Interventions to Prevent and Manage Infections in Pregnancy

One of the key parameters of the third Sustainable Development Goal is to end preventable deaths of newborns and children under 5 years of age by 2030 [1]. The first 28 days of life is the most vulnerable period for a newborn. In 2020, approximately 2.4 million newborns died during this period, and nearly 47% of all under-5 deaths occurred in the first month. The leading causes of neonatal death include preterm birth, intra-partum-related complications, infections, and birth defects. Nine out of ten countries with the greatest number of neonatal deaths in 2020 were lower-middle-income countries (LMICs) [2].

Reduction of the maternal mortality ratio to less than 70 per 100,000 live births has long been a global health priority and is a target in the Sustainable Development Goal 3 framework. Most maternal deaths are preventable through appropriate access to quality healthcare and timely management of perinatal complications. In 2020, 95% of all maternal deaths occurred in LMICs and nearly 800 women died from preventable causes related to pregnancy and childbirth [3].

Newborn and maternal health are closely connected. For the newborn to develop and survive to the fullest potential, a healthy pregnancy and a safe delivery are essential. Promoting maternal health through access to quality antenatal, intrapartum, and postnatal care is imperative for optimal neonatal outcomes.

Pregnancy-related infections in mothers can have serious consequences for both the mother and the fetus. Urinary tract infections, bacterial vaginosis, yeast infections, hepatitis B, human immunodeficiency virus/acquired immunodeficiency syndrome, and sexually transmitted diseases (including syphilis, gonorrhoea, and chlamydia) are among the common infections that affect mothers, and are linked to adverse neonatal outcomes such as stillbirth, preterm birth, neonatal mortality, congenital anomalies, neonatal morbidity, and sepsis [4]. Bacterial vaginosis, in particular, is a common reproductive tract illness in women of childbearing age globally, accounting for one-third of vaginal infections [5]. It is essential to treat bacterial vaginosis in pregnant women to minimize the risk of complications during pregnancy and delivery. Bacterial vaginosis is often treated with antibiotics; however, caution needs to be exercised in the first trimester of pregnancy due to the risk of potential harm to the developing fetus.

Preventive interventions, early identification, and proper treatment of maternal infections can effectively mitigate maternal infections and improve outcomes for both the mother and the infant. The objective of this overview of reviews is to synthesize the current literature on different interventions aimed at preventing and managing maternal infections during the antenatal period, with the goal of curbing adverse neonatal outcomes. We place a particular focus on LMIC-specific data to provide a comprehensive summary of strategies that can be optimized to improve neonatal health in regions where unique challenges and limited resources in the healthcare sector may influence the effectiveness and implementation of these interventions.

Following a review of the preceding Lancet Series [6] and consultation with the technical advisory group, specific interventions pertaining to immunization, screening, and management of maternal infections in the antenatal period were chosen.

The evidence from the series was updated, and the most current interventions relevant to the topic of interest were identified, and where applicable, a sub-group analysis of LMICs was conducted. This paper is a part of a supplement that offers a comprehensive synthesis of various existing interventions examining different prevention and treatment strategies of maternal infections during the antenatal period. A range of methodological approaches were used to synthesize the overall and LMIC-specific evidence, and the detailed methodology is published elsewhere, and below is the brief methodology for this paper [7].

Thirteen topics encompassing interventions to prevent and manage infections in the antenatal period to improve perinatal and newborn outcomes were included, which were sub-grouped under three broad categories to assess similar interventions together.

• Tetanus toxoid vaccination during pregnancy.

• Influenza virus vaccination administered during pregnancy.

• Screening for tuberculosis in pregnancy in endemic areas.

• Provision of insecticide-treated bed nets (ITNs) in pregnancy.

• Changing a two-dose intermittent preventive treatment (IPTp) regimen to more frequent IPTp dosing.

• Addition of antibacterial antibiotic to the IPTp regimen.

• Screening and treatment for asymptomatic bacteriuria in pregnancy.

• Preventative anthelmintic treatment during pregnancy.

• Clindamycin or metronidazole treatment of pregnant women with current bacterial vaginosis.

• Metronidazole treatment of pregnant women with current bacterial vaginosis and a history of previous preterm birth.

• Antibiotic treatment for syphilis and chlamydia during pregnancy on birth outcomes.

• Treatment of documented periodontal disease during pregnancy.

• Treatment of documented deep caries or periapical periodontal disease during pregnancy.

