Safety of Vaccination During Pregnancy | Article

This chapter should be cited as follows:
Fell DB, Håberg SE, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.418023

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 17

Maternal immunization

Volume Editors: Professor Asma Khalil, The Royal College of Obstetricians and Gynaecologists, London, UK; Fetal Medicine Unit, Department of Obstetrics and Gynaecology, St George’s University Hospitals NHS Foundation Trust, London, UK
Professor Flor M Munoz, Baylor College of Medicine, TX, USA
Professor Ajoke Sobanjo-ter Meulen, University of Washington, Seattle, WA, USA

Chapter

Safety of Vaccination During Pregnancy

First published: May 2023

AUTHORS

Deshayne B Fell, PhD

Associate Professor, School of Epidemiology and Public Health, University of Ottawa, Scientist, Children’s Hospital of Eastern Ontario (CHEO) Research Institute, Adjunct Scientist, ICES, Ottawa, Ontario, Canada

Siri E Håberg, MD, PhD

Director, Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway

Annette K Regan, PhD

Assistant Professor, School of Nursing and Health Professions, University of San Francisco, San Francisco, California, USA

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INTRODUCTION

Assessment of vaccine safety during pregnancy involves several unique considerations, notably, the need to evaluate safety for the vaccine recipient (mother) and also for the fetus/infant,¹ and to assess numerous pregnancy-specific outcomes. Although vaccination during pregnancy is not new, much of the research on safety emerged after the global 2009 A/H1N1 influenza pandemic, when immunization campaigns in many countries prioritized pregnant women.²

Since the 2009 A/H1N1 influenza pandemic, the evidence base on the safety of vaccination during pregnancy has evolved further with randomized clinical trials (RCTs)³ and observational studies of seasonal influenza immunization, observational studies of acellular-pertussis-containing vaccines, and most recently, observational studies of COVID-19 vaccination. While these vaccines are now commonly administered during pregnancy, each was initially licensed based on efficacy and safety studies in non-pregnant populations.⁴ It follows, therefore, that most assessments of vaccine safety during pregnancy have been post-licensure studies. Several new vaccine candidates, intended specifically for use during pregnancy, are at varying stages of clinical development; inclusion of pregnant women in the early stages of their creation marks the start of a new and evolving chapter in evaluation of vaccine safety during pregnancy.

EVALUATION OF VACCINE SAFETY IN PREGNANCY

Approaches for monitoring vaccine safety

Prior to product licensure, vaccines are evaluated for their safety in RCTs. While RCTs are considered the “gold standard” study design for assessing efficacy and safety of interventions and have been instrumental in developing new maternal vaccines, RCTs of vaccines intended for use in the general adult population usually exclude special populations, such as pregnant individuals, necessitating the use of alternate approaches to post-licensure.¹ Comprehensive post-licensure vaccine safety assessment involves complementary systems using different approaches and types of data, each with their own strengths and weaknesses.⁵^,⁶ Typically, this includes both passive (spontaneous reporting; for example, Vaccine Adverse Event Reporting System [VAERS])⁷ and active (prospective monitoring; for example, Canadian Immunization Monitoring Program ACTive [IMPACT])⁸ systems, which are important for rapid “signal detection.”⁶^,⁷^,⁹ Industry-led prospective pregnancy exposure registries may also be established.¹⁰ Comparative epidemiologic studies using linked databases capturing whole populations, or subsets of populations (such as those with medical insurance), can be used to follow-up on signals detected by passive/active approaches,⁷ as well as assess safety of rare and longer-term outcomes.¹^,⁵ The expanding availability of routinely collected electronic medical records and healthcare databases since the early 1990s¹ has made it possible to conduct observational epidemiologic studies of maternal, fetal, and infant outcomes following vaccination during pregnancy in populations from many countries around the world.

Outcomes

In all populations, pre-licensure vaccine RCTs and post-licensure vaccine safety surveillance systems monitor general adverse events following immunization (e.g., local and systemic reactions, serious adverse events). However, when vaccines are administered during pregnancy, additional pregnancy and birth outcomes must also be evaluated. The Brighton Collaboration’s Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) initiative has undertaken extensive work to identify core recommended outcomes, with corresponding detailed case definitions, to standardize outcome assessment in vaccine RCTs that include pregnant women (Table 1).¹¹^,¹²

Many of the currently recommended GAIA outcomes are among those most commonly evaluated in observational epidemiological studies (Table 1). A small, but increasing, number of observational studies has assessed longer-term health outcomes in offspring exposed to influenza and pertussis vaccination during pregnancy.¹³^,¹⁴ Outcomes assessed have included immune-mediated conditions (e.g., infectious, atopic, autoimmune), neurodevelopmental conditions (e.g., epilepsy, autism spectrum disorders), and all cause morbidity and mortality (Table 1), ascertained for up to 5–6 years of age in the children. While the studies to date have not identified any long-term offspring health concerns following vaccination during pregnancy, the number of studies remains low¹³^,¹⁴ and standardization of outcomes and case definitions would enhance the ability to further assess maternal immunization safety.¹⁵

Outcomes recommended and assessed in pregnancy vaccine safety studies.

Recommended outcomes: Brighton Collaboration Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA)¹¹
Hypertensive disorders of pregnancy¹⁶ Non-reassuring fetal status¹⁷ Postpartum hemorrhage¹⁸ Preterm birth¹⁹ Maternal death²⁰ Congenital anomalies²¹ Stillbirth²² Neonatal infections²³ Neonatal death²⁴ Antenatal bleeding²⁵	Congenital microcephaly²⁶ Dysfunctional labor²⁷ Failure to thrive²⁸ Fetal growth restriction²⁹ Gestational diabetes mellitus³⁰ Low birth weight³¹ Neonatal encephalopathy³² Neonatal respiratory distress³³ Small for gestational age³⁴ Spontaneous abortion and ectopic pregnancy³⁵
Pregnancy and birth outcomes assessed in existing studies^a³⁶
Spontaneous abortion Stillbirth Chorioamnionitis Congenital anomalies Microcephaly Neonatal death	Neonatal infection Preterm birth Low birth weight Maternal death Small for gestational age
Longer-term offspring outcomes assessed in existing studies³⁷^,³⁸^,³⁹
Infections (common cold, pharyngitis, otitis media, influenza, pneumonia, fever, gastrointestinal infection) Mortality (1 year and 5 year) Infection-related primary care contact Hospitalizations and emergency department visits Autoimmune diseases	Neurological diseases Behavioral disorders (autism spectrum disorder, attention deficit hyperactivity disorder) Atopic diseases Neoplasms Sensory disorders Complex chronic conditions Infant growth up to 6 months

^a Not an exhaustive list, but those most commonly summarized in systematic reviews.

VACCINES CURRENTLY RECOMMENDED IN PREGNANCY

Influenza vaccines

Pregnancy is a well-established risk factor for severe influenza⁴⁰ and influenza during pregnancy is associated with adverse pregnancy outcomes.⁴¹^,⁴² Influenza vaccination is, therefore, recommended during pregnancy to prevent complications from infection among mothers and their infants.⁴³^,⁴⁴ Inactivated influenza vaccine is the most widely used vaccine during pregnancy globally.⁴⁵ Many countries recommend inactivated influenza vaccine during any stage of pregnancy, with some restricting recommendations to the second or third trimester or to women with special-risk medical conditions.⁴⁶^,⁴⁷^,⁴⁸ Live attenuated influenza vaccines are contraindicated in pregnancy.⁴⁹

Local and systemic reactions

The safety of influenza vaccination during pregnancy has been documented since the 1960s. The first evidence supporting the safety of inactivated influenza vaccination was published in the 1960s and 1970s and indicated no severe reactions and no differences in outcomes between vaccinated and unvaccinated pregnancies.⁵⁰^,⁵¹ In the early 2000s, retrospective cohort studies and analysis of passive surveillance data also reported no serious adverse events following inactivated influenza vaccination during pregnancy.⁵²^,⁵³ The landmark Mother’s Gift RCT from Bangladesh was published in 2008 – 340 women were randomized to receive either seasonal inactivated influenza vaccine or 23-valent pneumococcal polysaccharide vaccine during their third trimester.⁵⁴ This trial documented minor local and systemic adverse events during the 7 days post-immunization, but no increased risk of small-for-gestational age (SGA) birth or low birth weight.⁵⁵

