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This chapter should be cited as follows:
Stergachis A, Sevene E, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419533

The Continuous Textbook of Women’s Medicine SeriesObstetrics 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


Maternal and Neonatal Safety Surveillance Systems

First published: May 2023

Study Assessment Option

By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
See end of chapter for details


Maternal immunization is an effective strategy for reducing the morbidity and mortality from infectious diseases in pregnant women, the fetus, and infants. Vaccines currently recommended for use in pregnant women, such as tetanus toxoid, influenza vaccine, and pertussis vaccine, are safe and effective in controlling neonatal tetanus, influenza during pregnancy, and pertussis in young infants, respectively.1,2,3 Additionally, certain vaccines are recommended for use by pregnant women in specific situations if the benefits outweigh the risks, e.g., for hepatitis A and B and meningitis.4,5,6 A 2014 World Health Organization (WHO) review found no evidence of increased risk to the fetus with the use of inactivated viral and bacterial vaccines and toxoids, i.e., inactivated influenza vaccine, tetanus toxoid, and acellular pertussis, administered during pregnancy.7 While the review by the WHO indicated that certain vaccines are safe for pregnant women and fetuses, it went on to state that “policy formulation is challenging because the evidence base to guide decisions is still limited for some vaccines.” Monitoring the safety of maternal immunizations is essential to ensure timely data collection and access to vaccines for pregnant women and instill public confidence.

The advent of emerging and re-emerging diseases has accelerated interest in maternal immunization in vaccine development plans to allow for timely data collection and timely vaccine access for pregnant women. Pregnant women are at a higher risk of morbidity and mortality to certain pathogens, such as Zika virus, Ebola, Lassa fever, influenza, and SARS-CoV-2.8,9 Yet with few exceptions, vaccines and drugs are licensed and approved for marketing, with limited, if any, information on their safety and effectiveness during pregnancy.10 Pregnant women and women of childbearing age without adequate contraception are routinely excluded from pre-licensure and pre-registration clinical trials, primarily due to fear of harm to the fetus.11 Consequently, vaccines used during pregnancy require post-approval safety surveillance beyond routine safety surveillance. With newer vaccines, the data are even more limited because not only pregnant women are excluded from clinical trials, but there may be a lack of systematic investigation of the post-licensing experience. This situation is particularly challenging since promising new vaccines for use during pregnancy are under development and have progressed to phase III clinical trials or are in the registration phase, i.e., for Group B streptococcus (GBS) and respiratory syncytial virus (RSV). As new maternal immunizations become available, there is an increasing need and imperative for safety surveillance through the life-cycle of vaccines. No or limited information on the safety of medicines during pregnancy hinders informed benefit–risk clinical and policy decisions about life-saving medicines for women of childbearing age.12

Global attention to the importance of safety surveillance of medicines began in earnest because of the thalidomide disaster in the 1960s when the use of this drug during pregnancy resulted unexpectedly in thousands of cases of a previously rare, severe congenital anomaly, phocomelia.13,14 Stimulated by the thalidomide disaster, the WHO established a unit in 1968 to collect and analyse adverse drug reaction (ADR) reports from national drug monitoring organizations, initially launched with ten high-income countries. The original aim of this effort, that continues to this date, was to identify rare, but serious ADRs as early as possible, i.e., signals of potential new ADRs, primarily via spontaneous reporting systems.15 The now-called WHO Program for International Drug Monitoring (PIDM) has expanded to include over 170 countries and territories as full or associate members.16 Spontaneous reporting systems are necessary but insufficient as maternal and neonatal safety surveillance systems. As discussed later in this chapter, spontaneous reporting systems have certain advantages and limitations for safety surveillance of vaccines and drugs used during pregnancy.