We searched PubMed and CENTRAL to find the most recent systematic reviews on each of the interventions. The objective was to use the findings of existing systematic reviews exactly as they were if the evidence was up-to-date, update existing systematic reviews if the evidence was out-of-date, and conduct de-novo reviews if none were found to be relevant to the intervention of interest. We also conducted a scoping search to find overviews of systematic reviews pertinent to our interventions and outcomes of interest.

Our approach was as follows: (1) to identify a relevant overview of systematic reviews, (2) to go over the included systematic reviews and their included trials to identify individual randomized controlled trials (RCTs) from the LMIC setting, and (3) to perform a LMIC-only reanalysis of the existing reviews after de-duplication.

We extracted all relevant data and outcomes with effect estimates after identifying the most recent systematic review. To conduct a sub-group analysis for outcomes of interest, we cross-referenced the countries in which the primary studies were conducted in with the World Bank list [6] of countries based on the year they were conducted in. If the studies in the review were from multiple income groups, the data for a given outcome were classed as overall, and if the studies were from low-income countries (LICs) or LMICs, the data were classified as LMIC-only. The analysis of the data was carried out by two authors to get sub-group estimates for evidence from LMIC-only. We obtained the pooled effect estimates using the same statistical process as outlined in the original review.

For reviews that were updated, the search was conducted by two reviewers, and following the inclusion criteria, we included all eligible studies and extractions were done. We updated all the outcomes where new studies reported those outcomes. Data for new studies were entered in Review Manager 5.4.1, and the existing forest plots were updated, with new estimates reported as RR with 95% confidence interval for dichotomous and mean difference (MD) with 95% confidence interval for continuous outcomes. For all meta-analysis, we applied a random-effects model if the heterogeneity was high (I² less than 0.05) and a fixed-effects model if the heterogeneity was low (I² more than 0.05).

We identified an overview of systematic reviews [8]. For each intervention of interest, the overview performed a comprehensive literature search in “MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL Complete.” The last search date was from March 2020. The overview included relevant systematic reviews and RCTs if “at least one of the following outcomes were reported: low birthweight (LBW), preterm birth, small for gestational age (SGA), or stillbirth.” We extracted and analyzed the overall and LMIC-specific data from each of the systematic reviews of interest.

Findings are summarized in Tables 1, 2, and 3. Additional information including forest plots for LMIC analysis and study characteristics can be found in online supplementary files 1 and 2 (for all online suppl. material, see https://doi.org/10.1159/000543690).

Vaccination during pregnancy plays a pivotal role in protecting both the mother and the developing fetus from preventable diseases. Maternal immunisation provides a safe and efficient means of protecting them from potentially fatal infections until their own adaptive immunity can develop [9].

This review [10] focused on the impact of maternal tetanus vaccination. Adverse birth outcomes of interest were not reported. However, the review reported a protective effect against deaths caused by tetanus among the neonates of pregnant women who received tetanus toxoid vaccine.

For this topic, an existing review was used [11] and included three studies, of which two were from LMICs. The review evaluated the effect of trivalent inactivated influenza vaccine (IIV) on neonatal outcomes.

Overall, the intervention had no effect on stillbirth, preterm birth, SGA or LBW. Evidence from LMICs showed no impact on stillbirth (RR 0.93 [0.65–1.33]; 2 studies) (online suppl. Fig. 1.1), preterm birth (RR 0.94 [0.83–1.06]; 2 studies) (online suppl. Fig. 1.2), SGA (RR 0.98 [0.91–1.05]; 2 studies) (online suppl. Fig. 1.3), or LBW (RR 0.98 [0.73–1.31]; 2 studies) (online suppl. Fig. 1.4) (Table 1).

Some infections, though asymptomatic, can have detrimental effects on maternal and fetal health [12]. By detecting infections early on, screening enables healthcare providers to begin treatment or take preventative measures to reduce the risk of transmission from mother to baby during the antenatal period or childbirth. Additionally, screening and preventative strategies can vary widely based on the prevalence of certain infections in different geographical locations [12].

No evidence of previous or ongoing studies that sufficiently addressed the research question or reported pertinent findings was found.

The review [13] compared the effect of using ITNs during pregnancy with no use of bed nets. Four trials were meta-analyzed for this intervention, all of which hailed from LMICs.

Evidence suggested that ITN significantly reduced the likelihood of fetal loss (RR 0.68 [0.48–0.98]; 3 studies) and significantly increased birthweight (MD 33.00 [5.00–62.0]; 4 studies). The intervention had no effect on preterm births or on LBW babies. Additional information can be found in Table 2.

