To develop a set of core outcomes on maternal and perinatal health to be reported in research and surveillance studies during emerging and ongoing epidemic threats, and to reach a consensus on the definitions of outcomes and methods of measurement, based on the results of a literature review and expert consensus-building process.

This protocol was developed following the COS-STAP (Core Outcome Set-STAndardised Protocol Items) Statement.

Health conditions and population. The domain of the study focuses on maternal and perinatal health. The COS will be applicable to epidemiological, clinical, and post-authorization research and surveillance studies concerning pregnant women, women in the postpartum or post-pregnancy period, and their offspring (embryos, fetuses, neonates) who are exposed to disease outbreaks (including epidemics and pandemics), in any country or setting. The study population includes all persons with gestational capacity, which here are being referred to as women.

An epidemic can be considered the simultaneous consolidation of multiple outbreaks over a wide geographical area. This usually involves the occurrence of a large number of new cases in a short time, which is greater than the expected number ¹⁴ .

Type of exposure. Any ongoing or emerging infectious disease epidemic, including those specified in the list of pathogens with epidemic and pandemic potential, regardless of the interventions eventually assessed. This may include, but is not limited to, Influenza, Ebola, Zika, Chikungunya, Dengue, Cholera, Yellow fever, and Coronaviruses of epidemic/pandemic potential.

Context. The COS will be developed for use in maternal and perinatal epidemiological studies, clinical studies assessing the safety and efficacy of preventive and therapeutic interventions, and post-authorization safety, effectiveness, and disease surveillance in the context of disease outbreaks (including epidemics and pandemics).

It is expected that this COS will be applied in any country (including LMICs) or setting (community, primary health care, secondary, and tertiary care), in both rural and urban settings.

We will define a set of maternal and perinatal outcomes to be reported in epidemiological studies, product development (vaccines and therapeutics), and post-authorization safety, effectiveness, and disease surveillance during emerging and ongoing epidemic threats following COMET guidelines ¹² , by conducting a systematic review of the literature and building consensus among key stakeholders.

When developing a COS, the first step in determining “What to measure” is to explore existing knowledge about outcomes to inform the consensus process that follows. A systematic review of published and ongoing studies will be conducted according to the recommendations outlined in The Cochrane Handbook of Systematic Reviews of Interventions ¹⁵ and PRISMA ¹⁶ . The purpose is to identify maternal and perinatal outcomes reported by researchers conducting studies during disease outbreaks, epidemics, or pandemics.

This systematic review will answer the following question: What are the maternal and perinatal health outcomes assessed during disease outbreaks, including pandemics and epidemics, in ongoing studies as well as those published in the period between 2015 and March 2023? The methods for this review are detailed in PROSPERO ( ID=CRD42023423196), and the search strategy is available at https://www.crd.york.ac.uk/PROSPEROFILES/423196_STRATEGY_20230502.pdf.

For data synthesis, the review team will systematically categorize each outcome under a new taxonomy for outcome classification that was developed from outcomes extracted from all published COS in the COMET database, selected Cochrane reviews, and clinical trial registries ¹⁷ to provide a structured conceptual framework and facilitate the presentation and interpretation of outcomes. The following categories may be considered as other options for group outcomes.

The outcomes will also be categorized according to the type of research: a) epidemiological studies to understand disease burden and severity, risk factors, and case ascertainment; b) intervention studies that aim to test novel or repurposed preventive and therapeutic interventions; and c) studies on post-authorization safety and effectiveness surveillance.

The outcomes identified through this systematic review will be considered in the Delphi survey.

Expert consensus on a core outcome set for maternal and perinatal health to be reported in studies during emerging and ongoing epidemic threats will be achieved through an iterative fourth-stage modified Delphi process ( Figure 1). The consensus process will start with an international two-round online modified Delphi survey involving four key stakeholder panels; a virtual meeting to analyze and deliberate on the results of the second round, and resolve any disagreements; and conclude with a face-to-face meeting to finalize the above-mentioned COS and agree on the definitions of outcomes and methods of measurement. The Delphi process is a well-established tool with the advantage of being initially anonymous, thereby avoiding the overinfluence of dominant individuals and allowing participation from multiple geographies ¹⁸ . The modified Delphi version was chosen, with a virtual meeting in the third round and a face-to-face meeting in the last round, because it enables a more effective interaction in the final round, given that further clarification or in-depth discussion might be required to resolve any potential disagreements ¹⁹ .

