INTRODUCTION

Vaccinations are an essential part of general and pregnancy health. They are the most effective way to prevent common infectious diseases such as influenza.¹ There are over 20 life-threatening diseases that can be prevented by vaccines, and vaccines have become the foundation of global public health.² Worldwide, vaccinations have saved millions of lives, with the measles vaccine preventing 21.1 million deaths between 2000 and 2017.³ Unfortunately, the benefits of vaccination are not evenly shared with all global citizens, with the poorest, most marginalized, and most vulnerable people having limited access to vaccination services. Pregnant persons are uniquely poised to receive vaccinations due to their frequent access and contact with healthcare systems during prenatal care. Thus, pregnancy can be an opportunity to administer vaccines recommended during pregnancy and screen for, offering catch-up vaccines, for all other vaccines recommended for general health, either during pregnancy or postpartum. Vaccination during pregnancy directly reduces severe maternal diseases, indirectly reduces neonatal diseases by immunizing a newborn through passive transfer of protective antibodies across the placenta from mother to baby, and improves public health by increasing vaccination rates within a population.⁴ The World Health Organization (WHO), US Centers for Disease Control (CDC), and American College of Obstetricians & Gynecologists (ACOG) have identified several vaccines that are recommended and safe to receive during pregnancy (Table 1). This chapter presents recommended vaccines starting with routine vaccines recommended for pregnant and non-pregnant individuals, prenatal vaccines recommended during pregnancy, and vaccines recommended in special pregnant populations. For each vaccine, the preventable disease or diseases are briefly reviewed, and the general and obstetric-specific risks discussed. A brief vaccine history and dosing are presented, to assist with screening for unvaccinated, with WHO recommendations for vaccination during pregnancy at the end. The chapter starts by reviewing prepregnancy healthcare recommendations, and ends by reviewing the facilitators and barriers to vaccine-preventable disease elimination.

PREPREGNANCY HEALTH

The general health of a person prior to pregnancy often determines their risk of pregnancy complications such as vaccine-preventable diseases. Optimizing general health prior to conception, prepregnancy health, should be addressed at every healthcare visit during the almost four decades that make up a person’s reproductive years.⁷ The initial reproductive health visit should take place between the ages of 13 and 15 years with the primary goal of providing preventative health services, educational information, and guidance to adolescents, in addition to problem-focused care.⁸ During this visit, providers should counsel and educate adolescents about common topics related to general health and reproduction including vaccination (Table 2), while providing services in a “youth-friendly” manner, meaning they are accessible, equitable, acceptable, appropriate, comprehensive, effective, and efficient for youth as recommended by the WHO.⁹ This visit is intended to establish trust with the individual and their parent or guardian, which can then be maintained throughout an individual’s reproductive years. Healthcare providers should continue to engage individuals during subsequent visits in supportive, respectful conversations about their pregnancy intentions to facilitate further counseling on vaccination, evidence-based prepregnancy interventions, and improving general health, such as diet, exercise, and safe-sex practices.

Addressing prepregnancy vaccination status directly decreases the risk of vaccine-preventable diseases and should occur during each visit when reviewing a patient’s past medical history. Review of recommended vaccines, such as measles, mumps, rubella, varicella, hepatitis B, human papilloma virus (HPV), should be performed with verification of administered vaccines through national, state, or local health departments. In addition, screening can be offered by laboratory testing for antibody titers.¹¹ If missing or incomplete recommended vaccinations are identified, catch-up vaccination should be offered per recommended schedules.

ROUTINE VACCINES

Measles, mumps, rubella vaccine

Measles, mumps, and rubella are acute viral diseases that result in serious illness and complications in pregnancy and can be prevented with vaccination. The most common vaccine to prevent measles, mumps, and rubella is the combination live attenuated measles, mumps, rubella (MMR) vaccine. There are additional combination live-attenuated vaccines available, such as the measles and rubella (MR) vaccine, the measles, mumps, rubella, and varicella (MMRV) vaccine, as well as a monovalent live-attenuated measles, mumps, and rubella vaccines.