The review [14] aimed to determine whether regimens containing three or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy, compared to standard 2-dose regimens, curbed adverse neonatal outcomes. Seven trials were included, all of which were from LMICs.

Evidence from LMICs (Table 2) suggested the intervention significantly reduced the risk of LBW (RR 0.80 [0.69–0.94]; 7 studies) and improved birthweight (MD 56 g [29 g–83 g]; 7 studies), but had no effect on the risks of miscarriage (RR 1.43 [0.88–2.33]; 6 studies), stillbirth (RR 1.14 [0.85–1.55]; 7 studies), preterm birth (RR 0.95 [0.80–1.12]; 7 studies) or neonatal mortality (RR 0.88 [0.57–1.35]; 6 studies).

Our source review [8] identified a systematic review and four RCTs for this topic. The effect estimate was based on one study [15] conducted in Malawi. In this RCT, the researchers found that adding two doses of azithromycin to sulfadoxine-pyrimethamine per month could lead to a 50-g higher birth weight in newborns but showed no significant effect in reducing the risk of LBW (RR 0.86 [0.55–1.36]) (Table 2). For the remaining records identified by the source review, though conducted in LMICs, these studies either used different IPTp drug doses or had different combinations in the comparison group. Therefore, their results could not be pooled together.

Our source review [8] identified five systematic reviews and nine RCTs for this topic. Among all the RCTs included in the five systematic reviews, only one study was conducted in LMIC but did not report our outcomes of interest (i.e., LBW and preterm birth). Among the nine RCTs identified by the source review, one RCT conducted in Bangladesh [16] showed that screening and treating asymptomatic bacteriuria in pregnancy led to a significant lower risk of developing SGA (RR 0.86 [0.80–0.93]; 1 study) but had no effect on preterm birth (RR 1.06 [0.97–1.16]; 1 study), LBW (RR 1.00 [0.90–1.12]; 1 study), stillbirths (RR 1.20 [0.98–1.46]; 1 study), or neonatal mortality rate (RR 0.83 [0.65–1.06]; 1 study). The other eight RCTs were all conducted in high-income countries (HICs). Additional details about the intervention can be found in Table 2.

The review [17] included four trials, all of which were from LMICs, and evaluated the effects of administration of anthelmintics for soil-transmitted helminths during the second or third trimester of pregnancy on neonatal outcomes.

Evidence shows the intervention had no effect on preterm birth (RR 0.88 [0.43–1.78]; 2 studies), LBW (RR 1.00 [0.79–1.27]; 3 studies), or perinatal mortality (RR 1.09 [0.71–1.67]; 2 studies) (Table 2).

The impact of maternal infections on neonatal mortality and morbidity underscores the importance of prompt and appropriate treatment strategies. The use of certain medications, especially antibiotics during pregnancy, requires caution, and risks can sometimes outweigh the benefits as some drugs can be teratogenic to the developing fetus or can lead to antibiotic resistance [18].

For this intervention, fifteen studies [19‒33] were identified. Eleven studies were from HICs and four were from LMICs.

Overall, the intervention reduced the risk of miscarriages (RR 0.61 [0.38–0.98]; 3 studies) but had no effect on the risks of stillbirth, preterm birth, LBW, or neonatal mortality. Evidence from LMICs show the intervention had no effect on the risks of miscarriage (RR 0.64 [0.36–1.15]; 2 studies) (online suppl. Fig. 2.1), stillbirth (RR 0.81 [0.46–1.41]; 1 study), preterm birth (RR 0.97 [0.80–1.17]; 4 studies) (online suppl. Fig. 2.2), LBW (RR 1.12 [0.95–1.33]; 3 studies) (online suppl. Fig. 2.4), or on neonatal mortality (RR 0.76 [0.33–1.72]; 1 study). More data on the intervention can be found in Table 3.

Brocklehurst et al. [34] evaluated the effect of metronidazole treatment in pregnant women with current bacterial vaginosis who had a history of previous preterm birth. Three studies conducted in HICs were included. The intervention had no effect on preterm birth (RR 0.58 [0.08–4.08]; 2 studies) or LBW (RR 1.25 [0.35–4.49]; 1 study) (Table 3).

