Antenatal Care Strategies to Improve Perinatal and Newborn Outcomes

Perinatal health and newborn health are pivotal facets of public health and can adversely affect individual well-being, cause disparities within communities, and significantly weaken health systems. Women and children are potentially more vulnerable, and the risk exponentially increases in pregnant women and neonates residing in low- and middle-income countries (LMICs). The goal of antenatal intervention strategies is to improve perinatal and neonatal outcomes through a variety of healthcare strategies and interventions [1].

Approximately 6,700 newborns die per day, amassing 2.4 million neonatal deaths annually in 2020. Out of the total neonatal deaths, 75% occur in the first week of life, and nearly a million newborns pass away within the first 24 h of life. The primary causes of most neonatal deaths include preterm delivery, intrapartum-related issues like birth asphyxia, infections, and birth abnormalities [2].

The high rate of maternal fatalities in LMICs reflects unequal access to adequate healthcare services. In 2020, LMICs had a maternal mortality rate of 430 per 100,000 live births, compared to high-income countries’ (HICs’) maternal mortality rate of 12 per 100,000 live births, and the leading causes include postpartum hemorrhage, infections, and hypertensive disorders of pregnancy (HDP) [3]. Maternal health can be improved through good nutrition, detecting and preventing diseases, by providing psychological support to women of reproductive age especially to those experiencing intimate partner violence [4], and strengthening healthcare systems.

Antenatal supplementation refers to essential nutritional supplements to pregnant women to improve maternal and fetal health. These supplements include, among others, calcium, iron, folic acid, zinc, and various vitamins [5] and various factors including dietary and personal preferences as well as health conditions can influence the specific supplements advised during pregnancy.

WHO recommends a series of interventions relating to antenatal care, promoting early and regular antenatal visits, routine maternal and fetal assessments, education and counseling, nutritional support, screening and management of diseases such as diabetes and hypertension, prevention of rhesus alloimmunization, providing emotional and psychological support, and monitoring for signs of domestic violence [6]. The objective of this paper was to summarize the current literature on antenatal care interventions aimed at improving maternal and fetal outcomes from studies conducted globally, with a particular focus on low-income and lower-middle-income countries (LICs/LMICs).

Interventions targeting maternal and neonatal health were identified by the “Lancet Every Newborn” series published in 2014 [7]. The evidence from the series was updated, and the most current interventions relevant to the topic of interest were identified, and where applicable, a subgroup analysis of LMICs was conducted. This paper is a part of a supplement that provides a thorough synthesis of antenatal care strategies (ANC) by examining various interventions. 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 [8].

We conducted a search to identify all the recent pertinent systematic reviews that focused on interventions in the antenatal period and focused on outcomes for the pregnant women and their fetuses. The specific interventions were selected a priori, after reviewing the previous Lancet Series [7] and consulting the technical advisory group. The detailed methodology on search and selection criteria of reviews and additional information on data collection and synthesis can be found in Harrison et al. [8]. Twenty-seven interventions encompassing ANC to improve perinatal and newborn outcomes were included, which were subgrouped under three broad categories to facilitate a more comprehensive understanding of how these components work in conjunction.

• Multiple micronutrient supplementation;

• iron and folic acid (IFA);

• vitamin A supplementation;

• vitamin D supplementation;

• zinc supplementation;

• calcium supplementation;

• balanced protein and nutrient supplementation;

• lipid-based nutrient supplements (LNS);

• omega-3 fatty acid supplementation;

• dietary education without supplementation.

• Doppler velocimetry;

• low-dose aspirin for prevention of preeclampsia;

• antithrombotic therapy for placental dysfunction.

• Calcium supplementation for preeclampsia;

• magnesium sulfate;

• antihypertensives for mild to moderate hypertension.

• Combined diet and exercise for prevention of gestational diabetes mellitus (GDM);

• lifestyle interventions for the treatment of women with GDM;

• exercise for pregnant women with GDM;

• different types of dietary advice for women with GDM;

• treatment for GDM.

• Psychosocial interventions to reduce smoking in pregnancy;

• treatment of depressed pregnant women with antidepressant medication;

• professionally provided psychosocial support;

• intimate partner violence prevention.

