
==== Front
Drug Saf
Drug Saf
Drug Safety
0114-5916
1179-1942
Springer International Publishing Cham

38907172
1445
10.1007/s40264-024-01445-1
Review Article
Pharmacovigilance in Pregnancy Studies, Exposures and Outcomes Ascertainment, and Findings from Low- and Middle-Income Countries: A Scoping Review
Shafi Jenine 1
Virk Maneet K. 1
Kalk Emma 2
Carlucci James G. 3
Chepkemoi Audrey 4
Bernard Caitlin 3
McHenry Megan S. 3
Were Edwin 4
Humphrey John 3
Davies Mary-Ann 2
Mehta Ushma C. 2
http://orcid.org/0000-0001-9893-5856
Patel Rena C. renapatel@uabmc.edu

15
1 https://ror.org/00cvxb145 grid.34477.33 0000 0001 2298 6657 University of Washington, Seattle, WA USA
2 https://ror.org/03p74gp79 grid.7836.a 0000 0004 1937 1151 Centre for Infectious Disease Epidemiology & Research, School of Public Health, University of Cape Town, Cape Town, South Africa
3 grid.257413.6 0000 0001 2287 3919 Indiana University, Indianapolis, IN USA
4 https://ror.org/04p6eac84 grid.79730.3a 0000 0001 0495 4256 Moi University, Eldoret, Kenya
5 https://ror.org/008s83205 grid.265892.2 0000 0001 0634 4187 University of Alabama at Birmingham, Birmingham, AL USA
21 6 2024
21 6 2024
2024
47 10 957990
12 5 2024
© The Author(s) 2024, corrected publications 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Introduction

Pharmacovigilance (PV), or the ongoing safety monitoring after a medication has been licensed, plays a crucial role in pregnancy, as clinical trials often exclude pregnant people. It is important to understand how pregnancy PV projects operate in low- and middle-income countries (LMICs), where there is a disproportionate lack of PV data yet a high burden of adverse pregnancy outcomes. We conducted a scoping review to assess how exposures and outcomes were measured in recently published pregnancy PV projects in LMICs.

Methods

We utilized a search string, secondary review, and team knowledge to review publications focusing on therapeutic or vaccine exposures among pregnant people in LMICs. We screened abstracts for relevance before conducting a full text review, and documented measurements of exposures and outcomes (categorized as maternal, birth, or neonatal/infant) among other factors, including study topic, setting, and design, comparator groups, and funding sources.

Results

We identified 31 PV publications spanning at least 24 LMICs, all focusing on therapeutics or vaccines for infectious diseases, including HIV (n = 17), tuberculosis (TB; n = 9), malaria (n = 7), pertussis, tetanus, and diphtheria (n = 1), and influenza (n = 3). As for outcomes, n = 15, n = 31, and n = 20 of the publications covered maternal, birth, and neonatal/infant outcomes, respectively. Among HIV-specific publications, the primary exposure-outcome relationship of focus was exposure to maternal antiretroviral therapy and adverse outcomes. For TB-specific publications, the main exposures of interest were second-line drug-resistant TB and isoniazid-based prevention therapeutics for pregnant people living with HIV. For malaria-specific publications, the primary exposure-outcome relationship of interest was antimalarial medication exposure during pregnancy and adverse outcomes. Among vaccine-focused publications, the exposure was assessed during a specific time during pregnancy, with an overall interest in vaccine safety and/or efficacy. The study settings were frequently from Africa, designs varied from cohort or cross-sectional studies to clinical trials, and funding sources were largely from high-income countries.

Conclusion

The published pregnancy PV projects were largely centered in Africa and concerned with infectious diseases. This may reflect the disease burden in LMICs but also funding priorities from high-income countries. As the prevalence of non-communicable diseases increases in LMICs, PV projects will have to broaden their scope. Birth and neonatal/infant outcomes were most reported, with fewer reporting on maternal outcomes and none on longer-term child outcomes; additionally, heterogeneity existed in definitions and ascertainment of specific measures. Notably, almost all projects covered a single therapeutic exposure, missing an opportunity to leverage their projects to cover additional exposures, add scientific rigor, create uniformity across health services, and bolster existing health systems. For many publications, the timing of exposure, specifically by trimester, was crucial to maternal and neonatal safety. While currently published pregnancy PV literature offer insights into the PV landscape in LMICs, further work is needed to standardize definitions and measurements, integrate PV projects across health services, and establish longer-term monitoring.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40264-024-01445-1.

http://dx.doi.org/10.13039/100000060 National Institute of Allergy and Infectious Diseases U01AI069911 U01A1069924 http://dx.doi.org/10.13039/100000071 National Institute of Child Health and Human Development K23HD109056 K23HD105495 Carlucci James G. Humphrey John http://dx.doi.org/10.13039/100009633 Eunice Kennedy Shriver National Institute of Child Health and Human Development K23MH116808 R61HD103093 R01HD080465 Shafi Jenine McHenry Megan S. http://dx.doi.org/10.13039/100000865 Bill and Melinda Gates Foundation INV-004508 issue-copyright-statement© Springer Nature Switzerland AG 2024
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pmcKey Points

The current scope of work related to drug/vaccine safety among pregnant individuals living in LMICs largely focuses on infectious diseases, and are frequently from Africa, and are often funded by high-income countries.	
These publications largely failed to include maternal outcomes as an outcome of interest overall and longer-term maternal, birth, or neonatal/infant outcomes.	
Current gaps in pregnancy PV in LMICs exist in terms of specificity of exposure timing (timing of initiation and duration of treatment) and the need to broaden focus to include non-communicable diseases.	

Introduction

Pharmacovigilance (PV), or the ongoing safety monitoring that occurs after a medication or intervention has been licensed [1], plays a crucial role in pregnancy, as clinical trials often exclude pregnant people. Although PV encompasses a broad umbrella of activities, from animal testing to population-level surveillance, its main approaches include passive and active surveillance, targeted post-marketing studies, and record linkage studies utilizing patient data sources [1]. In this review, we utilize the term “PV projects” to maximize inclusion of PV-related work, such as cohort studies, programs, etc., that assess pregnancy outcomes in low- and middle-income countries (LMICs) to allow us to capture a larger breadth of PV in pregnancy projects, address a clear gap in knowledge regarding various exposure and adverse outcome associations that are not explicitly investigated in clinical trials. Currently, studies focused on therapeutic and vaccine efficacy continue to exclude pregnant people, resulting in them having delayed or no access to potentially beneficial interventions [2–4]. Furthermore, some adverse maternal, birth, and neonatal/infant outcomes are rare, requiring a large sample size, and cannot feasibly be studied in pre-approval trials. Thus, real-world evidence is needed to ensure pregnant people and their newborns are not exposed to harmful therapeutic agents, or denied access to treatments with a favorable benefit-risk profile.

Pregnancy PV projects in LMICs are of particular interest because some adverse maternal, birth, and neonatal/infant outcomes are more prevalent in LMICs compared to high-income countries (HICs) [5, 6]. Additionally, certain exposures, such as therapeutics for HIV, tuberculosis (TB), and malaria, are more prevalent in LMICs than in HICs. Investments in post-marketing surveillance systems may not be routine in many LMICs and population-level electronic health records, which can be quickly leveraged for pregnancy PV activities in HICs, are relatively uncommon. Additional data collection requirements may challenge overburdened health systems in LMICs.

The disproportionate lack of data from LMICs poses a threat to global health equity, with the majority of the world’s pregnant population living in LMICs. Thus, it is important to understand how pregnancy PV projects in LMICs have conducted their work to assess exposure-outcome relationships and learn enduring lessons for future related work.

In 2014, the World Health Organization (WHO) created the Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) initiative in order to create a global standard for monitoring vaccine safety in pregnancy, especially focusing on LMICs [7]. This initiative has greatly supported standardization of case definitions and outcomes for vaccine safety research, and especially surveillance; however, it has not translated to more PV in pregnancy projects nor harmonization of related outcomes in LMICs. The challenges lie in ensuring that such standardized approaches align with realities of clinical maternal and neonatal care in LMICs beyond a focus on vaccine safety surveillance. Developing robust PV in pregnancy projects continues to be a challenge in LMICs due to many factors, including scarcity of medical personnel, under-resourced and often fragmented health infrastructure, and limited investment in pregnancy PV projects [3]. Yet, these projects are vital for ensuring optimal treatment of pregnant people and infants and it is important to understand how PV projects currently function and what can be learned for effective implementation in LMIC settings. To fill these knowledge gaps, we conducted a scoping review to assess how exposures and outcomes were measured/operationalized in recently published PV in pregnancy projects throughout LMICs.

Materials and Methods

Aim and Objectives

The aim of this scoping review was to examine measures and metrics for exposure-outcome relationships in relation to PV projects in pregnancy in LMICs. Specifically, we sought to evaluate how different published pregnancy PV projects have measured and operationalized their exposures and outcomes of interest. Exposures of interest were therapeutics or vaccinations utilized before or during pregnancy and outcomes of interest included maternal, birth, and neonatal/infant outcomes. This scoping review was conducted between October 2022 and September 2023. The conduct of our scoping review was informed by the PRISMA reporting guidelines for scoping reviews [8] (see supplementary materials for checklist).

The specific research questions that guided this scoping review were:What published PV in pregnancy projects exist in LMICs?

How were exposure and outcomes measured/operationalized in pregnancy PV projects based in LMICs?

How may gaps in existing pregnancy PV projects guide future projects?

Literature Search

We conducted the first search of all relevant, indexed publications on December 28, 2022. We began our search by first meeting with a librarian, specializing in scoping reviews, at the University of Washington Health Sciences Library. This librarian aided us in creating a complete and relevant search string to be used in PubMed and Embase. After noticing a lack of LMIC results within these databases, we improved our search string by adding a comprehensive LMICs search term, based on World Bank categorization [9], to our existing search string, in addition to editing our search strings to be used in SciELO and Global Index Medicus. The updated search string was run on February 6, 2023. Search terms focused on the subjects, pregnant, birth, maternal, newborn, and neonatal outcomes, as well as pregnancy PV projects and an extensive list of LMICs (see supplementary materials for full search string). After primary review of our search results, from July 2023 to September 2023, we conducted a secondary review of the references from the primary publications. Additionally, using team knowledge, we compiled a list of key publications that were not identified in our primary or secondary search.

Eligibility Criteria

While inputting the search string into the databases, filters were placed to select publications in English pertaining to “Humans” and “Female” (see supplementary materials for full search string). Publications were selected from a 10-year range (from 2012 to 2022). Publications pertaining to animals were excluded. The LMICs strings were based on the Cochrane Effective Practice and Organization of Care (EPOC) LMICs filters 2020 v.4 with additional terms added to increase comprehensiveness [10].

These parameters were chosen for numerous reasons including comprehensiveness, practicality, and efficiency. Publications were selected from a 10-year range for the scoping review to be thorough, yet feasible for the research team. Animal studies were excluded to focus on the target population of the scoping review, pregnant people and their newborns. Last, we limited the search results in PubMed and Embase to publications in English, the common language spoken by the research team. Notably, SciELO publishes literature originating in Latin American, Caribbean, and Iberian countries and Global Index Medicus is a database created by the WHO that provides access to literature produced by LMICs. Thus, for these databases, search results were not limited to English. The research team wanted to make sure we were not excluding any important and relevant publications and so for these databases, if the English text was available for the publication, it was reviewed.

Publication Selection

After the finalization of the search string, two members of the research team (JS, MKV) conducted an initial selection of relevant publications based on title review, recording notes in a Google Sheet. Deduplication of publications was done via a validated deduplication tool through the Systematic Review Accelerator developed by Bond University [11]. The abstracts of these publications were then screened for relevance, and those meeting our inclusion criteria were compiled in a Google Sheet. Inclusion criteria at this stage included: (1) exposure delineated as a therapeutic and/or vaccine, (2) reported on maternal, birth and/or neonatal/infant outcomes, (3) assessment of relationship between exposure and outcome existed, (4) pregnant people were a main study population or publication contained significant data on pregnant people and neonates, and (5) publication focused on LMICs or global data. Although “pharmacovigilance” was a term included in our search string, authors did not need to explicitly name their project a PV project in order to be eligible for this review. Once a list of all potentially relevant publications based on abstract-only screening was compiled, full copies of the publications were obtained and entered in Zotero. We were successful in obtaining full copies of all publications at this stage. The list of publications was split between the two members (JS, MKV) conducting the publication review, and one member read the full publication to determine relevance. Additionally, case series and case reports were excluded, because we were interested in pregnancy PV projects as a whole, rather than particular cases of adverse events (AEs) or outcomes. When we included relevant systematic reviews or meta-analyses, we chose not to review each source included in the review as the goal of this scoping review was synthesis of existing publications, and not enumeration of specific findings as would be done in a systematic review or meta-analysis. A subset of publications was reviewed by both (JS, MKV) to ensure reliability in the review process. Any discrepancies were resolved via discussion and consensus with inclusion of a third reviewer (RCP). Publications felt to have unclear relevance based on the initial review were discussed during regular meetings with the core research team (JS, MKV, and RCP), and decisions to include or exclude were made by consensus. The same process was used for the secondary review of references from the primary publications. Two members of the research team (JS, MKV) conducted an initial selection of the reference publications based on publication title. The abstracts of these publications were screened for relevance and compiled in a separate page on the same Google Sheet. The inclusion and exclusion criteria was the same as before. After full copies of the publications were obtained, the publications were split for review between the two members.

