Antimalarial drugs for preventing malaria during pregnancy and the risk of low birth weight: a systematic review and meta-analysis of randomized and quasi-randomized trials

Abstract

Background: It is known that antimalarial drugs reduce the risk of low birth weight (LBW) in pregnant patients. However, a previous Cochrane review did not evaluate whether the level of antimalarial drug resistance could modify the protective effect of antimalarial drugs in this regard. In addition, no systematic review exists comparing current recommendations for malaria prevention during pregnancy to alternative regimens in Africa. Therefore, we conducted a comprehensive systematic review and meta-analysis to assess the efficacy of antimalarial drugs for malaria prevention during pregnancy in reducing the risk of LBW.

Methods: We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for articles published up to 21 November 2014, in English or French, and identified additional studies from reference lists. We included randomized and quasi-randomized studies reporting LBW as one of the outcomes. We extracted data and assessed the risk of bias in selected studies. All pooled analyses were based on a random effect model, and we used a funnel plot and trim and fill method to test and adjust for publication bias.

Results: A total of 25 studies met the inclusion criteria (37,981 subjects). Compared to no use, all combined antimalarial drugs were associated with a 27% (RR 0.73, 95% CI 0.56-0.97, ten studies) reduction in the risk of LBW. The level of antimalarial drug resistance modified the protective effect of the antimalarial drug used for prevention of LBW during pregnancy. Sulfadoxine-pyrimethamine was not associated with a reduction in the risk of LBW in regions where the prevalence of the dihydropteroate synthase 540E mutation exceeds 50% (RR 0.99, 95% CI 0.80-1.22, three studies). The risk of LBW was similar when sulfadoxine-pyrimethamine was compared to mefloquine (RR 1.05, 95% CI 0.86-1.29, two studies).

Conclusion: Prophylactic antimalarial drugs and specifically sulfadoxine-pyrimethamine may no longer protect against the risk of LBW in areas of high-level resistance. In Africa, there are currently no suitable alternative drugs to replace sulfadoxine-pyrimethamine for malaria prevention during pregnancy.

Fig. 1

PRISMA flow chart for systematic review of antimalarial drugs for malaria prevention during pregnancy and the risk of low birth weight (LBW)

Fig. 2

Antimalarial drugs compared to no use of antimalarial drugs and risk of LBW. Each study is displayed as a square and horizontal line, representing the relative risk together with its confidence interval. The area of the square represents the weight that the study contributes to the meta-analysis. The combined relative risk and its confidence interval are represented by the diamond. The P value after I² represents chi-square test for heterogeneity. DerSimonian and Laird were used to calculate the random effect model. CI, confidence interval; LBW, low birth weight; RR, relative risk

Fig. 3

All the combined antimalarial drugs compared to no use of antimalarial drugs and risk of LBW stratified by level of drug resistance and gravidity. Each study is displayed as a square and horizontal line representing the relative risk together with its confidence interval. The area of the square represents the weight that the study contributes to the meta-analysis. The combined relative risk and its confidence interval are represented by the diamond. The P value after I² represents chi-square test for heterogeneity. DerSimonian and Laird were used to calculate the random effect model. G1–G2 indicates first and second pregnancy; G3 and more indicates two or more previous pregnancies. Test for subgroup difference between each level of drug resistance (P <0.01). Test for subgroup difference between each stratum of gravidity (P = 0.102). CI, confidence interval; LBW, low birth weight; RR, relative risk

Fig. 4

Three doses or more compared to two doses of the main type of antimalarial drug used for prevention of malaria during pregnancy and risk of LBW. Each study is displayed as a square and horizontal line representing the relative risk together with its confidence interval. The area of the square represents the weight that the study contributes to the meta-analysis. The combined relative risk and its confidence interval are represented by the diamond. The P value after I² represents chi-square test for heterogeneity. DerSimonian and Laird were used to calculate the random effect model. *Relative risk has been calculated with the Mantel–Haenszel method instead of using the odds ratio (OR) provided in the paper. CI, confidence interval; LBW, low birth weight; RR, relative risk

Fig. 5

Sulfadoxine-pyrimethamine compared to different antimalarial drug alternatives for malaria prevention during pregnancy and the risk of LBW. Each study is displayed as a square and horizontal line representing the relative risk together with its confidence interval. The area of the square represents the weight that the study contributes to the meta-analysis. The combined relative risk and its confidence interval are represented by the diamond. The P value after I² represents chi-square test for heterogeneity. DerSimonian and Laird were used to calculate the random effect model. *Relative risk has been calculated with the Mantel–Haenszel method instead of using the odds ratio (OR) provided in the paper. CI, confidence interval; LBW, low birth weight; RR, relative risk