Dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria in pregnancy: a systematic review and individual participant data meta-analysis
Authors: Roh Michelle E. , Gutman Julie , Murphy Maxwell , Hill Jenny , Madanitsa Mywayiwawo , Kakuru Abel , Barsosio Hellen C. , Kariuki Simon , Lusingu John P.A. , Mosha Frank , Kajubi Richard , Kamya Moses R. , Mathanga Don , Chinkhumba Jobiba , Laufer Miriam K. , Mlugu Eulambius , Kamuhabwa Appolinary A.R. , Aklillu Eleni , Minzi Omary , Okoro Roland Nnaemeka , Geidam Ado Danazumi , Ohieku John David , Desai Meghna , Jagannathan Prasanna , Dorsey Grant , ter Kuile Feiko O. 
Published: November 2024

Background

High-gradePlasmodium falciparumresistance 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];I2=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 highP. falciparumsulfadoxine-pyrimethamine resistance, dihydroartemisinin-piperaquine 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.

Research in context

Evidence before this study

We searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.Gov, PubMed, and the Malaria in Pregnancy Consortium Library for randomised trials comparing intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine to sulfadoxine-pyrimethamine, using the search term: (“intermittent preventive treatment” OR “IPTp”) AND ((“sulfadoxine-pyrimethamine” OR “sulphadoxine-pyrimethamine”) AND (“dihydroartemisinin-piperaquine”)). The initial search was conducted on July 30, 2020, and updated on September 24, 2024, without any restrictions on publication date, peer-review status, or language. We found eight studies, of which six were eligible for inclusion in this meta-analysis. Two previous meta-analyses had been conducted: a 2018 review by Desai et al that included the first two trials, and a subsequent pooled analysis by Roh et al in 2020 that included the first three trials and focused disentangling the antimalarial and non-malarial effects of sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine. These reviews highlighted the superior antimalarial efficacy of dihydroartemisinin-piperaquine compared to sulfadoxine-pyrimethamine, but also suggested the potential superior non-malarial benefits of sulfadoxine-pyrimethamine. A recent meta-analysis by Muthoka et al evaluated the safety of IPTp with dihydroartemisinin-piperaquine in pregnancy. However, an updated meta-analysis comparing the efficacy of all currently completed trials of IPTp with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine has not been conducted.

Added value of this study

This study represents the first and only meta-analysis using individual participant data from all six available trials conducted in areas with high sulfadoxine-pyrimethamine resistance. By pooling data from 6646 pregnancies across multiple African countries, we were able to conduct a more robust and nuanced analysis comparing the efficacy of dihydroartemisinin-piperaquine to sulfadoxine-pyrimethamine for IPTp. Our findings confirm the superior antimalarial efficacy of dihydroartemisinin-piperaquine but also reveal that sulfadoxine-pyrimethamine is associated with better birth and infant outcomes, particularly in reducing the risk of small-for-gestational age and infant malnutrition. This meta-analysis provides strong evidence for the existence of non-malarial benefits of sulfadoxine-pyrimethamine in pregnancy, which appear to outweigh its reduced antimalarial efficacy in terms of pregnancy outcomes, even in areas of high resistance.

Implications of all the available evidence

Based on our comprehensive analysis, we recommend against switching from sulfadoxine-pyrimethamine to dihydroartemisinin-piperaquine for IPTp, even in areas with very high sulfadoxine-pyrimethamine resistance. Such a change would likely reduce gestational weight gain, lower mean newborn birthweights, increased risk of SGA, and poor early infant growth. Instead, we recommend further studies combining sulfadoxine-pyrimethamine with dihydroartemisinin-piperaquine (or another potent malaria strategy) to harness the non-malarial benefits of sulfadoxine-pyrimethamine and target the malaria-associated causes of adverse pregnancy outcomes. Additionally, more research is needed to better understand the mechanisms underlying the non-malarial effects of these drugs, including their direct antimicrobial activity, effects on gut and vaginal health, and/or influence on maternal systemic inflammation. This research is crucial for optimising malaria prevention strategies in pregnancy and improving maternal and neonatal outcomes in malaria-endemic regions.