Gaps in available evidence on safety and efficacy of vaccines for pregnant women at the time of marketing necessitate reliance on data extrapolated from studies of non-pregnant women. Yet physiologic changes associated with pregnancy limit the inference of pharmacokinetic and pharmacodynamic data from non-pregnant adults to pregnant women.17,18 As a result, the value of vaccines and drugs used during pregnancy cannot be assessed with the same criteria and certainty of evidence as compared with most medical interventions, limiting the ability of pregnant women to receive evidence-based care.19,20 Consequently, most medicines are not recommended during pregnancy due to the lack of information on their risk–benefit profile. For new medicines, a consequence of this situation has been referred to as a “Catch-22”, i.e., medicines not recommended during pregnancy, therefore not prescribed – not prescribed therefore no information.21 This situation was particularly evident during the COVID-19 pandemic since the exclusion of pregnant and lactating persons from COVID-19 vaccine clinical trials resulted in delayed access of pregnant women to the vaccines after emergency use authorization was granted.22 The COVID-19 pandemic disproportionately affects pregnant people, resulting in multiple calls for data on COVID-19 vaccine reactogenicity, efficacy, and safety in pregnancy.23,24 The exclusion of pregnant women from the COVID-19 vaccine trials resulted in vaccine recommendations for pregnant women based on little data, though subsequent postmarketing surveillance supported these recommendations.25


Various study designs and methods are used to generate information on the safety of vaccines and drugs used during pregnancy and lactation. Pre-clinical and clinical development studies provide useful information on the safety of vaccines and drugs used during pregnancy. However, since pregnant women are actively excluded from most clinical trials, spontaneous reporting systems, active surveillance (e.g., pregnancy registries), and other types of epidemiological study designs are important tools for safety data collection in the post-licensure setting. A valid estimate of gestational age, from which a conception date may be estimated, is critical for determining the timing of an exposure during pregnancy and avoiding misclassification of exposure. Several methods exist for identifying gestational age, including ultrasound, uterine fundal height, and estimation of last menstrual period (LMP). A broad range of stakeholders in vaccine safety surveillance include the Expanded Program on Immunization (EPI), national medicine regulatory agencies (MRAs), the WHO and its Global Advisory Committee on Vaccine Safety (GACVS) and Global Vaccine Safety Blueprint, Brighton Collaboration, Gavi, the Vaccine Alliance, and vaccine manufacturers/developers who have requirements for risk-management plans and pharmacovigilance plans. Collaboration and communication among such organizations can promote strengthening surveillance systems for the collection and use of data to better inform maternal immunization.


A prerequisite for clinical studies of vaccines intended specifically for maternal immunization is developmental and reproductive toxicology (DART) studies in animal models whereby the potential reproductive risk of the vaccine is assessed. DART studies in animal models are recommended as an important step in drug and vaccine development and offer one approach to screen for potential hazards before including pregnant women in a clinical trial. However, DART studies have inherent limitations in determining the safety of vaccines and drugs used during pregnancy. This is due, in part, to the ambiguous predictive value of animal reproductive toxicology studies for human teratogenesis because of variations in species–specific effects.26 For example, animal studies of thalidomide failed to reveal significant teratogenicity in every animal species tested in pre-clinical studies.27,28 Generally, DART studies are conducted late during the drug-development program, resulting in the exclusion of pregnant women from enrollment and withdrawal of women from pre‐licensure trials if they become pregnant.29 For these reasons, stringent MRAs, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), recommend that for products indicated specifically for immunization of pregnant women, that data from DART studies be available prior to the initiation of any clinical trial enrolling pregnant women.30 Findings from DART studies can generate safety signals and should be used to help assess the risks versus the benefits of vaccines intended for use by pregnant women and/or females of childbearing potential.

Randomized controlled clinical trials are designed to assess the efficacy of a medicinal product and represent the requirement for medicine regulatory authority approval based on demonstration of its efficacy and safety. The clinical trial environment is well-prepared to closely monitor for possible adverse events and has the advantage of a control group as a comparator. Yet, Singh and Loke described multiple challenges to identifying reliable drug safety signals in clinical trials, including lack of an evidentiary gold standard, limited statistical power, inadequate ascertainment and classification of adverse events, and limited generalizability.31 Despite these limitations, randomized control trials continue to be the primary basis for assessing safety and efficacy of a medicinal product and requirement for regulatory approval. When clinical trials are specifically designed to include pregnant women, considerations include the need for large sample sizes due to the rarity of certain events and the long duration of the studies to include follow-up information on infant outcomes (Box 1).