Pregnancy and birth outcomes

The 2009 influenza A/H1N1 pandemic triggered one of the world’s largest mass immunization campaigns. Monovalent adjuvanted and unadjuvanted pandemic vaccines were rapidly developed and disseminated.⁵⁶ Clinical evidence identified pregnant women as being at higher risk of severe infection,⁵⁷ and they were prioritized for immunization in many countries.² Rates of immunization during pregnancy increased dramatically, as did research supporting the safety of maternal immunization. Observational evidence from mass immunization campaigns showed no severe adverse events among pregnant women and no increase in the risk of gestational diabetes, pre-eclampsia, stillbirth, preterm birth, SGA birth, low birth weight, neonatal death, or congenital malformations.⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴ Clinical trials of pandemic H1N1 vaccine administered during pregnancy found no increase in serious adverse events for mothers or newborns.⁶⁵^,⁶⁶^,⁶⁷ A systematic review of pandemic vaccines administered during pregnancy indicated that adjuvanted vaccines had more local, but not more serious, adverse events than unadjuvanted vaccines.⁵⁶

After the 2009 influenza A/H1N1 pandemic, RCTs and observational studies continued to investigate the effects of seasonal inactivated influenza vaccines on perinatal health, largely because of the increasing demand, acceptance, and uptake of influenza vaccination during pregnancy.⁶⁸^,⁶⁹ Phase 4 RCTs in Mali, Nepal, and South Africa conducted between 2011 and 2013 showed that while immunized pregnant women reported common side effects (injection site reactions, fatigue, headache, malaise, nausea, myalgia, joint pain, rigors),³⁹^,⁷⁰ seasonal inactivated influenza vaccination was not associated with severe maternal or neonatal health outcomes.³⁹ Data from these RCTs showed no association with increased risk of fetal death, preterm birth, low birth weight, or SGA birth.³⁹^,⁴⁶^,⁵⁵^,⁷¹^,⁷²

Active and passive vaccine safety surveillance of recently immunized pregnant women also confirmed the safety of inactivated influenza vaccine during pregnancy,⁷³^,⁷⁴^,⁷⁵ documenting similar rates of adverse events after immunization among non-pregnant women.⁷³ Severe reactions were uncommon among pregnant women;⁷⁰^,⁷⁶ fewer than 1% reported seeking medical care to treat an adverse event,⁷⁴^,⁷⁵^,⁷⁷ similar to the prevalence in the general population.⁷⁸^,⁷⁹ Although incidental exposure to live attenuated influenza vaccines is uncommon (<0.1% of pregnancies),⁸⁰ several registry-based studies documented no maternal or fetal harm.⁸⁰^,⁸¹

Retrospective observational cohort studies have played a major role in the assessment of the safety of inactivated influenza vaccination. The most commonly examined fetal outcomes have been stillbirth, preterm birth, SGA birth, and low birth weight, with studies indicating no increase in risk.³⁶^,⁸²^,⁸³^,⁸⁴ Fewer analyses have evaluated spontaneous abortion, congenital anomalies, and neonatal death, but again, existing evidence supports no harmful association with inactivated influenza vaccination.³⁶^,⁸⁵ Observational studies that examined the risk of congenital malformations after first-trimester immunization with inactivated influenza vaccines consistently documented no increased risk for adjuvanted or unadjuvanted vaccines.⁸⁶ Findings on the risk of spontaneous abortion have been inconsistent. Four analyses suggested no association;⁶²^,⁸⁷^,⁸⁸^,⁸⁹ two, a protective association;⁶⁰^,⁹⁰ and one, a harmful association.⁹¹ Given methodological shortcomings of observational studies and limited data from RCTs, safety assessment of early pregnancy exposure to inactivated influenza vaccines is an area of ongoing research.⁸⁵ Another evolving area is the evaluation of potential non-specific effects of maternal vaccination – a systematic review and meta-analysis of four RCTs of influenza vaccination during pregnancy evaluated this research question. Results showed that although influenza immunization during the second or third trimester of pregnancy reduced influenza infection, immunized women and their infants were more likely to be diagnosed with non-influenza infections.⁹²

Longer-term offspring outcomes

More recently, researchers have used these cohorts and other large administrative databases for longitudinal follow-up of offspring exposed to influenza vaccines in utero. Analyses of the Phase 4 RCTs from Nepal, Mali, and South Africa were updated to include measures of infant growth at 6 months.³⁹ Pooled analysis of these trials showed no association between maternal influenza vaccination and infant growth.³⁹ Pooled analysis of two placebo-controlled clinical trials showed that maternal influenza immunization was not associated with differences in infant all-cause mortality.⁹³ Observational cohort data from the Vaccine Safety Datalink revealed no association with infant hospitalization or mortality.⁹⁴

Relatively few studies have evaluated offspring outcomes after 12 months. Nonetheless, studies of the incidence of influenza and other childhood infections, primary care utilization, hospital admission, autoimmune diseases, atopic conditions, neurologic diseases, neoplasms, behavioral, neurodevelopmental and sensory disorders, and mortality through 5 years of age showed no evidence of increased risks associated with maternal influenza vaccination with either monovalent pandemic 2009 A/H1N1 vaccines or seasonal influenza vaccines.³⁷^,⁹⁵

Tetanus toxoid vaccines

Maternal and neonatal tetanus predominantly affects the least developed low-income countries. These countries have used tetanus toxoid vaccine during pregnancy since the 1960s,⁹⁶ and since the mid-1990s, it has been a key component of the global tetanus elimination campaign.⁹⁷^,⁹⁸

Despite a limited number of epidemiological studies, single antigen tetanus toxoid vaccination during pregnancy is considered safe – mild local reactions such as erythema and injection site pain are common, but severe adverse events are rare.⁹⁷^,⁹⁹^,¹⁰⁰ Most safety evidence originates from studies of tetanus toxoid in combination with diphtheria toxoid and pertussis antigens (discussed in the subsequent section). Studies of single antigen tetanus toxoid vaccination include a non-randomized experimental study conducted in New Guinea in the 1960s, which reported no severe adverse events or adverse birth outcomes after up to three doses during pregnancy, compared with no vaccination.⁹⁶ A hospital-based case-control study of 34,293 cases and 34,477 controls across nine South American countries found tetanus toxoid vaccination in early pregnancy was not associated with congenital malformations.¹⁰¹ Another hospital-based case-control study in Hungary from 1980–1994 compared 21,563 case infants with a congenital anomaly and 35,727 control infants and found no association with tetanus toxoid vaccination in the first three months of pregnancy.¹⁰² A 1995 case-control study in a government maternity hospital in Manila, Philippines evaluated risk of spontaneous abortion before 20 weeks’ gestation.¹⁰³ Cases (n = 100) were women who had a spontaneous abortion and controls (n = 318) were the next three women admitted to hospital immediately after each case with a full-term live birth. No association was observed between spontaneous abortion and receipt of tetanus toxoid vaccine from before pregnancy up to 19 weeks’ gestation. No association was found for those receiving their first dose in early pregnancy, and no difference was related to the number of doses received before or during early pregnancy.¹⁰³

Pertussis-containing vaccines

In 2011 and 2012, the United States and the United Kingdom, respectively, adopted recommendations that pregnant women be immunized with acellular pertussis-containing vaccines (tetanus-diphtheria-acellular pertussis [Tdap] or diphtheria-tetanus-acellular pertussis [dTpa]) to protect newborns.¹⁰⁴^,¹⁰⁵ Similar recommendations have since been implemented in other high- and middle-income countries.⁴^,¹⁰⁶ Several systematic reviews of research published since 2012 reported no association between immunization with pertussis-containing vaccines during pregnancy and serious adverse events in the mother or adverse pregnancy, fetal, or neonatal outcomes in the perinatal period.¹⁰⁷^,¹⁰⁸^,¹⁰⁹^,¹¹⁰^,¹¹¹