Data Items and Synthesis of Results

Our Google Sheet was populated with each publication’s URL, title, project name, authors, publication year, main objective, overall study design, target population, inclusion and exclusion criteria, comparator groups, primary exposure(s), primary exposure measure(s), primary outcome(s), primary outcome measure(s), findings, and funding sources. The exposure variables reviewed were largely therapeutics for malaria, TB, and HIV, as well as vaccinations. The outcomes reviewed were maternal (e.g., maternal death, preeclampsia/eclampsia, and adverse therapeutic-/immunization-related events), birth (e.g., major congenital anomalies, stillbirth, and small for gestational age [SGA]), and neonatal/infant outcomes (e.g., neonatal mortality and infant mortality). Exposures were grouped by infectious diseases (with therapeutic use as exposure) and vaccinations based on topic frequency emerging among the publications. In order to standardize outcome categories, outcome variables were grouped by maternal, birth, and neonatal/infant outcomes based on recent WHO recommendations [12].

Results

Selection of Sources of Evidence

In our primary review, our search string produced 53 publications across all databases. After deduplication, there were 50 publications remaining (Fig. 1, [13]). We identified 25 publications meeting our inclusion criteria based on title and abstract alone. We included these 25 publications for full text review. Of these, 14 were excluded for the following reasons: irrelevant (i.e., did not report maternal, birth, or neonatal/infant outcomes, n = 7), publication focus was non-LMICs (n = 5), or publication was a case series or case report (n = 2). The database sources for the 11 included publications were: PubMed (n = 8), Embase (n = 2), SciELO (n = 1), and none were identified from Global Index Medicus.Fig. 1 Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) publication selection procedure flow chart. LMIC low- and middle-income country

From the secondary review of the references of the primary publications, we identified 632 references, of which 87 publications met our inclusion criteria based on title alone (Fig. 1 [13]). After abstract review, we excluded 66 publications and included 21 publications for full text review. These publications were excluded for being duplicates (n = 6), non-LMICs (n = 19), irrelevant (i.e., did not report maternal, birth, or neonatal/infant outcomes, n = 40), or for not being within the publication range (2012–2022, n = 1). After a full text review, we excluded 5 additional publications for the following reasons: retracted study ( n = 1), irrelevant (i.e., did not report maternal, birth, or neonatal/infant outcomes, n = 3), unclear exposure-outcome ascertainment (i.e., publication was a hypothetical trial, n = 1), leaving 16 secondary review publications.

After a full text review of all publications included in the primary and secondary review, we included 31 publications in our synthesis, with n = 11 included from the primary search string, n = 16 from secondary review, and n = 4 from team knowledge (Table 1). Table 1 Publications included in scoping review (N = 31)

Variable	N (%)	
Year (2012–2022)		
 2012–2015	11 (35.5)	
 2016–2020	14 (45.2)	
 2021–2022	6 (19.4)	
Population		
 Pregnant people only	30 (96.8)	
 Adolescents and adults, including pregnant people	1 (3.2)	
Region		
 Africa	28 (90.3)	
 North & South America	5 (16.1)	
 South-East Asia	8 (25.8)	
 Europe	2 (6.5)	
 Eastern Mediterranean	0 (0.0)	
 Western Pacific	4 (12.9)	
 2 or more LMICs	8 (25.8)	
 2 or more LMICs & HIC	3 (9.7)	
Disease/condition		
 Infectious diseases therapeutics		
  HIV	17 (54.8)	
  Malaria	7 (22.6)	
  TB	9 (29.0)	
  Multi-disease therapeutics exposure	2 (6.5)	
Immunizations/vaccinations		
 Pertussis, tetanus, diphtheria	1 (3.2)	
 Influenza	3 (9.7)	
Study design		
 Prospective cohort	12 (38.7)	
 Retrospective cohort	6 (19.4)	
 Cross-sectional	2 (6.5)	
 Systematic review, meta-analysis	5 (16.1)	
 Feasibility assessment	1 (3.2)	
 Post-marketing surveillance	1 (3.2)	
 Randomized controlled trial	4 (12.9)	
 Exposure		
 Therapeutic	27 (87.1)	
 Vaccine	4 (12.9)	
Outcomes		
 Maternal	15 (48.4)	
 Birth	31 (100)	
 Neonatal/infant	20 (64.5)	
Funding sources		
 National governments, e.g., MOH, FDA, PEPFAR	13 (41.9)	
 International organizations, e.g., UN, WHO	1 (3.2)	
 Research entities, e.g., NIH, UK Wellcome Trust	12 (38.7)	
 Non-governmental organizations, e.g., BMGF	6 (19.4)	
 Pharmaceutical companies, e.g., BioNet Asia	1 (3.2)	
 Other	3 (9.7)	
 No external funding	1 (3.2)	
 Not discussed/missing	2 (6.5)	
Percentages may not add to 100 % due to rounding

BMGF Bill and Melinda Gates Foundation, DR-TB drug-resistant tuberculosis, FDA US Food and Drug Administration, HIC high-income country, HIV human immunodeficiency virus, LMICs low- and middle-income countries, MDR-TB multi-drug resistant tuberculosis, MOH Medical Officer of Health, NIH National Institutes of Health, PEPFAR President’s Emergency Plan for AIDS Relief, TB tuberculosis

Certain publications belong to multiple regional categories, regional categories based on WHO regional offices, regional, disease/condition, and outcome categories are not mutually exclusive, thus add up to more than 28 publications

Outcome categories based on WHO’s Long Acting Antiretroviral Meeting, key pregnancy, maternal, and child safety endpoints: harmonized approach to collecting pregnancy and infant outcome data for antiretroviral-based prevention presentation [12]

Characteristics of Sources of Evidence

After compiling the data extraction for the 31 included publications, we further categorized the publications into two groups: publications relating to therapeutics for infectious diseases (n = 27, Table 2) and vaccines (n = 4, Table 3). The publications ranged across more than 28 countries, with several publications covering more than one country (n = 11); the majority of studies were from Africa (n = 28). Most publications ( n = 30) had pregnant people as the only study population. All of the publications covered infectious diseases/conditions, with most publications (n = 27) focusing on a therapeutic exposure (n = 17 for HIV, n = 7 for malaria, n = 9 for TB, n = 2 for multi-class therapeutics exposure) compared to publications about vaccinations (n = 1 for pertussis, tetanus, and diphtheria, n = 3 for influenza). As for outcomes, n = 15, n = 31, and n = 20 of the publications covered maternal, birth, and neonatal/infant outcomes, respectively. Table 2 Summary of infectious disease-related publications

Project	Country	Disease	Main objective	Target population	Inclusion & exclusion criteria	Exposure(s)/exposure measure(s)	Outcome(s)/ outcome measure(s)	Comparator groups	Findings	
Primary Publications	
Van De Ven et al. (2020)	Global	HIV	To analyze pharmacovigilance databases focus on dolutegravir safety during pregnancy, focus on NTDs	Pregnant individuals	Inclusion: Pregnant individuals taking antiretrovirals with data included in one of the following 4 pharmacovigilance databases: WHO VigiAccess (international), UK MHRA; EMA EudraVigilance (European Union); FAERS Public Dashboard (United States); infants born to these individuals	Exposed to one of the following: 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), or 2 non-nucleoside reverse transcriptase inhibitors (nevirapine [NVP], efavirenz [EFV]); Measure: counts	Neural tube defects (used search terms: "neural tube defect,” “spina bifida,” “meningocele,” “meningomyelocele,” “encephalocele,” “anencephaly,” and “iniencephaly") and adverse drug reactions; Birth outcomes of interest: Neonatal invasive bloodstream infection (NBSI); Neonatal death; Congenital microcephaly; Low birth weight (LBW); Preterm birth; Small for gestational age (SGA); Stillbirth (sub-divided into antepartum and intrapartum); Measure: Count per ARV; Note: A prevalence rate cannot be determined as NTD cases are identified from spontaneous ADR reports taken from a population where the overall number of exposed pregnancies is not known	Meta-analysis	WHO VigiAccess Database- As of 21 August 2018, there were 8 NTD reactions for DTG: 2 unspecified NTDs, 1 anencephaly, 1 encephalocele, 2 meningocele, 1 spina bifida, and 1 iniencephaly. The highest number of reactions were reported for EFV and NVP, with earliest reports from 1999 and 1997, respectively; UK MHRA Database- As of 31 July 2018, no NTD cases on DTG were reported; European EudraVigilance Database- Up to 2 August 2018, no NTDs for DTG were reported to the EMA. Four NTD cases for raltegravir were identified. EFV and NVP had the most NTD cases with the oldest ADR reports on the database; FDA FAERS Database- As of 30 June 2018, 6 NTD cases for DTG were identified. Four cases were reported from Botswana, including 1 case each of anencephaly, spina bifida, iniencephaly, and encephalocele; 1 from Namibia with an unspecified NTD; and one case from the United States with a meningocele and an unspecified NTD	
Sevene et al. (2012)	Southern Mozambique	Malaria, STDs, others	To describe the association between drug exposure level during pregnancy and adverse pregnancy outcomes in rural Mozambique, an area with high malaria endemicity	Pregnant individuals and their newborns in rural Mozambique	Inclusion: Pregnant individuals who were admitted to a hospital for any illness during pregnancy or for delivery at the maternity clinic in the study area located in southern rural Mozambique	Drug exposure during pregnancy; Measure: Number of drugs used during pregnancy (categories are no drugs, 1–2 drugs. 3–5, 6–9, >/= 10); proportion = # of individuals in each category/total number of participants; mean and SD of number of drugs reported per individual	Diseases reported during pregnancy (includes malaria, STDs, general symptoms and signs, anemia, respiratory tract diseases. obstetric-related conditions, skin diseases including herpes zoster, pre-eclampsia/eclampsia, AIDS, UTI, TB, hepatomegaly, and splenomegaly); Measure: Individual counts for each disease reported; # of no diseases/total # of participants; # of malaria/total # of participants; # of other diseases/total # of participants; # malaria + other diseases/total # of participants	-	High drug exposure during pregnancy in this region; > 40% of individuals reported taking one or more drug during pregnancy; 30.5% of participants received three or more drugs during their pregnancy; 35% of pregnant individuals exposed to drugs were exposed to drugs classified by the FDA as being of teratogenic risk C and D; stillbirths were associated with drug exposure during pregnancy; The most frequent, clinically observed malformation was polydactyly; The number of cases with specific congenital defects was low	
Rulisa et al. (2012)	Rwanda	Malaria	To determine whether adverse outcomes were more frequent after AL administration for malaria among urban and rural pregnant individuals receiving AL for malaria compared to pregnant individuals without malaria and who were not exposed to AL	Pregnant individuals with malaria	Inclusion: individuals prescribed AL for an episode of malaria in their second and third trimester of pregnancy, according to the national Rwandan guidelines for treatment of malaria. individuals could be included immediately after the decision to treat AL for malaria had been made, hereafter called “prospective” inclusion. individuals who, during antenatal clinic attendance, were found to have been treated with AL during that pregnancy could also be included “retrospectively” if treatment could be verified from the patient prescription and treatment register at the health center. The unexposed group consisted of pregnant individuals with no history of previous or current treatment with AL in the existing pregnancy and without any signs or symptoms of malaria; Pregnant individuals above the age of 18 years were included in the study if the individual was to be treated with AL after diagnosis of simple (uncomplicated) P. falciparum malaria. This study also tried to capture inadvertent AL treatment during the first trimester by retrospective inclusion; an individual with a similar stage of pregnancy and without history of previous or current treatment with AL in the existing pregnancy was selected at the same health center during routine attendance at the antenatal clinic and invited to participate in the study as part of the control group. These control individuals were confirmed as at the moment of enrolment having no malaria by a negative blood smear. Previous malaria episodes that were treated with quinine instead of AL were considered as control individuals as well	Having been prescribed AL for an episode of malaria in their second and third trimester of pregnancy; Measure: proportion = # of individuals prescribed and taking artemether-lumefantrine during pregnancy	Adverse obstetric outcomes (abortion, perinatal mortality, stillbirth, preterm delivery, and unexplained neonatal death ≤ 7 days after birth), adverse infant outcomes (congenital malformations regardless of the pregnancy outcome, and neurological problems) and other AEs. Serious AEs (SAEs), were those which resulted in death; were immediately life-threatening; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect of the newborn; required inpatient hospitalization or prolonged existing hospitalization or were deemed “important medical events” by the investigator; Measures: proportions = # of outcomes among individuals in control group/total # in control group

