Globally, an estimated 213 million pregnancies occur annually [1]. Women represent 71 % of the global workforce of the health sector and this percentage is likely to be higher in low- and middle-income countries (LMICs) [2–4]. It is estimated that at any given time in the United States (US) there are over 300,000 women of child-bearing age, i.e., 15–49 years old in the healthcare workforce, and in the WHO regions, 67 % of the healthcare workforce are female, particularly in the nursing and midwifery workforce [5,6]. Healthcare-related occupations are critical during an epidemic or pandemic responses and should, therefore, be prioritized for vaccine allocation, as was seen during the COVID-19 pandemic [7]. In addition, women often have jobs that are associated with high risk of exposure, such as childcare providers, teachers, public-facing and hospitality workers, and caregivers. The COVID-19 pandemic highlighted the urgent need for guidance on immunization strategies for pregnant and breast-feeding women, especially for those who rely on employment in these high-risk occupations.

In addition, pregnant women and their fetuses are at increased risk for severe disease and death from SARS-CoV-2 and other respiratory and emerging pathogens, often in association with pregnancy physiology [8–12]. Older pregnant women (36–44 years), and those who have underlying medical conditions, such as obesity, gestational diabetes or hypertension, might be at higher risk of severe disease, similar to the higher risks seen in older individuals and those with underlying medical conditions in the general population [13–16]. Data from high income countries (HICs) suggest that adverse birth outcomes, such as preterm delivery and stillbirth, are more common among pregnant women infected with SARS-CoV-2, while in endemic areas, pregnant women infected with Ebola and Lassa fever also have higher risk of these outcomes compared with non-infected individuals [13,16–20].

Healthcare access disparities affect pregnant women worldwide. Studies from the US and the United Kingdom reported that Black and Hispanic pregnant women were at higher risk of severe disease and hospitalization than nonpregnant women [12,18]. Limited pregnancy-specific data are available from LMICs, mainly due to a lack of data collection infrastructures. The results from a meta-analysis showed that the overall risk of adverse pregnancy outcomes was higher in LMICs than in HICs (OR 2.4) [21]. COVID-19-related abortion (OR 6.2), still-births (OR 2.0), and maternal death (OR 7.8) were more common in LMICs compared with HIC [21]. Additional data will be needed to inform local decision-making and improve acceptance of vaccines for pregnant and breast-feeding women.

Vaccines for pregnant women are one of the most important public health measures undertaken globally to reduce the burden of disease in mothers and infants from tetanus, pertussis and seasonal influenza. During previous pandemics caused by respiratory pathogens, such as influenza A/H1N1pdm09, infection in pregnant women was associated with an increased risk for severe disease and hospitalization, and pregnant women have subsequently been prioritized for immunization [22–24]. Ebola vaccines are being evaluated in pregnant women in epidemic regions in West Africa, with observational studies evaluating vaccines since 2016 and interventional studies since 2020 [25,26].

Various organizations, including the U.S. National Academy of Medicine (NAM), the American College of Obstetrics and Gynecology (ACOG), the Pregnancy Research Ethics for Vaccines, Epidemics, and new Technologies (PREVENT) group, and the World Health Organization (WHO), supported the position that pregnant and breast-feeding women are a priority population that must not be excluded from COVID-19 vaccine allocation strategies [23,27–30]. Reports from observational cohort studies conducted in countries that included pregnant women early in their COVID-19 vaccine implementation strategies, such as Israel, demonstrated a significantly lower risk of SARS-CoV-2 infection among vaccinated pregnant women compared with unvaccinated pregnant women (adjusted hazard ratio 0.22, 95 % CI: 0.11–0.43) [31].

The Council for International Organizations of Medical Sciences (CIOMS) and the United Nations AIDS/World Health Organization guidelines, in 2002 and 2005, respectively, encouraged the inclusion of pregnant women in clinical studies [32,33]. More recently, the U.S. Food and Drug Administration (FDA) draft guidance for the pharmaceutical industry also supported for the inclusion of pregnant women in clinical trials [34]. Exclusion of pregnant women from clinical trials can lead to a lack of data that is needed to make informed decisions about the potential benefits and risks of medications and vaccines administered during pregnancy.

It has been reported that recruitment and retention of pregnant women in clinical trials is challenging [35–37]. Although pregnant women have been reported to be willing to participate in clinical research, they are more willing to participate in observational or retrospective studies or life-style interventional studies than randomized trials, particularly those including placebo groups [38,39]. Strategies for encouraging pregnant women to participate in clinical trials should be evaluated [39].

In 2020 in their guidance for developing and licensing COVID-19 vaccines FDA encouraged vaccine manufacturers to collect and consider “data that might support inclusion of pregnant women and women of childbearing potential who are not actively avoiding pregnancy in prelicensure clinical trials” because the use of “COVID-19 preventive vaccines during pregnancy and in women of childbearing potential will be an important consideration for vaccination programs” [40]. However, the guidance did not specify what data should be collected.