Box 1 Advantages and disadvantages of randomized controlled trials to assess maternal and neonatal safety of vaccines
  • Advantages:
    • Randomization reduces the possibility of confounding
    • Prospective monitoring of adverse events
    • Time and type of exposure is well defined
  • Limitations:
    • Unless seeking an indication for use in pregnancy, pregnant women are excluded
    • Exclusion of participants with underlying conditions that may increase the risk of adverse events
    • Relatively small sample sizes limit the detection of rare events
    • Complex and expensive
    • Short duration of study limits follow-up time of infants born to pregnant women

Pregnancy exposures to investigational medicinal products during clinical trials may occur inadvertently or intentionally. Intentionally if the study is specifically designed for seeking label indications in pregnant women. Inadvertently if a clinical trial includes women of child-bearing age who experience inadvertent pregnancy exposures to the investigational product. In either of these instances, it is important to collect and report the pregnancy outcomes, including pregnancy loss, stillbirth, and congenital anomalies, in accordance with applicable regulatory guidance documents.32,33 Pregnant women were inadvertently vaccinated for MenAfriVac, a meningococcal A conjugate vaccine trials in Africa, and their pregnancy outcome followed and recorded.34 Small numbers of pregnant women were also inadvertently enrolled in the SARS-CoV-2 vaccine clinical trials.35 Although the information generated by the follow-up of inadvertently exposed pregnant women is unlikely to provide conclusive evidence regarding vaccine safety or efficacy, it is relevant as it can be pooled with data from other studies and contribute valuable information as was done with data pertaining to COVID-19 vaccines.36,37,38

Clinical trials of vaccines specifically targeting pregnant women have been increasing in number. Oftentimes, when they are conducted, clinical trials during pregnancy occur during the post-approval or phase 4 studies in order to seek labeling for use in pregnancy.39 According to FDA, pre-licensure safety database for preventive vaccines for infectious diseases typically consists of at least 30,000 study participants vaccinated with the dosing regimen intended for licensure.40 Until the trial was discontinued, BioNTech SE and Pfizer conducted a phase 2/3, randomized, placebo-controlled, observer-blind study evaluating the safety, tolerability, and immunogenicity of their COVID-19 vaccine or placebo in approximately 350 healthy pregnant women 18 years of age or older vaccinated at 24 to 34 weeks' gestation.41 Secondary outcome measures include assessing the safety of maternal immunization in infants born to maternal participants who were vaccinated during pregnancy.


A mainstay of post-licensure vaccine safety surveillance is spontaneous or passive adverse event reporting. In this system, any healthcare provider, pharmaceutical company, and patient can report a suspected adverse event to a public health, governmental organization, or manufacturer via various mechanisms, including phone, internet, or paper-based systems. It is the most common way in which adverse events following immunization (AEFI) are identified and reported. For vaccine and drug manufacturers in most countries, adverse event reporting from the manufacturer to the appropriate regulatory agency or public health agency is a requirement. Spontaneous reporting systems are relatively easy and inexpensive to conduct and serve a vital role in detecting potential safety signals, such as identifying unexpected and rare adverse events. In the US, the Vaccine Adverse Event Reporting System (VAERS) identifies potential vaccine safety signals that can be further evaluated. VAERS has identified multiple safety concerns involving rotavirus, yellow fever, smallpox, and COVID-19 vaccines.42,43,44,45 Further, in the US healthcare providers are required by law to report to VAERS any adverse event listed in the VAERS Table of Reportable Events Following Vaccination that occurs within the specified time period after vaccinations as well as adverse events listed by the vaccine manufacturer as a contraindication to further doses of the vaccine.46,47 Notably, under emergency use authorization (EUA) healthcare providers are required by the US FDA to report COVID-19 vaccine associated serious adverse events (SAEs) and adverse events of special interest (AESIs) to VAERS.48 A review of reports to VAERS following COVID-19 vaccines in pregnant persons did not identify any concerning patterns of maternal or infant–fetal outcomes.49

For a variety of reasons, spontaneous surveillance systems have limited utility as a platform for maternal immunization surveillance, particularly in low- and middle-income (LMIC) settings (Box 2). Passive mechanisms of spontaneous reporting of adverse drug effects are generally inadequate to detect drug-induced fetal risks or the lack of such risks. A major limitation of spontaneous surveillance systems in LMICs is the extremely low reporting of AEFIs by healthcare providers. Spontaneous surveillance systems have other limitations in monitoring adverse events during pregnancy and pregnancy outcomes. Importantly, lack of a well-defined population denominator precludes measurement of incidence. Spontaneous reporting systems can be time consuming for already overburdened health professionals, reflect biases by both subjects and healthcare professionals. Patients and providers in LMICs may not have sufficient training, empowerment, or mechanisms for understanding and reporting events. These issues are prevalent in maternal health and perinatal outcomes, where the challenge of monitoring the pregnancy until delivery and postpartum could exacerbate the existing limitations. AEFIs from EPI programs are not commonly shared with national pharmacovigilance centers and therefore are not usually forwarded to the WHO Uppsala Monitoring Centre (UMC) for signal analysis. For these reasons, spontaneous surveillance systems cannot be relied on by themselves to identify post-market safety concerns with vaccines but can be useful for detecting signals of risk for further evaluation.

