Effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on maternal gestational weight gain in low-income and middle-income countries: a systematic review and individual participant data meta-analysis of randomised clinical trials

Background: Studies have consistently demonstrated beneficial effects of intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) on reducing malaria infection and improving birth outcomes among pregnant women in endemic areas. However, data on its impact on maternal gestational weight gain (GWG) are very limited. We aimed to conduct a two-stage meta-analysis of individual participant data to examine the effect of IPT with SP on GWG compared to other antimalarial regimens. Methods: In this systematic review and individual participant data meta-analysis, we conducted electronic literature searches of PubMed, Embase, Web of Science, and the Cochrane Library to identify eligible RCTs among pregnant women. We did not apply any language or publication date restrictions in the search. The initial search was conducted on August 4th, 2021, and updated on February 15th, 2025. The study-level inclusion criteria were as follow: 1) the studies must be randomised controlled trials (RCTs), which could be individually randomised, cluster randomised, or a combination of both; 2) study participants were pregnant at enrollment or enrolled before pregnancy and followed up in pregnancy; 3) studies were conducted in a low-income, lower-middle-income, or upper-middle-income economy defined by the World Bank country classification for the 2021 fiscal year; 4) antimalaria and/or antibiotic interventions were provided during pregnancy; and 5) the intervention was provided alone or in combination with a co-intervention that was similar across arms. Since we focused on the intervention's effect on GWG in generally healthy pregnant women, we applied the following study-level exclusion criteria: 1) studies without any measures of maternal weight during pregnancy; and 2) studies conducted exclusively among women with pre-existing health conditions, such as anemia, human immunodeficiency virus (HIV) infection, or diabetes. Within each eligible trial, we further applied individual-level criteria to identify eligible individual participants, including 1) singleton pregnancies, 2) at least one weight measurement in the second or third trimesters, 3) known gestational ages at the time of weight measurements, and 4) availability of maternal height measure. Risk of bias for each trial was assessed using the Cochrane risk-of-bias tool, version 2 (RoB 2). GWG percent adequacy (%) and total weight gain (gram) at delivery were calculated according to the Institute of Medicine 2009 guidelines. Linear regression models were used to estimate mean difference (MD) and 95% confidence intervals (CIs) in GWG percent adequacy and total weight gain across intervention arms. Results from individual trials were pooled using fixed-effects inverse-variance meta-analysis models. This study is registered with PROSPERO, CRD42023428794. Findings: A total of 97 trials were identified in the search and sough for IPD, of them eight trials including 8550 pregnant women were included in the current analysis. Women who received IPTp with only 2 doses of SP had a greater GWG percent adequacy (MD: 5.61%; 95% CI: 2.61%, 8.60%; P = 0.0002; I² = 84.26%), and total GWG in grams at delivery (MD: 702; 95% CI: 321, 1083; P = 0.0003; I² = 83.78%) than those who received weekly chloroquine as prophylaxis. No significant differences in GWG percent adequacy (MD: −0.53%; 95% CI: −2.89%%, 1.83%; P = 0.66; I² = 0.00%) or GWG grams (MD: −80; 95% CI: −380, 221; P = 0.60; I² = 0.00%) were found between IPTp with 2-dose SP and monthly IPTp-SP (3-dose or more). Compared to women who received monthly IPTp-SP, those who received monthly IPTp with dihydroartemisinin-piperaquine (IPTp-DHA + PPQ) had a lower GWG percent adequacy (MD: −5.56%; 95% CI: −8.22%, −2.90%; P < 0.0001; I² = 13.47%) and total GWG in grams (MD: −723; 95% CI: −1037, −410; P < 0.0001; I² = 46.29%). Adding azithromycin to an antimalarial regimen was associated with a greater GWG percent adequacy (MD: 2.75%; 95% CI: 0.46%, 5.05%; P = 0.19; I² = 0.00%) and total GWG in gram at delivery (MD: 485; 95% CI: 210, 760; P = 0.0005; I² = 75.66%). Interpretation: Our findings suggest that monthly IPTp-SP has superior effect on GWG compared to weekly chloroquine or IPTp-DHA + PPQ in malaria-endemic areas. The result provides further evidence indicating that IPTp-SP improves maternal weight gain, an important determinant of fetal growth beyond its antimalarial effects. Due to the limited number of trials with weight and height measures available for the IPD meta-analysis we were likely underpowered to detect any significant difference between 2-dose SP and monthly IPTp-SP. More efforts are warranted to examine the potential beneficial effect of adding azithromycin or DHA + PPQ to the standard antimalarial regimens. Funding: Gates Foundation.