proportion = # of outcomes in treatment group/total # in treatment group; OR

	Contemporaneous/concurrent comparator groups and matched pregnant people with malaria given artemether-lumefantrine with pregnant people without malaria and no exposure to artemether-lumefantrine	Total of 129 obstetric adverse events (AEs) in 127 subjects were reported (7.3% in the treatment group, 5.0% in the control group). In a multivariate regression model, obstetric complications were more frequent in the treatment group (OR [95% CI]: 1.38 [0.95, 2.01]), and in primigravidae (OR [95% CI] 2.65 [1.71, 4.12]) and at higher age (OR per year: 1.05 [1.01–1.09])"; No statistically significant differences between any of the outcomes except for obstetric complications	
Van der Walt et al. (2020)	South Africa	DR-TB and HIV	To review retrospective data from records of pregnant individuals in South Africa’s DR-TB facilities to provide insight into DR-TB treatment outcomes, occurrence of ADEs (including medication errors, adverse drug reactions and allergic reactions) and birth outcomes	Pregnant individuals in South Africa with DR-TB	Inclusion: individuals who were pregnant before or while receiving individualized DR-TB therapy, with pulmonary TB disease between January 2010 and December 2018. individuals who attended MDR-TB hospitals of Northern Cape, North West, and Free State Provinces. individuals aged between 15 and 44 years with any bacteriological confirmed RIF mono resistance, MDR-TB or XDR-TB and initiated on DR-TB treatment were included in the study	Treated for rifampicin-resistant tuberculosis; Measure: proportion = # treated/total # of participants (categories of treatment: New- never treated for tuberculosis before, Receive first-line tuberculosis treatment before, Receive drug-resistant tuberculosis treatment before)	Adverse drug events, live birth, abortion/miscarriage, stillbirth; Measure: proportion = # of cases/total # of participants in subgroup	–	11 (42.3%) were previously treated with first-line TB drugs, 11 (42.3%) never treated before and 4 (15.4%) were previously treated for DR-TB. Of the 26 individuals, 15 (57.7%) had at least one ADE, but most had more than one ADE. 17 were successfully treated, and 22 live births recorded. Live birth outcome was significantly associated with trimester of initiation of DR-TB treatment (p = 0.036). The proportion of live births for the pregnancy trimester when DR-TB treatment was initiated, were 60.0%, 90.9% and 100.0%, for first, second and third trimester, respectively	
Mosha et al. (2014)	Eastern Tanzania	Primarily malaria, then HIV, TB and pneumonia	To assess outcomes of various drugs used by pregnant Tanzanian individuals using a pilot PV system	Pregnant individuals in Eastern Tanzania	Inclusion: Pregnant individuals with a gestational age < 20 weeks and residing in the Eastern Tanzania area	Various drug exposure; Measure: proportion = # of individuals who self-reported taking medication during pregnancy/total # of individuals in study; duration of treatment in days (median, IQR, range)	Stillbirth/miscarriage, low birth weight, or premature birth; Measure: OR	Contemporaneous/concurrent comparator group in their analysis, comparing pregnant people with antimalarial exposure during pregnancy with those not exposed during pregnancy to assess the relationship between medication exposure and pregnancy outcome	Antibiotics exposure was neither associated with an increased risk of miscarriage/stillbirth (adjusted OR 0.8; 95% CI 0.4–1.6; p = 0.526), low birth weight (adjusted OR 0.6; 95% CI 0.2–1.6; p = 0.295) or premature birth (adjusted OR 1.4; 95% CI 0.7–2.8; p = 0.348)".. Drug exposure to drugs under US FDA pregnancy risk category ‘A’ (primarily included ferrous sulfate and folic acid) were associated with a reduced risk of miscarriage/stillbirth (adjusted OR 0.1; 95% CI 0.08–0.3; p <  0.001). No significant association of adverse pregnancy outcome in relation to exposure to drugs under category ‘B’, ‘C’ and ‘D’	
Dellicour et al. (2013)	Rural Senegal	Malaria	To assess the feasibility of record linkage using routinely collected healthcare data as a pragmatic means of monitoring the safety in early pregnancy of artemisinin-based combination therapies (ACTs) in Senegal	Pregnant individuals living in Senegal and other malaria-endemic countries	Inclusion: individuals of childbearing age (15–49 years) with a prescription for an ACT between January 2004 and December 2007 were extracted from the outpatient register (from Mlomp dispensary covering the period 2004–2008)	Exposed to artemisinin-based combination therapies (ACTs) in early pregnancy; Measure: proportion = # of individuals exposed to ACTs/total # of participants	Live birth, stillbirth, preterm birth, miscarriage; congenital abnormalities- Anophthalmia, Ambiguous genitalia, Anencephaly, Down syndrome, Club foot, Hydrocephalus, imperforate anus, unspecified malformations; Measure: proportion = # of outcomes/total number of cases	–	94.6 % of 685 pregnancies resulted in live births, 2.6 % in stillbirths and 2.8 % in miscarriages. Major congenital malformations were identified in 1.6 % of births. Record linkage identified seven exposures to ACTs in the first trimester, all of which resulted in normal live-births	
Tinto et al. (2015)	Burkina Faso, Kenya, and Mozambique	Malaria	To describe the methods and implementation of a study aimed at developing surveillance systems for identifying exposures to antimalarials during early pregnancy and for monitoring pregnancy outcomes using health and demographic surveillance platforms	Pregnant individuals with malaria in Sub-Saharan Africa	Inclusion: Pregnant individuals residing in the defined catchment areas of each site, who planned to remain in the study area through delivery and who were willing and able to provide written informed consent; Exclusion: Refusal to participate or be followed up at the end of pregnancy and any condition that would interfere with the ability to provide written informed consent or provide an accurate medical history	Exposure to artemisinin-based combination therapy (ACT) during early pregnancy; Measures: proportion = projected number of exposures per year/embryo sensitive period 6 weeks (exposure risk %); ratio of exposed to unexposed; Counts

*The timing of possible drug exposures and possible periconceptional exposure was dated retrospectively using estimated gestational age (multiple methods were used to estimate this date of last menstrual period, Ballard Score, fundal height and ultrasound)

	Miscarriages, congenital malformations; Measure: proportion = # of cases/total # of participants	Contemporaneous groups - compared pregnant people exposed to antimalarials in early pregnancy to those not exposed to antimalarials during early pregnancy	The optimal methodology for drug safety surveillance in pregnancy in resource-limited settings will likely vary based on local needs and available resources; including available methods for gestational age determination, possibility of community-based pregnancy detection, assessment of pregnancy outcomes, measurement of antimalarial exposure, and confirmation of malaria cases	
Alene et al. (2022)	South Africa, Peru, Brazil, Iran, and Uganda	MDR-TB	To conduct a review of the treatments given (and their outcomes) and AEs among pregnant patients with MDR-TB	Pregnant patients with MDR-TB	Inclusion: Studies with cohorts of pregnant patients with a defined treatment outcome; Exclusion: Studies conducted only on drug-susceptible TB or animal studies, abstracts, case reports, case series with fewer than 5 pregnant patients, correspondence, reviews, editorials, and duplicate studies	MDR-TB treatment (linezolid); Measure: OR using the number of pregnant individuals with MDR-TB who were treated (mainly with linezolid) and pregnant individuals who were not	Treatment outcome: treatment success, treatment failure, death, and loss to follow-up. Secondary outcomes included drug-related AEs for mothers such as liver impairment, kidney function impairment, hypokalemia, hearing loss, gastrointestinal disorders, psychiatric disorders, anemia and pregnancy outcomes, such as preterm birth, miscarriage, neonatal death, stillbirth, low birth weight; Measures: OR using # of exposed pregnant individuals with adverse effects compared to number of pregnant patients who did not experience adverse effects	Systematic review and meta-analysis	Pooled results showed that treatment success was significantly higher in studies in which the proportion of patients taking linezolid was greater than the median (20.1 %) compared with studies in which this proportion was lower than the median (odds ratio, 1.22; 95 % CI, 1.05–1.42). More than 50% of pregnant patients (54.7%; 95% CI, 43.5%–65.4%) experienced at least 1 type of adverse event, most commonly liver function impairment (30.4 %; 95% CI, 17.7%–45.7%), kidney function impairment (14.9%; 95% CI, 6.2%–28.3%), hypokalemia (11.9%; 95% CI, 3.9%–25.6%), hearing loss (11.8%; 95% CI, 5.5%–21.3%), gastrointestinal disorders (11.8%; 95% CI, 5.2%–21.8%), psychiatric disorders (9.1%; 95% CI, 2.5%–21.6%), or anemia (8.9%; 95% CI, 3.6%–17.4%). Overall, high treatment success and favorable pregnancy outcomes were reported	
Secondary Publications	
Mehta et al. (2019)	South Africa	HIV	To assess the risk of major congenital malformations (CM) and other adverse birth outcomes (ABOs) detected at birth, in children born to individuals exposed to ART during pregnancy	Pregnant individuals taking ART treatment	Inclusion: Positive HIV status, pregnant, currently taking ART treatment; Exclusion: Unknown HIV status, HIV status was recorded as positive but there was no record of ART, unknown birth outcomes, multiple births recorded	Taking ART during pregnancy; Measure: Count and percentage of individuals taking ART during pregnancy/ total number of individuals in study

– ART exposure was divided into subcategories based on timing of ART treatment in relation to pregnancy (ART treatment before conception was defined as at least 2 weeks before last menstrual period and during pregnancy was based on the trimester when pregnancy was initiated)