Local and systemic reactions

Studies of local and systemic reactions after Tdap immunization during pregnancy have found that the vaccine is generally well tolerated. A prospective observational study in New Zealand followed 793 pregnant women for solicited and unsolicited adverse outcomes after Tdap vaccination during pregnancy; mild injection site reactions were common, but none of the serious adverse events reported were deemed vaccine-related.¹¹² Another study from the United States found increased frequency of moderate/severe injection-site pain in 374 pregnant women, compared with 255 non-pregnant women after Tdap vaccination, but no differences in other moderate/severe reactions or in adverse events requiring medical attention.¹¹³ A large matched retrospective cohort study of 53,885 Tdap-exposed and 109,253 unexposed pregnancies in the United States found no increased risk of medically attended allergic reactions, fever, malaise, seizures, altered mental status, or other reactions within 3 days of vaccination, and no differences in the incidence of neurologic events, thrombotic events, new onset proteinuria, gestational diabetes, or cardiac events within 42 days of vaccination. Decreased rates of venous thromboembolic events and thrombocytopenia were observed within 42 days of vaccination among Tdap-vaccinated, compared with unvaccinated, pregnant women.¹¹⁴

Pregnancy and birth outcomes

Overall, studies to-date provide reassuring evidence that Tdap vaccination during pregnancy is not associated with adverse pregnancy or birth outcomes. A systematic review of 14 studies published up to January 10, 2019 (1.4 million pregnant women) found no significant differences in congenital anomalies, pre-eclampsia/eclampsia, low birth weight, neonatal intensive care unit (NICU) admission, neonatal death, or neonatal sepsis between Tdap-vaccinated and unvaccinated women.¹¹¹ Four studies reported an increase in maternal fever among Tdap-vaccinated women¹¹¹ – three were RCTs with few events;¹¹⁵^,¹¹⁶^,¹¹⁷ however, the fourth was a matched retrospective cohort study conducted by the Vaccine Safety Datalink in the United States.¹¹⁴ The study included 53,885 Tdap-vaccinated and 109,253 unvaccinated women; a significantly increased risk of medically attended maternal fever was observed (adjusted incidence rate ratio: 2.16; 95% CI: 1.65–2.83).¹¹⁴

Three cohort studies have reported a small, but significantly increased, risk of chorioamnionitis associated with Tdap vaccination (relative risks ranged from 1.11 to 1.23).¹¹⁸^,¹¹⁹^,¹²⁰ Because these studies found no accompanying increases in risk of adverse perinatal outcomes often associated with chorioamnionitis (preterm birth, NICU admission, respiratory distress, neonatal sepsis), the clinical significance of the finding is unclear.¹¹⁸^,¹¹⁹^,¹²⁰ It should be noted that this outcome was also assessed by at least four other studies in which no association was observed.¹²¹^,¹²²^,¹²³^,¹²⁴ One study reported an increased risk of postpartum hemorrhage among women who received prenatal Tdap,¹¹⁸ but this association was not observed in several other studies,¹²²^,¹²⁵^,¹²⁶ including a recent population-based retrospective cohort study from Canada, that included 11,519 women vaccinated during pregnancy (postpartum hemorrhage aRR: 1.01, 95% CI: 0.91–1.13; severe postpartum hemorrhage aRR: 0.79, 95% CI: 0.55–1.13).¹²⁶

At least 12 studies have assessed preterm birth after Tdap vaccination during pregnancy, including three small randomized controlled trials with too few preterm birth outcomes to draw conclusions.¹¹¹^,¹²⁶^,¹²⁷ In the remaining observational studies, preterm birth was either not associated with vaccination, or was reduced among vaccinated women;¹¹¹^,¹²⁶^,¹²⁷ the single exception found an increased risk when Tdap was administered before 27 weeks’ gestation, but a lower risk at 27 weeks or later.¹¹⁸ Six studies evaluated stillbirth risk after Tdap vaccination during pregnancy (one RCT¹¹⁵ and five observational studies).¹²³^,¹²⁴^,¹²⁵^,¹²⁶^,¹²⁸ While none reported an increased risk of stillbirth, most of the studies had fewer than 10 events; thus, this is an area that would benefit from future large studies.

Longer-term offspring outcomes

Assessments of longer-term offspring outcomes after Tdap vaccination during pregnancy are more limited than assessments of outcomes proximal to birth. Table 2 summarizes studies that have investigated offspring health beyond 6 months; outcomes evaluated included infectious, atopic, autoimmune, and neurodevelopmental disorders/diseases, as well as all-cause morbidity and mortality.

Two RCTs evaluated growth and development of infants exposed to maternal Tdap immunization. Munoz et al. randomly allocated 33 women to receive a Tdap vaccine and 15 to receive a placebo injection at 30 to 32 weeks’ gestation, followed by crossover vaccination postpartum.¹¹⁶ Outcomes were infant growth (weight, length, and head circumference) at 2, 7, and 13 months and infant development at 13 months assessed using the Bayley-III Scales of Infant and Toddler Development, which measures cognitive, communication, and motor skill development; no statistically significant differences in these measures were found between the two groups.¹¹⁶ Halperin et al. randomly allocated 273 pregnant women to receive either Tdap or tetanus-diphtheria vaccine and compared infant development at 18 months, assessed using the Bayley-III Scales; no developmental differences between groups were detected.¹²⁹

A small retrospective cohort study by Shakib et al. compared the incidence of complex chronic conditions (composite indicator derived from health administrative data) within the first year among infants exposed and unexposed to Tdap in utero.¹²⁸ A total of 138 women vaccinated during pregnancy were compared with 552 randomly selected controls; infants exposed to Tdap were no more likely than non-exposed infants to have a complex chronic condition.¹²⁸ A case-control study from the Vaccine Safety Datalink examined 413,034 singleton, live births between 2004 and 2014 and compared the odds of maternal Tdap vaccination among infants who were hospitalized or died in their first 6 months, with control infants. No association with Tdap vaccination during pregnancy was found for infant hospitalization (adjusted odds ratio [aOR]: 0.94, 95% CI: 0.88–1.01) or infant mortality (aOR: 0.44, 95% CI: 0.17–1.13).⁹⁴

Few studies of associations between Tdap vaccination during pregnancy and pediatric health outcomes have followed infants beyond 18 months.¹³⁰^,¹³¹^,¹³² The outcomes assessed varied widely across studies and included infant growth and development, hospitalization, death, complex chronic conditions, autism spectrum disorder, and attention deficit/hyperactivity disorder, but no study found any increased risk for these outcomes among children born to mothers who received Tdap during pregnancy (Table 2).

Summary of findings from studies of longer-term offspring health outcomes after Tdap vaccination during pregnancy.