Each expert panel should have between 7 and 15 members ¹⁹ . We will recruit a minimum of 20 participants for each stakeholder group (maternal and perinatal health, neonatal health, public health and emergency response, and civil society), assuming a potential 20% attrition with a balanced gender and regional representation. Participant Information Sheets will be developed and piloted to clarify the terminology among representatives of the civil society.

The first round will begin by administering a piloted questionnaire that will include the complete list of coded outcomes derived from the systematic review. Before starting the first survey, we will ask participants to verify their eligibility, interest in participating and commitment to participate in at least two surveys that will be conducted two months apart. Participants will be asked to rate the importance of each outcome to be reported in studies undertaken during disease outbreaks on a nine-point differential Likert scale ranging from 1 to 9 and categorized as:1–3 ‘not important’; 4–6 ‘important but not critical’; and 7–9 ‘critical.’ ²⁰ . Each questionnaire will have a set of closed-ended and open-ended questions to collect expert ratings, allow participants propose additional outcomes, and provide comments. Electronic surveys will be designed and administered by Delphi Manager ( www.comet-initiative.org/delphimanager/). Experts will be given three to four weeks to complete each survey.

The second survey will involve re-rating items which were the subject of disagreement within and among stakeholder groups. The additional outcomes listed by the participants will be incorporated into the second survey. To build a consensus, differing views need to be reconciled. Feedback between rounds will be presented to enable different opinions to be considered before re-rating an outcome.

Weekly reminders will be sent out during three consecutive weeks to participants who have not completed the survey with the intention of reaching a minimum of 80% response rate in each round. Participants will be asked to complete the surveys independently, anonymously, and in a manner that reflects their personal views. In round 1, they will also be asked to provide a short set of sociodemographic variables (i.e., age, gender, geographical location, and expertise).

After completing the two online surveys, a purposive sample of approximately 20 experts representing four key stakeholder groups will review the findings from previous rounds and discuss all disagreements and draft the COS in an online meeting. Experts will be selected in a manner that respects equitable geographical representation of all six WHO regions, gender balance and diverse technical expertise.

All participants of the online meeting will gather again at a WHO in-person consultation in Geneva, which will be dedicated to finalizing the above-mentioned COS and reaching a consensus on the definitions of the outcomes and methods of their measurement.

Presentations and discussions will be held in plenary sessions, and electronic platforms will be used to record the final decisions made anonymously by members of the expert group.

A guidance document will be offered to the participants prior to the consultation to help steer discussions and promote inclusiveness. The chair of the meeting will ensure that all participants can express their opinions freely and that their views are equally valued.

Following the COMET Handbook criteria ¹² for retaining or dropping items between rounds, the following definitions will be applied to select core outcomes and determine agreement:

In cases where the systematic review yields an extensive list of outcomes and a greater-than-anticipated level of disagreement arises, we will apply more adaptable selection criteria, aligning them with the established criteria used by other research groups. These refined criteria will be clearly communicated to participants in the subsequent rounds of the process.

In addition, we will determine the degree of agreement stability by measuring the increase or reduction in variability of individual outcome ratings across rounds (comparison of interquartile ranges across rounds for each outcome).

To ensure an appropriate and acceptable core outcome set, it is essential to incorporate a diverse range of views and expertise. With this goal in mind, we will actively seek the participation of key stakeholders from around the world in the consensus process, to discuss, advise, and rate the core outcomes. We will divide the stakeholders into four distinct panels:

Panel 1: Maternal and perinatal health. This panel will consist of senior clinical experts and researchers with proven knowledge and experience in the field of maternal and perinatal health. We are specifically looking for individuals who have expertise in antepartum, intrapartum, and postpartum care and research, as well as abortion and post-abortion care; preferably, who have conducted research or been involved in operational or policy aspects during previous epidemic threats. Midwives, nurses, obstetricians, gynecologists, anesthetists, general/family medical doctors, maternal critical care specialists, clinical investigators/trialists, and perinatal epidemiologists will be invited to participate in this panel. Regulators, funders, safety experts, and pharmacists working in the maternal and perinatal fields will also be invited.