Measles is a highly contagious disease transmitted by direct contact with respiratory droplets or airborne spread.¹² Measles symptoms usually start with cough, fever, malaise, conjunctivitis, coryza, and bluish-white Koplik’s spots seen in the oral mucosa. These prodromal symptoms are followed by the characteristic morbilliform rash starting 2–4 days after onset of fever and lasting about 3–5 days with full recovery in 7 days from rash onset in uncomplicated cases.¹³ Death due to measles is rare with the greatest risk of death in children less than 1 year of age, adults older than 20 years of age, pregnant people, undernourished children (vitamin A deficiency), and persons with immune suppression (e.g., HIV infection, cancer). Measles infection during pregnancy is associated with an increased risk of spontaneous abortion, preterm birth, neonatal low birth weight, and maternal death from complications such as pneumonia, encephalitis, and intracranial hemorrhage.^14,15 The increased risk of spontaneous abortion, preterm birth, and low birth weight is suspected to result from placental infection with virus and resulting maternal–fetal rejection, although further investigations are needed in this subject.¹⁵ No fetal malformations have been associated with measles infection during pregnancy.¹⁵ Maternal infection shortly before or after delivery is also associated with increased risk of infant subacute sclerosing panencephalitis (SSPE), a degenerative disease of the central nervous system resulting in irreversible intellectual decline, behavioral changes, seizures, and neonatal death.¹⁶ Post-exposure prophylaxis with human immune globulin should be offered within 6 days of exposure to measles infection to prevent illness or reduce severity in unvaccinated or immunocompromised pregnant persons.¹² In addition, household members and other close contacts of the pregnant person should be offered vaccination with the MMR vaccine as soon as possible if unvaccinated. HIV-infected persons are at increased risk for severe complications if infected with measles and should be offered vaccination. Several studies have shown no serious adverse effects following MMR vaccine administration in persons with HIV infection without evidence of severe immunosuppression or on antiretroviral therapy (ART).¹² However, the MMR vaccine is not recommended for persons with HIV infection who have evidence of severe immunosuppression (CD4+ T-lymphocytes <15% at any age or CD4 count <200 lymphocytes/mm³ at >5 years of age) and MMRV vaccine is not approved for use in persons with HIV infection. The first measles vaccine was licensed in 1963 and estimated worldwide measles vaccine coverage in 2015 was 85% for the first dose 61% for the second dose.¹⁷ Measles is one of the most contagious diseases of humans and the herd protection threshold for measles is the highest of all vaccine-preventable diseases, ranging from 89 to 94%.¹⁸

Mumps is an acute, mild, and self-limited viral infection characterized by fever and inflammation of the salivary gland (parotitis).¹² In the vaccine era, mumps has a low risk of serious complications in non-pregnant people, such as orchitis, oophoritis, mastitis, permanent hearing loss, and aseptic meningitis. Mumps infection during the first 12 weeks of pregnancy is associated with a 25% incidence of spontaneous abortion or intrauterine fetal death.¹⁹ The mechanism for this clinical outcome is not known. No fetal malformations have been associated with mumps infection during pregnancy.¹⁹ The first mumps vaccine was a killed mumps virus vaccine first licensed in 1948 and used between 1950 and 1978.¹⁹ This vaccine induced only short-term immunity with low protective efficacy. Live-attenuated mumps vaccines were first licensed in 1967 and have high seroconversion and/or short-term protective efficacy rates following administration of one dose of the vaccine. Since 2005, two-dose schedules for mumps vaccination were implemented in >80% of countries that included mumps vaccine in their national immunization programs.

Rubella infection is transmitted by direct or droplet contact from nasopharyngeal secretions and is characterized by mild symptoms of rash, low-grade fever, lymphadenopathy, and malaise.¹² Rubella infection during pregnancy, especially during the first trimester, can result in spontaneous abortion, stillbirth, and congenital rubella syndrome (CRS). Rubella is the most common infectious cause of birth defects worldwide accounting for an estimated 100,000 infants born with CRS annually.²⁰ CRS is a constellation of birth defects including ophthalmic (cataracts, microphthalmia, glaucoma, pigmentary retinopathy, chorioretinitis), auditory (sensorineural deafness), cardiac (peripheral pulmonary artery stenosis, patent ductus arteriosus, or ventricular septal defects), and craniofacial (microcephaly) anomalies. It can also present with meningoencephalitis, hepatosplenomegaly, hepatitis, thrombocytopenia, interstitial pneumonitis, and radiolucency in the long bones, a characteristic radiological finding in CRS. The first live, attenuated rubella vaccine was licensed in 1969.¹² Rubella vaccines are highly effective with a single dose conferring life-long protection in ≥95% of vaccinated persons.²⁰ The Rubella vaccine is usually administered in combination with measles as the MR, MMR, or MMRV vaccines. In cases where the single-component rubella vaccine is being administered, blood products should be avoided at least 3 months before vaccination and up to 2 weeks after vaccination. There are no reported cases of CRS associated with inadvertent rubella vaccination during pregnancy.^12,21