	Congenital malformations, pregnancy loss, neonatal death, birth weight in relation to gestational age, preterm delivery, low birth weight; Measure: risk ratio	Contemporaneous/concurrent comparator groups, where the authors compared any ART exposure during pregnancy to a comparator group of HIV-uninfected individuals not exposed to ART. Also conducted a second risk analysis to assess the composite endpoint of adverse birth outcomes in which the comparator group was singleton birth outcomes of HIV-uninfected individuals	Congenital malformations rates in births exposed to Efavirenz during the first trimester (T1) (RR 0.87 [95% CI 0.12–6.4; p = 0.895]) were similar to births not exposed to ART during T1. However, T1 exposure to Nevirapine was associated with the increased risk of CM (RR 9.28 [95% CI 2.3–37.9; p = 0.002]) when compared to the same group. Other ABOs were more frequent in the combination of HIV/ART-exposed births compared to HIV-unexposed births (29.9% vs 26.0%, adjusted RR 1.23 [1.14–1.31; p < 0.001])	
Hill et al. (2018)	Global- Botswana, USA, 7 European countries	HIV	To analyze all available data on birth outcomes and congenital anomalies in the infants of pregnant individuals treated with DTG	Pregnant individuals living with HIV and their infants	Inclusion: Pregnant individuals living with HIV and taking DTG; Exclusion: Studies excluded if data had been reported in other larger research programs, or if # of pregnant individuals treated was less than five	DTG treatment during pregnancy; Measure: N of individuals who were exposed to/treated with DTG per trimester (was not available for all articles)	Birth outcomes and congenital anomalies: from Botswana study: stillbirth, preterm birth (> 37 weeks), very preterm birth (> 32 weeks), SGA (> 10th percentile), very SGA (> 3rd percentile) and neonatal death. Congenital anomalies were assessed in both live and stillbirths by nurse surface exam at the time of birth; Antiretroviral Pregnancy Registry: stillbirths, spontaneous abortions, SGA and low birth weight. Congenital anomalies were reported from only the live births in this cohort-- polydactyly, hypoglossia, Down's syndrome; EPPICC, PANNA and NEAT-ID: stillbirth, spontaneous abortion, SGA and low birthweight. Congenital anomaly data were available for 81 of the 84 live births – patent foramen ovale, polydactyly, hypospadias, ankyloglossia, hyperpigmentation; DTG Phase 3 Trials –pregnancy was excluded because clinical trial, adverse events reported in ViiV-sponsored Phase 2 and Phase 3 trials of DTG, Ventricular septal defect; DTG post marketing surveillance: includes reports of congenital anomalies and birth outcomes sent from clinicians to ViiV, for patients taking DTG in pregnancy, congenital anomalies – polydactyly, intracranial calcifications and growth retardation, bilateral hydroureter, hydronephrosis, and pyelocaliectasis. This reporting of pregnancy outcomes is not mandated by the originator company; IMPAACT-- congenital anomalies: multicystic dysplastic right kidney, cyst in left kidney; Measure: # of adverse birth outcomes/# of births (N and %), or # infants born from DTG-treated mothers with anomalies/#total number of infants born to individuals treated with DTG	Systematic review	This systematic review of DTG use in HIV-positive pregnant individuals shows no evidence for increased risks of stillbirth, preterm birth, SGA or congenital anomalies, compared to historical control studies of ARV-treated pregnant individuals. There were no reports of vertical HIV transmission in any of the studies, but data were only available for 42 infants in four studies at the time of the analyses. Botswana—no significant difference in birth outcomes between DTG and EFV, in multivariate analysis adjusted for maternal age, gravidity and education; Looking at all studies in main analysis, There were no clear differences in the risk of stillbirth, preterm birth (> 37 weeks) or SGA between the studies of DTG-treated individuals and the historical control studies. For the six main studies, there were 442 live births with information available on congenital anomalies. There were 16 infants with congenital anomalies reported. The most common anomaly in the babies born to mothers who took DTG was polydactyly, with five cases. Polydactyly is also a very common anomaly in babies unexposed to HIV, seen in more than 1% of births to individuals of African descent. In some of the studies, polydactyly was classified as a normal variant and not included in the final results (for example in the IMPAACT P1026s study). The percentage of infants with congenital anomalies varied between the studies, ranging from 0/116 infants in the Botswana study (0%) to 2/15 infants in the IMPAACT P1026S study (13.3%). In IMPAACT P1026S, five of the 15 DTG-exposed babies were reported to have congenital anomalies; there were two other babies whose anomalies were judged to be ‘normal variants’. The investigators judged that, based on the nature of the anomalies and the timing of first exposure in pregnancy, the association of DTG with these anomalies could be ruled out for all but two of the anomalies (renal cysts, shown in Table 4). Owing to the gestational age at which DTG was started and the nature of the renal cysts, the investigators also considered it unlikely that these were related to exposure to DTG. There was no clear pattern of specific congenital anomalies recorded across all the studies. Detailed evaluation of the potential causality for these anomalies would require more information on the timing of initiation of DTG in each pregnant mother—this information is not available for all studies in the systematic review. Note: The data from Botswana are reported separately due to it being the only study with a control group.	
Zash et al. (2018)	Botswana	HIV	To comment on previously published research that stated that the risk of adverse birth outcomes or congenital abnormalities among individuals starting dolutegravir-based ART after conception was not higher than risk among individuals who started efavirenz-based therapy after conception (the objective of the previous paper was: To compare birth outcomes among individuals initiating dolutegravir-based ART with those among individuals initiating efavirenz-based ART in pregnancy in Botswana )	Pregnant individuals living with HIV in Botswana	Inclusion: Individuals who delivered liveborn or stillborn infants at 24 weeks' gestational age or later at eight government maternity wards in Botswana and had obstetric records on file	ART regimen- dolutegravir vs efavirenz-based; Measure: n and % on each ART regimen	Primary outcomes: combined endpoints of any adverse outcome and any severe adverse outcome. Adverse outcomes- stillbirth, preterm birth, small for gestational age (SGA), or neonatal death; Severe adverse outcomes- stillbirth, very preterm birth, very SGA, or neonatal death; Congenital abnormalities are a further secondary outcome; Measure: N and % of individuals with poor outcomes; comparison of % with poor outcomes between treatment groups and between individuals living with HIV and individuals not living with HIV	Several contemporaneous/concurrent comparator groups: pregnant people not living with HIV, pregnant people who had non-dolutegravir ART exposure, those having non-efavirenz ART exposure at conception, and those having dolutegravir treatment started during pregnancy to examine neural tube defects prevalence in relation to maternal HIV infection and ART exposure	In April 2018, detected a higher-than-expected number of neural-tube defects among infants born to individuals who started treatment with dolutegravir before conception. As of May 1, 2018, a total of 89,064 births had been included in our surveillance; 88,755 births (99.7%) had an infant surface examination that could be evaluated, with 86 neural-tube defects identified (0.10% of births; 95% confidence interval [CI], 0.08–0.12) (57% identified with a photograph, 43% identified by description). The defects included 42 instances of meningocele or myelomeningocele, 30 of anencephaly, 13 of encephalocele, and 1 of iniencephaly. Among the 426 infants born to HIV-positive individuals who had been taking dolutegravir-based antiretroviral therapy from the time of conception, 4 (0.94%) had a neural-tube defect. The defects in these 4 infants were encephalocele, myelomeningocele (along with undescended testes), and iniencephaly (along with major limb defect), all three of which were identified with photos, and anencephaly, which was identified by description. The 4 mothers delivered in three geographically separated hospitals over a 6-month period; none had epilepsy or diabetes or received folate supplementation at conception. In comparison, neural-tube defects occurred in 14 (0.12%) of 11,300 infants born to individuals who had been exposed to any non-dolutegravir antiretroviral therapy from the time of conception, 0 (0.00%) of 2812 infants born to individuals who had been exposed to dolutegravir treatment that was started in pregnancy, and 61 (0.09%) of 66,057 infants born to HIV-uninfected individuals. Seven neural-tube defects occurred in other exposure groups. In the analysis of the prevalence of neural-tube defects associated with exposure to antiretroviral therapy from the time of conception, the difference between non–dolutegravir-based antiretroviral therapy (prevalence, 0.12%) and dolutegravir-based antiretroviral therapy (0.94%) was − 0.82 percentage points (95% CI − 0.24 to − 2.3)	
Malaba et al, 2017	South Africa	HIV	To compare birth outcomes between HIV-infected and -uninfected individuals and HIV-infected individuals who initiated ART before vs during pregnancy	Pregnant individuals living with HIV in sub-Saharan Africa	Inclusion: Consecutive individuals >18 years old attending the clinic, individuals who identified as HIV-infected through antibody tests enrolled in HIV-cohort, and those eligible for ART based on CD4 cell count. For comparison group, individuals were eligible with a negative result on the same test; Exclusion: HIV-infected individuals who were not eligible for ART at their first ANC visit (receiving zidovudine prophylaxis)	HIV infection and ART exposure (fixed combination of TDF+FTC+EFV); Measure: proportion- N of individuals infected with HIV/total pregnant individuals, N of individuals initiating ART before pregnancy, first half of second trimester, second half of second trimester, third trimester/total HIV-infected individuals taking ART treatment	Preterm birth (< 37 ), low birthweight (< 2500 g), small for gestational age deliveries; Measure: OR; % odds of low birth weight, preterm birth, miscarriage between HIV-infected individuals and non-infected individuals, odds of subcategories based on initiation of ART	Contemporaneous/concurrent comparison group of HIV-uninfected pregnant people who were consecutively enrolled at a primary-level antenatal facility	Higher levels of preterm birth and low birthweight in individuals living with HIV vs individuals not living with HIV (22% vs 13%; OR 1.94, 95% CI: [1.34, 2.82] and LBW [14% vs 9%; OR 1.62, 95% CI: 1.05, 2.29]). Among individuals living with HIV- no association between ART initiation and adverse birth outcomes. No difference was observed in pregnancy loss outcome by HIV status or timing of ART initiation. Individuals not living with HIV experienced a higher proportion of miscarriages compared to individuals living with HIV; the opposite was observed with stillbirths, with individuals living with HIV experiencing a higher proportion	
Ramokolo et al, 2017	South Africa	HIV	To evaluate the effect of utero-HIV and ART exposure on infant adverse outcomes- preterm delivery, low birthweight, small for gestational age, and underweight for age	Individuals living with HIV in South Africa and their infants	Inclusion: All consenting mother-infant pairs that were attending the immunization facilities were enrolled regardless of maternal HIV status; Exclusion: Sick infants requiring emergency care, infants < 4 weeks or >8 weeks. Infants whose mothers only started ART postnatally	Maternal HIV infection and ART use; ART use grouped in 3 categories – (1) ART use primarily for mother's health based on WHO option A guidelines (2) antenatal ZDV as MTCT prophylaxis (ZDV-group), and (3) no ARV use antenatally (None group); Measure: Count % – e.g., N of individuals infected with HIV/total pregnant individuals, N of individuals initiating ARV or not and then stratified by pre- or post-conception exposure	Preterm delivery (< 37 weeks), low birth weight (< 2.5 kg), small for gestational age (using birthweight-for-gestational age z scores based on international intergrowth 21st standards), and underweight for age (UFA) at 6 weeks; Measure: OR; % odds of adverse infants outcomes between HIV-unexposed-uninfected and HIV-exposed-uninfected infants, odds of subcategories based on timing of initiation of ART (post- or pre-conception),	Contemporaneous/concurrent comparator groups using the data from a national facility-based cross-sectional survey, where ART use was grouped into three categories: (1) ART use primarily for mother's health based on WHO option A guidelines), (2) antenatal zidovudine as prevention of maternal to child transmission, and the primary comparator group, (3) no antenatal ART use	HIV-exposed and uninfected Infants whose mothers did not receive ARVs carried higher odds of PTD than post-conception ART-exposed infants (AOR, 1.7; 95% CI, 1.1–2.5) but no increased odds for LBW, SGA, and underweight. In addition, among ART-exposed pregnancies, PTD was more common among infants whose mothers initiated ART preconception than post-conception	
Bengston et al, 2015	Zambia	HIV	To analyze the association between duration of combination antiretroviral therapy (cART) during pregnancy and low infant birth weight among individuals of > 37 weeks’ gestation	Pregnant individuals living with HIV in Zambia	Inclusion: Individuals who entered clinic after Jan. 1, 2009 and delivered before Sept. 2013, were living with HIV (CD4 count < 350 cells per microliter), were not on cART at time of initial recruitment, singleton pregnancy at >/ 37 weeks of gestation (to term pregnancy); Exclusion: Those who conceived while on cART, did not deliver to term (preterm pregnancy < 37 weeks)	Duration of cART during pregnancy before delivery (categories: < / 8 weeks, 9–20 weeks, 21–36 weeks – early, mid, late pregnancy); Measure: N and % in each subgroup (e.g., number of individuals receiving < /8 weeks of cART/ total number of individuals who initiated cART	Low-birth weight (< 2500 g); Measure: Risk ratios (individuals on cART were compared with non-initiators for the same duration of time -# of low birth infants/total number of infants)	Contemporaneous/concurrent comparison group of pregnant people who never started combination ART compared to pregnant people who started combination ART at various gestational durations (≤8 weeks, 9–20 weeks, 21–36+ weeks)	Among the sample population (HIV-infected individuals who delivered at >/37 weeks), long duration of cART was not correlated with increased risk of LBW or decreased mean birthweight. (When individuals on cART were compared with non-initiators with the same duration of ANC, the RR was 4.20 (95% CI: 0.81 to 21.82) for < /8 weeks of cART, 1.08 (95%CI: 0.71 to 1.64) for 9–20 weeks of cART, and 0.95 (95% CI: 0.18 to 4.92) for 21–36 weeks of cART	
Li et al, 2015	Tanzania	HIV	To investigate the associations between ARV use and adverse birth outcomes, specifically comparing ZDV monotherapy during pregnancy and HAART started before and/or during pregnancy	Pregnant individuals living with HIV in Tanzania	Inclusion: All pregnant individuals living with HIV with uninfected HIV-exposed infants at birth that attended the HIV care and treatment center;	ARV treatment – ZDV prophylaxis or HAART (before 2010, affected individuals received ZDV prophylaxis (starting at 28 weeks), from 2010 to 2011, started as early as 14 weeks. Individuals who met WHO criteria initiated HAART); Measure: N and % in each subgroup (e.g., number of individuals receiving ZVD monotherapy/total individuals receiving ARV during pregnancy)	Preterm delivery- (< 37 weeks VPTD < 34 weeks), small for gestational age (used gender-specific reference values to define this), low birth weight(< 2500 g); Measure: Risk ratios comparing subgroups (e.g., individuals on ARV were compared with non-exposed, individuals only exposed to ZVD monotherapy compared to individuals who initiated HAART during pregnancy)	Contemporaneous/concurrent comparator groups (some of the data was collected prior to the WHO recommendation to provide universal provision of highly active ART (HAART) to pregnant people. Before 2010, women living with HIV received zidovudine prophylaxis starting at 28 weeks, while from 2010 to 2011 this was initiated as early as 14 weeks. Those who met WHO stage 3 or 4 criteria initiated HAART). In the primary analysis, those who did not receive ARVs were excluded and those who received monotherapy constituted the reference group (and this was then compared to comparison groups: HAART initiated before pregnancy and HAART initiated after pregnancy)	Demonstrated increased risk of adverse birth outcomes and use of HAART during and before pregnancy. Compared to ZVD monotherapy, HAART exposure before pregnancy was associated with significantly higher risk of PTD (38% compared to 26%). The initiation of HAART during pregnancy was significantly independently associated with a 47% increase in the risk of severe SGA compared with pregnancies with ZDV monotherapy. HAART exposure from before pregnancy was independently associated with higher risk of severe SGA with borderline significance (relative risk [RR] = 1.34, 95% confidence interval [CI], 0.98–1.84)	
Chen et al, 2012	Botswana	HIV	To understand whether adverse birth outcomes are associated with HAART among pregnant individuals living with HIV	Pregnant individuals living with HIV in Botswana	Inclusion: All individuals who delivered live births or stillbirths at a gestational age > 20 weeks at any of the 6 government study facilities in Botswana	HIV infection and HAART exposure (defined as 3 or more antiretroviral drugs), HAART exposure further divided into subcategories depending on timing (Antiretroviral use during pregnancy was classified as HAART continued from before the current pregnancy, HAART initiated during pregnancy, ZDV monotherapy, or no antiretroviral drugs received prior to delivery); Measure: N and % in each subgroup (e.g., number of individuals receiving HAART/total individuals)	Stillbirth, preterm delivery, small for gestational age, neonatal death; Measure: OR; % odds of adverse infants outcomes between HIV-unexposed-uninfected and HIV-exposed-uninfected infants, odds of subcategories based on timing of initiation of HAART (before pregnancy, during, etc.)	Contemporaneous/concurrent comparator group similar to Li et al, (2015). Data collected prior to and after WHO recommendation for universal ART; compared various ART exposures (zidovudine prophylaxis, HAART, etc.)	Maternal HIV was significantly associated with SB, PTD, SGA, and NND. Compared with all other HIV-infected individuals, those continuing HAART from before pregnancy had higher odds of PTD (adjusted odds ratio [AOR], 1.2; 95% confidence interval [CI], 1.1, 1.4), SGA (AOR, 1.8; 95% CI, 1.6, 2.1) and SB (AOR, 1.5; 95% CI, 1.2, 1.8). Among individuals initiating antiretroviral therapy in pregnancy, HAART use (vs zidovudine) was associated with higher odds of PTD (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9)	
Zash et al, 2017	Botswana	HIV	To compare the risk for selected birth outcomes by maternal ART regimen	Pregnant individuals living with HIV in Botswana	Inclusion: Pregnant individuals who were ART exposed from conception- Individuals living with HIV who started 3-drug ART regimens before their last menstrual period and did not switch or stop ART during pregnancy; individuals who delivered live-born or stillborn infants at 8 government maternity wards in Botswana; Exclusion: Births that occurred before arrival at the hospital and at a gestational age of < 24 weeks were excluded	Individuals living with HIV exposed to ART before or after conception; Measure: n and % of total births HIV exposed, unexposed, or unknown exposure status and n and % ART exposed at conception or after conception or unknown timing	Adverse birth outcomes- stillbirth, preterm birth (< 37 weeks), small size for gestational age (SGA; < 10th percentile of weight for gestational age) or neonatal death (< 28 days from delivery); Severe adverse outcome- very preterm birth (< 32 weeks), very SGA (< 3rd percentile of weight for gestational age), stillbirth, and neonatal death; Measure: Comparison of adverse outcomes by exposure group using ARR and %	Several contemporaneous/concurrent comparator groups: pregnant people not living with HIV, pregnant people who had non-dolutegravir ART exposure, those having non-efavirenz ART exposure at conception, and those having dolutegravir treatment started during pregnancy to examine neural tube defects prevalence in relation to maternal HIV infection and ART exposure	Among infants exposed to ART from conception, TDF-FTC-EFV was associated with a lower risk for adverse birth outcomes vs other ART regimens; Among 11,932 HIV-exposed infants, 5780 (48.4%) were ART exposed from conception. Adverse birth outcomes were more common among HIV-exposed infants than HIV-unexposed infants (39.6% vs 28.9%; adjusted relative risk [ARR], 1.40; 95% CI, 1.36-1.44). The risk for any adverse birth outcome was lower among infants exposed from conception to tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TDF-FTC-EFV) (901 of 2472 [36.4%]) compared with TDF-FTC and nevirapine (NVP) (317 of 760 [41.7%]; ARR, 1.15; 95% CI, 1.04–1.27); TDF-FTC and lopinavir-ritonavir (TDF-FTC–LPV-R) (112 of 231 [48.5%]; ARR, 1.31; 95% CI, 1.13–1.52); zidovudine, lamivudine, and NPV (ZDV-3TC-NVP) (647 of 1365 [47.4%]; ARR, 1.30; 95% CI, 1.20–1.41); or ZDV-3TC–LPV-R (75 of 167 [44.9%]; ARR, 1.21; 95% CI, 1.01-1.45). The risk for any severe adverse outcome was also lower among infants exposed from conception to TDF-FTC-EFV (303 of 2472 [12.3%]) compared with TDF-FTC-NVP (136 of 760 [17.9%]; ARR, 1.44; 95% CI, 1.19-1.74), TDF-FTC–LPV-R (45 of 231 [19.5%]; ARR, 1.58; 95% CI, 1.19-2.11), ZDV-3TC-NVP (283 of 1365 [20.7%]; ARR, 1.68; 95% CI, 1.44-1.96), or ZDV-3TC–LPV-R (39 of 167 [23.4%]; ARR, 1.93; 95% CI, 1.43-2.60) from conception. Compared with TDF-FTC-EFV, all other regimens were associated with higher risk for SGA; ZDV-3TC-NVP was associated with higher risk of stillbirth, very preterm birth, and neonatal death; and ZDV-3TC-LPV-R was associated with higher risk for preterm birth, very preterm birth, and neonatal death	