Panel 2: Neonatal health. This panel consists of senior clinical experts and researchers with proven knowledge and experience in the field of neonatal health (newborns up to 28 days of life). We are seeking individuals who have expertise in various aspects of neonatal care, including postnatal care, newborn immunization, breastfeeding, managing small and sick newborns, newborns with congenital abnormalities, and requiring admission to intensive care units. Preferably, panelists will have conducted research during previous epidemic threats. Nurses, neonatologists, pediatric infectious disease specialists, lactation consultants, and specialists in birth defects who meet the specified inclusion criteria will be invited to participate. Regulators, funders, safety experts, and pharmacists working in the neonatal and pediatric fields will also be invited.

Panel 3: Public health and emergency response. This panel will consist of senior experts with proven knowledge and experience in planning (prevention and preparedness), management (mitigation, early response, recovery, and reconstruction), and responding to public health emergencies during epidemic threats at different levels (such as regional, national, and district). A range of health professionals with diverse backgrounds, including program managers, medical doctors, nurses, laboratory technicians and professionals, infectious disease experts, experts in public health, infection prevention and control experts, psychologists, social workers, epidemiologists, surveillance experts, and funders, will be invited to participate. It is preferable that these experts possess some experience in the field of maternal and perinatal health.

Panel 4: Representatives of the civil society. This panel will consist of individuals with diverse backgrounds and areas of expertise dedicated to ensuring the well-being of women and families during the various stages of pregnancy, childbirth, and post-pregnancy, especially during epidemic threats. This panel will include women representatives, community advocates, and patient representatives.

Special emphasis will be placed on including participants from LMICs and from geographies where outbreaks are common and practice and make decisions in less resourced settings.

Participants in panels 1, 2, and 3 will be selected from a wide range of groups and organizations, including the World Health Organization (WHO) collaboration networks such as Guideline Development Groups. Experts from the WHO regional offices and leading researchers in the field will also be considered.

Partnerships, alliances, and other non-governmental organizations (NGOs) dedicated to women and children's health, such as the Partnership for Maternal, Newborn, and Child Health (PMNCH) ²¹ and the IBP Network ²² , among others, will be contacted to identify potential panelists with diverse expertise and practical experience to participate in Panel 4.

Representatives of the civil society will be invited to participate in online surveys to rate the proposed outcomes and propose additional outcomes not identified in the systematic review. This group will take the form of an independent panel to reduce the influence of professionals ²³ and will be given as much weight as the rest of the panels. In the third round, 25% of the participants who will meet virtually and face-to-face to discuss the final COS will be representatives of women and the community of patients. This group will participate in the development and execution of the dissemination plan.

Outcome scoring/feedback. Participants will be asked to rate the importance of each outcome on a nine-point differential Likert scale ranging from 1= ‘not important’ to 9= ‘critically important’ to be reported on studies during emerging and ongoing epidemic threats ²⁰ .

Feedback between rounds will be presented to enable the consideration of different opinions before re-rating an outcome. At the end of each round, the results for each outcome will be summarized and presented with descriptive statistics and graphical representations (histograms) when appropriate. The median rating of each stakeholder group will be incorporated into the second survey. The analysis of open-ended questions with openly stated reasoning behind the given ratings will be included in the feedback.

Open-ended questions and group discussions will be analyzed using content analysis. The responses will be coded by one researcher and reviewed by another researcher. Matrices will then be developed to help interpret these findings. The analysis process will be facilitated using the qualitative data management software Atlas.ti 8.4. All comments and opinions provided by the panelists will be included in the findings, regardless of whether one or more panelists mentioned them.

Outcome definitions. During the systematic review of the literature, outcomes will be extracted using verbatim wording, and definitions will be grouped under the same outcome name. We will prepare a report describing different definitions, data sources, and frequencies.

The COMET handbook recommends that the outcome definition be generated after identifying the outcome set to deepen the discussion on a limited set of outcomes, rather than working with the original list, which is usually quite extensive. If the selected outcomes already have validated definitions previously published by the WHO, CDC, or Brighton Collaboration, it may not be necessary to discuss definitions based on the results of the systematic review with experts participating in the meetings. Conversely, some outcomes that do not have validated, detailed definitions may be selected, and in such a case, these definitions could be discussed and voted on during the face-to-face meeting.

Measurement instruments. An outcome measurement instrument is a means by which a particular outcome is assessed and quantified. These instruments can take various forms, such as single questions, questionnaires, performance-based tests, physical examinations, laboratory measurements, and imaging techniques ²⁴ .