First author (year of publication)	Location and time period	Study design	Study population and size	Infant outcomes and length of follow-up	Results
Studies with 6–12 months of follow-up
Munoz et al. (2014)¹¹⁶	Houston, Durham, Seattle (USA), 2008–2012	Randomized clinical trial	33 women randomized to receive Tdap and 15 randomized to placebo	Outcomes: infant growth at 2, 7, or 13 months (weight, length, and fronto-occipital circumference); development (Bayley III screening test) Follow-up: up to 13 months of age	No difference in infant growth at 2, 7, or 13 months or development measured at 13 months
Shakib et al. (2013)¹²⁸	Utah (USA), 2005–2009	Retrospective cohort study	138 women vaccinated with Tdap, 552 randomly selected unvaccinated women	Outcomes: pediatric complex chronic conditions Follow-up: up to 12 months of age	No significant association between Tdap during pregnancy and pediatric complex chronic conditions within 12 months of age
Sukumaran et al. (2018)⁹⁴	5 Vaccine Safety Datalink sites in California, Colorado, Wisconsin, and Oregon (USA), 2004–2014	Case-control study	413,034 singleton, live births	Outcomes: all-cause hospitalization, hospitalizations from respiratory causes; all-cause mortality Follow-up: up to 6 months of age	No significant association between Tdap during pregnancy and all-cause hospitalization or mortality within 6 months, but significantly lower odds of hospitalizations from respiratory causes
Studies with >12 months of follow-up
Halperin et al. (2018)¹²⁹	Nova Scotia (Canada), 2007–2014	Randomized clinical trial	135 women allocated to receive Tdap and 138 to Td	Outcomes: infant development (Bayley III screening test) Follow-up: at 18 months of age	No difference in development assessed at 18 months
Becerra-Culqui et al. (2018)¹³⁰	Kaiser Permanente hospitals in Southern California (USA), 2011–2014	Retrospective cohort study	All singleton live births (n = 81,993) 39,077 vaccinated	Outcomes: autism spectrum disorder (ASD) Follow-up: 3 to 6.5 years of age	No increased risk of ASD following Tdap vaccination during pregnancy
Becerra-Culqui et al. (2020)¹³¹	Kaiser Permanente hospitals in Southern California (USA), 2011–2014	Retrospective cohort study	41,781 women vaccinated with Tdap, 43,826 unvaccinated	Outcomes: attention deficit/hyperactivity disorder (ADHD) Follow-up: 3 to <8 years of age	No association between Tdap vaccination during pregnancy and ADHD
Laverty et al. (2021)¹³²	Ontario (Canada), 2012–2017	Retrospective cohort study	12,045 live births exposed to Tdap in utero, 613,598 unexposed	Outcomes: immune-related outcomes, pediatric infections, sensory disorders, neoplasm and urgent and inpatient health service utilization Follow-up: up to 6 years of age	No significantly increased risks of adverse childhood outcomes following prenatal Tdap exposure, but inverse associations with upper respiratory infections, gastrointestinal infections, and urgent and inpatient health service use

Tdap, tetanus-diphtheria-acellular pertussis; Td, tetanus-diphtheria.

COVID-19 vaccines

Early in the COVID-19 pandemic, pregnant individuals were determined to be at higher risk of severe disease, with associated adverse pregnancy outcomes.¹³³ Pre-licensure vaccine RCTs excluded pregnant women,¹³⁴ which created some hesitancy in recommending vaccination for pregnant individuals when the vaccines became available in late 2020. However, in the early months of 2021, mRNA COVID-19 vaccines were recommended during pregnancy in the United States¹³⁵^,¹³⁶ and Israel.¹³⁷ As of February 2022, 105 countries now have similar recommendations.¹³⁸ Systematic reviews continue to confirm a higher risk of maternal and infant morbidity and mortality from SARS-CoV-2 infection during pregnancy,¹³³^,¹³⁹ thus supporting the importance of vaccination.¹³⁵

Local and systemic reactions

The prevalence of local and systemic reactions post-COVID-19 vaccination has been similar in pregnant and non-pregnant people.¹⁴⁰^,¹⁴¹^,¹⁴²^,¹⁴³ The most common symptoms include injection site pain, fatigue, headache, and myalgia. The last three symptoms are generally more prevalent after dose 2 than after dose 1 of an mRNA vaccine, and also more prevalent among recipients of mRNA-1273 than of BNT162b2, but otherwise, little difference is apparent by pregnancy status.¹⁴¹^,¹⁴²

Pregnancy and birth outcomes

Descriptive studies of COVID-19 vaccination safety in pregnancy published early in 2021 did not observe increases in the cumulative incidence of preterm birth or other pregnancy outcomes compared with background incidence rates.¹⁴¹^,¹⁴⁴ As of August 2022, a number of large comparative epidemiological studies have since been published and provide more robust evidence (Table 3). At least two population-based case-control found no increased risk of miscarriage in women vaccinated during their first trimester.¹⁴⁵^,¹⁴⁶

Three large cohort studies from Scandinavia (Norway and Sweden)¹⁴⁷ and Ontario,¹⁴⁸^,¹⁴⁹ Canada that used population-wide birth registry information found no association between COVID-19 vaccination during pregnancy and adverse outcomes, including postpartum hemorrhage, chorioamnionitis, cesarean delivery, preterm birth, SGA birth, stillbirth, NICU admission, or lower Apgar scores. This held for all mRNA vaccine types and all trimesters, although the number of women vaccinated in their first trimester was considerably lower than the number who were vaccinated in the second or third trimester of pregnancy. Two additional large cohort studies of pregnant individuals insured through large health maintenance organizations in the United States (Vaccine Safety Datalink)¹⁵⁰ and Israel¹⁵¹ observed no associations between COVID-19 vaccination during pregnancy and risk of preterm birth or SGA birth.

Despite the small number of large, comparative observational studies as of August 2022, findings thus far consistently support the safety of COVID-19 vaccination during pregnancy¹⁵²^,¹⁵³^,¹⁵⁴ and complement evidence that COVID-19 vaccination provides effective protection against infection for pregnant women¹⁵⁵^,¹⁵⁶ and their newborns.¹⁵⁷^,¹⁵⁸ Further evaluation is needed for outcomes following first-trimester vaccination and for longer-term offspring outcomes. Initial assessments of both show no indication that vaccination increases the risk of congenital anomalies or indicators of poor health in infants up to 7 months of age (for example, risk of hospitalization or mortality).¹⁵¹ Finally, there is limited safety evidence available on the use of non-mRNA COVID-19 vaccines during pregnancy;¹⁵²^,¹⁵⁹ this remains an important evidence gap as of August 2022.

Summary of findings from large comparative epidemiological studies of outcomes after COVID-19 vaccination during pregnancy.