Liu et al, 2014	South Africa and Zambia	HIV	To evaluate the safety of combination antiretroviral therapy (ART) in conception and pregnancy in different health systems	Pregnant individuals living with HIV in South Africa and Zambia	Inclusion: Pregnant individuals living with HIV on combination ART at conception and age at least 18 years and their infants; attending the antenatal or HIV care clinic in Zambia/South Africa; Exclusion: History of mental illness, any condition that would make participation in the study unsafe, inability to provide informed consent	HAART start date in months (timing prior to conception), antiretroviral drug regimen at time of conception, HIV infection diagnosis (timing prior to conception); Measure: n and % in each timing/drug subgroup over total number of participants and over total in SA and in Zambia and p values	Live birth- term and preterm, Abortion, stillbirth- term and preterm, ectopic pregnancy, gestational age at delivery, number of fetuses, sex of infant, birth weight, length of newborn at delivery, mode of delivery- vaginal delivery, Cesarean delivery, neonatal death- preterm and term, congenital anomaly at delivery; Measure: n and % for each outcome over total number of participants and over total in SA and in Zambia and p values	Did not specifically identify comparator groups, but did compare a study group in Zambia with their study group in South Africa when examining the relationship between ART and pregnancy outcomes and birth defects	The median CD4+ cell count at study enrollment was lower in South Africa than Zambia (320 vs 430 cells/μL; p < 0.01). The most common antiretroviral drugs at the time of conception included stavudine, lamivudine, and nevirapine. There were 16 abortions (2.7%), one ectopic pregnancy (0.2%), 12 (2.0%) stillbirths, and 571 (95.2%) live infants. Deliveries were more often preterm (29.7 vs 18.4%; p = 0.01) and the infants had lower birth weights (2900 vs 2995 g; p = 0.11) in Zambia compared to South Africa. Thirty-six infants had birth defects: 13 major and 23 minor. There were more major anomalies detected in South Africa and more minor ones in Zambia. No neonatal deaths attributed to congenital birth defects	
Zash et al, 2019	Botswana	HIV	To examine the prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status throughout several Botswana hospitals	Pregnant individuals and their infants in Botswana	Not specified	Exposure: use of ART treatment (ART at conception was defined as maternal ART that started before the calculated date of the last menstrual period, and ART that started during pregnancy was defined as maternal ART that started after that date. Deliveries were classified according to ART exposure at conception for the analyses of congenital malformations and were excluded if the timing of ART or the type of ART regimen was not known) Measure: prevalence ratio- # of pregnant individuals exposed/total number of pregnancies reviewed; # exposed per 1000 births	Outcome: Neural tube defects (defined as definite [confirmed by photograph] or probable [diagnosed on the basis of a description but with no photograph]), myelomeningocele, meningocele, encephalocele, anencephaly with or without craniorachischisis, or iniencephaly. Other adverse birth outcomes were stillbirth, preterm birth (< 37 weeks of gestation), very preterm birth (< 32 weeks of gestation), small for gestational age (body weight < 10th percentile for gestational age), very small for gestational age (body weight < 3rd percentile for gestational age), and neonatal death at less than 28 days among infants who never left the hospital; Measure: Prevalence ratio (Calculated as number of neural tube defects and external structural malformations divided by total number of births [including live births and stillbirths] per 1000 births)	Several contemporaneous/concurrent comparator groups: pregnant people not living with HIV, pregnant people who had non-dolutegravir ART exposure, those having non-efavirenz ART exposure at conception, and those having dolutegravir treatment started during pregnancy to examine neural tube defects prevalence in relation to maternal HIV infection and ART exposure	The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception. Major external structural defects were found in 0.95% of deliveries among individuals exposed to dolutegravir at conception and 0.68% of those among individuals exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, −0.13 to 0.87).	
Mosha et al, 2014	Tanzania	Malaria	To assess birth outcome among pregnant individuals inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of individuals exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy	Pregnant individuals living in Tanzania	Inclusion: Pregnant individuals with gestational age < 20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery	Use of any antimalarial during first trimester of the presenting pregnancy (Artemether-lumefantrine (AL) only, AL and quinine, quinine only, Sulfadoxine-pyrimethamine (SP), amodiaquine, none; Measure: n and % of individuals who used anti-malarial drugs in first trimester, n and % of which drug they used	Abortion, stillbirth, live birth, birth maturity (preterm birth or full term birth), birth weight (LBW, normal birth weight), congenital anomalies; Measure: crude and adjusted OR for association between exposures and certain outcomes; n of individuals with birth outcome and % (n of individuals with birth outcome/total number of individuals in each exposure group)	Contemporaneous/concurrent comparator group and compared antimalarial medication use during a period of pregnancy (Artemether-lumefantrine only, artemether-lumefantrine and quinine, quinine, sulfadoxine-pyrimethamine, or amodiaquine) compared to pregnant people that had not used any antimalarial drug(s) during the same period of pregnancy	Quinine exposure during first trimester was associated with an increased risk of miscarriage/stillbirth (adjusted OR 2.5; 95% CI 1.3–5.1; p = 0.009) and premature birth (adjusted OR 2.6; 95% CI 1.3–5.3; p = 0.007) as opposed to AL, SP and amodiaquine exposure which were not associated with increased risk of either miscarriage/stillbirth, low birth weight or premature birth. Potential confounders: Increase of maternal age in years was associated with 5% decreased risk of low birth weight (OR 0.95; p = 0.009), 5% increased risk of miscarriage/stillbirth (OR 1.05; p = 0.001), and 3% increased risk of preterm birth (OR 1.03; p = 0.016). Multi-gravidae had 50% decreased risk of low birth weight (OR 0.5; p = 0.006), 60% increased risk of miscarriage/stillbirth (OR 1.6; p = 0.048), and 30% increased risk of preterm birth (OR 1.3; p = 0.099) compared to primigravidae	
McGready et al, 2012	Thai-Burmese border (Thailand, Myanmar)	Malaria	To assess the outcomes of malaria-exposed and malaria-unexposed first-trimester pregnancies and outcomes after antimalarial treatments (chloroquine-based, quinine-based, or artemisinin-based treatments)	Pregnant individuals living near the Thai-Burmese border	Inclusion: Pregnant individuals who began attending the clinic during first-trimester and had a single episode of malaria in first trimester (no further episode later in pregnancy); Exclusion: Pregnant individuals had multiple malaria episodes, exposure to different antimalarial drugs, no valid estimate of gestation, malaria in second or third trimester, or unknown outcome	Exposure to antimalarial drugs (chloroquine-based, quinine-based, or artemisinin-based treatments) between 6 and 12 weeks (±14 days); Measure: N and % – first trimester malaria/total number of pregnancies, number of individuals treated for malaria/total	Miscarriage (pregnancy ending before 28 weeks), birth outcomes (stillbirth – delivery from 28 weeks different than WHO 22 weeks’ cut-off because no infant respiratory support was available), congenital abnormality, birthweight, estimated gestational age at birth); Measure: odds ratios (% odds of first-trimester malaria-affected individuals miscarrying or delivering compared to unaffected pregnant individuals, odds of subcategories based on malaria symptoms (asymptomatic, symptomatic) and severity). Similar analysis of antimalarial treatment comparing no malaria, no treatment, and chloroquine, quinine, artesunate	Contemporaneous/concurrent comparator group in their analysis, comparing outcomes of pregnant people without malaria in pregnancy to outcomes of pregnant people who had a single episode of malaria in the first trimester	Malaria in first trimester associated with miscarriage, higher for individuals with asymptomatic and symptomatic malaria than unaffected individuals. Single episode of malaria treated in the first trimester (without infection later) did not significantly affect birthweight. Antimalarial treatment (especially artemisinin treatments) was not associated with miscarriage after adjustment. Birth outcomes did not differ significantly among treatment types. Study suggests adverse effects of malaria in first trimester outweigh adverse effects of treatment	
Alene et al, 2021	Global- South Africa, Peru, USA, Iran, India, Mexico, France, Bhutan, Turkey	MDR-TB	To examine the impact of MDR-TB and its medications during pregnancy on maternal and perinatal outcomes	Pregnant individuals with MDR-TB	Inclusion: Studies that evaluated any maternal morbidity and mortality as well as perinatal adverse outcomes among pregnant individuals with MDR-TB (with or without MDR-TB medications); Exclusion: Correspondence, reviews, editorials and conference abstracts and studies conducted only on drug-susceptible TB or in animals were excluded	Exposed to MDR-TB or on treatment for MDR-TB (co-infection with HIV was also reported in 3 articles [%]); Measure: Length of MDR-TB treatment regimen at birth (months) for each article	Perinatal adverse outcomes and maternal morbidity and mortality- preterm birth, LBW, SGA, severe growth restriction, stillbirth, miscarriage, congenital anomalies, neonatal mortality, maternal morbidity, maternal mortality; Measure: n of each adverse outcome per article and % of total number of individuals; pooled prevalence for each outcome also given with 95% CI	Systematic review and meta-analysis	Overall the prevalence of adverse maternal and fetal outcomes was high among individuals with MDR-TB and exposed to MDR-TB medicines during pregnancy. The main adverse outcomes reported were maternal death, pregnancy loss, preterm birth and LBW. The overall prevalence of maternal death rate was 7.5% (95% CI 3.2–12.8%). Pooled prevalence of pregnancy loss (including miscarriage and stillbirth) was 10.6% (95% CI 6.0–16.3%). Preterm birth weight pooled prevalence rate was 12.9% (95% CI 0.0–38.0%), but the weighted pooled prevalence rate for LBW was 23.7% (95% CI 17.0–31.0%). The most common types of adverse birth outcomes that have been reported in the existing literature were maternal death, pregnancy loss, preterm birth and LBW. Our study showed that the pooled prevalence of maternal death among pregnant individuals with MDR-TB was 7.5%, which is substantially higher than the prevalence of maternal death among all pregnant individuals reported from previous systematic reviews (0.4–0.7%). The present study revealed a considerably high pooled prevalence of pregnancy loss among pregnant individuals receiving MDR-TB medication (10.6%), which is higher than a pooled prevalence of pregnancy loss among pregnant individuals with other infectious diseases such as human parvovirus (7.6%) and brucellosis (3%), reported in previous systematic review and meta-analysis	
Mokhele et al, 2021	South Africa	MDR-TB and rifampicin-resistant (RR) TB	To describe TB treatment and pregnancy outcomes among pregnant individuals receiving second-line anti-tuberculosis treatment for MDR/RR-TB in Johannesburg, South Africa	Pregnant individuals with MDR/RR-TB in South Africa	Inclusion: Pregnant individuals (aged 18–49 years) diagnosed with laboratory-confirmed MDR/RR-TB, who initiated second-line anti-TB treatment (defined as a regimen containing at least two second-line agents, including at least one of a fluoroquinolone or second-line injectable agent), between 01/2010–08/2016 at three public outpatient treatment sites in Johannesburg, South Africa and had a pregnancy overlap with their TB treatment	Previously treated TB resistance profile (RR-TB, MDR-TB), previously treated TB treatment outcomes (completed, cured, treatment failure), TB disease type (Pulmonary TB PTB], Extrapulmonary [EPTB], both PTB and EPTB), resistance profile (RR-TB, MDR-TB, Extensively drug-resistant TB [XDR-TB]), TB treatment regimen (standard second-line TB regimen, individualized regimen with second-line drugs); Measure: n and % in each subgroup, and % of individuals with each exposure among individuals living with HIV and individuals not living with HIV	Maternal ADEs (categorized as mild [grade 1], moderate [grade 2], severe [grade 3], potentially life-threatening [grade 4]); Live birth, miscarriage, stillbirth, and termination of pregnancy. Preterm birth (<  37 weeks’ gestation), stillbirth, and miscarriage were categorized as adverse pregnancy outcomes. No infant outcome classification proposed as infant outcomes were not available in the records; Measure: n and % in each subgroup, and % of individuals with each exposure among individuals living with HIV and individuals not living with HIV; comparison of percentages with p-values	Contemporaneous/concurrent comparator groups to compare second-line TB treatment and pregnancy outcomes among pregnant people living with HIV compared to those not living with HIV, where both groups were assessed for drug-resistant TB infection	In conclusion: Pregnant individuals with MDR-TB/RR-TB suffer from high rates of adverse pregnancy outcomes. Results from our study highlight the need for close monitoring and coordinated obstetric, HIV and TB care for these patients; Overall, 17/35 (48.6%) individuals experienced AEs during their MDR/RR-TB treatment while also pregnant. The majority, 82.4%, experienced only one adverse event while 17.6% experienced two or more AEs. Adverse events were more common in individuals living with HIV (62.5%) vs individuals not living with HIV (18.2%). The most prevalent adverse event reported was nephrotoxicity 6/17 (35.3%), of which (2/6) 33.3% were moderate. This was followed by anemia 4/17 (23.5%), hypokalaemia 4/17 (23.5%) and equal number 2/17 (11.8%) experiencing ototoxicity or rash. Hypothyroidism, weight loss and dizziness were less common 1/17 (5.9%) respectively; A higher proportion of HIV-negative individuals had a history of TB treatment failure (100% vs 11.1%, p <  0.05) and a higher proportion were infected with MDR-TB and XDR-TB, (55.6%, 22.2%, vs 30.4%, 0%, p <  0.05), while more patients living with HIV presented with RR-TB infection (69.6% vs 22.2%, p <  0.05). Furthermore, individuals not living with HIV experienced fewer AEs (18.2% vs 62.5%; p <  0.05); A total of 24 (68.6%) individuals were living with HIV; The majority of the individuals 31/35 (88.6%) were pregnant at the time of MDR/RR-TB treatment initiation; More than 50% of the individuals were resistant to rifampicin only (RR-TB), 34% were resistant to rifampicin and other drugs (MDR-TB), and 2 individuals not living with HIV had XDR-TB. The majority of second-line anti-TB drug regimens were individualized, with only 28.6% of individuals receiving standard second-line regimens. Pyrazinamide and terizidone were the most commonly used drugs in the initial treatment regimen in the study cohort; Seven (20.0%) of the individuals did not have outcomes assigned because they were transferred out of the study site for continued care. Among individuals with outcomes assigned, 17/28 (60%) completed treatment, of these 4 were cured, whereas 28.6% individuals were lost to follow-up, and 10.7% died; Pregnancy outcomes were available for 20/35 (57.1%) individuals. There were 15 live births documented (11 preterm), one miscarriage, one neonatal death and three pregnancy terminations. Overall, 13/20 (65.0%) of the individuals with known pregnancy outcomes had an adverse pregnancy outcome. TB treatment and pregnancy outcomes did not differ by HIV status among those with known outcomes	
Loveday et al, 2021	South Africa	MDR/RR-TB	To describe maternal treatment and pregnancy outcomes, and to conduct a clinical assessment to describe infant outcomes among pregnant individuals starting treatment for MDR-RR-TB	Pregnant individuals with MDR/RR-TB in South Africa	Inclusion: Pregnant individuals starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017	Individuals exposed to second-line TB treatment for at least 2 weeks while pregnant; Measure: n and % for treatment initiation (started MDR/RR-TB treatment prior to become pregnant, during first trimester, during second trimester, third trimester	Maternal treatment, pregnancy, and infant outcomes- favorable treatment outcomes: cured, treatment completion; unfavorable treatment outcomes: died, treatment failed, lost to follow-up; pregnancy outcomes: newborn characteristics- live births (gestational age at delivery, birth weight), fetal and neonatal deaths (stillbirth, miscarriage, termination of pregnancy); favorable pregnancy outcomes: ≥37 weeks, birthweight >≥2500 g; unfavorable pregnancy outcomes: fetal and neonatal deaths, preterm < 37 weeks, LBW < 2500 g; infant outcomes: no infant outcomes at 12 months (fetal and neonatal deaths, lost to follow up after birth), infant outcomes at 12 months (favorable infant outcomes- thriving normally, normal development), unfavorable infant outcomes (failure to thrive, delayed development, early neonatal death, infant death, diagnosed with TB disease in the 1st year of life); Measure: unadjusted HR for individuals living with HIV with risk of unfavorable pregnancy outcome; n (and sometimes %) of pregnancies/mom/infants with each outcome; comparison of percentages with p values of favorable outcomes comparing individuals with fetuses exposed to bedaquiline (a treatment) vs those who were not exposed; SD for meal gestational age; IQR for median birth weight	Contemporaneous/concurrent comparator groups to compare pregnant people treated for MDR-TB with bedaquiline compared to pregnant people who had no exposure to bedaquiline	Favorable treatment outcomes reported in 72 (67%) individuals; Multivariate analyses identified lower maternal hemoglobin at baseline as a predictor of an unfavorable maternal treatment outcome (unadjusted hazard ratio [uHR] 0.67, p = 0.006); Eight individuals died a median of 67 days (interquartile range [IQR]: 32–299) after childbirth, but all 8 infants survived. Four maternal deaths were related to tuberculosis disease; No maternal deaths were considered related to tuberculosis medication; Ninety-nine (91%) of the 109 fetuses, including a set of twins, were born alive; Only 57 (52%) pregnancies had a favorable pregnancy outcome; individuals living with HIV had a higher risk of an unfavorable pregnancy outcome (uHR 3.35; p = 0.030); Four infants born alive had congenital anomalies; an umbilical hernia, a ventral septal defect, kyphoscoliosis, and 1 infant had Ehlers-Danlos syndrome. Four of the 109 fetuses were lost early in pregnancy, and of the 6 stillborn babies, 5 were delivered at a gestational age < 37 weeks. In 9 of the 10 fetal deaths the mother was living with HIV. All HIV-exposed babies were given nevirapine at birth for 6 weeks, and all tested HIV-negative at 6 weeks; Favorable infant outcomes were documented in 72 (84%) of the liveborn infants; No baseline maternal characteristics, tuberculosis drugs, or ART were associated with unfavorable infant outcomes; No baseline maternal characteristics, tuberculosis drugs, or ART were associated with unfavorable infant outcomes; Two infants (out of 86) were diagnosed and treated for MDR/RR-tuberculosis in their first year of life; No significant differences in baseline characteristics were identified between individuals treated with bedaquiline, compared to those who were not treated with bedaquiline; There was no difference in pregnancy outcomes between individuals whose fetuses were exposed to bedaquiline in utero (49% favorable pregnancy outcome) compared to those unexposed (57% favorable outcome, p = 0.312). However, a higher proportion of newborns exposed to bedaquiline in utero had a birth weight < 2500 g (45% vs 24%; p = 0.034); Exposure to bedaquiline, clofazimine, and levofloxacin in utero were all associated with an increased risk of low birth weight. In a multivariate model, bedaquiline and levofloxacin remained significant predictors of low birth weight	