Box 2 Advantages and disadvantages of spontaneous reporting system to assess maternal and neonatal safety of vaccines
  • Advantages:
    • Relatively easy to implement
    • Captures a wide range of events
    • Useful to detect safety signals, especially for rare events
  • Limitations:
    • Low reporting
    • Lack of denominator data
    • Incomplete reports, lack of causality assessment
    • Subject to reporting biases including a general bias toward reporting more severe outcomes
    • Limited data on background population rates, and lack of comparison groups


Case-control studies compare a group of cases with a disease of interest to controls without the disease of interest. This type of study is useful for measuring multiple risk factors potentially associated with a disease or condition of interest, i.e., cases. Other advantages include the ability to study rare health events since a case-control study can be designed to identify a sufficient number of cases. A classic example is the study of diethylstilbestrol exposure during pregnancy and the risk of clear cell vaginal adenocarcinoma in young women that required the study of only eight cases and 40 controls.50 Case-control studies are typically faster to set up and less expensive to conduct than prospective cohort studies. Limitations of case-control studies are related with challenges on control selection and the risk of bias in collecting information about past exposures to medicines and other risk factors of interest (Box 3).51

Box 3 Advantages and disadvantages of case-control studies to assess maternal and neonatal safety of vaccines
  • Advantages:
    • Relatively easy to set up
    • Less expensive than a prospective study
    • Can often be completed in a short period of time
  • Limitations:
    • Challenges in selecting the appropriate control group
    • Bias (information bias and selection bias) in collecting vaccine and other exposures
    • Time of exposure can be affected by recall bias. This issue is particularly relevant in maternal health, where the exposure time can encounter the embryo in a sensitive period and result in birth defects. This means ensuring a correct time exposure collection is needed

The Slone Epidemiology Center at Boston University has been conducting case-control surveillance for birth defects since 1976.52,53 Briefly, infants with major structural defects (cases) are identified at study centers as well as from birth defect registries in selected states. Non-malformed infants (controls) are randomly selected each month from study hospitals’ discharge lists or state-wide vital statistics records. The Center’s work includes the National Birth Defects Prevention Study (NBDPS), followed by the Birth Defects Study to Evaluate Pregnancy Exposures (BD-STEPS). Data from the Slone Epidemiology Center studies assessed the safety of Tdap vaccine in both early and late pregnancy and found no evidence of appreciable risks was observed for selected specific major malformations associated with Tdap vaccine exposure during early or late pregnancy.54 Data from the Sloane Epidemiology Center’s Birth Defects Study were also used for the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) to evaluate the risks and safety of the medications and vaccines used by pregnant women using a prospective cohort and case-control surveillance.55,56 Another example is the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), now the basis of the Hungarian Congenital Abnormality Registry (HCAR), one of the largest case-control data sets of congenital abnormalities' surveillance in the world.57


Active surveillance seeks to ascertain completely the number of adverse events among a group of persons exposed to the medical product of interest, e.g., vaccine or drug, through a continuous pre-organized process. Data identified in active surveillance systems can be used to determine incidence rates, risk factors, and, if a comparison group is also studied, relative risks. Active surveillance designs include prospective and retrospective cohort studies, cohort event monitoring (a type of prospective cohort study), and pregnancy registries. A cohort study identifies a group of persons (or the records of a group of persons) without the disease or condition of interest at the onset of the study, ascertains the exposure status of each person, and then follows them over time to determine health outcome(s) of interest. Cohort studies (also called longitudinal studies) typically involve the comparison of the incidence of one or more outcomes of interest among those receiving the exposure of interest compared with an appropriate comparison group of non-exposed persons. Cohort studies can be prospective, whereby persons are followed over time and data about them is collected as their outcomes of interest occur. Conducting active surveillance in sentinel sites is an efficient approach to overcoming some of the logistical challenges of prospective cohort studies. Alternatively, cohort studies can be retrospective whereby individuals are sampled, and information is collected about their past exposures and other characteristics from pre-existing data sources. Retrospective cohort studies are useful when persons exposed to the vaccine of interest can be identified at some time in the past from pre-existing databases and followed via records' linkage over time to ascertain health outcome(s) of interest.58