In April 2020, in response to the COVID-19 pandemic, a global collaboration, the Access to COVID-19 Tools (ACT) Accelerator, was launched to facilitate the development, production of COVID-19 tests, treatments, and vaccines, and to ensure equitable access [41]. The ACT Accelerator’s SARS-CoV-2 vaccine research, development and manufacturing workstream included a Clinical Development and Operations Specialized Working Team (SWAT) to identify tools and provide support for vaccine developers to facilitate COVID-19 vaccine licensure. The SWAT team established the COVID-19 Vaccines Global Access and Coalition of Epidemic Preparedness Innovation (COVAX-CEPI) Maternal Immunization Working Group (MIWG) in August 2020 to address the needs of pregnant and breast-feeding women during the COVID-19 pandemic. In 2022 the group integrated into the Special Populations MIWG of the Safety Platform for Emergency Vaccines (SPEAC)-Brighton Collaboration project supported by CEPI. The members of the MIWG included professionals with expertise in various aspects of maternal immunization that represented diverse backgrounds, organizations, and geographical settings (Appendix 1).

The principal goal of the MIWG is to facilitate access to vaccine candidates that are suitable for use in pregnant and breast-feeding women by:

Three work stream groups were set up to cover issues relevant to the inclusion of pregnant women in the vaccine development pathway, from the pre-clinical phase through to the post-licensure phase. During weekly or bi-weekly meetings, work stream representatives shared their findings with the group and identified areas of consensus to refine and address their key questions. The groups also solicited input from external subject matter experts as needed. Ethics and regulatory advisors in the group reviewed work stream discussions and outputs and provided guidance.

The MIWG developed key questions to be used as an evaluation framework for all stages of vaccine development for different vaccine platforms for use in pregnant and breast-feeding women, including in future pandemics or outbreaks (Table 1). The framework was designed to guide the evaluation of candidate vaccines rather to be used as a mandatory checklist. It is not intended to be either exhaustive or required in all instances and should not hinder the development of clinical trial protocols.

The key questions table is divided into sections addressing general topics for the evaluation of candidate vaccines in pregnant and breast-feeding women (Table 1). The questions were developed to be used as a guide for the assessment of vaccines. It is recommended to start with the questions in Section A and work through the sections sequentially to Section E. These questions serve as a guide and it is possible that not all questions will be completely answered, and, in some situations, some may not even be addressed if data is not available (e.g. in LMIC). The sources of information, as well as the date of the data review should be documented for each answer. These sources may include publications, studies in progress, guidance documents, policy statements, vaccine recommendations, and others, as pertinent. The key questions may be readdressed, as new information emerges.

The questions in section A establish the impact and burden of the disease or pathogen in this population, as well as in the infants’ fetal and neonatal periods. Those is section B aims to seek product or platform specific information. Some of this information will not be unique to this population, but any data from adult populations, particularly women of childbearing age, will be informative. It is recommended to use the BRAVATO (Brighton Collaboration Benefit-Risk Assessment of Vaccines by Technology) templates for specific vaccine constructs to gather product-specific information, and to complete these with additional pregnancy-related questions provided in the questionnaire [42].

The questions in section C aim to collect information relevant to all vaccines that can be considered for pregnant and breast-feeding women, irrespective of the specific product or vaccine platform. Some of the questions may need to be fully addressed before vaccine studies or implementation are possible. It is recommended to seek relevant regulatory agency guidance to determine which items need to be addressed at each phase of vaccine development.

The questions in section D seek information for the safety evaluation of all vaccines to be used in pregnant and breast-feeding women, both during clinical trials as well as post-licensure. It is recommended to consider the establishment of safety surveillance plans, registries, retrospective studies and evaluation, etc. These activities should include clear communications and risk mitigation plans, educational activities, and promotion of vaccination.

Lastly, the questions in section E provide a suggested framework to summarize the results of the evaluation and assessment of candidate vaccines used in pregnant and breast-feeding women, identify data gaps, and serve as a tool for generating hypotheses for further research and surveillance, as well as for developing vaccine implementation plans.

It is essential to include pregnant and breast-feeding women in studies assessing vaccines against emerging pathogens, as they are often at high-risk for severe disease and potential adverse maternal and neonatal outcomes. Their inclusion in studies is critical to generate robust pre-licensure data on vaccines. Data for pregnant and breast-feeding women should continue to be assessed in post-licensure surveillance and other evaluations, to help identify which candidate vaccines and which approved vaccines are safe and optimal for use in these special populations. Concerted efforts are needed to alleviate concerns that vaccines for emerging pathogens will be rushed to market without adequate safety evaluation in pregnant and breast-feeding women.

The key questions developed by the MIWG will be a valuable tool for researchers and other key stakeholders to assess the suitability of new vaccines for pregnant and breast-feeding women. When feasible, pregnant and breast-feeding women should be included in vaccine trials to help guide regulatory and policy recommendations at the time of licensure or shortly after. Post-approval (e.g., under emergency or compassionate use authorization) or continued post-licensure surveillance studies will be necessary to characterize the benefit-risk profile in larger populations of pregnant and breastfeeding women.

The purpose of this tool is to provide a template for researchers and decision makers to consider the relevant aspects necessary to support the use of a vaccine in pregnancy or post-partum, with all elements considered important, and therefore not prioritized or mandated. The use of this tool should not hinder the development of clinical trials in emergency situations, including in LMIC, where the availability of some data might be limited. Input from pertinent regulatory agencies should be sought throughout the process of evaluation and implementation of vaccines for pregnant and breast-feeding women.