For syphilis, the review [35] included twenty-two observational studies and compared pregnant women with active syphilis who received less than two doses of 2.4-million-unit penicillin or equivalent treatment to those who received two or more doses of penicillin treatment. Ten studies were from LMICs. Overall, the intervention lowered the risk of preterm birth (RR 0.48 [0.39–0.58]; 15 studies), stillbirth (RR 0.21 [0.12–0.35]; 8 studies), LBW (RR 0.50 [0.42–0.59]; 7 studies), and perinatal mortality (RR 0.39 [0.20–0.76]; 4 studies). Evidence from LMICs suggested a significant reduction in the risk of preterm birth (RR 0.31 [0.24–0.40]; 7 studies) (online suppl. Fig. 3.1), stillbirth (RR 0.10 [0.06–0.17]; 5 studies) (online suppl. Fig. 3.2), and LBW (RR 0.37 [0.28–0.49]; 2 studies) (online suppl. Fig. 3.3), but no effect was noted on perinatal mortality (RR 0.32 [0.02–4.15]; 2 studies) (online suppl. Fig. 3.4).

For chlamydia, the review [35] included five observational studies and two RCTs. Six studies were from HICs and one hailed from an LMIC setting. Overall, pregnant women who received either azithromycin or erythromycin for chlamydia showed a reduction in the risk of preterm births (RR 0.58 [0.36–0.93]; 7 studies), but no effect was seen on the risk of giving birth to LBW babies (RR 0.60 [0.36–1.00]; 4 studies). Evidence from a RCT conducted in LMICs showed no reduction in the risk of preterm birth (RR 0.45 [0.17–1.22]; 1 study) but significantly reduced the likelihood of LBW babies (RR 0.31 [0.12–0.79]; 1 study). Additional information can be found in Table 3.

The review [36] compared the treatment of periodontal disease during pregnancy with no treatment. Eleven studies were included, of which three studies were from LMICs. Overall, treatment of periodontal disease had no effect on the risk of preterm birth, LBW, SGA, or perinatal mortality. Evidence from LMICs suggested the intervention had a significant effect on the risk of LBW (RR 0.48 [0.33–0.71]; 2 studies) (online suppl. Fig. 4.2), but no evidence of difference was seen on preterm birth or perinatal mortality (Table 3).

No evidence of previous or ongoing studies that addressed the research question or reported relevant findings was found.

A total of thirteen interventions constituting antenatal infection prevention and management strategies were identified and analyzed. Overall and LMIC-specific evidence suggested that influenza virus vaccination had no effect on stillbirth, preterm birth, SGA, or LBW. Evidence from LMICs suggested that ITNs in pregnancy reduced the risk of fetal loss due to stillbirth/miscarriage and improved the babies’ birthweight but had no effect on preterm birth or LBW. Changing a two-dose IPTp regimen to more frequent IPTp dosing decreased the risk of LBW babies and significantly improved babies’ birthweight; however, the intervention had no effect on stillbirth, preterm birth, or neonatal mortality in LMIC-only setting. The addition of antibacterial antibiotic to the IPTp regimen significantly reduced the risk of LBW babies. Overall, screening and treatment for asymptomatic bacteriuria had no effect on preterm births, LBW babies, birthweight, or gestational age. LMIC-specific evidence suggested a decrease in the risk of SGA, but no effect was demonstrated on the risks of stillbirth, preterm birth, LBW, or neonatal mortality rate. Preventative anthelmintic treatment during pregnancy had no effect on preterm birth, LBW, or perinatal mortality.

Overall and LMIC-specific evidence suggested clindamycin or metronidazole treatment of pregnant women with bacterial vaginosis had no effect on stillbirth, preterm birth, LBW, extremely LBW, or neonatal mortality. No LMIC evidence was available for metronidazole treatment of pregnant women with current bacterial vaginosis and a history of previous preterm birth. Overall evidence suggested that antibiotic treatment for syphilis reduced the risks of stillbirth, preterm birth, LBW, and perinatal mortality, while a significant reduction was noted for risk of stillbirth, preterm birth, and LBW. Overall evidence suggested that antibiotics for the treatment of chlamydia reduced the risk of preterm birth, but no significant effect was noted in LMICs. Overall and LMIC evidence demonstrated the treatment of documented periodontal disease during pregnancy reduced the risk of LBW babies, but no effect was observed on the risks of preterm births, LBW, or SGA babies.

