Dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria in pregnancy: a systematic review and individual participant data meta-analysis

Abstract

Background: High-grade Plasmodium falciparum resistance to sulfadoxine-pyrimethamine in East and Southern Africa has prompted numerous trials evaluating intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine as an alternative to sulfadoxine-pyrimethamine.

Methods: We conducted individual participant data meta-analyses of randomised trials comparing IPTp with dihydroartemisinin-piperaquine to sulfadoxine-pyrimethamine on maternal, birth, and infant outcomes. We searched the WHO International Clinical Trials Registry Platform, ClinicalTrials.Gov, PubMed, and the Malaria in Pregnancy Consortium Library. Eligible trials enrolled HIV-uninfected pregnant women, followed participants to delivery, included participants with no prior IPTp use during the current pregnancy, and were conducted in areas with high-level parasite resistance to sulfadoxine-pyrimethamine (i.e., PfDHPS 540E≥90% and/or 581G>0%). Only singleton pregnancies were analysed. Meta-analyses used a two-stage approach: first, study-specific estimates were generated and then pooled using a random-effects model. Gravidity subgroup analyses were performed. Causal mediation analyses were used to investigate the maternal mechanisms underlying the effect of IPTp regimens on birth outcomes. The meta-analysis is registered in PROSPERO (CRD42020196127).

Findings: Of 85 screened records, six trials (one multi-country trial) contributed data on 6646 pregnancies. Compared to sulfadoxine-pyrimethamine, dihydroarteminsinin-piperaquine was associated with a 69% [95% CI: 45%-82%] lower incidence of clinical malaria during pregnancy, a 62% [37%-77%] lower risk of placental parasitaemia, and a 17% [0%-31%] lower incidence of moderate maternal anaemia (Hb<9 g/dL). In contrast, sulfadoxine-pyrimethamine was associated with higher mean weekly maternal weight gain (34 grams/week [17-51]). There were no statistically significant differences in the composite adverse pregnancy outcome between the two IPTp regimens (RR=1·05 [95% CI: 0·92-1·19]; I ²=48%), although the risk of small-for-gestational-age was 15% [3%-24%] lower in the sulfadoxine-pyrimethamine arm. Among multigravidae, participants of the sulfadoxine-pyrimethamine arm were 20% [8%-30%] and 35% [17%-49%] less likely to have stunted and underweight infants by two months compared to the dihydroartemisinin-piperaquine arm. Infant wasting by two months was 13% [3%-22%] lower in the sulfadoxine-pyrimethamine arm, regardless of gravidity. Mediation analyses indicated that 15% [0%-19%] of sulfadoxine-pyrimethamine's superior effect on reducing small-for-gestational-age risk was mediated by its greater impact on gestational weight gain.

Interpretation: In areas of high P. falciparum sulfadoxine-pyrimethamine resistance, dihydroartemisin-inpiperaquine is a more efficacious antimalarial than sulfadoxine-pyrimethamine. However, replacing sulfadoxine-pyrimethamine with dihydroartemisinin-piperaquine alone will not result in better maternal, birth, or infant outcomes. It could increase the risk of SGA, since much of the effect of sulfadoxine-pyrimethamine may be exerted through non-malarial mechanisms. Future research evaluating the alternative strategies for IPTp are needed, including with the combination of sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine.

Funding: This work was supported by the Bill and Melinda Gates Foundation and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Keywords: Plasmodium falciparum; antimalarial resistance; dihydroartemisinin-piperaquine; foetal growth; intermittent preventive treatment in pregnancy; malaria; meta-analysis; non-malarial effects; sulfadoxine-pyrimethamine.

Figure 1.. PRISMA flow diagram of included studies and participants.

Abbreviations: DP = dihydroartemisinin-piperaquine; IPD = individual participant-level data; IPTp=intermittent preventive treatment of malaria in pregnancy; SP = sulfadoxine-pyrimethamine; WHO ICTRP = World Health Organisation International Clinical Trials Registry Platform

Figure 2.. Forest plot comparing binary (A) and continuous live (B) birth outcomes between IPTp regimens.

All estimates reflect unadjusted differences between arms. Weighted prevalences and means for each outcome were calculated using a restricted maximum likelihood random-effects model. Abbreviations: CI=confidence interval; DP=dihydroartemisinin-piperaquine; MD=mean difference; RR=relative risk ratio; SP=sulfadoxine-pyrimethamine

Figure 3.. Forest plot comparing malaria outcomes between IPTp regimens.

All estimates reflect unadjusted differences between arms. Weighted prevalence and incidence rates for each outcome were calculated using a restricted maximum likelihood random-effects model. Abbreviations: CI=confidence interval; DP=dihydroartemisinin-piperaquine; IR=incidence rate; IRR=incidence rate ratio; PCR=polymerase chain reaction; py=person-year; RDT=rapid diagnostic test; RR=relative risk ratio; SP=sulfadoxine-pyrimethamine

Figure 4.. Forest plot comparing binary (A) and continuous (B) maternal outcomes between IPTp regimens.

All estimates reflect unadjusted differences between arms, except for mean MUAC and gestational weight gain, which adjusted for enrolment values. Weighted prevalence and means for each outcome were calculated using a restricted maximum likelihood random-effects model. Abbreviations: CI=confidence interval; DP=dihydroartemisinin-piperaquine; Hb=haemoglobin; MD=mean difference; MUAC=mid-upper arm circumference; RR=relative risk ratio; SP=sulfadoxine-pyrimethamine 1 Maternal anaemia summary estimates derived from seven of eight studies (except the Gutman unpublished study which only had haemoglobin measurements at delivery); Maternal MUAC summary estimates derived from five of eight studies (except the Kakuru 2016; Kajubi 2019; and Mlugu 2021 studies)

Figure 5.. Forest plot comparing binary (A) and continuous (B) infant outcomes between IPTp regimens.

All estimates reflect unadjusted differences between arms. Weighted prevalence and means for each outcome were calculated using a restricted maximum likelihood random-effects model. Abbreviations: CI=confidence interval; DP=dihydroartemisinin-piperaquine; LAZ=length-for-age z-score; RR = relative risk ratio; SP=sulfadoxine-pyrimethamine; WAZ=weight-for-age z-score; WLZ=weight-for-length z-score 1 Summary estimates derived from seven of eight studies (except the Mlugu 2021 study which did not collect infant follow-up data)