or those who cannot avoid infectious diseases that are prevented by vaccination should be vaccinated. Breastfeeding is not a contraindication for the administration of inactivated and attenuated vaccines. If influenza vaccination and dTpa vaccination were not carried out during pregnancy, they can be given immediately after delivery [49–51].

All newborns can be protected by the active transplacental transport of antibodies specific to microbes with which the woman has previously been in contact or which she has developed after vaccination [10]. After administration of vaccines in pregnant women, the concentration of antibodies increases, which are then transferred to the child in the II and III trimesters. They protect the baby in the first months of life (ie, during the period of greater susceptibility to infectious diseases, resulting from the risk of exposure and the relative immaturity of the infant’s immune system) [5,43]. Although none of the registered vaccines in the United States has a specific indication for use in pregnant women, vaccination during pregnancy is recommended if the risk of complications of an infectious disease in the mother or child outweighs the risk of developing adverse reactions to vaccination [4,47].

All inactivated and live vaccines recommended for adults not given before or during pregnancy may be administered during breastfeeding. Family members of a pregnant woman can also be vaccinated with a combined vaccine against measles, mumps, and rubella because the live, weakened viruses contained in this vaccine do not spread from the vaccinated person to other people. Similarly, children whose mothers are pregnant against chickenpox can be vaccinated. There is no known evidence of a risk of transmission to the mother from a vaccinated child [7,11,12].

Worldwide, vaccination of pregnant women against tetanus was considered a major public health success, which reduced the incidence of tetanus in newborns by 96%. A combined vaccine against diphtheria, tetanus, and pertussis (dTap) was first recommended for pregnant women by the WHO in 2015 [40]. Pertussis vaccination is recommended in the form of a combined vaccine against diphtheria, tetanus, and pertussis [19,21]. The U.S. Immunization Advisory Committee (ACIP) recommends vaccinating pregnant women between 27 and 34 weeks of each pregnancy, regardless of previous vaccinations. This is to protect the newborn and infant by increasing the concentration of maternal antibodies (passive immunization). Whooping cough is a highly contagious disease, the most dangerous in the youngest children, mainly in the first 6 months of life. The risk of dying from whooping cough is highest in this age group. Vaccination of a pregnant woman protects the newborn and infant more effectively than the vaccine given to the child [23].

The effectiveness and safety of vaccination of pregnant women against influenza have been confirmed in numerous clinical studies. Thanks to the specific antibodies transmitted by the placenta, vaccination reduces the risk of premature birth, low birth weight of the baby, as well as the baby’s illness in the first 6 months of life, (ie, during the period when he cannot be vaccinated against influenza). Since 2005, the WHO has recommended vaccination of expectant mothers against seasonal influenza as a group at high risk of illness, severe disease, and increased risk of complications and hospitalization. The recommendation to vaccinate pregnant women with influenza has contributed to the acceptance of other vaccines for pregnant women in many countries. Vaccination against influenza should be recommended for pregnant women during the flu season [6,9,10,50].

Vaccinations Against COVID-19, Including Against Omicron Variants of SARS-CoV-2, Pregnant and Breastfeeding Women

The first recommendations for COVID-19 vaccination for pregnant women by the American College of Obstetricians and Gynecologists and the Joint Committee on Vaccination and Immunization emerged in December 2020, shortly after the new vaccine formulations were authorized. These recommendations were based on the vast experience already gained in the use of other “killed” (ie, non-replicable) vaccines, mainly against influenza and pertussis, in pregnant women, as well as the results of preclinical studies carried out in animal models by manufacturers of COVID-19 vaccines [52]. Data suggesting that this vaccination should be contraindicated in pregnant women has not been confirmed. In addition, population surveillance in many countries of the safety of vaccination against COVID-19 in pregnant women has not revealed alarming symptoms regarding the risk of pregnancy complications and the negative impact of vaccination on the health of the fetus and newborn. Due to the much higher amount of evidence on mRNA vaccines in some countries (Great Britain, Canada, and Poland), they are preferred in pregnant women [7–10,53].

