In Sub-Saharan Africa, cisgender women of reproductive age represent the largest proportion of those with new HIV infections, making them a key focus for HIV testing, treatment, and prevention efforts (1). Pregnant and postpartum women, in particular, have higher rates of HIV acquisition compared with non-pregnant women (2–4). Yet, despite the potential increased susceptibility of HIV faced by women during these clinically complex periods of their lives, pregnant and postpartum women are frequently excluded from clinical trials evaluating investigational products for HIV treatment or prevention. This exclusion is not unique to the development of HIV-related interventions, but rather is due to paternalistic regulatory restrictions in place in many countries that aim to protect pregnant women and the fetus (5, 6). As a result of such restrictions, data on the safety of medications used in pregnancy are grossly limited, with the majority of the safety data collected through postmarketing surveillance (7).

There is a scientific and ethical imperative to responsibly include pregnant women in research evaluating the safety and efficacy of investigational products. In line with this imperative, the Microbicide Trials Network (MTN) is conducting the DELIVER study, a phase 3b, randomized, open-label safety trial of the dapivirine vaginal ring (25 mg), and oral preexposure prophylaxis (PrEP) (Truvada: 200 mg emtricitabine [FTC]/300 mg tenofovir disoproxil fumarate [TDF]) for HIV prevention in pregnant cisgender women (MTN-042; ClinicalTrials.gov Number: NCT03965923). The primary objectives of this study are to describe maternal and infant safety and pregnancy outcomes among women randomized to receive the dapivirine vaginal ring or oral Truvada. As all enrolled women will be using an HIV prevention product during pregnancy, the frequency of pregnancy complications, pregnancy outcomes, and neonatal outcomes will be compared with the rates in the general population in Malawi, South Africa, Uganda, and Zimbabwe, where the DELIVER study is being conducted.

Maternal and neonatal outcomes, such as stillbirth, preterm birth, low birthweight (LBW), neonatal mortality, and maternal mortality represent internationally recognized and monitored priority health indicators (8–11). In comparison, a lack of sufficient data has been noted for other important outcomes, such as hypertensive disorders of pregnancy, premature preterm rupture of membranes (PPROM), postpartum hemorrhage (PPH), and congenital anomalies. This presents a challenge not only for allocating resources to improve these outcomes but also for evaluating investigational therapeutics for pregnant women. Robust data summarizing the expected prevalence of these outcomes among women in low and middle income countries (LMICs) are critically important for these studies. To that end, the objective of this systematic literature review and meta-analyses was to estimate the prevalence of 12 pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe.

These systematic literature reviews and meta-analyses assessed the prevalence of 12 pregnancy and neonatal outcomes and pregnancy complications in Malawi, South Africa, Uganda, and Zimbabwe. The preponderance of published manuscripts reported data on the frequency of stillbirth, LBW, and preterm birth, which was expected given their status as priority health indicators (8). However, few studies reported on the prevalence of important pregnancy complications such as chorioamnionitis, postpartum endometritis, and PPROM. In many settings, including in LMICs, diagnoses of pregnancy complications can be challenging to ascertain, resulting in a paucity of data to inform reproductive and perinatal health initiatives, clinical care, and in the evaluation of investigational therapeutics, including those for HIV prevention and treatment, and for pregnant and breastfeeding individuals.

Collectively, the variability in outcome definition and ascertainment across studies reduces the ability to precisely estimate the prevalence of these pregnancy and neonatal outcomes. To address this challenge in the context of evaluating vaccine safety among pregnant people, the Global Alignment of Immunization Safety Assessment in pregnancy project (GAIA) was established in 2015 to “improve the quality of outcome data from clinical vaccine trials in pregnant women with a specific focus on the needs and requirements for safety monitoring in LMICs” (24). As part of the GAIA project, standardized case definitions for common obstetric and neonatal outcomes were established to improve the comparability of adverse outcomes across studies (25). Although some data may not be available from participant medical records to appropriately categorize certain outcomes, it is critical that studies of other biomedical interventions in pregnancy begin to collect data in support of the GAIA definitions to facilitate comparability.

The frequent exclusion of pregnant people from clinical trials of investigational products has created an environment where evidence-based guidelines for medication use during pregnancy are lacking, leading to suboptimal treatment. Data on the effect of pregnancy on drug pharmacokinetics, pharmacodynamics, and safety profiles often do not exist or are collected postmarketing, leaving patients and providers wary of medication use during pregnancy and while breastfeeding (5, 26, 27). Clearly, there is an ethical and public health imperative to include pregnant and breastfeeding women in clinical research (28). This need certainly extends to purposefully establishing the safety and efficacy of new HIV treatment and prevention methods in pregnant individuals with or at risk for HIV (5, 29). This can be illustrated by the 2019 finding from the Tsepamo study in Botswana that periconceptual dolutegravir use by women living with HIV may increase neural tube defects (30, 31). Sequential product development strategies that include safety studies among pregnant people are critical for ensuring that initial safety data on use in pregnancy are available for patients and providers at or near the time of product licensure (32). Since many pregnancy and neonatal outcomes are rare, the collection of additional postmarketing safety data must continue to be an important part of monitoring use in pregnant people.