Cohort event monitoring

Cohort event monitoring (CEM) enrolls a group of people taking a drug or vaccine in a prospective cohort study and then systematically records data on all adverse events that occur in those patients. Sentinel surveillance programs based on a few select sites can also provide substantial, high-quality data from a smaller population with the added benefit of logistical ease. CEM is especially useful in LMICs.59 Examples of CEM in LMICs include cohort studies of AEFIs associated with the administration of a pentavalent DTP-hepatitis B vaccine/Hib vaccine conducted in Ghana, Guatemala, and India and AEFIs following administration of Japanese Encephalitis vaccine in an endemic district in Sri Lanka.60,61,62,63

Pregnancy registries

Pregnancy registries, also known as pregnancy exposure registries, are an essential tool for monitoring the safety of vaccines and other medical products used during pregnancy. Pregnancy registries actively collect information on exposures of interest during pregnancy and associated pregnancy and infant outcomes (Table 1). When data from pregnancy registries are collected in a harmonized and standardized manner and properly assessed for causality, they contribute to benefit–risk assessments, product labeling, and guidance for regulators, healthcare providers, and the public throughout a medical product’s life-cycle. The US FDA and the EMA recommend active surveillance, such as pregnancy registries, for medical products on the market that are likely to be used during pregnancy or by women of childbearing age.64,65,66


Types of data useful for assessing the safety of vaccines used during pregnancy.67,68

Type of data



Vaccine administered, including the specific vaccine administered, doses given, whether provided during antenatal care or some other means, and the gestational timing of vaccine administration


Live birth

Miscarriage (loss before 20 weeks)

Elective termination

Fetal death/stillbirth (loss after 20 weeks)

Measures of fetal growth deficiency (small for gestational age)

Preterm delivery

Other pregnancy complications: developmental milestones or neurologic abnormalities in offspring of exposed mothers; abnormalities of immune system development in offspring of exposed mothers

Additional adverse events of special interest (AESI), both pregnancy outcomes and neonatal outcomes – general ones relevant to all vaccines and the specific vaccines or vaccine platforms

Covariates – potential confounders

Data should be collected on the pregnant woman’s pertinent medical history, current disease status, and overall management, including concomitant medications. Other potential confounders for which data should be collected include, for example, socioeconomic status, maternal age, tobacco and alcohol use, illegal drug use, maternal body mass index, folic acid and vitamin use during the pregnancy, obstetrical history, medical history, family history of adverse pregnancy outcomes, including MCMs, and other relevant confounders

While pregnancy registries are more common in high-income countries, there are few examples of pregnancy registries conducted in LMICs. The Western Cape Pregnancy Exposure Registry (PER) was established at two public sector healthcare sentinel sites in the Western Cape province, South Africa, to provide ongoing surveillance of drug exposures in pregnancy and associations with pregnancy outcomes.69 This PER integrated data collection into existing services and information platforms and supports routine operations. Another example of a pregnancy registry in LMICs is the Assessment of the Safety of Antimalarials used during Pregnancy (ASAP) study that took place in Kenya, Mozambique, and Burkina Faso.83 Conducted through the Malaria in Pregnancy Consortium, the researchers performed a meta-analysis of ASAP and other prospective observational studies and found no difference in the risk of miscarriage, stillbirth, or major congenital anomalies associated with artemisinins used during the first trimester compared with the use of quinine during the same gestational period.70 The MiMBa (Malaria in Mothers and Babies) Pregnancy Registry is a multi-country observational study being deployed in several field sites in Africa to generate robust evidence on the safety of a range of antimalarials when used in pregnancy, particularly in the first trimester of pregnancy.71

