Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis

Abstract

Importance: Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain.

Objective: To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens.

Data sources and study selection: ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy.

Data extraction: Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models.

Results: Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events.

Conclusions and relevance: Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr ter Kuile reports receiving reimbursement for meeting presentation expenses from Pfizer. Drs Luntamo and Ashorn report institutional support from Pfizer in the form of active drug and placebo for a trial of preterm delivery.

Figures

Figure 1

Meta-analysis of the Risk of Low Birth Weight in Trials Comparing the Standard 2-Dose vs 3 or More Doses of Intermittent Preventive Therapy During Pregnancy With Sulfadoxine-Pyrimethamine G1–G2 indicates first and second pregnancies; ≥G3, 2 or more previous pregnancies; HIV, human immunodeficiency virus; RR, relative risk. P values after the I2 statistics represent the χ2 test for heterogeneity. Dersimonian-Laird method used to calculate random-effects models; Mantel-Haenszel for fixed-effects models. Weights are from random-effects analysis. Data marker sizes indicate the weight applied to each study with random-effects meta-analysis. Test for subgroup differences: χ42=0.62, P= .96, l2= 0.0%.

Figure 2

Meta-analysis of Mean Birth Weight in 7 Trials Comparing the Standard 2-Dose vs 3 or More Doses of Intermittent Preventive Therapy During Pregnancy With Sulfadoxine-Pyrimethamine G1–G2 indicates first and second pregnancies; ≥G3, 2 or more previous pregnancies; HIV, human immunodeficiency virus status. P values after the I2 statistics represent the χ2 test for heterogeneity. Dersimonian-Laird method used for random-effects models; inverse-variance method used in the fixed-effects models. Weights are from random-effects analysis. Data marker sizes indicate the weight applied to each study with random-effects meta-analysis. Test for subgroup differences: χ42=3.14, P= .53, l2= 0.0%.