This project had several strengths. Since the original literature searches included studies from the 13 countries in Sub-Saharan Africa, we were able to generate prevalence estimates for less frequently reported pregnancy complications (e.g., PPROM). In addition, while the pregnancy and neonatal outcomes are explicitly defined for the DELIVER study, the inclusion criteria included studies with varying definitions of each outcome given the paucity of data on some pregnancy outcomes and the known challenges of measuring these outcomes in low-resource settings. The inclusion of a range of definitions allowed us to generate overall prevalence estimates and conduct sensitivity analyses that were restricted to studies that defined outcomes most similarly to the DELIVER study protocol. Finally, two independent reviewers assessed each potential full-text manuscript for inclusion, and all the manuscripts and abstracted data included in the meta-analyses were read and reviewed by a second reviewer to guarantee quality.

There were several limitations to these meta-analyses. First, there was heterogeneity in the study design, study objectives, study inclusion/exclusion criteria affecting the risk-level of the included pregnant population, methods of ascertaining outcomes, the underlying health status of included pregnant individuals, and prevalence estimates across the included manuscripts. Our analysis also excluded studies restricted to adolescents and was unable to include age-standardization due to limitations in the available data. Collectively, our findings should be interpreted with this context in mind. Second, the pooled prevalence estimates for rare outcomes and subgroup analyses were limited by the paucity of data. The confidence intervals are wide and country-specific estimates may rely on data from only a few studies. For example, these meta-analyses suggest that women living with HIV had a higher pooled prevalence for many of the included outcomes such as stillbirth, preterm birth, congenital anomalies, and LBW. However, a minority of included studies reported prevalence by HIV status, and so these results, especially for the rare outcomes, should be interpreted cautiously. Third, despite the robust search, the review was limited by how manuscripts are indexed in MEDLINE. Manuscripts were frequently identified for inclusion in the review during the search for a single outcome while also including data on multiple additional outcomes of interest. Often, these manuscripts were not subsequently identified through specific searches for those other outcomes despite providing relevant estimates; thus, their inclusion for certain outcomes in this project occurred as a result of chance findings in manuscripts identified for another outcome. In addition, only one database was searched. Therefore, it is certain that additional prevalence estimates for these outcomes from Malawi, South Africa, Uganda, and Zimbabwe were not included in these meta-analyses. Fourth, the search strategy only included English language manuscripts identified through one database, which may have contributed to missing some prevalence estimates. Fifth, having one reviewer conduct initial data abstraction with a second reviewing for accuracy (instead of independent data abstraction by two reviewers) could have introduced bias. However, a rigorous process for identifying and adjudicating any errors and disagreements in data abstraction that were identified was followed limiting our concern for bias from this approach. Finally, while these literature reviews were conducted systematically, this review intentionally varied from certain aspects of the PRISMA guidelines for systematic reviews to best address our research question about the prevalence of pregnancy and neonatal outcomes and in response to the available data (33). For example, eligible countries were modified after the initial development of the searches. In addition, because of the size and scope of the literature reviews and the goal of estimating general population prevalence (versus intervention effect), we elected to present a qualitative summary of potential bias as this better represented the range of important considerations for interpretation of these data.

The prevalence estimates generated by this literature review and meta-analyses will be compared with the results of a records review of pregnancy outcomes at primary care and referral facilities affiliated with the DELIVER study (34). Together, these results will be utilized to assess whether the frequency of pregnancy and neonatal outcomes among pregnant women randomized to the dapivirine vaginal ring or oral TDF are similar to those observed in the areas where the study will be conducted. Importantly, these prevalence estimates will be a valuable resource for future trials of investigational products in pregnancy, including several HIV prevention methods (e.g., long-acting injectable cabotegravir) and maternal immunizations that are in the process of development or newly approved (35–37), including COVID-19 vaccines. In addition, these estimates may inform the allocation of resources and policies to prevent adverse pregnancy outcomes and complications. While this review identified a robust volume of data for some outcomes, data were severely lacking for other important pregnancy-related conditions, the quality of outcome ascertainment was variable, and stratification by HIV status was not ubiquitous. Fundamentally, there is an urgent need for pregnant people to be included in clinical research to understand the safety and efficacy of investigational products. There is also an urgent need to routinely collect quality and standardized data as the current, unreliable estimates make it challenging to distribute resources and understand whether quality improvement efforts are effective. Understanding the true burden of adverse pregnancy outcomes and complications in LMICs is essential to better serve women and other individuals of reproductive potential globally.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author/s.

JB, KB, LF, and BM conceived of this project. EL and AM conducted the systematic review and meta analysis under supervision by JB. EL, AM, and JB drafted the first version of the manuscript. EL, KB, LF, BM, RB, LN, and JB interpreted the results. All authors reviewed, commented on, and approved the final manuscript.

The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, and UM1AI106707), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. EML was additionally funded by a National Institute of Child Health and Human Development fellowship (F32 HD100202). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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