The WHO and US CDC recommend the use of a two-dose schedule of MMR to prevent measles, mumps, and rubella infection, prioritizing prevention of measles and congenital rubella.¹⁹ Administration of a third dose of MMR vaccine during outbreaks has been shown to be safe with few adverse events reported.¹² Persons planning pregnancy should have measles, mumps, and rubella vaccination confirmed. If confirmation is not possible, screening with laboratory testing for measles, mumps, and/or rubella IgG should be offered. If IgG titers are equivocal or low, vaccination should be offered immediately if they are not pregnant or postpartum if they are pregnant. If vaccination is performed, the person should avoid becoming pregnant for 28 days due to this theoretical risk to the fetus. However, no significant adverse effects have been reported following inadvertent vaccination of pregnant women with measles, mumps, or rubella live-attenuated vaccines.^19,21,22 Although administration of these live, attenuated vaccines is contraindicated during pregnancy, vaccine administration is not considered an indication for pregnancy termination.

Varicella vaccine

Varicella-zoster virus (VZV) is a highly contagious virus causing both varicella (chickenpox), during childhood, and herpes zoster (shingles), later in adult life.²³ VZV is transmitted by direct contact with varicella or herpes zoster rash and by inhalation of aerosolized droplets from respiratory secretions or rarely, from vesicular fluid. After primary infection VZV remains dormant in the sensory nerve ganglia and can reactivate later in life to cause herpes zoster. Varicella is generally a benign, self-limiting disease but can be more severe in adults. Pregnant people are at increased risk for severe complications, such as pneumonia, because of the effect of the gravid uterus on respiratory function.^23,24 Varicella in pregnant women is also associated with risk of VZV transmission to the fetus or newborn, resulting in congenital varicella syndrome, neonatal varicella, or herpes zoster during infancy.²⁵ Intrauterine VZV infection between 13 to 28 weeks' gestation increases the risk of congenital varicella syndrome, characterized by low birth weight, cutaneous scarring, limb hypoplasia, microcephaly, cortical atrophy, chorioretinitis, cataracts, and other anomalies. Maternal varicella 5 days before to 2 days after delivery results in severe neonatal varicella disease with a risk of neonatal death of 21% due to lack of sufficient maternal antibodies to lessen the severity of disease.²⁶ Varicella-zoster immune globulin (VZIG) is indicated in these situations to reduce the incidence of severe neonatal varicella disease.²⁴ Pregnant persons should be screened for VZV immunization or natural infection prior to pregnancy since VZV vaccination is contraindicated during pregnancy. If unvaccinated or VZV IgG not detected at first prenatal visit, VZV vaccination should be offered immediately postpartum. VZV vaccines are administered as a single dose of either live-attenuated monovalent vaccine, first licensed in 1995, or live-attenuated combination vaccine with measles, mumps, and rubella (MMRV), first licensed in 2005.