First author (year of publication)	Location and time period	Study design	Study population and size	Outcomes	Results
Magnus et al. (2021)¹⁴⁶	Norway, February 15–August 15 2021	Case-control study	4,521 women with miscarriages before 14-weeks of gestation (cases), 13,956 confirmed ongoing pregnancies in the first trimester (controls)	Outcome: miscarriage before 14 weeks of gestational age	No association between first-trimester miscarriage and vaccination in the previous 3 weeks, and significantly reduced odds for vaccination in the previous 5 weeks Results were unchanged after stratifying by mRNA vaccine product
Kharbanda et al. (2021)¹⁴⁵	8 Vaccine Safety Datalink sites in California, Colorado, Minnesota, Oregon, Washington, Wisconsin (USA), 2020–2021	Case-control study	13,160 women with spontaneous abortion (cases), 92,286 ongoing pregnancies (controls)	Outcome: spontaneous abortion before 20 weeks of gestational age	Compared to ongoing pregnancies, no significantly increased odds of vaccination in the previous 28 days Results unchanged after stratifying by mRNA vaccine product and gestational age of vaccination (6–8 weeks, 9–13 weeks, 14–19 weeks)
Lipkind et al. (2022)¹⁵⁰	8 Vaccine Safety Datalink Sites in California, Colorado, Minnesota, Oregon, Washington, Wisconsin (USA), 2020–2021	Retrospective cohort study	46,079 singleton live births; 10,064 with ≥1 COVID-19 vaccine doses in pregnancy, 36,015 unvaccinated	Outcomes: preterm birth, SGA birth	Compared to unvaccinated pregnant women, COVID-19 vaccination in pregnancy was not significantly associated with increased risk for preterm birth overall or SGA birth Results were unchanged after stratifying by mRNA vaccine product and 2nd or 3rd trimester vaccination
Goldshtein et al. (2022)¹⁵¹	Maccabi Healthcare Services (one of four mandated health organizations), Israel, 2021	Retrospective cohort study	24,288 singleton live births; 16,697 exposed to COVID-19 vaccination in utero, 7,591 unexposed	Outcomes: preterm birth, SGA birth, congenital malformations, all-cause hospitalizations (>1 day and ≤28 days following birth), jaundice requiring phototherapy, infant death Follow-up: minimum of 1 month, up to a maximum of 7 months	No significant difference or increased risk between prenatal exposure to BNT162b2 vaccination and incidence of preterm birth, SGA birth, all-cause neonatal hospitalizations, postneonatal hospitalizations, congenital anomalies, or infant mortality
Magnus et al. (2022)¹⁴⁷	Sweden, Norway, 2021–2022	Retrospective cohort study	157,521 singleton pregnancies; 103,409 in Sweden and 54,112 in Norway 28,506 with ≥1 COVID-19 vaccine doses in pregnancy, 129,015 unvaccinated	Outcomes: preterm birth, stillbirth, SGA birth, low newborn 5-minute Apgar score (<7), neonatal intensive care unit admission	No significant association between COVID-19 vaccination during pregnancy and preterm birth, stillbirth, SGA birth, low 5-minute Apgar score, or neonatal intensive care unit admission Results were unchanged after stratifying by mRNA vaccine product, number of doses received during pregnancy (1 or 2), and 2nd or 3rd trimester vaccination
Fell et al. (2022)¹⁴⁸	Ontario (Canada), December 2020– September 2021	Population-based retrospective cohort study	97,590 pregnant individuals; 22,660 with ≥1 COVID-19 vaccine doses in pregnancy, 74,930 unvaccinated during pregnancy (44,815 initiated vaccination post-partum, 30,115 were never vaccinated at any point)	Outcomes: post-partum hemorrhage, chorioamnionitis, cesarean delivery (overall and emergency cesarean delivery), admission to neonatal intensive care unit, low newborn 5-minute Apgar score (<7)	COVID-19 vaccination during pregnancy, compared to unvaccinated during pregnancy (each comparison group separately), was not significantly associated with increased risk of post-partum hemorrhage, chorioamnionitis, cesarean delivery, admission to neonatal intensive care, or low 5-minute Apgar score Results were unchanged after stratifying by mRNA vaccine product, number of doses received during pregnancy (1 or 2), and 2nd or 3rd trimester vaccination
Fell et al. (2022)¹⁴⁹	Ontario (Canada), May to December 2021	Population-based retrospective cohort study	85,162 births; 43,099 exposed to ≥1 COVID-19 vaccine doses in pregnancy, 42,063 unvaccinated	Outcomes: preterm birth, SGA birth, stillbirth	No increased risk of preterm birth, SGA birth, or stillbirth associated with COVID-19 mRNA vaccination during pregnancy Results were unchanged after stratifying by mRNA vaccine product, number of doses received during pregnancy (1 or 2), or trimester of vaccination

SGA, small-for-gestational-age.

VACCINES CONSIDERED IN SPECIFIC CIRCUMSTANCES

Some vaccines are occasionally indicated for unvaccinated or under-vaccinated pregnant women, such as in circumstances when the risk of maternal infection is deemed to be high due to work with a high-risk population, during an outbreak, or during travel to an area with an outbreak or endemic disease.¹⁵³^,¹⁶⁰^,¹⁶¹ As a consequence of not being routinely recommended, vaccines in this category have limited evidence on safety following exposure during pregnancy. While not a complete list, vaccines in this category with the most safety information are summarized below.

Hepatitis A and B vaccines

Six studies have evaluated the safety of hepatitis A and B vaccines in pregnancy (two retrospective cohort studies from the U.S. Vaccine Safety Datalink¹⁶²,¹⁶³ two descriptive reports of passive surveillance data,¹⁶⁴^,¹⁶⁵ one industry-led prospective pregnancy exposure registry descriptive study,¹⁶⁶ and one RCT that described pregnancy outcomes among pregnant adolescents who received hepatitis B vaccine as part of the control group¹⁶⁷). The two Vaccine Safety Datalink studies assessed over 600,000 pregnancies between 2004 through 2015, of which 1,399 pregnant women received hepatitis B vaccine and 1,140 received hepatitis A vaccine.¹⁶²^,¹⁶³ Women vaccinated with hepatitis A or B vaccines during pregnancy were compared with women who received other vaccines in pregnancy and with those who were unvaccinated in pregnancy. No significant associations between hepatitis B vaccination during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, preterm birth, low birth weight, or SGA birth were observed;¹⁶² however, an association between hepatitis A vaccination and SGA birth was observed (aOR: 1.32, 95% CI: 1.09–1.60).¹⁶³ No serious or non-serious adverse events, or adverse pregnancy outcomes were identified from passive reporting,¹⁶⁴^,¹⁶⁵ or from the pregnancy registry¹⁶⁶ or RCT.¹⁶⁷

Meningococcal vaccines

A recent review summarized studies that have described pregnancy outcomes among women who received a meningococcal vaccine during pregnancy.¹⁰⁷ Across the ten studies summarized, including four RCTs (three in which meningococcal vaccine was compared with pneumococcal vaccine and the other in which it was compared with inactivated influenza vaccine), no safety concerns were identified. In the RCT with influenza vaccine as the active treatment group,¹⁶⁸ the rate of infant mortality was lower among mothers who received meningococcal vaccine; however, this difference was not statistically significant.⁹³ None of the other studies, including a descriptive cohort study from California¹⁶⁹ and two descriptive reports of passive surveillance data from VAERS,¹⁷⁰^,¹⁷¹ identified any safety concerns.¹⁰⁷

Pneumococcal vaccines

A Cochrane Collaboration review, published in 2015,¹⁷² identified seven RCTs investigating the use of pneumococcal vaccines in pregnancy.⁵⁴^,¹⁷³^,¹⁷⁴^,¹⁷⁵^,¹⁷⁶^,¹⁷⁷^,¹⁷⁸ While the review’s primary endpoint of interest was efficacy against infant pneumococcal infection, safety data were also evaluated; there were no differences between pneumococcal and control vaccines with respect to injection site tenderness¹⁷⁷^,¹⁷⁵ and no serious adverse events reported.¹⁷² More recently, two small RCTs of pneumococcal vaccination during pregnancy have been published – one among Aboriginal mothers in Northern Australia¹⁷⁹ and the other among HIV-positive mothers in Brazil.¹⁸⁰ The Australian RCT found a higher rate of preterm births among women who received 23-valent pneumococcal polysaccharide vaccine during pregnancy, compared to unvaccinated women.¹⁷⁹ While this finding was not statistically significant, the authors suggest that the finding warrants further research and consideration. The other RCT did not identify any safety concerns, nor did a descriptive report of passive surveillance data from VAERS.¹⁸¹

Rabies vaccines

Due to the severe consequences of rabies infection,¹⁸² pregnancy is not considered a contraindication to post-exposure prophylaxis with a dose of human rabies immunoglobulin (HRIG) and rabies vaccine. Although there is a theoretical risk of adverse effects from rabies HRIG and vaccination, studies of small cohorts of recently immunized pregnant women (ranging from 6 to 202 pregnant women) have indicated that adverse systemic reactions are similar among pregnant women compared to non-pregnant individuals¹⁸³ and identified no safety signals in terms of cesarean delivery, spontaneous abortion, stillbirth, congenital malformations, or preterm birth.¹⁸³^,¹⁸⁴^,¹⁸⁵^,¹⁸⁶ Although the size of existing studies and the range of pregnancy and fetal outcomes evaluated is small, leaving some uncertainty around the safety of rabies HRIG and vaccination during pregnancy, the clinical consensus is that the benefits of immunization of pregnant women far outweigh any theoretical risk of adverse effects from exposure to HRIG and killed rabies virus vaccines.¹⁰⁷