• Prophylactic cervical cerclage;

• anti-D administration in pregnancy for preventing rhesus alloimmunization.

Databases including CENTRAL and PubMed were searched to identify recent systematic reviews for all of these interventions. Aims were to perform de-novo reviews if no systematic reviews were determined to be pertinent to the intervention of interest, update existing systematic reviews if the evidence was no longer current, and use existing systematic reviews as is if the evidence was current. For reviews that were updated, we followed the same methodology including the search strategy and databases as outlined in the original review, and if no search strategy was mentioned in the review, the MeSH terms provided were used to curate a new search strategy and were run on databases such as PubMed, CINAHL, and Embase.

After identifying the most up-to-date systematic review, we extracted all the pertinent information and outcomes with effect estimates. Subgroup analysis was conducted where relevant for all outcomes of interest reported in studies from LICs/LMICs and classified according to the World Bank [9] list of countries for the respective years in which the studies were conducted. If the studies in the review were from multiple income groups, the data for a given outcome were classified as overall; if the studies were from LICs or LMICs, the data were classified as LMIC only. Their analysis was carried out by two authors to get subgroup estimates for evidence from LMICs only. We adhered to the same statistical procedure described in the original review to get the pooled effect estimates.

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 (CI) for dichotomous and mean difference (MD) with 95% CI for continuous outcomes. The risk of bias (ROB) was evaluated using the Cochrane ROB tool for all randomized controlled trials [10], and the original review authors’ assessment for studies included in each review was reported in this paper.

Antenatal intervention strategies are multifaceted and involve a range of interventions targeted at different perinatal and newborn outcomes. Findings are summarized in the following paragraphs and are discussed in further detail in Tables 1, 2, 3, 4, 5 and 6. Additional information including World Bank classification for LICs and LMICs, forest plots for LMIC analysis, figures for ROB, and study characteristics can be found in online supplementary Files 1 and 2 (for all online suppl. material, see https://doi.org/10.1159/000542702).

Effect estimates were taken from an existing review in which thirty-four trials were included, of which thirty were from LMICs. Keats et al. [11] compared multiple micronutrient supplementation (MMS) with IFA supplementation or placebo. Seventy-five percent of trial judgments were assessed to have low ROB.

Overall, the intervention significantly reduced the risks of stillbirth (RR 0.91 [0.86–0.98]; 22 studies), SGA (RR 0.93 [0.88–0.98]; 19 studies), and LBW (RR 0.85 [0.77–0.93]; 27 studies). LMIC evidence indicated that MMS was associated with a reduction in the risk of stillbirth (RR 0.91 [0.85–098]; 21 studies), SGA (RR 0.93 [0.88–0.98]; 18 studies), and LBW (RR 0.84 [0.77–0.92]; 25 studies). Additional data can be found in Table 1.

On subgroup analysis of multiple micronutrient supplementation containing more than four micronutrients only, the intervention significantly reduced the risks of stillbirth (RR 0.91 [0.85–0.98]; 17 studies), SGA (RR 0.90 [0.85–0.96]; 16 studies), and LBW (RR 0.79 [0.71–0.88]; 19 studies) overall, but no effect was noted on the risks of preterm birth (RR 0.97 [0.91–1.03]; 18 studies), neonatal (RR 0.97 [0.89–1.05]; 14 studies) or perinatal mortality (RR 0.97 [0.88–1.07]; 14 studies). Similarly, LMIC evidence demonstrated a significant impact of the intervention on stillbirth (RR 0.91 [0.85–0.98]; 16 studies), SGA (RR 0.90 [0.85–0.96]; 15 studies), and LBW (RR 0.79 [0.71–0.88]; 18 studies); however, no effect was noted on the risks of preterm birth (RR 0.97 [0.91–1.03]; 17 studies), neonatal (RR 0.97 [0.89–1.05]; 14 studies) or perinatal mortality (RR 0.97 [0.88–1.07]; 13 studies).