Hepatitis B virus vaccine

Hepatitis B virus (HBV) is highly infectious and can be transmitted through percutaneous or mucosal exposure to infectious blood or body fluids.²⁷ Infection with HBV results in acute hepatitis that can progress to chronic infection, cirrhosis, and can progress to hepatocellular carcinoma, the most common type of primary liver cancer.²⁸ Groups at increased risk of HBV infection include healthcare workers, others with occupational exposure to blood and body fluids or blood-contaminated environments, diabetic patients, patients with chronic renal failure on dialysis, patients with chronic liver disease, transplant recipients, patients frequently receiving blood or blood products, HIV-infected individuals, hepatitis C virus (HCV)-infected individuals, immunocompromised individuals, travelers, prisoners, injecting drug users, sex workers, and those living with HBV-infected persons. When a person planning pregnancy or currently pregnant is identified as being in a high-risk group, their HBV vaccine status should be confirmed, and if unvaccinated or incompletely vaccinated, catch-up vaccination offered.¹¹ Screening at prepregnancy or initial prenatal visit with laboratory tests for HBV infection with HBV surface antigen (HBsAg) and, if HBV vaccine status is unclear, testing for immunization with anti-hepatitis B surface antibody (anti-HBc), presents an opportunity to offer catch-up vaccination to persons planning pregnancy or pregnant persons. In areas where HBV is highly endemic, it is frequently transmitted perinatally from HBV-infected pregnant women to their newborns, with the majority of cases occurring during delivery.¹¹ Infants born to persons testing positive for HBsAg are treated with postexposure prophylaxis, HBV vaccine and hepatitis B immune globulin. HBV vaccines were first licensed in 1982 and the current recombinant HBV vaccines were first available in 1986.²⁸ HBV vaccines are administered in three doses either as a monovalent vaccine or combination vaccines with diphtheria-tetanus-pertussis (DTP), Haemophiles influenzae type b (Hib), inactivated polio vaccine (IPV), and hepatitis A virus (HAV). HBV vaccination with monovalent or combination vaccines is safe to administer to pregnant or lactating persons.²⁸

Human papilloma virus vaccine

Human papillomaviruses (HPV) are the most common viral infection of the reproductive tract and cause precancerous lesions in both male and female persons.²⁹ These precancerous lesions can progress to cervical, anogenital, and oropharyngeal cancers. HPV-related cancers are a significant burden on global health and resulted in 8% of all female cancer deaths in 2012.³⁰ The majority of this burden occurs in less-developed regions, where cervical cancer accounts for almost 12% of all cancers in women.²⁹ In addition, there is emerging evidence suggesting HPV infection during pregnancy is associated with preterm birth, preterm prelabor rupture of membranes, and adverse pregnancy outcomes.^31,32 Risk factors for HPV infection include multiple lifetime partners, a new partner, or non-monogamous partners.³³ HPV vaccines were first licensed in 2006 and are administered on two- or three-dose schedules depending on the age of vaccine administration, with most vaccination programs targeting vaccination before the onset of sexual activity in male and female children.²⁹ Vaccination during pregnancy is not currently recommended, however inadvertent vaccination during pregnancy has consistently been shown to be safe.²⁹ In some countries, catch-up vaccination is recommended, which can be offered prior to pregnancy or immediately postpartum, with no contraindication to HPV vaccination while breastfeeding.³⁴ Further studies are needed to establish the safety of HPV vaccination during pregnancy and to further determine long-term effectiveness.

COVID-19 vaccine

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in China in December 2019 before rapidly spreading throughout the world, resulting in a global pandemic. COVID-19 during pregnancy has an increased risk of serious illness with hospital admission, need for oxygen therapy, need for endotracheal intubation, ICU admission, and death.³⁵ Increased risk of disease severity during pregnancy may be due to mechanical change, such as decreased lung volume as the fetus grows, immunologic changes, and an increased risk of thromboembolic disease.³⁶ Risk factors for more severe COVID-19 in pregnancy are older maternal age, higher body mass index, preexisting comorbidities such as asthma, chronic obstructive pulmonary disease, chronic hypertension, or pregestational diabetes mellitus.³⁷ There are multiple mRNA and adenoviral vector vaccines available for COVID-19, with prenatal vaccination recommendations preferentially favoring the mRNA vaccines, which have more safety data in pregnancy, over the adenoviral vector vaccines.³⁷ Vaccination may occur in any trimester and should be administered as soon as possible to maximize maternal and fetal health. Vaccination is especially important in countries with high transmission or for individuals who have an occupation where they are at increased risk of being exposed to COVID-19. COVID-19 vaccination is also safe for postpartum and breastfeeding individuals who were not previously vaccinated. Continued vaccination efforts and studies on the safety of COVID-19 vaccination in pregnancy are important because COVID-19 is likely to become endemic.³⁸

PRENATAL VACCINES

The first prenatal care visit is a critical time for the healthcare provider to counsel the pregnant person on routine vaccinations administered during pregnancy and assess their risk of vaccine-preventable diseases. The influenza and Tdap (tetanus toxoid, reduced diphtheria toxoid, acellular pertussis) vaccines are routinely recommended during pregnancy, regardless of previous immunization history. In addition, if during routine prenatal care new risk factors are identified for hepatitis A, meningococcus, or pneumococcus infection during pregnancy, the pregnant person should be counseled and offered these recommended vaccines.