Cholera vaccines

Although cholera can have severe consequences for maternal health¹⁸⁷ and is known to have harmful effects on the fetus,¹⁸⁸^,¹⁸⁹ the safety of cholera vaccination during pregnancy remains controversial. Three killed whole-cell oral cholera vaccines are currently available and pre-qualified by the World Health Organization for use.¹⁸⁷ No specific clinical studies in pregnant women have been conducted, nor have animal studies been completed to evaluate reproductive toxicity and effects on embryo-fetal development; however, since these vaccines are inactivated, there are no theoretical concerns with respect to fetal health. Of five cohort studies that have assessed the safety of cholera vaccination during pregnancy, none identified significant safety risks.¹⁸⁸^,¹⁹⁰^,¹⁸⁹^,¹⁹¹^,¹⁹²^,¹⁹³ A meta-analysis of the 5,584 women included in these cohorts (2,920 vaccinated and 2,664 unvaccinated pregnant women) compared rates of spontaneous abortion, stillbirth, preterm birth, low birth weight, and congenital malformations.¹⁹⁴ Results identified no significant increase in risk of these adverse pregnancy outcomes associated with cholera vaccination.¹⁹⁴

VACCINES TYPICALLY CONTRAINDICATED IN PREGNANCY

Live vaccines, such as live attenuated viral vaccines, are typically contraindicated during pregnancy because of their ability to replicate in the host, thereby posing a theoretical risk that the virus could cross the placental barrier and either infect, or adversely affect, the fetus.⁴⁹^,¹⁹⁵^,¹⁹⁶^,¹⁹⁷ As a result, evidence on the safety of this group of vaccines during pregnancy is limited. With the exception of smallpox vaccines, the existing studies on other live virus vaccines are small in size and overwhelmingly pertain to inadvertent exposure to these vaccines, either early in the first trimester, prior to pregnancy recognition, or during the periconceptional period, often in the context of a mass vaccination campaign during an outbreak.¹⁹⁵

Smallpox vaccines

On July 23, 2022, the World Health Organization declared the monkeypox outbreak to be a Public Health Emergency of International Concern.¹⁹⁸ According to interim guidance released by the World Health Organization on June 14, 2022, mass vaccination is not recommended; however, post-exposure prophylaxis or pre-exposure prophylaxis may be considered for close contacts of monkeypox-infected individuals or groups with high risk of occupational exposure, respectively.¹⁹⁹ Pregnant women may be considered for post-exposure or pre-exposure prophylaxis using smallpox vaccine, if an appropriate vaccine is available, following a careful evaluation of risks and benefits, which may differ by type of vaccine product.¹⁹⁹Non-replicating (MVA-BN) smallpox vaccines (or minimally-replicating [LC16] smallpox vaccines) should be used when considering vaccination during pregnancy.¹⁹⁹ Although there are limited data on the use of MVA-BN vaccine during pregnancy, no adverse pregnancy outcomes have been reported to-date and there is no theoretical concern since it is a non-replicating vaccine.²⁰⁰

A systematic review of studies evaluating safety of smallpox vaccination during pregnancy included 37 articles published up to September 2014.²⁰¹ The review concluded that there was no association identified between smallpox vaccination during pregnancy and spontaneous abortion, preterm birth, or stillbirth. An increased risk of congenital anomalies associated with first-trimester vaccination was observed by the systematic review (pooled OR: 1.34; 95% CI: 1.02-1.77; 5 studies);²⁰¹ however, in the largest and most recent individual study included in the meta-analysis,²⁰² no association was observed with congenital anomalies overall (adjusted OR: 1.40; 95% CI: 0.94-2.07) or with seven specific types of anomalies.²⁰² The systematic review documented 21 cases of fetal vaccinia among women vaccinated against smallpox during pregnancy—notably, all cases were reported between 1809 and 1985,²⁰¹ before the availability of non-replicating smallpox vaccine (MVA-BN first became available in 2013).¹⁹⁹

Although another review reported statistically significant associations between smallpox vaccination during the first trimester and increased odds of miscarriage (pooled OR: 4.82; 95% CI 2.38-9.77), these findings were observed in two small studies published in 1964 and 1975; both were deemed to be of very low quality.²⁰³

Other live virus vaccines

A systematic review of 15 comparative studies published up to November 2019 assessed evidence on the safety of live virus vaccines administered during pregnancy and included the following vaccines: smallpox (eight studies), monovalent rubella (three studies), oral poliovirus (two studies), yellow fever (one study), and dengue (one study).²⁰³ No association with miscarriage was found across vaccines (pooled OR: 0.98, 95% CI 0.87–1.10; nine studies), or when assessed by individual vaccine type, with the exception of smallpox vaccine, as discussed above. There were no associations with stillbirth (nine studies), congenital anomalies (12 studies), preterm birth (five studies), or neonatal death (three studies) across vaccines, or when stratified by individual vaccine type.²⁰³ The authors of this review also evaluated 23 descriptive studies of outcomes after live virus vaccination during pregnancy and found no documented cases of congenital rubella syndrome among 3918 infants exposed to monovalent rubella vaccine in utero, but one probable case of intrauterine infection after yellow fever vaccination.²⁰³

A review of studies published up to December 2018 on the safety of travel vaccines for pregnant women provided narrative summaries of RCTs, descriptive and comparative cohort studies, and case series studies. Live virus vaccines covered by this review included yellow fever, rubella, and measles–mumps–rubella vaccines.¹⁰⁷ A total of 732 women were inadvertently exposed to yellow fever vaccine during pregnancy, documented by nine observational studies; although the quality of the studies was judged to be poor, no compelling evidence of safety concerns was reported. A similar conclusion was reached with respect to six studies of rubella vaccine. Little-to-no data are available on the safety of measles and mumps vaccines in pregnant women.¹⁰⁷^,¹⁹⁵

Data are very limited for other live virus vaccines, particularly those that are not targeted toward individuals of reproductive age (e.g., herpes zoster, rotavirus). Analysis of 17 years of data from a pregnancy exposure registry for varicella-zoster virus-containing vaccines documented 928 women vaccinated within 3 months before or during pregnancy. No cases of congenital varicella syndrome or congenital anomalies consistent with congenital varicella syndrome were reported, and the prevalence of major congenital anomalies was similar to background rates.²⁰⁴

Although Japanese encephalitis virus vaccine is a live vaccine and, thus, contraindicated during pregnancy, a study from 2003–2014 among active-duty U.S. military service members documented 513 exposures to Japanese encephalitis virus vaccine during pregnancy (92.4% were vaccinated during the first trimester), within a population of 192,570 pregnancies.²⁰⁵ The investigators evaluated a range of maternal (fever, rash, myalgia, anaphylaxis), pregnancy (spontaneous abortion, pre-eclampsia) and birth outcomes (preterm birth, low birth weight, major congenital anomalies). No statistically significant associations with receipt of one or more doses of Japanese encephalitis vaccine were reported, although the study was underpowered to rule out small risks for most outcomes.²⁰⁵

VACCINES NOT RECOMMENDED IN PREGNANCY

Human papillomavirus (HPV) vaccine is not recommended during pregnancy.²⁰⁶ Nevertheless, as this vaccine is largely targeted to females of early reproductive age, there are a number of studies that have evaluated outcomes following inadvertent pregnancy exposure.¹⁶⁷^,²⁰⁷^,²⁰⁸^,²⁰⁹^,²¹⁰^,²¹¹^,²¹²^,²¹³^,²¹⁴ One RCT described pregnancy outcomes among 777 pregnant adolescents who received HPV vaccine as part of an RCT in which the comparison group received hepatitis B vaccine; the incidence of pregnancy outcomes between the two groups were similar.¹⁶⁷ In a secondary analysis of RCT data from Costa Rica, Panagiotou et al. found no association, overall, with miscarriage for pregnancies conceived within 90 days of HPV vaccination; however, there was an increased risk of miscarriage at 13–20 weeks’ gestation among women who conceived at any point after HPV vaccination.²⁰⁷