For this intervention, effect estimates (Table 1) were taken from an existing review [11], which included seven studies, all from LMICs, in their meta-analysis comparing IFA supplementation with FA or placebo. Of all trial judgments, 75% were assessed as low ROB. The intervention suggested a significant effect on maternal hemoglobin concentration (MD 6.95 [2.80–11.11]; 7 studies), maternal anemia (RR 0.52 [0.41–0.66]; 4 studies), and LBW (RR 0.88 [0.78–0.99]; 4 studies). No effect was noted on the risks of preterm birth, SGA, perinatal mortality, or neonatal mortality.

Estimates (Table 1) for this intervention were taken from an existing review [12], which comprised evidence from eleven studies, with ten studies conducted in LMICs. The ROB varied across all studies (online suppl. Fig. 14).

Overall, vitamin A supplementation had no effect on maternal mortality or preterm birth. LMIC evidence suggested a lower predisposition to maternal night blindness (RR 0.79 [0.64–0.98]; 2 studies) in participants supplemented with vitamin A. No effect was noted on stillbirth, preterm birth, LBW, or perinatal and neonatal mortality.

Estimates (Table 1) were derived from an existing review. Palacios et al. [13] included twenty-two trials comparing vitamin D with placebo, six of which were from LMICs. The overall ROB varied across all studies (online suppl. Fig. 15).

Overall, the risk of preeclampsia in pregnant women (RR 0.48 [0.30–0.79]; 4 studies) and babies with LBW was decreased (RR 0.55 [0.35–0.87]; 5 studies). There was no reduction in the risks of caesarian section, stillbirth, preterm birth, or neonatal mortality. LMIC-specific estimates demonstrated a reduction in the risks of preterm births (RR 0.54 [0.30–0.96]; 2 studies) and LBW babies (RR 0.53 [0.35–0.79]; 4 studies). No difference was noted on the risks of caesarian section, stillbirth, or neonatal mortality.

Estimates were derived from an existing review. Carducci et al. [14] compared zinc with placebo and included twenty-five trials with sixteen trials from LMICs. The overall ROB was low in half of the trials (online suppl. Fig. 16). Overall and LMIC evidence showed no effect on the risks of preeclampsia, preterm birth, LBW, SGA, or neonatal mortality (Table 1).

Estimates were derived from an existing review. Buppasiri et al. [15] assessed the effect of calcium supplementation to curb adverse maternal and neonatal outcomes. Twenty-three studies were meta-analyzed, of which thirteen were from LMICs and two from a multicenter setting. Overall, most of the included studies were of low (online suppl. Fig. 17) risk of bias. Calcium supplementation had no effect on maternal mortality, caesarian section, intrauterine growth restriction, preterm birth, LBW, perinatal mortality, stillbirth, or NICU admissions (Table 1).

Effect estimates were taken from an existing review [16], which assessed the impact of balanced protein/energy supplementation through twelve trials, seven of which were from LMICs. The overall ROB varied from unclear to high (online suppl. Fig. 18).

Overall, the intervention was associated with a low risk of stillbirth (RR 0.60 [0.39–0.94]; 5 studies) and SGA (RR 0.79 [0.69–0.90]; 7 studies). No effect was seen on the risks of preterm birth or neonatal mortality. LMIC-specific evidence indicated a clear reduction in the risks of stillbirth (RR 0.52 [0.31–0.88]; 4 studies) and SGA (RR 0.80 [0.69–0.92]; 4 studies) (Table 1). No difference was noted on the risk of preterm birth or neonatal mortality.

For this topic, an existing review [17] evaluated the impact of LNS when compared to IFA through three studies conducted in LMICs. The overall ROB was assessed to be low (online suppl. Fig. 19). LNS reduced the risk of SGA (RR 0.94 [0.89–0.99]; 3 studies). The effect of the intervention on maternal mortality, gestational weight, preterm birth, and neonatal death was not significant (Table 1).

For this topic, an existing review [18] was included, which summarized findings from seventy trials and compared omega-3 LCPUFA (supplements and food) with placebo. Four studies were from LMICs and one conducted in a multicentered setting. The overall ROB varied (online suppl. Fig. 20).