Our findings suggest a paucity in available evidence on maternal infections. In regions with poor sanitation and a high burden of infections, maternal infections can have severe implications, with the greatest risks noted in LMICs [37]. Women in LMICs face disproportionate access to maternal healthcare services, likely due to poor healthcare delivery systems, inadequate healthcare facilities, untrained staff, and limited basic medical equipment and supplies. Often, there are social, cultural, and economic barriers to accessing maternal healthcare services in LMICs, such as distance to healthcare facilities, lack of transportation, and traditional beliefs and practices [38]. As a result, a substantial portion of the population does not have access to adequate antenatal care services. Amongst many other common causes of maternal infections, malaria contributes to a significant public health burden in LMICs, affecting millions each year. These countries often face challenges in implementing comprehensive malaria control measures and provision of appropriate quality of care [39] due to limited resources, inadequate healthcare infrastructure, and competing health priorities. Pregnant women are more vulnerable to contracting malaria than non-pregnant women [40]. Maternal malarial infection during pregnancy leads to placental infection [41], which results in a greater likelihood of stillbirths, intrauterine growth restriction, and LBW babies [42]. A systematic review of ten cross-sectional studies conducted in Ethiopia suggested that those pregnant women with a higher educational status (OR 3.47 [2.32–5.2]), those who had any number of antenatal care visits (OR 2.37 [1.97–2.65]), and those who were well aware about malarial prevention practices (OR  10.63 [5.31–21.29]) were more inclined towards ITN utilization [43]. A cross-sectional hospital-based study conducted in pregnant women in Ghana suggested that administration of at least 3 IPTp-SP doses was associated with an average birthweight increase of more than 360 g compared to women who did not take treatment [44].

Additionally, bacterial infections are common among pregnant women and require prompt screening and treatment to prevent potential complications as untreated bacterial infections in pregnancy pose risks to both the mother and the fetus. A prospective cohort conducted in rural India showed that pregnant women with late-detected asymptomatic bacteriuria had a greater incidence of preterm labor (RR 3.27 [1.38–7.72]), intrauterine growth restriction (RR 3.79 [1.80–79]), and LBW (RR 1.37 [0.71–2.61]) [45]. Another study conducted in India suggested that timely screening and provision of appropriate antibiotics reduced the incidence of preterm birth/LBW neonates [45]. A cross-sectional study conducted in pregnant women with bacterial sepsis in China demonstrated that among 86 pregnant women with sepsis, 51 delivered prematurely and 12 women suffered from miscarriages. Therefore, early detection and management of maternal infections is imperative to ensure healthy pregnancy outcomes and to minimize the risk of neonatal mortality and morbidity.

A key strength of our overview of review lies in its thoroughness. In addition to providing a comprehensive synthesis of well-recognized interventions relevant to the care of maternal infections, we also incorporate the findings from a recently published systematic review [8] that evaluates maternal infections and their prevention and treatment strategies. This ensures that no crucial information has been overlooked, providing an in-depth understanding of the topic. Medical professionals, policymakers, and researchers should utilize the findings from our paper and collaborate to overcome the unique obstacles associated with maternal infections, especially in settings with poor healthcare systems and inadequate medical resources, and work towards optimizing maternal, fetal, and neonatal health.

A potential limitation of our review is the presence of evidence gaps in the data pertaining to maternal infections, especially in that of maternal immunizations. This includes understanding the effectiveness and safety of vaccinations administered during pregnancy. Additionally, certain maternal infections have not been thoroughly researched, leading to gaps in understanding their screening, prevention, and treatment; this comprises less common infections such as periodontal diseases during pregnancy as well as those that are common in specific geographic regions, like tuberculosis, with the lack of data adding to the limitations of this overview of reviews.

Undoubtedly, our paper highlights that this aspect of maternal health remains largely unexplored, and substantial, multifaceted research efforts are needed, especially in regions where there are disproportionate burdens of maternal infections, to bridge this gap.

The scarcity in data on maternal infections during the antenatal period indicates that infections during pregnancy may be underreported, particularly in areas with limited access to healthcare. Interventions such as provision of ITNs in pregnancy, changing the two-dose IPTp regimen to a more frequent one, addition of antibiotic to the IPTp regimen, and antibiotic treatment for syphilis and chlamydia during pregnancy show promising results on neonatal outcomes; however, further initiatives and collaborative efforts need to be implemented to expand our understanding of infections during pregnancy and their impact on fetal and neonatal health.

We thank Aga Khan University for providing internal resources.

The authors have no conflicts of interest to declare.

This study is supported by the Bill & Melinda Gates Foundation Grant (#INV-042789). The funders played no role in the design, data collection, data analysis, and reporting of this study.

R.Y. and L.J. carried out the literature review, extracted data from the reviews/studies, entered data into RevMan, carried out the analysis, and interpreted the results. R.Y. drafted the paper. J.K.D. and Z.A.B. provided supervision for each step, conceptualization, and contributed to the critical revision of the manuscript.