In pregnant women, typical (as in the general population) local and systemic adverse reactions can be expected (ie, pain, swelling and redness at the injection site, chills, fever, fatigue, headache, and muscle and joint pain). The risk of myocarditis associated with mRNA vaccination is similar to that observed in the general population (approx. 1/million), as is the possibility of anaphylaxis (2–5/million). This allowed experts to conclude that the benefits of vaccination against COVID-19 in pregnant women at particular risk of the disease outweigh the theoretical risks associated with it. By April 2022, recommendations for vaccination against COVID-19 in pregnant women were issued in 162 countries around the world, including Poland. Preliminary data also suggest that vaccination of the mother during pregnancy also reduces the risk of contracting COVID-19 in the infant during the first 4–6 months of life [9,10].

In more than 3 years of the pandemic, the COVID-19 epidemiological situation has changed significantly. Thanks to widespread vaccination or infection, or both of these factors (so-called hybrid immunity), significant population immunity has been created. It is estimated that about 90% of the world’s population is seropositive. In March 2023, the WHO published new recommendations for the implementation of national COVID-19 vaccination programs in the context of the dominance of the SARS-CoV-2 Omicron variant and its sub-variants and increasing population immunity. They also take into account recommendations for vaccination of pregnant women [8,26].

Currently, most SARS-CoV-2 infections are caused by the Omicron variant and its subvariant (XBB). Omicron’s SARS-CoV-2 virus variants in circulation are: BA.2.86; XBB.1.9.1; XBB.1.9.2; XBB.2.3; XBB.1.16; XBB.1.5; BA.2.74; CHANNEL 1.1. [6,8,52]. The predominant subvariant is XBB.1.5, which is highly infectious, with the infection usually mild. This is due to the high percentage of seropositive people in the population. Less frequently, illnesses requiring hospitalization and fatal outcomes are observed, as well as complications in the form of long-term COVID-19 [8,26,53]. The greatest risk of infection and more severe infection concerns pregnant women aged ≥35 years, with a high BMI, with hypertension or gestational diabetes. The effectiveness of primary vaccination and the first booster dose decreases over time (ie, approximately 11% over 9 months against severe illness). Therefore, the administration of another booster dose increases the effectiveness of vaccination in the case of severe as well as mild COVID-19. Such a management strategy benefits people at risk, including pregnant women, and is cost-effective in countries with high population immunity [54].

Also, Novillo and Martínez-Varea [26] based on a systematic review on COVID-19 vaccines during pregnancy and breastfeeding, which analyzed 1,893 articles, 33 of which met the inclusion criteria for the study, demonstrated the safety of COVID-19 vaccinations during pregnancy and breastfeeding. pregnancy and breastfeeding. Minor side effects were pain at the injection site and fatigue. This indicates the effectiveness of vaccinations, given that they reduce the risk of severe COVID-19 in pregnant women. Moreover, passive immunity, both in terms of cellular and humoral immune response, to the COVID-19 vaccine has been proven. Vaccination is associated with a greater and more stable immunoglobulin G (IgG) response and infection with a rapid and long-lasting immunoglobulin A (IgA) response. Therefore, vaccination against COVID-19 is strongly recommended for pregnant and breastfeeding women to protect mothers and newborns.

The WHO recommends that national vaccination programs consider the concomitant administration of an updated COVID-19 vaccine adapted to circulating virus variants together with the seasonal influenza vaccine. Vaccination against COVID-19 can be done at any time, before or after other vaccines recommended for pregnant women. Coadministration of vaccines is widely recommended and safe, including in pregnant women. According to the WHO, expectant mothers belong to a special group in the classification of people covered by vaccination priority. Effective implementation of vaccination against COVID-19 in privileged populations, including during pregnancy, is crucial to achieving optimal effects of the universal vaccination program [3,6,9].