Overall, omega-3 fatty acid supplementation significantly decreased the risks of preterm birth (RR 0.89 [0.81–0.97]; 26 studies) and LBW (RR 0.90 [0.82–0.99]; 15 studies), but no effect was seen on preeclampsia, maternal mortality, stillbirth, SGA, perinatal mortality, or neonatal mortality. Evidence from LMICs showed no effect on the risks of stillbirth, preterm birth, LBW, SGA, perinatal mortality, or neonatal mortality. Further data can be found in Table 1.

For this intervention, an existing review [16] was included, which comprised five trials comparing dietary education without supplementation with placebo, with one trial from LMIC. Dietary education constituted educating women on nutritional values of food including benefits of adequate intakes of energy, protein, vitamins, and iron. It included teaching methods to purchase and store ingredients effectively and to prepare meals in a manner that optimized retention of nutrients. It also covered counseling sessions and nutrition assessments conducted at home. The overall ROB varied between unclear and high (online suppl. Fig. 18).

Evidence from HIC indicated that women given nutritional education had a lower risk of having preterm births (RR 0.46 [0.21–0.98]; 2 studies) but showed no reduction in the risks of stillbirth or neonatal mortality. Evidence from LMIC indicated a reduction in the risk of LBW babies (RR 0.04 [0.01–0.14]; 1 study) (Table 1).

Alfirevic et al. [19] identified nineteen studies conducted in HICs. Due to a lack of information, it was difficult to evaluate the quality of the 19 completed studies included, especially regarding randomization and allocation concealment (online suppl. Fig. 21). Umbilical artery Doppler offered to women in high-risk pregnancies suggested a decrease in induction of labor (0.89 [0.80–0.99]; 10 studies) and perinatal mortality (RR 0.71 [0.52–0.98]; 16 studies). There was no reduction in the risks of stillbirth, preterm labor, or neonatal outcomes (Table 2).

For this intervention, an existing review [20] was used, and two more studies were identified [21, 22] by the steering committee and the Lancet series “Small Vulnerable Newborn” [23]. Of the twelve studies included, three studies were from LMICs, with an overall low ROB (online suppl. Fig. 22).

Overall, low-dose aspirin was associated with a lowered risk of preeclampsia (RR 0.69 [0.55–0.86]; 12 studies), gestational hypertension (RR 0.80 [0.65–0.99]; 6 studies), stillbirth or death (RR 0.80 [0.65–0.99]; 5 studies), preterm birth (RR 0.86 [0.78–0.94]; 7 studies), and intrauterine growth restriction (IUGR) and SGA (RR 0.92 [0.87 to 0.97]; 9 studies). Evidence from LMICs indicated a lowered risk of gestational hypertension (RR 0.11 [0.01–0.86]; 1 study), but no difference was noted in the risk of preeclampsia, postpartum hemorrhage, preterm birth, stillbirth or death, IUGR or SGA, or LBW (Table 2).

For this topic, an existing review [24] summarized findings on antithrombotic therapy from ten trials; however, there was limited LMIC evidence with only one study conducted in China. The overall quality of trials was considered fair to good (online suppl. Fig. 23).

Overall, the intervention was associated with a statistically significant effect on preterm birth (RR 0.72 [0.58–0.90]; 5 studies), SGA (RR 0.41 [0.27–0.61]; 7 studies), and perinatal mortality (RR 0.40 [0.20–0.78]; 6 studies). LMIC evidence showed no effect on preterm birth or on SGA (Table 2).

Evidence for calcium supplementation for preeclampsia was derived from an existing review [25] that included fourteen trials, with seven studies from LMICs and three studies conducted in a multicenter setting. Overall, studies were deemed to have a low ROB, though bias was difficult to assess due to poor reporting and incomplete information on methods (online suppl. Fig. 24).

Overall, high-dose calcium in the antenatal period when compared with placebo minimized the risk of developing high blood pressure (with or without proteinuria) (RR 0.65 [0.53–0.81]; 12 studies), preeclampsia (RR 0.45 [0.31–0.65]; 13 studies), and preterm birth (RR 0.76 [0.60–0.97]; 11 studies). LMIC-specific evidence suggested a statistically significant effect on the risks of high blood pressure (RR 0.41 [0.25–0.69]; 6 studies), preeclampsia (RR 0.32 [0.22–0.46]; 7 studies), and preterm birth (RR 0.68 [0.49–0.95]; 5 studies). No effect was seen on SGA or LBW (Table 3).