Table 3 Summary of vaccine-related publications

Project	Country	Vaccine	Main objective	Target population	Inclusion & exclusion criteria	Exposure(s)/exposure measure(s)	Outcome(s)/outcome measure(s)	Comparator groups	Findings	
Primary publications	
 Fortuna et al. (2020)	Thailand	Pertussis, tetanus, diphtheria	To monitor the safety of the vaccines when given to a larger and less homogenous population and to report safety data on the use of various vaccines among individuals in Thailand	Adolescents and adults in Thailand	Inclusion: Adolescents or adults who received a dose of BioNet-Asia’s recombinant acellular pertussis vaccines through participating health care providers. Participating HCPs such as physicians, nurses, and pharmacists prescribing or administering aPgen and TdaPgen were sources of data; Pregnant individuals who were enrolled in a prospective observational study, or who were vaccinated through other hospitals and clinics in Thailand	Vaccinated with new generation recombinant monovalent aPgen or combination TdaPgen; Measure: proportion = # receiving vaccine/total # of individuals (totals divided into subgroups: age groups, pregnant individuals and also vaccine provider)	Adverse events (AEs) following immunization- lymphadenitis, local (pain, swelling, pruritus, redness, induration, hematoma, bruise), systemic (myalgia, malaise, fever, headache, fatigue); pregnancy outcomes- early abortion, complications; newborn outcome- stillbirth, congenital defect; 5 minute Apgar score; Measure: Incidence per 1000 participants		Of the 1778 pregnant individuals in this survey who were vaccinated with one of the two formulations of recombinant pertussis vaccine, two reported expected, non-serious AEFIs (incidence rate 1.1 per 1000 vaccinated pregnant individuals, 95% CI 0.3–4.1). One of the individuals reported pain at the injection site, and the other pain at the injection site and myalgia. In both cases symptoms were mild and resolved within a few days without taking medication and with no sequelae. Pregnancy safety outcomes were available for 833 individuals vaccinated with TdaPgen (n = 658) or aPgen (n = 175) during pregnancy. About half of the individuals (53.9%) received concomitant vaccines (mostly seasonal influenza and/or Td vaccines that are given to pregnant individuals in Thailand free of charge) at the time of vaccination with aPgen or TdaPgen; No early abortions occurred in this cohort, and 91.4% (95% CI 97.7–99.4) of the individuals had healthy uncomplicated pregnancies. Most common pregnancy complications were preterm labor (46/830, or 5.5% of vaccinated individuals, 95% CI 4.1–7.3) and pre-eclampsia (9/830, or 1.1% of vaccinated individuals, 95% CI 0.5–2.0). There were no differences in pregnancy safety outcomes for individuals vaccinated with the combination TdaPgen or monovalent aPgen vaccine. Of the 855 newborns, 11 children had congenital defects (1.3%, 95% CI 0.6–2.3). All cases were assessed by the reporting physician as unrelated to vaccination of the mother. The incidence of pregnancy complications or congenital defects was similar if individuals received concomitant vaccines during pregnancy	
 Hansen et al. (2021)	South Africa, Nepal, Mali	Inactivated influenza vaccine (IIV)	To assess the safety of IIV—typical results on safety measure influenza-related morbidity in mother and infant. This publication wanted to study RCT's to evaluate all-cause and infectious mortality and adverse events	Pregnant individuals given IIV	Inclusion: RCTs assessing the effect of an IIV vs either placebo or another non-influenza vaccine administered during pregnancy; RCTs that contained information about one or more of the following outcomes: miscarriage, stillbirth, maternal death, infant death, maternal non-influenza infectious adverse events, and child non-influenza infectious adverse events.	Administered IIV during pregnancy; Measure: risk ratios (# exposed to immunization/total # of subjects)	Maternal all-cause mortality (excluding accidents and suicide), maternal mortality from presumed infectious causes (excluded deaths related to hemorrhage, cancers, cardiovascular events, but included death due to infection after cesarean section, also included appendicitis) Miscarriage/stillbirths, Infant all-cause mortality (up to 6 months of age, excluding accidents, including influenza), Infant mortality (up to 6 months of age) from presumed infectious causes based on the classification in the trial paper. Infections included neonatal infection; respiratory infection; malaria; meningitis; gastrointestinal infection; unspecified infection; bacteremia; Measures: Risk ratios (# of miscarriages/stillbirth among exposed pregnant individuals/control group [unimmunized pregnant individuals]), (# of non-influenza-related AEs among pregnant individuals/control group [unimmunized pregnant individuals])	Utilized two contemporaneous/concurrent comparator groups. For the cohort in Bangladesh and Mali, the control group received a non-influenza vaccine, while the control group for the cohort from Nepal and South Africa received a saline placebo	IIV in pregnancy had no effect on all-cause mortality of individuals and infants and was associated with a twofold higher risk of non-influenza infectious adverse events in individuals and with a 36% higher risk in their offspring up to 6 months after delivery	
Secondary Publications	
 Omer et al. (2020)	Nepal, Mali, and South Africa	Influenza	To run a pooled analysis and report overall vaccine efficacy of maternal influenza immunization against maternal and infant PCR-confirmed influenza, duration of infant protection, the effect of gestational age at vaccination on vaccine efficacy, and the effect of vaccination on adverse birth outcomes and infant growth up to 6 months of age	Pregnant individuals and their infants	Inclusion: Pregnant individuals were screened and enrolled from nine Village Development Committees in rural southern Nepal (vaccinated at 17–34 weeks’ gestational age). Individuals accessing prenatal care were screened and enrolled in Bamako, Mali (vaccinated at ≥ 28 weeks’ gestational age) and Soweto, South Africa (vaccinated at 20–36 weeks’ gestational age)	Exposure to trivalent IIV in Nepal, Mali, South Africa or control group- saline placebo in Nepal and South Africa or quadrivalent meningococcal conjugate vaccine in Mali; Measure: n assigned to each exposure group in each country	Overall vaccine efficacy of maternal influenza immunization against maternal and infant PCR-confirmed influenza, duration of maternal and infant protection, the effect of gestational age at vaccination on vaccine efficacy, adverse birth outcomes (LBW, stillbirth, preterm birth, and SGA), and infant growth up to 6 months of age (infant weight-for-age, weight-for-length, length-for-age, median centile change from birth to 6 months, and mean weight and length at birth at 6 months); Measure: % and 95% CI; cases of influenza (by time after vaccination subgroup) and incidence per 1000 person-years and incidence rate ratio (95% CI) and p-values	Used two contemporaneous/concurrent comparator groups to examine vaccine efficacy of maternal influenza immunization. Individuals in the Nepal and South Africa cohort’s comparison group received a saline placebo, whereas the comparison group in Mali received a quadrivalent meningococcal conjugate vaccine	Pooled efficacy of maternal vaccination to prevent infant PCR-confirmed influenza up to 6 months of age was 35% (95% CI 19–47). The pooled estimate was 56% (28–73) within the first 2 months of life, 39% (11–58) between 2 and 4 months, and 19% (− 9 to 40) between 4 and 6 months. In individuals, from enrollment during pregnancy to the end of follow-up at 6 months postpartum, the vaccine was 50% (95% CI 32–63) efficacious against PCR-confirmed influenza. Efficacy was 42% (12–61) during pregnancy and 60% (36–75) postpartum. In individuals vaccinated before 29 weeks’ gestational age, the estimated efficacy was 30% (− 2 to 52), and in individuals vaccinated at or after 29 weeks, efficacy was 71% (50–83). Efficacy was similar in infants born to mothers vaccinated before or after 29 weeks’ gestation (34% [95% CI 12–51] vs 35% [11–52]). There was no overall association between maternal vaccination and low birthweight, stillbirth, preterm birth, and small for gestational age. At 6 months of age, the intervention and control groups were similar in terms of underweight (weight-for-age), stunted (length-for-age), and wasted (weight-for-length). Median centile change from birth to 6 months of age was similar between the intervention and the control groups for both weight and length	
 Steinhoff et al. (2018)	Nepal	Influenza	To assess the safety and efficacy of year-round maternal influenza immunization among infants and mothers in Nepal	Pregnant individuals and their infants in Nepal	Inclusion: Individuals were eligible if they were married, aged 15–40 years, 17–34 weeks at time of enrollment, and had not previously received any influenza vaccine that season or participated in another influenza trial; Exclusion: Those who had already participated in an influenza study, did not intend to deliver in the area, or were allergic to any vaccine component	Exposure: Influenza vaccination year-round of local trivalent inactivated vaccine (based on WHO local recommendations of northern and southern strains); Measure: N in cohorts; All individuals were given vaccine but stratified by gestational age (17–25 weeks vs 26–34 weeks). Based on this—2 cohorts, first cohort—individuals vaccinated as soon as pregnancy is confirmed, second cohort—individuals were identified as pregnant and then randomly allocated a week to receive the vaccine	Outcome: Incidence of maternal influenza-like illness (reported fever plus cough or sore throat on at least 1 day) in pregnancy and 0–180 days postpartum, incidence of low birthweight (<  2500 g), and incidence of laboratory-confirmed infant influenza 0–180 days (done by testing nasal swabs) Secondary outcomes: maternal laboratory-confirmed influenza, infant rate of influenza-like sickness (illness episode—any one of ever, cough, wheeze, ear discharge plus PCR), small for gestational age; Measure: Incidence rates and risk ratios; calculated incidence rates using the number of cases of laboratory-confirmed influenza divided by the number of days at risk for influenza by treatment group and compared groups using the risk ratio	Contemporaneous/concurrent control group, where they enrolled two cohorts during different times of the year and in each of these cohorts, pregnant people received either the inactivated influenza vaccine or a saline placebo	Vaccination reduced maternal influenza-like illness as well as in infants (overall efficacy of 19%), and low birthweight (by 15%). Number of adverse effects was similar regardless of immunization status	