Pregnancy registries have numerous advantages.72 By enrolling women before outcomes are known, the prospective approach of pregnancy registries avoids recall and reporting biases of both patients and providers, allows for the systematic recording of concomitant diseases and medications, and can use standardized methods to assess outcomes. The availability of both numerator and denominator data allows calculations of baseline rates of events (including AEFIs), and disease incidence in vaccinated and unvaccinated populations. Pregnancy exposure registries have had some success in providing reassurance that certain drugs or vaccines are overall not major teratogens.73,74 Pregnancy registries have also had success in generating signals of potential teratogenicity that require further investigation. Maternal and neonatal data collection systems in LMICs could potentially help to inform the conduct of maternal immunization active vaccine safety surveillance.75

Pregnancy registries, as do other active surveillance, have limitations (Box 4). Because reporting for some pregnancy registries is generally voluntary, prospectively reported pregnancies may lead to reporting bias toward high-risk pregnancies. Women who consent to take part in a study may have different characteristics from those who do not consent, introducing selection bias. Moreover, abnormal outcomes are more likely to be reported than normal outcomes. Enrollment of women limited to those who attend antenatal care may bias results and diminish the generalizability of findings. Late disclosure of pregnancy and late initiation of antenatal care limit information regarding the first trimester of pregnancy, gestational age dating, and early pregnancy loss. Without close attention to quality, data quality can be poor and non-standardized, including data on drug and vaccine exposures, pregnancy complications, and detection of adverse pregnancy outcomes. Home births and migration increase the potential for loss to follow-up, which may bias results. Few pregnancy registries follow the health of children beyond the newborn period.

Box 4 Advantages and limitations of pregnancy registries and other prospective active surveillance approaches to assess maternal and neonatal safety of vaccines
  • Advantages:
    • Designed to collect information on specific exposures of interest and monitor pregnancy outcomes
    • Relatively easy to collect accurate and complete data
    • Can be used to assess the risk of multiple exposures and pregnancy outcomes
  • Limitations:
    • Challenges in selecting the appropriate participants for the cohort, prone to selection bias
    • Large sample sizes are required when studying rare outcomes
    • Duration of follow-up may not be long enough for rare or delayed events to be recorded
    • Studies may be expensive to implement
    • Prone to high dropout rates. This issue is particularly relevant in maternal health, where follow-ups may be lost before pregnancy outcomes are recorded


Self-controlled designs

Self-controlled case series (SCCS) and self-controlled risk interval (SCRI) designs have been used in vaccine safety surveillance for influenza, MMR, and vaccines containing pertussis antigens. The SCCS method requires identification of events and times of vaccination occurring within a defined period of person-time to estimate the relative incidence of rare adverse events after vaccination.76,77,78 In this study design, incidence rates during exposed time are compared to incidence rates during unexposed time, but only cases are included, thus avoiding the need for large population cohorts or the need for selecting controls. Another advantage of the method is its implicit control for non-time-varying covariates, such as sex, birth order, and socioeconomic status – covariates that may not always be available in some settings. The SCCS design was used to study H1N1 vaccination during pregnancy and the risk of spontaneous abortions based on computerized data from the Taiwan National Health Insurance database and the Taiwan Birth Registry.79 The self-controlled risk interval (SCRI) method includes vaccinated individuals only and compares the incidence rates during risk and non-risk timeframes.80,81 A population-based cohort study with nested self-controlled risk interval (SCRI) was conducted using healthcare data from five European databases to study COVID-19 vaccines and the risk of myo-/pericarditis.82

Records' linkage

Cohort studies, especially retrospective cohort studies, using records' linkage with various health and administrative databases are now commonly used and have the advantage of identifying large numbers of pregnant women exposed to particular vaccines and other medicines.

Health and Demographic Surveillance Systems

Health and Demographic Surveillance Systems (HDSS) are sentinel surveillance sites that monitor demographic events including births, deaths, migration, and key health indicators of the entire population living in a defined geographic area with all households mapped and enumerated.83 HDSS data are collected via face-to-face household interviews in which household residents are asked about events that occurred since the prior survey. Data collection is organized at the household and individual levels, thereby making it possible to link information on mothers and children longitudinally over time, which provides crucial information for monitoring AEFIs following maternal immunization. Many HDSS sites are coordinated by the International Network for the Demographic Evaluation of Populations and their Health (INDEPTH), which is made up of 46 member sites in 20 countries, mostly based in Africa and Asia where civil registration systems have been historically lacking. All INDEPTH sites collect a core set of standard indicators that allow for data to be compared, although, to date, many sites do not strictly adhere to standardized definitions or measures, with data collection being flexible and modified according to country and program needs.