Two reviews were identified for short-term [26] and long-term [27] outcomes and used as existing. Shepherd et al. [26] evaluated short-term neonatal outcomes of magnesium sulfate administered to manage preeclampsia in pregnant women through six trials, five of which were from HICs and one of which was conducted in a multicentered setting. The overall ROB varied from unclear to low (online suppl. Fig. 25). Magnesium sulfate had no effect on stillbirth, perinatal mortality, or neonatal mortality.

Wolf et al. [27] evaluated the long-term outcomes of magnesium sulfate through five trials conducted in HICs and one in a multicentered setting. Overall, studies had a low ROB. Magnesium sulpfate reduced the risk of moderate-to-severe cerebral palsy (RR 0.63 [0.45–0.89]; 4 studies) but had no effect on mild cerebral palsy or all-mortality till follow-up (Table 3).

For this intervention, an existing review [28] was used and explored different antihypertensive treatments for mild to moderate hypertension and included thirty-one papers in their review, of which two studies took place in an LMIC setting. The overall ROB was moderate to high (online suppl. Fig. 26).

Overall, antihypertensives reduced the risk of developing severe hypertension (RR 0.49 [0.40–0.60]; 20 studies). No effect was seen on maternal mortality, severe preeclampsia, eclampsia, preterm birth, or SGA. Evidence from LMICs suggested the treatment reduced the risk of developing severe hypertension (RR 0.27 [0.15–0.51]; 2 studies) and severe preeclampsia (RR 0.30 [0.10–0.89]; 2 studies). A statistically significant reduction in the risk of SGA was noted (RR 0.58 [0.35–0.95]; 1 study). Refer to Table 3 for a complete overview of the data.

For this topic, an existing review [29] was included. Twenty-three studies were included, twenty-two were conducted in HICs and one in LMIC, and captured data on combined diet and exercise compared with standard care. The total ROB was determined to be uncertain, mostly because of inadequate reporting (online suppl. Fig. 27). Evidence suggested the intervention reduced the risk of preterm births [RR 0.80 (0.60–0.98); 11 studies], with no difference between the two groups seen in the risks of preeclampsia, perinatal mortality, or stillbirth (Table 4).

For this topic, an existing review was included where Brown et al. [30] meta-analyzed fifteen trials, with LMIC data stemming from only one trial conducted in China in 150 women. The overall ROB varied (online suppl. Fig. 28). A combination of different interventions including diet, exercise advice, face-to-face education about GDM, relaxation training, self-monitoring of blood glucose, insulin if required, fortnightly specialist review, mindfulness eating, yoga, and nutritional counseling were evaluated.

Overall, lifestyle interventions were associated with a decreased risk of preterm births (RR 0.71 [0.53–0.96]; 3 studies), but no reduction was noted on risks of caeserian sections, development of type 2 DM, SGA, or neonatal hypoglycemia. LMIC evidence showed a statistically significant reduction in the number of caesarian sections (RR 0.80 [0.66–0.98]; 1 study). Detailed data are given in Table 4.

Estimates for this topic were derived from an existing review [31] and included eleven trials, all from HICs, in their review evaluating any type of physical activity as an intervention in women with GDM to improve maternal and fetal outcomes. The overall ROB was gauged to be unclear (online suppl. Fig. 29). The intervention optimized fasting blood glucose concentration (SMD −0.59 [−1.07 to −0.11]; 4 studies), postprandial blood glucose concentration (SMD −0.85 [−1.15 to −0.55]; 3 studies), and HbA1c (MD −0.43 [−0.51 to −0.35]; 2 studies) at the end of intervention (Table 4).

For this intervention, an existing review was used [32] and described a range of different types of dietary advice by meta-analyzing nineteen trials. One trial was conducted in an LMIC region in 95 women, with GDM diagnosed at 24–26 weeks’ gestation, and compared low-to-moderate GI diet with moderate-high GI diet. The studies had unclear to moderate ROB (online suppl. Fig. 30).