New vaccines against group B streptococcus and respiratory syncytium virus (RSV) are currently being studied in pregnant women to protect newborns. There is more and more data on the vaccination of pregnant women against pneumococcus, meningococcus, and Haemophilus influenzae type b. When safe and effective new-generation vaccines are available, vaccination of pregnant women can be used in the prevention of various neonatal infections acquired during childbirth (eg, HIV, herpes virus), shortly after birth (eg, viruses causing inflammation of the respiratory tract) and infections with other microorganisms during the first months of life [55,56]. A promising target for maternal vaccination is Streptococcus agalactiae (group B streptococci), the leading cause of invasive diseases in newborns. Protection of newborns occurs through both transplacental antibody transfer and reduced mother-to-child transmission of pathogens [57,58].

The Role of the Doctor, Midwife, and Nurse in the Care of a Pregnant Woman Regarding Immunization

Persons caring for pregnant women (doctors, nurses, midwives) should conduct antenatal education on the prevention of infectious diseases in the perinatal period, including the possibility of preventive vaccination (Table 3) [6,9,10]. According to the applicable rules, the nurse performing the vaccination is obliged to check whether each pregnant woman applying for vaccination has undergone a qualified medical examination, which aims to detect possible contraindications to vaccination. Such examination shall be valid for 24 hours. Vaccination always takes place in treatment rooms and is performed by qualified nurses or midwives. Vaccines are most often administered intramuscularly (most vaccines) or subcutaneously in the deltoid muscle. If several vaccines are planned during one visit, each injection should be given in a different anatomical region [59].

In the new Polish standard of perinatal care [10], developed by the Minister of Health and by the Polish Society of Gynecology, an important element is prenatal education for undertaking pro-health behaviors during pregnancy, childbirth, and postpartum, as well as caring for a newborn and infant. Prevention of infectious diseases, including vaccination, is an integral part of this care. In preparation for pregnancy, it is recommended to supplement vaccination against rubella and hepatitis B. Recommendations for vaccination during pregnancy are in line with the recommendations of the Advisory Committee on Immunization Practices (ACIP), WHO, and public health organizations in Canada, Great Britain, Australia, and other countries [3,6]. Medical workers in Poland (doctors, nurses, and midwives) have a professional and ethical obligation to inform people in the reproductive period and pregnant women about the benefits of vaccination and the need to vaccinate people from the immediate environment of the newborn and infant to strengthen the cocoon strategy.

Future Directions

The field of maternal vaccinations is developing rapidly. In pregnant and breastfeeding women, vaccination achieves double immunization (ie, active artificial immunization for the mother and passive natural immunization for the fetus). There is increasing evidence confirming the safety, immunogenicity, and effectiveness of vaccinations during pregnancy, including against SARS-CoV-2. However, many challenges and key knowledge gaps remain, including the acceptance of an increasing number of vaccines for use in pregnancy, the optimal timing of vaccination, the impact of antigen type on antibody transfer across the placenta, correlations with protection against key pathogens, and the impact on subsequent infant immune responses for vaccination. Despite these challenges, vaccinations during pregnancy play an important role in protecting women’s health or fetuses and infants from infection.

Conclusions

Pregnancy is a stressful situation for the mother’s body. The maternal immune system must achieve immunological tolerance towards the fetus, which results in a reduced response to infections, including COVID-19. The best strategy to fight infections during pregnancy and breastfeeding is immunization through vaccination.

Understanding vaccine safety is critical when making vaccine decisions. Our goal was to present data on the current recommendations for vaccination of people in the reproductive period and pregnant women, including COVID-19 vaccines. Many observational studies confirm the safety of vaccination of adults and during pregnancy against COVID-19, and the benefits of vaccination far outweigh the potential risks associated with it. There is a need to strengthen the role of healthcare providers over people in the reproductive period and during pregnancy vaccinations, which is associated with the need to improve the preparation of medical staff to meet these expectations.

It is important to develop effective strategies for information policy on vaccination based on sound scientific foundations and denying negative media reports. The priority should be to increase knowledge and awareness about the safety and effectiveness of vaccines among pregnant women and their families, which influence individual decisions regarding active immunoprophylaxis of expectant mothers. The ultimate goal should be to ensure sustainable access to existing immunization programs for adults and expectant mothers.