Influenza vaccine

Influenza viruses typically circulate in a seasonal pattern with most persons who are infected recovering without serious complications.³⁹ Pregnant persons are at increased risk of severe infection requiring hospitalization and adverse pregnancy outcomes such as stillbirth if they are infected with influenza.¹ This risk of severe infection is increased by the presence of comorbidities, such as asthma, HIV infection, diabetes mellitus, and increased body mass index greater than 30 kg/m².³⁹ The influenza vaccine is routinely recommended as soon as it is available to pregnant persons at any gestational age during each pregnancy or prior to conception if pregnancy is planned during influenza season. It is effective at preventing influenza infection in pregnant persons, and their newborns via passive transfer of maternal antibodies across the placenta.⁴⁰ There are two types of seasonal influenza vaccines available – inactivated and live attenuated. The inactivated influenza vaccine is safe and recommended for administration during pregnancy while the live-attenuated influenza vaccine should be avoided during pregnancy. If the live-attenuated influenza vaccine is administered prepregnancy, pregnancy should not be attempted for 1 month, as with other live-attenuated vaccines.

Tetanus-diphtheria-pertussis vaccine

Neonatal pertussis and tetanus are prevented by maternal vaccination with the combination Tdap vaccine. Pertussis or whooping cough, is an important cause of morbidity and mortality in infants worldwide, and prior to the availability of vaccines, was one of the most common childhood diseases.⁴¹ Neonatal tetanus occurs primarily in low-income countries following unhygienic deliveries with poor postnatal and cord-care practices, such as using non-sterile instruments to cut the umbilical cord or cover the umbilical stump.⁴² The Tdap vaccine is routinely recommended during each pregnancy because of the protection it offers the newborn against pertussis and tetanus. Vaccination against diphtheria is not necessary to protect infants against diphtheria.⁴³ Tdap vaccination results in maternal production of pertussis- and tetanus-specific IgG antibodies that are transferred across the placenta to the fetus resulting in passive immunization that lasts.⁴² This transplacental transfer of maternal IgG in both pertussis and tetanus vaccination is highly efficient. However, reduced transplacental transfer has been reported in short interval (<14 days) between administration and delivery, prematurity, maternal HIV infection, hypergammaglobulinemia, and chronic placental malaria infection.

VACCINES IN SPECIAL PREGNANT POPULATIONS

Screening for population-specific risk factors for infectious diseases such as hepatitis A, meningococcus, and pneumococcus should also be performed and corresponding vaccines administered, if not previously vaccinated.

Hepatitis A virus vaccine

Hepatitis A virus (HAV) vaccination should be offered to individuals who have not been previously vaccinated for HAV and are at increased risk of infection or severe disease. Israel was the first country to start universal childhood vaccination programs for HAV with the United States and Argentina following shortly after.⁴⁴ Since then, Panama, Uruguay, Greece, Kingdom of Saudi Arabia, China, and Brazil have introduced universal vaccination programs starting at 12 to 24 months with catch-up vaccination programs for children and adolescents aged 2 to 18 years who were not previously vaccinated. Unvaccinated individuals who are at increased risk of infection with HAV such as those traveling to a country where HAV is common, using or injecting illicit drugs, with occupational risks of exposure, who anticipate close personal contact with international adoptees, and experiencing homelessness should be offered vaccination.⁴⁵ In addition, individuals with increased risk of severe disease, such as those with chronic liver disease, including HBV and HCV, and those with HIV should be vaccinated for hepatitis A.⁴⁵ The inactivated HAV vaccine is administered as a standard two-dose vaccine or as a single dose.⁴⁶ There are several different manufactured versions of the inactivated HAV vaccine, which are interchangeable and safe to administer during pregnancy. There is also a live-attenuated vaccine available in a few countries, which should not be administered during pregnancy.