Low-to-moderate GI index did not have a significant effect on outcomes such as severe hypertension or preeclampsia, eclampsia, postpartum hemorrhage, postpartum infection. The intervention improved postprandial glucose level (MD −0.71 [−1.21 to −0.21]; 1 study). Evidence evaluating the effect of different types of dietary advice on the risk of preterm birth, LGA, SGA, stillbirth, perinatal mortality, and neonatal mortality was solely collected from HICs (Table 4).

For this intervention, an existing review [33] was used, and different anti-diabetic pharmacological therapies were evaluated and included eleven trials conducted with four trials from LMICs. Since no LMIC-specific data comparing oral anti-diabetic agents with placebo were available, we have discussed other comparisons with LMIC evidence. The overall ROB was low (online suppl. Fig. 31).

Overall, metformin on comparison with glibenclamide had no effect on pregnancy-induced hypertension (PIH), maternal hypoglycemia, shoulder dystocia, neonatal hypoglycemia, or macrosomia. LMIC-specific estimates indicated that metformin decreased the risk of neonatal death or serious morbidity composite (RR 0.54 [0.31–0.94]; 1 study) but had no effect on PIH, maternal hypoglycemia, shoulder dystocia, or macrosomia. One study from LMIC region compared glibenclamide with acarbose for treatment of GDM on 43 participants and found no reduction on the risks of caesarian section, macrosomia, gestational age at birth (weeks), or on neonatal hypoglycemia (Table 4).

For this topic, an existing review [34] was used which evaluated the impact of pregnancy-related smoking cessation strategies through data from 88 trials, with all trials from HICs, with the exception of one multicentered trial conducted in Argentina, Brazil, Cuba, and Mexico. The interventions included incentives, counseling, health education, social support, feedback, exercise, and dissemination. The studies’ total ROB varied greatly (online suppl. Fig. 32). Psychosocial interventions had a significant effect on birthweight (MD 55.60 [29.82–81.38]; 26 studies) and low birthweight (RR 0.83 [0.72–0.94]; 18 studies) but had no effect on stillbirth, preterm birth, perinatal mortality, or neonatal mortality (Table 5).

For this intervention, an existing systematic review without meta-analysis [35] measuring whether treatment of depressed pregnant women with antidepressant medication improved maternal and neonatal outcomes was utilized; however, no randomized controlled trials were included in the review.

For additional psychosocial support, an existing review was used [36], which evaluated the impact of programs providing supplementary social support (informational, practical, and emotional) in expectant mothers considered to be at a high risk of giving birth to either preterm or LBW neonates. Of the 21 studies meta-analyzed, two studies were from LMICs, and one study was conducted in a multicentered setting including Argentina, Brazil, Cuba, and Mexico. The overall ROB of included studies was gauged to be unclear to low (online suppl. Fig. 33).

Overall, the intervention implemented by healthcare professionals had a significant effect on caesarian sections (RR 0.90 [0.83–0.97]; 15 studies). No effect was noted on preterm birth, stillbirth/neonatal death, and LBW. Evidence from LMICs showed no effect of additional psychosocial support on preterm births, stillbirth/neonatal death, or on LBW (Table 5).

For this intervention, an existing review [37] was used, which included ten trials from HICs, with data for the meta-analyses extracted from seven trials. The study population of one study [38] that evaluated our outcomes of interest was African-American pregnant women. The studies’ total ROB varied widely (online suppl. Fig. 34). The implementation of psychosocial interventions demonstrated a significant effect on gestational age in weeks (MD 1.40 [0.33–2.47]; 1 study) but had no effect on preterm birth, birthweight in grams, or on low birthweight (Table 5).

For cervical cerclage, an existing review [39] was used, which meta-analyzed ten trials, of which two trials were from LMICs and two were conducted in a multicentered setting. The ROB of studies varied overall (online suppl. Fig. 35).