For each outcome included in the COS, we will list and describe the definitions and measurement instruments/techniques reported by authors in the following sources of information: a) systematic review that we will conduct in phase 1; b) other maternal and newborn health published COS; c) GAIA ¹³ ; and d) COSMIN database ( https://database.cosmin.nl/). To describe the psychometric properties of the instruments, we will review the COSMIN database of systematic reviews of measures of outcomes in addition to the above sources. The collected information will be reported and disseminated among participants as pre-reading materials. During the in-person meeting, the results will be presented, a plenary discussion will be facilitated, and participants will be asked to rate definitions and measurement methods guided by pre-established criteria, such as feasibility, accuracy, acceptability and resources required.

This study will be prospectively registered with the COMET. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with ID CRD42023423196. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement ( http://www.prisma-statement.org/) to report the systematic review findings, and the Core Outcome Set–STAndards for Reporting (COS-STAR) Statement to report the final COS ²⁵ .

The Core Outcome Set-STAndard for Reporting (COS-STAR) ²⁵ will be used to report the COS. These guidelines were developed as reporting guidelines for COS studies. The COS-STAR statement comprises an 18-item checklist that has been deemed essential for complete and transparent reporting in COS studies. The checklist items are centered on the introduction, methods, results, and discussion sections of manuscripts describing the development of a certain COS. While it was developed by a panel of developers, methodologists, journal editors, potential users, and patient representatives, a possible limitation of COS-STAR is that it was largely developed without input from representatives from middle- or lower-income countries. The guidelines can still be applied to studies carried out in these settings, but may require some adaptations to encompass the additional challenges of developing COS in these settings. Given the numerous ongoing COS studies, the COS-STAR Statement is poised to serve as a valuable tool for enhancing the reporting of COS studies, ultimately benefiting all users of COS.

As part of the data management strategy, we will have designated staff to monitor missing data in the databases, and we will send reminders to participants if their records exceed a 20% missing data threshold.

The frequency of missing responses will be quantified and reported with the results of each Delphi round. If the second round shows more than a 20% loss of follow-up responses, then the rating distribution of the first round will be compared between participants who completed both rounds and those who completed only one round to compare and eventually identify any potential attrition bias.

Ethics approval/informed consent. The modified Delphi process does not usually require an ethics approval. Nevertheless, the protocol and its annexes were submitted to the Research Ethics Review Committee (Geneva) and the RESPIRE Research Ethics Committee (Argentina) to assess whether they required a full review. This Delphi was exempt from WHO Ethics Review Committee review. However, invited participants will be asked to provide written consent and declare any potential conflicts of interest before completing the first online Delphi survey.

Potential external contributors to the development of the core outcomes set will be asked to complete the standard WHO declaration of interests form and declare any potential academic, professional, financial, or other conflict before invitations to participate are finalized. WHO staff will assess the declaration of interests and determine if a conflict of interest exists, and the risk of conflict adversely affects the development of the core outcome set. WHO standard criteria for assessing the severity of a conflict of interest will be used. Decisions are made on a case-by-case basis, depending on the severity of the conflicts of interest. Where a conflict of interest is not considered significant enough to affect an individual’s ability to make objective judgements or reduce process credibility, a summary of all disclosed interests will be reported in the final publication. When a declared conflict of interest is deemed serious enough, the expert will be precluded from participating in the process.

All participant information will be securely stored in the systems with password-protected access. Participants will be assigned unique identification codes to ensure anonymity in online surveys. Voting during consensus meetings will be anonymous through an electronic platform. Participants' information will be used to prepare individualized reports and follow-up between rounds. However, only the selected researchers will have access to the participants’ identification data. Opinions and comments by participants will not be attributed to any participant in any publication or report. Experts participating in the face-to-face meeting will be informed that the list of experts will be catalogued on the annex of the publication.

The goal of this project is to integrate this core outcome set into all future epidemiological, product development, and post-authorization surveillance research on maternal and perinatal health conducted during emerging and ongoing epidemic threats. We will employ various methods to disseminate the core outcome set and encourage its adoption. The findings of the systematic review and consensus process will be published in peer-reviewed journals, shared with various research and surveillance networks, presented at national and international conferences, and promoted through community organizations and social media platforms. We will provide an overview of the core outcome set for the CROWN and COMET initiatives. Additionally, we will leverage social media platforms. To maximize the implementation of the final set of core outcomes, we will share the results with professional associations, relevant university research departments, and developers of clinical guidelines. By doing so, we aim to facilitate the widespread adoption of the core outcome set in the field of maternal and perinatal health research.