Meningococcus vaccine

Meningococcus vaccination should be offered to individuals who have not been previously vaccinated for meningococcus and are at increased risk of infection, and to all individuals who live in or are traveling to the 26 African countries known as the African meningitis belt.⁴⁷ Individuals at increased risk of meningococcus infection who should be offered vaccination are those with persistent complement component deficiencies, persons using complement inhibitors, persons with anatomic or functional asplenia, persons living with HIV infection, microbiologists routinely exposed to N. meningitidis isolates, persons at increased risk during an outbreak of meningococcal disease, travelers to countries where meningococcal disease is hyperendemic or epidemic, college students, and military recruits.⁴⁸ There are several polysaccharide-peptide conjugate vaccines to the serotypes A, C, W, and Y, and several protein-based vaccines directed at serogroup B, all of which are safe to administer during pregnancy.⁴⁸

Pneumococcus vaccine

Pneumococcus vaccination should be offered to individuals who are at increased risk of infection because of the risk of serious respiratory infection and meningitis. Pneumococcal vaccination should be offered to persons with a history of alcoholism, chronic heart, liver, or lung disease, cigarette smoking, diabetes mellitus, cochlear implants, cerebrospinal fluid leak, congenital or acquired asplenia, sickle cell disease or other hemoglobinopathies, chronic renal failure, nephrotic syndrome, congenital or acquired immunodeficiencies, HIV, iatrogenic immunosuppression, generalized malignancy, and solid organ transplant.⁴⁹ There are two types of pneumococcal vaccines, conjugate and polysaccharide vaccines that are both safe to administer during pregnancy but differ in dosing.

Other vaccine-preventable diseases

The WHO has published vaccine position papers on several additional vaccine-preventable diseases and included specific recommendations regarding pregnancy and lactation. These recommendations are summarized in Table 3 with references to the WHO vaccine position papers listed in the references. Most of these vaccines are recommended during disease outbreaks, in disease endemic regions, or for individuals at increased risk of disease exposure.

SUMMARY

Vaccine-preventable diseases have serious consequences for both mother and fetus during pregnancy regardless of where the pregnant person is in the world. Several facilitators and barriers to vaccine uptake have been identified in the literature. Major facilitators of vaccine uptake during pregnancy were provider recommendation and motivation to protect infant.⁵⁸ Barriers to vaccine uptake during pregnancy were lack of provider recommendation, concerns about vaccine safety, lack of access to prenatal care, and disparities among minority groups and marginalized populations.⁵⁸ Unfortunately, there are a limited number of studies from low- and middle-income countries investigating barriers to vaccine uptake. Key factors enabling success in maternal vaccination and prevention of vaccine-preventable diseases are improving the immunization journey for pregnant persons by providing clear and timely information on vaccinations, removing barriers to vaccine access, ensuring adequate supply of vaccines with human resources and infrastructure for distribution, making the health service experience positive, and establishing integrated information systems that allow the monitoring of progress towards vaccination goals.⁵⁹ In high-income countries, emerging barriers to vaccine-preventable disease elimination are vaccine rejection and the antivax movement, amplified by social media, spreading myths and misconceptions.^13,37 Provider recommendation has consistently been one of the most important facilitators of vaccine uptake globally and listening and responding to patient concerns regarding vaccines with empathy is recommended to improve vaccine uptake, specifically when facing this barrier.³⁷

In summary, there are several factors to consider when offering vaccines to pregnant persons or persons planning pregnancy. Live virus vaccines pose a theoretical risk for the fetus and individuals receiving these vaccines should be counseled to wait at least 1 month after vaccination before attempting pregnancy. Administering catch-up vaccines in persons planning pregnancy usually requires extensive counseling on the benefits of the specific vaccine in preventing disease. Vaccine administration during the same visit as counseling facilitates informed and shared decision making between the patient and provider. These topics should be revisited at each visit, annually and with initiation of prenatal care, when reviewing the persons medical history, reviewing risk factors for vaccine-preventable diseases. Vaccination status should be verified, and where deficiencies in vaccination are identified, catch-up vaccines should be offered in order to progress towards elimination of vaccine-preventable diseases.

PRACTICE RECOMMENDATIONS