Overall, cervical cerclage had a significant effect on the risk of preterm birth before 37 weeks (RR 0.80 [0.69–0.95]; 9 studies) and before 34 weeks (RR 0.77 [0.66–0.89]; 9 studies) but did not reduce the risk of preterm birth before 28 weeks, perinatal deaths, or neonatal deaths before discharge. Evidence from LMICs suggested no effect on preterm birth, perinatal death, or neonatal deaths. Additional data are given in Table 6.

For this intervention, an existing review [40] was used, which included two studies from HICs with moderate to high ROB (online suppl. Fig. 36) and investigated the effect of anti-D prophylaxis during pregnancy for preventing rhesus alloimmunization. The meta-analysis showed no reduction in the risks of immunization (RR 0.42 [0.15 to 1.17]; 2 studies) when women received anti-D at 28 and 34 weeks’ gestation. A reduction in the incidence of positive Kleihauer test was noted, both at birth 32–35 weeks of gestation (RR 0.60 [0.41–0.88]; 1 study) and at birth of Rh-positive infant (RR 0.60 [0.46–0.79]; 1 study) (Table 6).

A total of twenty-seven interventions constituting ANC were identified and analyzed. The evidence suggested that MMS resulted in a clear reduction in the risks of stillbirth, preterm birth, SGA, and LBW in LMICs.

Vitamin A supplementation did not have a significant effect on fetal outcomes such as preterm birth, LBW, or perinatal mortality but lowered the risk of maternal night blindness in LMICs. The overall evidence showed no impact of vitamin D supplementation on caesarian sections and preterm births, but evidence from LMICs suggested a significant reduction in the risk of preterm birth and low birthweight.

Zinc or calcium supplementation showed no difference in the effects of stillbirth, preterm birth, SGA, LBW, or perinatal mortality. Balanced energy-protein supplements reduced the likelihood of SGA and stillbirth. Lipid-based supplements had a significant effect on preterm birth but not on other outcomes. Omega-3 fatty acids had a statistically significant effect on preterm births overall and not in LMICs. Limited evidence indicated dietary education to pregnant women lowered the risk of LBW in LMICs.

Evidence for Doppler ultrasound was limited only to HICs, with a significant effect seen on perinatal mortality. Low-dose aspirin significantly decreased the likelihood of developing gestational hypertension in LMICs, with only one study contributing data to the outcome. Antithrombotic therapy reduced the probability of preterm births and SGA overall, but its effectiveness was not observed in LMICs.

High-dose calcium supplementation was associated with a significant reduction in the likelihood of developing high blood pressure, preeclampsia, and preterm birth both overall and in LMICs. Magnesium sulfate had no effect on stillbirth, perinatal mortality, or neonatal mortality. LMIC evidence showed antihypertensives demonstrated a clear reduction in the risks of severe hypertension, proteinuria/preeclampsia, severe preeclampsia, and SGA babies.

Lifestyle interventions showed a reduction in caesarian sections in LMIC setting but not overall. LMIC evidence indicated that incorporation of low-moderate GI diet by pregnant women improved their postprandial glucose levels. Metformin when compared to glibenclamide had no effect on PIH, maternal hypoglycemia, caesarian sections, shoulder dystocia, LGA, or macrosomia.

Evidence evaluating mental health in pregnant women was primarily limited to HICs. Psychosocial interventions to reduce smoking lowered the risk of giving birth to LBW babies. Additional psychosocial support reduced the likelihood of caesarian sections.

Cervical cerclage had a significant effect on preterm births before 37 and 34 weeks overall but not in LMIC settings. The intervention had no effect on stillbirths, perinatal mortality, or neonatal mortality. Only two studies from HICs evaluated the effect of anti-D administration. The intervention improved the probability of a positive Kleihauer test at 32–35 weeks of gestation and at birth.

The review [11] evaluating MMS and IFA as interventions only analyzed studies from LICs, LMICs, and upper-middle-income countries; therefore, our overall estimates did not capture data from HICs. Additionally, for MMS, certain demographics such as pregnant women with micronutrient deficiencies, anemia, high-risk pregnancies, or chronic illnesses were excluded, despite being prevalent in these settings.

