Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis

Roh, Michelle E, terKuile, Feiko ORCID: https://orcid.org/0000-0003-3663-5617, Rerolle, Francois, Gylmore, M Maria, Shiboski, Stephen, Gosling, Roly, Gutman, Julie, Desai, Meghna, Kajubi, Richard, L'lanzvia, Anne, Kamya, Moses R, Dorsey, Grant and Chico, Matthew R (2020) 'Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis'. Lancet Global Health, Vol 8, Issue 7, e942-e953.

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Abstract

Background
Trials of intermittent preventive treatment (IPTp) of malaria in pregnant women that compared dihydroartemisinin-piperaquine with the standard of care, sulfadoxine-pyrimethamine, showed dihydroartemisinin-piperaquine was superior at preventing malaria infection, but not at improving birthweight. We aimed to assess whether sulfadoxine-pyrimethamine shows greater non-malarial benefits for birth outcomes than does dihydroartemisinin-piperaquine, and whether dihydroartemisinin-piperaquine shows greater antimalarial benefits for birth outcomes than does sulfadoxine-pyrimethamine.

Methods
We defined treatment as random assignment to sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine before pooling individual participant-level data from 1617 HIV-uninfected pregnant women in Kenya (one trial; n=806) and Uganda (two trials; n=811). We quantified the relative effect of treatment on birthweight (primary outcome) attributed to preventing placental malaria infection (mediator). We estimated antimalarial (indirect) and non-malarial (direct) effects of IPTp on birth outcomes using causal mediation analyses, accounting for confounders. We used two-stage individual participant data meta-analyses to calculate pooled-effect sizes.
Findings Overall, birthweight was higher among neonates of women randomly assigned to sulfadoxine-pyrimethamine compared with women assigned to dihydroartemisinin-piperaquine (mean difference 69 g, 95% CI 26 to 112), despite placental malaria infection being lower in the dihydroartemisinin-piperaquine group (relative risk [RR] 0·64, 95% CI 0·39 to 1·04). Mediation analyses showed sulfadoxine-pyrimethamine conferred a greater non-malarial effect than did dihydroartemisinin-piperaquine (mean difference 87 g, 95% CI 43 to 131), whereas dihydroartemisinin-piperaquine conferred a slightly larger antimalarial effect than did sulfadoxine-pyrimethamine (8 g, –9 to 26), although more frequent dosing increased the antimalarial effect (31 g, 3 to 60).

Interpretation
IPTp with sulfadoxine-pyrimethamine appears to have potent non-malarial effects on birthweight. Further research is needed to evaluate monthly dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine (or another compound with non-malarial effects) to achieve greater protection against malarial and non-malarial causes of low birthweight.

Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation, and Worldwide Antimalarial Resistance Network.

Item Type:	Article
Subjects:	WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases WA Public Health > Health Problems of Special Population Groups > WA 310 Maternal welfare WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WQ Obstetrics > Pregnancy > WQ 200 General works WS Pediatrics > By Age Groups > WS 420 Newborn infants. Neonatology
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1016/S2214-109X(20)30119-4
Depositing User:	Tracy Seddon
Date Deposited:	19 Jun 2020 08:45
Last Modified:	19 Jun 2020 08:48
URI:	https://archive.lstmed.ac.uk/id/eprint/14766

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