Intermittent screening and treatment with artemisinin-combination therapy versus intermittent preventive treatment with sulphadoxine-pyrimethamine for malaria in pregnancy: a systematic review and individual participant data meta-analysis of randomised clinical trials.

Julie R Gutman,Mwayiwawo Madanitsa,Simon Kariuki,Steve M Taylor,Victor Mwapasa,Steve Meshnick,Meghna Desai,Anne Joan L'Lanziva,Brian Greenwood,Harry Tagbor,Carole Khairallah,Kephas Otieno,Kasia Stepniewska,Feiko O Ter Kuile,Linda Kalilani,Matthew Cairns,Daniel Chandramohan

doi:10.1016/j.eclinm.2021.101160

Abstract

BackgroundIn sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections.MethodsWe searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789.FindingsFive trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I2=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I2=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I2=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I2=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57).InterpretationISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections.FundingCenters for Disease Control and Prevention and Worldwide Antimalarial Resistance Network.

Highlights

11.6 million pregnancies in sub-Saharan Africa were exposed to malaria in 2019 [1], a significant cause of poor birth outcomes.[2]
This study suggests that ISTp with the current generation of rapid diagnostic tests (RDTs) is not a suitable alternative to IPTp-SP even in high SP resistance areas where the dihydrofolate reductase/dihydropteroate synthase quintuple mutant parasites are saturated or have reached near saturation, but where the sextuple mutants are still rare, as is the case in most of East and southern Africa
We examined the effect of subpatent malaria infections missed by rapid diagnostic tests but detected by nucleic acid amplification tests like polymerase chain reaction (PCR) on adverse pregnancy outcomes in these trials

Summary

Introduction

11.6 million pregnancies in sub-Saharan Africa were exposed to malaria in 2019 [1], a significant cause of poor birth outcomes.[2]. The highest levels of resistance to SP undermine the ability of IPTp-SP to minimise the adverse consequences of malaria in pregnancy [3,4], necessitating alternative approaches [5,6]. In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTpACT) compared to IPTp-SP, and understand the importance of subpatent infections. Methods: We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57).

Methods

Results

Conclusion