Synthesis of Results

The results are presented in two sections pertaining to infectious diseases-related (1) therapeutics and (2) vaccines. We discuss in detail common themes arising from the publications, including ascertainment of exposures and outcomes, timing of exposures during pregnancy, and comparator groups used in the exposure-outcome relationship assessment.

Infectious Diseases Therapeutics-Related Publications (Table 2)

For the 27 infectious diseases therapeutics-related publications, the major diseases analyzed in relation to pregnant people and their newborns were HIV (n = 17), malaria (n = 7), drug-resistant tuberculosis (DR-TB)/multidrug-resistant tuberculosis (MDR-TB) (n = 9), along with multi-class therapeutics exposure (n = 2; Table 2).

HIV

Among publications with HIV as the infectious disease of study, the primary exposure-outcome relationship of focus was exposure to maternal antiretroviral therapy (ART) (primarily dolutegravir-, efavirenz-, nevirapine-containing ART or zidovudine monotherapy) and adverse maternal, birth, and neonatal/infant outcomes.

For the vast majority of HIV-centered publications (n = 17), a focal point of analysis was the time of ART initiation and the duration of treatment in relation to gestation, and birth, maternal, and neonatal/infant outcomes [14–25]. For example, some publications categorized the time of initiation into subcategories based on stages of pregnancy such as early (< 8 weeks), mid (9–20 weeks), and late pregnancy (21–36 weeks) [22] or first trimester (< 14 weeks), first half of second trimester (14–20 weeks), second half of second trimester (21–27 weeks), and third trimester (>28 weeks) [20]. Notably, Mehta et al specifically evaluated first trimester ART exposure and found that there was no association between first trimester exposure to efavirenz-containing ART regimens and congenital malformations yet found that first trimester exposure to nevirapine was associated with a greater risk of congenital malformations compared to births not exposed to ART during the first trimester [15]. The evaluation of first trimester exposure allowed Mehta et al to specifically comment on birth and infant outcomes in relation to specific exposure timing, as this cohort excluded pregnant people for whom the timing of ART was uncertain [15]. Similarly, by evaluating ART exposure based on varying lengths of treatment, Bengston et al was able to report that there was no evidence of elevated risk of low birth weight (LBW) infants for individuals receiving combination ART for any treatment length compared to individuals who never initiated ART [22].

However, most publications defined the categories of ART initiation as pre- (before) or post-conception (during pregnancy) (n = 8) [17–21, 23–25]. For publications defining ART initiation as pre- or post-conception, ART initiation preconception was defined as maternal ART that started before the calculated date of the last menstrual period (LMP), and post-conception ART initiation was defined as maternal ART that started after that date. To account for errors in estimation, one publication defined ART exposure prior to conception as 2 weeks before LMP, with broader exposure categories being based on the trimester in which ART treatment was initiated (e.g., 15 weeks post-LMP) [15].

Notably, many publications were able to comment on the significance of the timing of treatment initiation in relation to maternal, birth, and neonatal/infant outcomes due to exposure initiation stratification. To illustrate, Zash et al (2019) specifically sought to evaluate the effects of dolutegravir exposure at conception on the prevalence of neural tube defects and found that neural tube defects were more prevalent in association with dolutegravir-based treatment at conception than with non-dolutegravir ART at conception [18]. Ramokolo et al reported higher preterm delivery rates among pregnant people who initiated ART preconception compared to those who initiated ART post-conception [21]. Last, Chen et al evaluated ART exposure based on timing of ART initiation (before or after 32 weeks’ gestation), and thus were able to report that there were no significant differences in preterm delivery, SGA infants, or stillbirth rates based on timing of ART initiation [24].

To estimate gestational age in relation to the time of ART initiation, various factors were utilized across the publications. All publications utilized the estimated date of LMP and other factors depending on the data available in the publication. Some publications utilized LMP along with fundal height (n = 4) [20, 22–24], some used LMP and a dating ultrasound (if available) (n = 4) [15, 20, 24, 25], and one publication further assessed the accuracy of estimation by comparing the mean birthweight for each week of gestation age to a reference growth curve adjusted for the population [22]. For the majority of the reviewed HIV-related publications, whether they utilized data from a larger PV database or medical records, there was some degree of uncertainty in the exact timing of ART initiation relative to conception and/or trimester of exposure.

For HIV-centered publications that utilized comparator groups or had explicit information detailing their comparator groups, we found that all publications used contemporaneous/concurrent comparator groups (n = 10). Among these, the comparator groups included: pregnant people not living with HIV [15, 17–20], pregnant people living with HIV with various ART exposures [17–19, 21, 23, 24], pregnant people living with HIV with ART exposures at various gestational durations [22], and pregnant people living with HIV with no antenatal ART use [21]. Some publications collected data prior to WHO guidelines for universal ART use for pregnant people, thus overall ART exposure before and after this time period shifted [17–19, 23, 24].

Malaria

For publications with malaria as the infectious disease of study, the primary exposure-outcome relationship of interest was the association between antimalarial medication exposure during pregnancy and adverse maternal, birth, and neonatal/infant outcomes. These publications analyzed various antimalarial medications: artemisinin derivatives, such as artemisinin-based combination therapies (n = 6, [26–31]), quinoline derivatives, such as chloroquine, quinine, and amodiaquine (n = 3, [27, 28, 32]), and antifolates, such as sulfadoxine-pyrimethamine (n = 2, [28, 32]). The birth outcomes of interest were live birth, stillbirth, and miscarriages; birth maturity (preterm birth or full-term birth); birth weight; and congenital malformations. Among these publications there was an emphasis on examining the timing of exposure in relation to the outcome. Particularly, these publications sought to understand the effect of antimalarial medication exposure during the first trimester or preconception and adverse maternal, birth, and neonatal/infant outcomes [27, 29, 32], although two publications sought to understand the effect of antimalarial medication exposure during the second and/or third trimester compared to first trimester and preconception exposure (n = 2) [30, 31].

Many publications noted limitations in determining the timing of therapeutic exposure (due to incomplete records and related factors), particularly periconceptional exposure, which was dated retrospectively using estimated gestational age. Gestational age was most often estimated using LMP accompanied by other factors, depending on the publication [27, 29–32]. There were several combinations of estimation methods: 1) LMP, ultrasound, Dubowitz newborn assessment, fundal height formula validated for population [27], 2) LMP, Ballard score, fundal height, and ultrasound [31], or 3) LMP, fundal height, and date of quickening [30]. Last, one publication did not have such data available and used descriptive statistics to link records from outpatient and delivery/pregnancy complication registers [26].

For malaria-centered publications that utilized comparator groups or had explicit information detailing their comparator groups, we found that all publications used contemporaneous/concurrent comparator groups (n = 6). Among these 6 publications, the comparator groups included: pregnant people without malaria [27], pregnant people with an episode of malaria in first trimester [27], pregnant people with antimalarial therapeutic exposure during any period of pregnancy [28–32], and pregnant people (with or without malaria) with no therapeutic exposure [28–32].

Tuberculosis

For publications where the infectious disease of focus was TB, there were two main exposure groupings: 1) second-line DR-TB or MDR-TB therapeutics and 2) isoniazid-based therapeutics. The publications that focused on second-line therapeutics exposure investigated linezolid [33], a fluoroquinolone [34, 35] and bedaquiline, clofazimine, and levofloxacin specifically [35] to treat DR-TB or MDR-TB. The publications focused on isoniazid-based therapeutics and analyzed the safety of isoniazid preventive therapy (IPT) among pregnant people living with HIV [36–38].

Among these publications, common outcomes of interest were adverse birth and neonatal/infant outcomes such as preterm birth, LBW, stillbirth/miscarriage, neonatal mortality, and congenital anomalies [28, 33–36, 38–40]. All publications analyzed some maternal TB/IPT treatment outcomes and adverse maternal outcomes, but they differed in the specific outcomes that were analyzed. Some publications defined adverse maternal outcomes as overall maternal morbidity and mortality [33], whereas other publications defined adverse maternal outcomes as therapeutics-related adverse events such as liver impairment, kidney function impairment, gastrointestinal disorders, or psychiatric disorders [33] or loss of weight, dizziness, rash, nausea, and ototoxicity [34]. It is also notable that Gupta et al had a primary focus on treatment-related, maternal, AEs [36]. Tuberculosis treatment outcomes were typically framed by WHO TB guidelines that defined outcomes as: cured, completed, died, lost to follow up, or not evaluated [33–35, 39, 40].

While some publications focused on IPT among pregnant people living with HIV [36–38], the primary objective of most publications was to assess the safety of second-line TB therapeutics in relation to maternal, birth, and neonatal/infant outcomes [28, 33–35, 39, 40]. In some publications, particularly the publications centered on IPT in pregnant people living with HIV, a key point of analysis was the timing of exposure during pregnancy [36–38]. Specifically, some of these publications compared the effects of IPT initiated immediately during pregnancy for 28 weeks or at a deferred time after delivery (12 weeks after delivery) [36, 37], while another analyzed the effects of IPT at any time during the second or third trimester of pregnancy [38]. It should also be noted that, among the publications with a focus on second-line TB medication, one publication compared the timing of exposure between the first, second, or third trimester [40]. This publication noted that the outcome of live birth was significantly associated with trimester of initiation, with first trimester initiation being associated with the lowest rates of live birth [40]. Analyzing outcomes based on trimester exposure allowed this publication to conclude that TB treatment should be initiated in either the second or third trimester (preferably third), but not in the first trimester [40].

For TB-centered publications that utilized comparator groups or had explicit information detailing their comparator groups, we found that all publications used contemporaneous/concurrent comparator groups (n = 9). For publications with a focus on second-line TB therapeutics, these publications compared pregnant people with DR-TB using second-line TB treatment and those with DR-TB not using second-line TB treatment [34, 35]. However, Mokhele et al specifically compared pregnant people living with DR-TB and HIV with pregnant people living with DR-TB [34]. For publications that focused on IPT in pregnant people living with HIV, most compared a group that was immediately given IPT during pregnancy to a deferred group that received IPT after delivery (12 weeks after) [36, 37], while one matched pregnant people living with HIV exposed to IPT with a control comparison group of pregnant people living with HIV but with no IPT exposure [38].

Vaccine-Related Publications

Among the vaccine-related publications, the specific vaccines studied were for pertussis, tetanus, and diphtheria (n = 1) and influenza (n = 3; Table 3). Some of the publications (n = 2) assessed vaccine safety [41, 42], one publication focused on vaccine efficacy [43], and one publication focused on both vaccine safety and efficacy [44].

The exposure for vaccine safety-focused publications was during a specific time during the pregnancy. Some publications focused on vaccination during the second or third trimester [41, 42]. One publication assessed both vaccine safety and efficacy in Nepal and included two cohorts, one cohort in which individuals were vaccinated as soon as pregnancy was confirmed and a second cohort where individuals were identified as pregnant and then randomly allocated a week during pregnancy to receive the vaccine [44]. The primary outcomes of interest for this publication was incidence of maternal influenza-like illness, incidence of LBW, and incidence of laboratory-confirmed infant influenza [44]. The secondary outcomes for this publication were maternal laboratory-confirmed influenza, rate of infant influenza-like sickness, and SGA [44].

One publication assessed safety of two pertussis, tetanus, and diphtheria vaccines and had the following outcomes of interest: AEs following immunization, pregnancy outcomes (early abortion and complications like preterm labor and preeclampsia), and infant outcomes (congenital anomalies, APGAR scores, stillbirth) [41]. Another publication assessing influenza vaccine safety assessed whether the inactivated influenza vaccine may have non-specific effects that increase the risk of other infections in pregnant people. Thus, the outcomes of interest in this publication were maternal all-cause mortality, maternal mortality from presumed infectious causes, miscarriage/stillbirths, infant (aged up to 6 months) all-cause mortality, and infant (aged up to 6 months) mortality from presumed infectious causes (non-influenza related) [42].