A considerable limitation of some reviews evaluating antenatal nutritional supplementation, such as that of MMS, vitamin A supplementation, and calcium supplementation, was the variations and uncertainty pertaining to the dosages and ideal durations of supplementation. Additionally, the baseline assessments of some supplements, such as that of vitamin A, were unavailable, making comparisons challenging.

Limitations include the small sample sizes and scarcity of data from LICs/LMICs for interventions such as vitamin D, omega-3 fatty acids, dietary education without supplementation, Doppler ultrasound, antithrombotic therapy, magnesium sulfate, antihypertensives, and various interventions to manage/treat GDM and improve mental health during pregnancy, and cervical cerclage is a major drawback, emphasizing the need for more robust research to reduce healthcare inequalities in maternity care between HICs/upper-middle-income countries and LICs/LMICs and to deduce the degree of effectiveness of these interventions.

Antenatal nutritional supplementation, crucial for several reasons, can have a significant impact on the health and well-being of both the mother and the developing fetus. Statistics from De Kok et al.‘s review [41] showed a reduction in the risk of low birthweight babies and an improvement in the neonates’ birth weight and birth length as a result of the prenatal balanced protein-energy supplementation.

Placental insufficiency [42] is a common and prevalent clinical concern and can have a significant impact on maternal and fetal health, with repercussions for the cardiovascular, metabolic, and neurological systems up to adulthood. It can lead to premature births, preeclampsia, IUGR, and stillbirths, commonly affecting 10–15% of pregnancies [43].

Evidence indicates that high-dose calcium supplementation effectively reduced the risk of high blood pressure, preeclampsia, and preterm births. Pregnant women are advised by the WHO to take a daily calcium supplement (1.5–2.0 g oral elemental calcium) to lower their risk of preeclampsia, especially in populations with poor dietary calcium consumption [44]. HDP are associated with a higher risk of caesarian sections, stillbirths, preterm births, low birthweight, and sepsis [45]. In comparison to women who had normotensive pregnancies, women with HDP have a twofold increased risk of later developing cardiovascular disease [46].

The diabetes epidemic presents a significant implication on public health; however, the evidence is extremely scarce in LMIC settings and majorly stems from HICs. GDM is linked to a substantial number of poor health outcomes for both the mother and the baby, including a greater number of caesarian sections, preeclampsia, premature delivery, shoulder dystocia, a higher risk of neonatal hypoglycemia, and requirement for neonatal intensive care [47]. Numerous variables, including advanced mother age, ethnicity, previous history of GDM, and a family history of type 2 diabetes mellitus, have been identified as risk factors for GDM [48]. A meta-analysis [49] of 51 population-based studies suggested that South Asia and Australia exhibited the lowest and highest rates of GDM prevalence (pooled P = 11.4%, 95% CI 11.1–11.7%) and (pooled P = 3.6%, 95% CI 3.6–3.7%), respectively.

Anti-D is commonly given at 28 or 32 weeks of gestation and is an essential intervention in case of antepartum hemorrhages, miscarriages, ectopic pregnancies, and invasive prenatal procedures such as amniocentesis or chorionic villus sampling. It appears that evidence is limited in LMICs, which makes it difficult to thoroughly monitor and investigate the use and effects of therapies such as anti-D administration.

These findings highlight the varying effects of different antenatal interventions between HIC and LMIC settings. Given the disparities in the prevalence of unfavorable antenatal outcomes between the two settings, it may be incorrect to implement guidelines in LMICs in daily practice that are solely based on HIC data. Additional research is needed in LMICs, both to address the unique health challenges these areas tackle and to contribute to public health, equity, and well-being.

There is a pressing concern that must be addressed about the lack of studies, especially relating to noncommunicable diseases, from LMICs in global research. Further initiatives need to be undertaken to not only support LMICs but to also adapt a more thorough and successful response to global health. Evidence-based policies and guidelines should be developed, tailored especially to the needs of more vulnerable populations residing in LMICs to ensure that antenatal care reaches those who need it the most.

We thank the Aga Khan University for providing internal resources.

The authors have no conflicts of interest to declare.

This study is supported by the Bill and 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., M.A., and Z.A. 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 and conceptualization and contributed to the critical revision of the manuscript.