Four population-based comparative retrospective cohort studies have been conducted.²⁰⁸^,²⁰⁹^,²¹⁰^,²¹¹ In Denmark, Faber et al. found no increased risk of spontaneous abortion, stillbirth, or 1-year infant mortality among women who received HPV vaccine from 4 weeks before conception up to 22 weeks of gestational age, compared with unvaccinated; there were no differences in findings according to the number of doses received during pregnancy, or whether the vaccination was received before, or during, pregnancy.²⁰⁸ Scheller et al. also used the Danish national registries over a similar time period and found that HPV vaccination during pregnancy was not associated with a significantly higher risk of spontaneous abortion, stillbirth, major birth defect, small size for gestational age, low birth weight, or preterm birth, compared with unvaccinated women.²⁰⁹ Similarly, no associations with adverse pregnancy outcomes were observed in a large study of U.S. military women who received HPV vaccine during pregnancy,²¹⁰ or in a study from the United Kingdom that assessed outcomes among pregnancies conceived within 30 days before and 45 days after HPV vaccination.²¹¹

No other studies, including one descriptive study of passive surveillance data from VAERS²¹² and three industry-based pregnancy exposure registry studies,²¹³^,²¹⁴^,²¹⁵ have reported any concerning or unexpected patterns in pregnancy and birth outcomes among HPV-vaccinated pregnant women. Despite a generally favorable safety profile, HPV vaccine is not recommended during pregnancy and if a woman becomes pregnant prior to series completion, current recommendations are to delay second and/or third doses until after pregnancy.²⁰⁶

VACCINES UNDER DEVELOPMENT FOR FUTURE USE IN PREGNANCY

A number of new vaccine products that are currently at different stages of development or implementation have potential future implications for pregnancy. This includes vaccines that are (i) specifically indicated for use during pregnancy to passively protect newborns via transplacental transfer of maternal vaccine-derived antibodies (respiratory syncytial virus [RSV], Group B Streptococcus [GBS]); (ii) intended for use in general populations, including pregnant women, in regions with high disease burdens that, in some cases, extol disproportionately increased risks during pregnancy (Ebola, Malaria); or (iii) intended for use in reproductive-age individuals to prevent congenital infections (Zika virus, cytomegalovirus).⁴

Respiratory syncytial virus (RSV) vaccines

Among RSV vaccine candidates intended for use during pregnancy to confer neonatal protection, the development of recombinant vaccines containing the RSV-F protein is most advanced. Several clinical trials in pregnant individuals have been completed or are underway to explore the safety, immunogenicity, and efficacy of maternal vaccination against infant RSV outcomes. These trials monitor general safety outcomes (solicited and unsolicited adverse events for mothers and infants, including any leading to study withdrawal) and pregnancy-specific outcomes. Of two completed phase 2 and phase 3 studies in pregnant participants, no major safety signals were identified, although short-term reactogenicity and local reactions were more common among vaccine recipients than placebo recipients.²¹⁶^,²¹⁷ A phase 3 study, which was published in 2020 and included 4,636 pregnant women (3,051 received the vaccine),²¹⁶ is the largest RCT completed to-date to have evaluated a vaccine specifically developed for use during pregnancy.²

Group B Streptococcus (GBS) vaccines

Three phase 2 studies²¹⁸^,²¹⁹^,²²⁰ and one phase 1/2 study²²¹ of a trivalent protein-conjugated capsular polysaccharide GBS vaccine candidate have been completed in pregnant participants; the vaccine was well tolerated, and no safety signals were reported. The focus of clinical studies has recently shifted to GBS vaccine candidates covering more serotypes. An ongoing phase 1/2 study of a hexavalent capsular polysaccharide GBS vaccine in pregnant women will include a range of maternal and infant outcomes up to 12 months (NCT03765073). Two phase 2 studies of a recombinant protein-based GBS vaccine are in progress, one with healthy pregnant participants (NCT05154578), and the other, with pregnant women with and without HIV infection (NCT04596878). The primary outcome of the former is immunogenicity, but the primary outcomes in the latter (NCT04596878) are adverse events and pregnancy- and birth-related outcomes such as gestational age, growth measures and APGAR scores at birth, and developmental outcomes at 6 months.

Ebola vaccines

Even though pregnancy was an exclusion criterion during the clinical development of Ebola vaccines,²²² five studies recorded inadvertent exposures in early pregnancy or in new conceptions within 60 days after vaccination.²²³^,²²⁴^,²²⁵^,²²⁶^,²²⁷ One study documented a higher frequency of pregnancy loss among vaccinated than unvaccinated participants who became pregnant, but the difference was not statistically significant and may have been due to a reporting bias.²²³^,²²⁴ Two phase 3 studies are currently evaluating EBV vaccine (Ad.26.ZEBOV) during pregnancy (NCT04556526 and NCT04152486). Both will assess maternal and infant adverse events, such as maternal and neonatal death, spontaneous abortion, postpartum hemorrhage, congenital malformation, and preterm birth.

Malaria vaccines

A phase 2 placebo-controlled study underway in Mali is exploring the safety and efficacy of PfSPZ malaria vaccine in females of childbearing potential (NCT03989102). Pregnancy is an exclusion criterion, but participants must report interest in becoming pregnant within 2 years. The primary outcomes are local and systemic adverse events within 7 days of vaccination. Although there is a stated intention to follow those who become pregnant until the end of pregnancy and through the infants’ first year of life, specific outcomes are not listed in the summary on clinicaltrials.gov.

Zika virus and cytomegalovirus vaccines

No Zika or cytomegalovirus vaccine studies involving pregnant participants are currently registered, but a phase 2 trial of an mRNA vaccine candidate in healthy adults is underway (NCT04232280). It will evaluate traditional safety endpoints, in order to inform a phase 3 trial in the target population of females of reproductive age. When available, both Zika and cytomegalovirus vaccines would optimally be administered before pregnancy to prevent adverse outcomes associated with early pregnancy infection.¹⁶¹

CHALLENGES FOR VACCINE SAFETY ASSESSMENT DURING PREGNANCY

While in-depth discussion is beyond the scope of this chapter, it is important to highlight several challenges for vaccination safety assessment during pregnancy, for both currently available and future vaccines.

Exclusion of pregnant individuals from pre-licensure vaccine research

A major issue – amplified during the COVID-19 pandemic and recent Ebola outbreaks – is the routine exclusion of pregnant women from pre-licensure vaccine research, resulting in a lack of pregnancy-specific safety data and, ultimately, delayed or limited access to potentially life-saving vaccines.¹³⁴^,¹⁹⁷^,²²⁸ Ethical considerations for including pregnant women in RCTs are complex. While there may be justification for exclusion from the earliest stages of safety assessment, a requirement that developmental and reproductive toxicity studies are completed during early developmental phases of new vaccine candidates can help ensure that pregnant women can be responsibly included, when appropriate, in pre-licensure RCTs to expedite equitable access.¹³⁴^,²²⁸

Surveillance systems and data requirements for vaccine safety assessment in pregnancy

Given the typical exclusion of pregnant women from RCTs, it follows that vaccine safety surveillance and observational studies of vaccination during pregnancy using “real-world” health data are critical during all phases of vaccine program implementation in this population. Key resources essential for such assessments include population-level information on background rates of pregnancy-related maternal and infant outcomes; active and passive vaccine surveillance capacity; and, ideally, linkable individual-level sources of information on pregnancy outcomes and vaccination status during pregnancy.

