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

Background: 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 (ISTp-ACT) 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. 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. Findings: Five 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). Interpretation: ISTp-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. Funding: Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network. An electronic literature search, using the search terms: ((intermittent AND screening) AND malaria) AND pregnan* AND Clinical Trial[ptyp] AND Humans[Mesh]) was conducted on August 8, 2016, and updated on May 6, 2021, following PRISMA guidelines [20]. The following databases were searched: MEDLINE and the Malaria in Pregnancy Consortium (MiPc) Library, which includes references from Web of Knowledge, Scopus, CINAHL, Bioline, the Cochrane Library databases, WHO Global Health Library, as well as ‘grey literature’ and conference abstracts [21]. A multi-concept Boolean search strategy was applied using keywords and MeSH terms. Randomised controlled trials among pregnant women comparing ISTp-ACT versus IPTp-SP were eligible (Supplement 1, page 2). The search was conducted in English but without language or date restriction. Two independent reviewers (JRG and MM or CK) screened titles, abstracts, and full texts of all citations. For eligible studies, authors were contacted to request de-identified individual-level data. Three attempts were made to contact authors. Data were analysed using STATA/MP2 16.0 (StataCorp LP), according to an a priori defined statistical analysis plan. Reviewers were unblinded to the authors of the source study. Two reviewers (JRG and CK) independently assessed the risk of bias for the included trials using the Cochrane risk-of-bias tool for randomised trials version 2 (RoB2) [22] (Supplement 2, page 2). The study is registered in PROSPERO (CRD42016043789). The co-primary outcomes for the comparison of the effect of ISTp-ACT vs IPTp-SP were 1) maternal malaria infection at delivery, defined as any Plasmodium infection detected in peripheral or placental blood by PCR, microscopy, RDT, or histopathology (acute and/or chronic infection) and 2) adverse live-birth, defined as the composite of LBW (<2500 grams), small-for-gestational-age (SGA, <10th percentile relative to INTERGROWTH-21st gender-specific chart) [23], or preterm delivery (<37 weeks gestation). Secondary outcome definitions are provided in Supplement 3, page 2. The analyses of the impact of ISTp-ACT versus IPTp-SP during pregnancy excluded enrolment and delivery time points from incidence data. Analysis of the impact of patent and subpatent (PCR-positive, RDT/microscopy-negative) infection on adverse pregnancy outcomes included enrolment and delivery time points. Log-binomial generalised linear regression models were used to obtain risk ratios (RR) and 95% confidence intervals (CI). When convergence was not achieved, we followed suggestions from Cummings.[24] For continuous outcomes, mean differences and 95% CIs were obtained from linear regression. The primary analyses of the primary and secondary outcomes used two-stage IPD meta-analysis. Because the number of studies was small, fixed-effect models were used [25,26]. Because IPD data was not available for one study [27], aggregated data of this study were included in the second stage [28]. Unadjusted models were used for the primary analysis. The stratification factors study site (i.e., health facility) and gravidity were included a priori as covariates in all unadjusted models because the randomisation was stratified by study site in all IPD studies and by gravidity in Malawi [18]. Heterogeneity was measured using the I2 statistic [29] (Supplement 4, page 3). To explore potential modification of treatment effect by prevailing SP resistance levels, we classified studies into low (≤90% prevalence of Plasmodium falciparum dihydropteroate synthase (Pfdhps) K540E mutation) and high (>90% PfdhpsK540E) resistance [3]. Supportive secondary analyses using covariate adjusted and subgroup analyses were performed using the 2-stage model. Potential effect modifiers and confounding variables were pre-specified. In addition to the stratification factors study site and gravidity, these included the baseline factors maternal haemoglobin concentration, bed net use, and gestational age. Maternal socioeconomic status, maternal education, and malaria status at enrolment were excluded because they were missing in a large proportion of participants in at least one of the studies. Further sensitivity analyses to assess the robustness of the primary analysis were conducted using 1-stage models, with site and gravidity included as covariates, and random-effect models. The effect of exposure to subpatent malaria on pregnancy outcomes was examined using fixed-effect models with robust Poisson regression for binary outcomes and linear regression for continuous outcomes, accounting for study and the total number of malaria tests conducted, including the number of patent infections detected. In the binary models, risk ratios (RR) correspond to the change in the risk of the adverse outcome associated with one additional positive test (i.e. a patent or subpatent malaria infection) during pregnancy. In models with continuous outcomes, the mean difference in the outcome measure associated with each additional patent or subpatent infection was estimated. Both types of models included a robust estimator of variance. Crude models included study arm and the number of patent and subpatent infections as the two exposure variables of interest. Adjusted models (primary analysis) also included gestational age at enrolment, maternal age, gravidity (paucigravidae [G1-G2]/multigravidae), and the number of sick visits (Supplement 5, page 3). A sensitivity analysis was conducted to determine if the method used to assess gestational age influenced the conclusions for outcomes requiring gestational age at delivery (preterm delivery, SGA) (Supplement 6, page 4; Supplement 8, page 12; Table S5). Details of the performance of the RDTs to detect PCR-positive infections have been described previously [30]. The five original studies were approved by the relevant local and international partner ethical committees and institutional review boards. The protocol for the meta-analysis was reviewed by the US Centers for Disease Control and Prevention (CDC) Human Research Protection Office and deemed exempt from further review. Written consent was required from each patient for participation in each individual study. WWARN had no role in study design, data collection, data analysis, data interpretation, or writing of the report. CDC staff were involved in study design, data collection, data analysis, data interpretation, and writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.