Advantages of HDSS sites includes their capture of standardized data on all residents of a particular area that provides denominator data and therefore the capacity to calculate rates. While HDSS sites vary in size, they have the advantage of monitoring populations with a relatively large sample size. HDSS systems have a number of limitations. Population size may be limited, and results may not be generalizable to other national or regional populations. Health information is self-reported and can be affected by limitations in the informant’s medical knowledge, recall bias particularly in sites where household visits are less frequent, lack of validation by medical records, and lack of awareness of asymptomatic events. Despite these limitations, HDSS and other sentinel population cohorts provide a platform for adding information relevant for monitoring MNCH health and disease and standard reporting for AEFIs.84 Some HDSS sites have integrated electronic data collection from health facilities that are linked to the household interviews.85,86 HDSS sites have already been used for pharmacovigilance projects in pregnancy.87,88

Vaccine Safety Datalink

The US FDA The Vaccine Safety Datalink (VSD) is a collaborative project between CDC’s Immunization Safety Office and nine healthcare organizations.89 The VSD started in 1990 and continues today in order to monitor safety of vaccines and conduct studies about rare and serious adverse events following immunization. The VSD uses electronic health data from each participating site, including information on vaccines, such as the type of vaccine given to each patient, date of vaccination, and other vaccinations given on the same day. The VSD also uses information on medical illnesses that have been diagnosed at doctors’ offices, urgent care visits, emergency department visits, and hospital stays. The VSD conducts vaccine safety studies based on questions or concerns raised from the medical literature and reports to the Vaccine Adverse Event Reporting System (VAERS). When there are new vaccines that have been recommended for use in the US or if there are changes in how a vaccine is recommended, the VSD monitors the safety of these vaccines. The VSD has a long history of monitoring and evaluating the safety of vaccines. Investigators from the VSD have published studies to address vaccine safety concerns related to pregnancy and vaccination during pregnancy.90,91 The VSD has developed algorithms to identify pregnant women and determine the start and end dates of the pregnancy. VSD is also able to use data to study the health of children born to women who were vaccinated during pregnancy.92


In 2018, the Bill & Melinda Gates Foundation convened a global expert meeting to discuss a framework for appropriate pharmacovigilance for vaccines used during pregnancy based on integrated maternal interventions vigilance systems and collection of appropriate data to inform timely decision-making by and for pregnant women. Recommended priority actions relevant to safety surveillance systems were the following:

  • Develop and utilize background rates for disease and pregnancy events and outcomes to evaluate vaccine safety and effectiveness.
  • Adopt standardized definitions to assess and allow comparability of MCH events and outcomes through the work of Global Alignment of Immunization safety Assessment in pregnancy (GAIA) and the WHO and adopt standardized AEFI reporting terms based on the Medical Dictionary for Regulatory Activities (MedRA) and International Classification of Diseases-11 (ICD-11).93,94
  • Implement passive safety surveillance systems (local and regional).
  • Implement active safety surveillance programs (sentinel sites in strategic locations).
  • Develop product-specific safety surveillance guidance documents and protocols.
  • Develop communication plans and risk-management plans.

Since some adverse reproductive outcomes are relatively rare, pooling of data, especially for systematic reviews and meta-analysis, is needed to allow for the study of rare events as well as comparisons of vaccine performance in different populations. This requires standardized definitions and reporting terms as well as harmonized protocols for pregnancy registries and associated tools.


  • Health professionals should assess or reassess the need for drugs and vaccines in women planning a pregnancy, or who become pregnant, taking into account and balancing risks of against the benefits for the mother and fetus. Work with patients to ensure that they are taking only what is necessary.
  • Health professionals should consider participating in a prospective pregnancy registry study if a patient is taking certain drugs or vaccines during pregnancy in order to provide much-needed information on medication and vaccine safety in pregnancy.
  • Healthcare providers can contribute to our knowledge of vaccine safety by reporting clinically important adverse events following vaccination to the national public health agency or pharmacovigilance program.


Andy Stergachis serves on the executive board of the CEPI-funded Safety Platform for Emergency Vaccines (SPEAC), is a member of the the CEPI Maternal Immunization Working Group, serves as a consultant to PATH on landscape assessment of pregnancy exposure registries, and his university currently receives research support for pharmacovigilance work from USAID the Bill Melinda Gates Foundation.

Esperanca Sevene has no conflicts of interest.



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