Low- and middle-income country (LMIC) settings

The above-listed resources for vaccine safety monitoring in pregnant individuals may be limited, or even entirely lacking, in low- and middle-income countries (LMICs).²²⁹^,²³⁰^,²³¹^,²³²^,²³³ Specifically, many LMICs lack data sources with information on pregnancy and birth outcomes, due to inadequate birth registration systems and lack of central repositories for antenatal care records (most of which are still paper-based and poorly maintained).²³¹^,²³³ This poses important challenges for establishing local background rates of adverse pregnancy outcomes and monitoring safety after vaccine introduction.²²⁹^,²³⁴ Strengthening health information systems and pregnancy registries in settings currently lacking these resources is likely to become even more important in the future, as new vaccines targeting the pregnant population are licensed and implemented, particularly in LMICs with high disease burdens.²³²

Recommended outcomes and standardized case definitions

Despite Brighton Collaboration’s GAIA initiative to align core outcome definitions for maternal immunization safety studies (Table 1), the types of outcomes and definitions used in vaccination studies are often heterogeneous⁸³ (partly owing to jurisdiction-specific birth registration requirements and/or data systems). As well, gestational age thresholds and local reference standards are often poorly reported. Such heterogeneity impedes evidence synthesis through meta-analysis, which is important for rare outcomes, such as stillbirth and congenital anomalies.¹¹^,¹² Of particular value to vaccine safety evaluation are networks that can share or combine data across geopolitical boundaries, thereby enabling harmonized study definitions and analytical methodologies in large populations.¹ The Vaccine Safety Datalink, which collects vaccination and healthcare data on more than 10 million insured people in the United States per year,²³⁵ is one example.

Methodological challenges facing observational studies of vaccination during pregnancy

Comparative observational studies provide complementary evidence to RCTs and, together, they can inform clinicians’ and policymakers’ risk–benefit decisions about vaccination during pregnancy. However, observational epidemiological studies assessing vaccination during pregnancy face some unique methodological challenges, such as achieving adequate control of confounding factors and accounting for complex temporal issues (for example, seasonality, immortal time, and cohort truncation) that can severely distort results particularly for vaccines available only at specific times (seasonal influenza vaccine or during a period of intense vaccine deployment [2009 A/H1N1 pandemic influenza vaccine, COVID-19 vaccine]) and for outcomes that are time dependent (preterm birth, stillbirth).²³⁶^,²³⁷^,²³⁸

PRACTICE RECOMMENDATIONS

Safety assessment of vaccination during pregnancy involves diverse and complementary approaches – adverse event reporting (passive and active) for rapid detection of safety signals, ideally followed by epidemiological studies designed to compare risks of adverse pregnancy and birth outcomes in vaccinated and unvaccinated pregnant individuals.
There are robust safety data for several vaccines currently recommended during pregnancy that can be used during clinical counseling of pregnant patients: influenza; monovalent tetanus toxoid; tetanus toxoid, inactivated reduced diphtheria toxoid, and acellular pertussis (Tdap).
- Influenza: a large number of published studies, including clinical trials, have documented the safety of inactivated influenza vaccination during pregnancy for mother and infant. Studies of longer-term offspring outcomes are fewer in number, but have not documented increases in the risk of adverse childhood health outcomes.
- Monovalent tetanus toxoid: a limited number of studies of monovalent tetanus toxoid vaccination during pregnancy are available; most safety evidence is for combination vaccines (see below). Nevertheless, tetanus toxoid vaccine is considered safe during pregnancy, and it is widely administered during pregnancy in many low- and middle-income countries. Mild local reactions such as erythema and injection site pain are common, but severe adverse events are rare and there is no evidence of any adverse pregnancy and birth outcomes.
- Tetanus-diphtheria-acellular pertussis (Tdap): research published since 2012 reported no association between Tdap immunization during pregnancy and serious adverse events in the mother or adverse pregnancy, fetal, or neonatal outcomes in the perinatal period. An increasing number of studies of longer-term offspring outcomes has not documented increases in the risk of adverse childhood health outcomes.
COVID-19 vaccination is also currently recommended for pregnant individuals in many countries due to the increased risk of adverse maternal and newborn outcomes associated with SARS-CoV-2 infection during pregnancy.
- Safety evidence from descriptive and comparative epidemiological studies is rapidly emerging and, to-date (as of August 2022), is reassuring and suggests there are no associations between mRNA COVID-19 vaccination during pregnancy with miscarriage, preterm birth, SGA birth, stillbirth, or other adverse outcomes.
- Nevertheless, evidence on other important outcomes, including congenital anomalies, remains limited. Studies following periconceptional and 1st trimester vaccination are required, in addition to longer-term follow-up of newborn health outcomes after birth, and evidence on safety of non-mRNA COVID-19 vaccines used during pregnancy.
Additional inactivated vaccines may warrant consideration for unvaccinated or under-vaccinated pregnant women with chronic health conditions or in specific circumstances, such as during an outbreak or travel/prolonged stay in areas with endemic disease; there are relatively limited data on outcomes following exposure to these vaccines during pregnancy.
- These vaccines include hepatitis A and B, meningococcal conjugate, pneumococcal, rabies, cholera, and anthrax.
- Care providers should balance patient-specific risks and benefits and consider offering the vaccine to pregnant patients when potential benefits outweigh potential risks.
Live virus vaccines, and other live vaccines, are typically contraindicated during pregnancy due to a theoretical risk that the agent could replicate, cross the placental barrier, and harm the fetus; there are very limited data on outcomes following exposure to these vaccines during pregnancy.
- These live vaccines include BCG vaccine, live attenuated influenza vaccine, measles–mumps–rubella vaccine, varicella vaccine, yellow fever vaccine, zoster vaccine, Japanese encephalitis virus vaccine, oral polio vaccine, typhoid toxoid vaccine, and dengue vaccine.
- In the context of the global monkeypox outbreak in 2022, the World Health Organization recommends that pregnant women may be considered for post-exposure or pre-exposure prophylaxis using a non-replicating smallpox vaccine, following a careful evaluation of risks and benefits.
- Despite theoretical concerns about safety, inadvertent vaccination with a live vaccine during the periconceptional period or during early gestation, before pregnancy recognition, is not a reason to terminate pregnancy.
HPV vaccine is not recommended during pregnancy and if a woman becomes pregnant prior to series completion, current recommendations are to delay second and/or third doses until after pregnancy.
Since recommendations for vaccination during pregnancy differ by country/jurisdiction, care providers should refer to country-specific guidance. Note that in the context of an outbreak, such as COVID-19 or monkeypox, recommendations concerning vaccination during pregnancy may change during the course of the outbreak as additional data become available.

Care providers should be aware of local passive and active vaccine safety surveillance programs and report any suspected vaccine-associated adverse events following vaccination during pregnancy.

CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

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AUTHORS

INTRODUCTION

EVALUATION OF VACCINE SAFETY IN PREGNANCY

Approaches for monitoring vaccine safety

Outcomes

VACCINES CURRENTLY RECOMMENDED IN PREGNANCY

Influenza vaccines

Local and systemic reactions

Pregnancy and birth outcomes

Longer-term offspring outcomes

Tetanus toxoid vaccines

Pertussis-containing vaccines

Local and systemic reactions

Pregnancy and birth outcomes

Longer-term offspring outcomes

COVID-19 vaccines

Local and systemic reactions

Pregnancy and birth outcomes

VACCINES CONSIDERED IN SPECIFIC CIRCUMSTANCES

Hepatitis A and B vaccines

Meningococcal vaccines

Pneumococcal vaccines

Rabies vaccines

Cholera vaccines

VACCINES TYPICALLY CONTRAINDICATED IN PREGNANCY

Smallpox vaccines

Other live virus vaccines

VACCINES NOT RECOMMENDED IN PREGNANCY

VACCINES UNDER DEVELOPMENT FOR FUTURE USE IN PREGNANCY

Respiratory syncytial virus (RSV) vaccines

Group B Streptococcus (GBS) vaccines

Ebola vaccines

Malaria vaccines

Zika virus and cytomegalovirus vaccines

CHALLENGES FOR VACCINE SAFETY ASSESSMENT DURING PREGNANCY

Exclusion of pregnant individuals from pre-licensure vaccine research

Surveillance systems and data requirements for vaccine safety assessment in pregnancy

Low- and middle-income country (LMIC) settings

Recommended outcomes and standardized case definitions

Methodological challenges facing observational studies of vaccination during pregnancy

PRACTICE RECOMMENDATIONS

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REFERENCES