One publication focused on assessing vaccine efficacy of maternal influenza vaccination but also assessed birth, maternal, and neonatal/infant outcomes [43]. This publication based in Nepal, Mali, and South Africa had different vaccination administration timing, ranging from 17 to 36 weeks gestation, depending on site location [43]. Omer et al examined maternal, birth, and neonatal/infant outcomes based on vaccination-site location and assessed vaccine efficacy at differing periods after vaccination [43]. For example, Omer et al concluded that vaccine efficacy against infant influenza was higher in the first 2 months of life yet did not demonstrate efficacy after 4 months of life [43]. This publication had several outcomes of interest, including: overall vaccine efficacy against maternal and infant PCR-confirmed influenza, duration of protection, the effect of gestational age at vaccination on efficacy, adverse birth outcomes (including LBW, stillbirth, preterm birth, and SGA), and infant growth up to 6 months [43].

For vaccine-centered publications that utilized comparator groups or had explicit information detailing their comparator groups, we found that all publications used contemporaneous/concurrent comparator groups (n = 3). Among these 3 publications, comparator groups included: pregnant individuals given a vaccine of interest during different times of the year [44], pregnant individuals given a vaccine other than the vaccine of interest [42, 43], and pregnant individuals given a saline placebo [42–44].

Discussion

Summary of Evidence

In this scoping review, we identified 31 publications spanning at least 24 LMICs for PV in pregnancy projects that focused on therapeutics or vaccines for infectious diseases, including HIV, malaria, TB, pertussis, and influenza. The study settings were frequently from Africa, study designs varied from cohort or cross-sectional studies to clinical trials, contemporaneous comparator groups were commonly used, and birth and neonatal/infant outcomes were most commonly reported, although marked heterogeneity existed in definitions and ascertainment of specific measures. While currently published pregnancy PV literature offers insights into the PV landscape in LMICs, further work is needed to standardize definitions and measurements in these projects. Given recent interest in pregnancy PV projects (e.g., since we ran our search string, there has been a number of highly pertinent publications [45–48]), we believe this scoping review will aid persons working in this field to better strategize for the next steps.

The following are some common themes arising from the publications included in this review, which also illuminates gaps to address in future work: (1) we identified that all publications regarded infectious diseases and largely took place in Africa, (2) most included neonatal/infant outcomes, and (3) almost all covered a single therapeutic exposure. First, the heavy focus on infectious diseases may reflect their large burden and sizable treatment campaigns in the African region [49] but also the funding priorities of sponsors, largely coming from HICs [50]. For instance, our review yielded no publications on vaccinations largely only applicable in LMICs, such as yellow fever, meningococcal, or malaria vaccinations. Related to this, the burden of non-communicable diseases is increasing in LMICs [51] and is predicted to become the leading cause of morbidity and mortality in LMICs in coming decades. Thus, expansion of PV projects to include non-communicable disease medications is urgently needed. Second, all publications included birth outcomes and a majority included neonatal outcomes, usually assessed at birth or within the first 30 days after birth. Some (48 % of publications) included maternal outcomes, such as maternal death and preeclampsia/eclampsia, though maternal safety measures, such as AEs, or chronic exposures pre-pregnancy were often overlooked (noting only one publication used the WHO Vigibase system meant to standardize adverse drug events reporting for LMICs) [52]. Perhaps the most overlooked set of outcomes was longer-term child outcomes; 65% of publications included short-term infant outcomes but no studies tracked child growth outcomes out to two years past birth, let alone tackled neurodevelopmental outcomes out to even longer periods of time (though admittedly, such data exist outside of the PV paradigm) [53–56]. Last, nearly all the publications focused on one therapeutic only, i.e., a “vertical” approach to the work. If these projects were better leveraged to cover additional medications, including for vaccines, the broadened scope of the work would have greater returns for the investments and be uniform across health services, regardless of diseases or therapeutics. For instance, no studies investigated exposures of known teratogens, such as valproic acid or certain antiepileptics, newly emerging HIV pre-exposure prophylaxis (PrEP) drugs in their settings, especially for the various HIV-focused projects, which could have quickly pivoted to include this (though PrEP rollout has been relatively recent) [57], or COVID-19 vaccinations (similarly recent), as highlighted in the WHO COVID-19 pregnancy cohort study and similar initiatives [58–60]. This is a missed opportunity across many of the projects covered in this review and would be more scientifically robust while also maximizing benefits. Funder priorities or investments in single-topic projects drive such decisions, rather than building broader PV projects in existing health systems, which could more nimbly pivot towards additional analyses when needed. Undoubtedly, work to expand beyond single disease or therapeutic focus and to include longevity in the projects that span multiple years, requires long-term investments to strengthen health systems and research.

For many of the publications, the timing of treatment initiation or vaccination, specifically by trimester, was important, sometimes even deemed “critical,” in determining maternal and neonatal safety. However, a frequent barrier highlighted throughout the infectious diseases therapeutics-related publications is the underreporting of and inaccessibility to health data, including accurate gestational age data within LMICs. To illustrate, many of the analyzed HIV-related publications were concerned with the timing of ART initiation, especially prior to conception. However, it is difficult to calculate the exact time of exposure in terms of gestational days or weeks. While many publications used a variety of factors to assess periconceptual exposure, such as LMP or fundal height, these data were not uniform across publications. This is a substantial concern that hinders pregnancy PV efforts, since without accurate gestational age data, it is difficult to assess whether adverse outcomes are a result of disease exposure or therapeutic exposure (e.g., both malaria itself or anti-malaria drugs in pregnancy that lead to pregnancy loss). Furthermore, there are fundamental issues in some overlap, or even risk of confounding by indication, where the underlying condition being treated may contribute, alongside the treatment exposure itself, to the specific adverse pregnancy outcome; thus, PV projects need to effectively disentangle the two. It is also likely that each exposure-outcome relationship ascertainment is uniquely tied to gestational week-level development in a pregnancy. Therefore, the ultimate goal in PV projects in pregnancy would be to have granularity in exposure timing down to the gestational week or days, especially as a growing number of pregnant people may be exposed to medications in early pregnancy due to the increasing availability of various chronic or short-term medications. An additional challenge in LMICs would be capturing exposures to prescription medications accessed directly from private pharmacies, over-the-counter medications, herbal therapeutics, or intermittent medications. Incomplete pregnancy PV impedes the accessibility to safe, evidence-based, and successful treatment for pregnant people and their infants, as well as supports the continued use of potentially harmful treatments.

In our review, we found a wide breadth of outcomes being measured and reported, including for maternal or neonatal mortality, congenital malformations detected by birth surface exams, stillbirth, preterm birth, LBW and SGA. Among these outcomes, we noticed that definitions of congenital malformations varied the most (especially for neural tube defects), while stillbirth, preterm birth, and LBW were the most standardized. We found that for publications that were explicit in their definition of stillbirth, the gestational age cutoff was between 22 to 28 weeks. This is most likely the result of WHO guidelines that define stillbirth as no signs of life in the fetus after 22 gestational weeks but recommend that this cutoff be extended to 28 weeks if resources for care of very premature neonates are lacking [61]. Furthermore, Loveday et al noted that in South Africa, the legal definition of stillbirth is an infant born dead after 27 complete weeks [35]. Additionally, across the majority of publications, preterm birth was defined as birth prior to 37 weeks of gestation and LBW was defined as birth weight below 2500 g.

Collectively, this work highlights challenges facing PV in pregnancy work in LMICs. First, that our use of the term “PV” in our search string likely limited inclusion of relevant publications and raises the fundamental concern that consensus is lacking around what types of activities constitute PV, which becomes ever more relevant in LMIC settings since post-marketing or government-supported surveillance is not frequently conducted. For instance, medication testing with animal models often offers us the earliest evidence of possible teratogenicity. Spontaneous reporting, although passive, also offers some early signals of possible safety concerns. Thus, some conceptual work and consensus building is required on how best to incorporate various study designs or models for PV work when related nomenclature varies markedly by fields. Second, exposure-outcome relationships in pregnancy require granularity on the frequency, type, and timing of exposure throughout pregnancy and postpartum, and the feasibility of accurate exposure timing in relation to the pregnancy are often limited in LMIC settings. This may be in part because of incomplete records on LMP or exposures, limited access to ultrasonography for dating gestational duration in early pregnancy, delayed antenatal care-seeking, and suboptimal linkages between medication exposures and pregnancy outcomes in LMICs. Third, a focus on building comprehensive, consistent medical record systems in LMICs is paramount in order to inform maternal and neonatal care and safety and to quickly pivot towards a new or emerging threat. While future projects may utilize both active and passive PV surveillance, active forms of PV surveillance are needed to facilitate signal detection and assessment in pregnancy in particular by improving underlying quality of clinical data collected [62]. New pregnancy PV projects in LMICs may expand on existing structures, often bolstered by local or national governments, to become more robust and adapt to the needs of LMICs with changes in health patterns or disease burden. Such an example is the recent Western Cape Pregnancy Exposure Registry [63], which leverages electronic health records collected at the district level. Our findings may help guide future policy to address the gaps identified in existing PV structures, such as in quality and consistency of data collected or study designs utilized, as the limited existing evidence surrounding medication and vaccination use during pregnancy often shapes conservative guidelines that may negatively impact the health of pregnant people. Despite unique challenges facing PV work in LMICs, our review demonstrates that significant work is already underway and lessons from these published studies can help strengthen ongoing or planned PV in pregnancy projects in LMICs.

Limitations

Although the first of its kind, there are limitations in our work. First, to make our scoping review reproducible, we limited our search of the pregnancy PV projects to published studies. If we expanded our search to non-published projects, for example through gray literature or co-author networks, we would have been able to include a larger number of projects. However, many of the details needed for abstraction could not have been collected in a standard or reproducible fashion. Second, although we had developed search strings to be comprehensive and include terms to pull LMICs pregnancy PV publications, LMICs publications were scarce in PubMed. Furthermore, although we decided to use databases such as Global Index Medicus and SciELO to help mitigate these concerns, we found very few publications from these databases to be relevant to our scoping review focus. This may have skewed the selection of publications that we were able to review and our review may not fully encompass the extent of PV in pregnancy in LMICs. Additionally, the majority of the relevant publications identified were based in sub-Saharan Africa. While this may reflect the burden of infectious diseases and funding priorities of HICs, it is important to note that this may be indicative of a geographical bias and affect the generalizability of our findings. Third, although we altered our search strings to capture the most relevant publications, we still found it necessary to conduct a secondary review to develop a more comprehensive collection of publications. We did not originally plan to incorporate this secondary review; however, it yielded many relevant publications. We also note that our secondary review identified more relevant publications than our primary review, which may indicate that our search string is suboptimal. This could largely be due to our inclusion of the term “PV”, which as we have already discussed, may not be a term universally used. Broader terms, such as “surveillance,” “monitoring,” or “evaluation,” or more specific terms, such as “safety surveillance,” could capture a greater breadth of publications. Indeed, preliminary alterations of our search string to include such terms yielded higher hit results, but we did not identify any additional applicable publications on title review alone. Notwithstanding these limitations, this scoping review is the first of its kind to document published PV in pregnancy work in LMICs and help guide existing and planned related efforts.

Conclusion

Our scoping review of pregnancy-centered PV in LMICs publications examined the focus and methodology of current pregnancy PV projects and highlighted the need for more comprehensive projects that thoroughly promote the health of pregnant people and their infants. The selection and defining of exposure variables appeared to be heterogeneous among current projects, particularly in relation to the timing of initiation and duration of treatment, indicating a need for a more harmonized approach. Definition and measurement of outcomes were more consistent throughout the current pregnancy PV literature, likely reflecting the feasibility of measurement of certain adverse maternal, birth, and neonatal/infant outcomes. In order to create the most effective, comprehensive, and responsive PV in pregnancy projects, significant challenges in LMICs will have to be overcome, from capacitating exposure timing granularity to building electronic health records systematically to broadening the focus from infectious diseases to include non-communicable diseases. This scoping review highlights the need for a more thorough body of pregnancy PV research in LMICs and to address the current gaps in LMICs pregnancy PV projects, to ensure access to safe, evidence-based, and effective health care for pregnant people and their infants.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 177 KB)

Supplementary file2 (PDF 162 KB)

We would like to acknowledge the University of Washington librarian, Teresa E. Jewell, for her contributions in developing the search string for this scoping review.

Declarations

Funding

The following individuals’ efforts were supported by funding from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Developments, the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, the Fogarty International Center, and the National Library of Medicine: James G. Carlucci (K23HD109056), John Humphrey (K23HD105495), and Audrey Chepkemoi, Caitlin Bernard, Megan S. McHenry, Edwin Were, and Rena C. Patel (U01AI069911). The funders had no role in study design, analysis, or decision to publish.

Conflicts of Interest

The authors have no conflicts of interests to declare that are relevant to the content of this article.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Materials

All data supporting the findings of this study are available within the paper and its Supplementary Information. Any other information is also available from the corresponding author (renapatel@uabmc.edu) upon request.

Code Availability

Not applicable.

Authors’ Contribution

Conceptualization: Rena C. Patel, Emma Kalk, Ushma Mehta, John Humphrey, Jenine Shafi, Maneet K. Virk. Performance of literature search: Jenine Shafi, Maneet K. Virk. Data analysis: Jenine Shafi, Maneet K. Virk, Rena C. Patel. Initial draft of manuscript: Jenine Shafi, Maneet K. Virk, Rena C. Patel. Critical review of manuscript: Emma Kalk, Jimmy Carlucci, Ushma Mehta, Jenine Shafi, Maneet K. Virk, Rena C. Patel, Megan S. McHenry. Full review of manuscript: All authors. Decisions for submission of manuscript: Jenine Shafi, Maneet K. Virk, Rena C. Patel. All authors read and approved the final version of this body of work.

Jenine Shafi, Maneet K. Virk have contributed equally as co-first authors.

Change history

7/1/2024

The original article has been corrected. Author comment removed from article note.
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