Format

Send to

Choose Destination
PLoS Med. 2018 Jul 17;15(7):e1002606. doi: 10.1371/journal.pmed.1002606. eCollection 2018 Jul.

Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial.

Author information

1
Department of Medicine, Stanford University, Stanford, California, United States of America.
2
Infectious Diseases Research Collaboration, Kampala, Uganda.
3
Department of Obstetrics and Gynecology, Makerere University College of Health Sciences, Kampala, Uganda.
4
Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, United Kingdom.
5
Burnet Institute, Melbourne, Australia.
6
Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
7
Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, California, United States of America.
8
Department of Pediatrics, University of California, San Francisco, San Francisco, California, United States of America.
9
Center for AIDS Prevention Studies, University of California, San Francisco, San Francisco, California, United States of America.
10
Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.

Abstract

BACKGROUND:

Intermittent preventive treatment of malaria in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) has been shown to reduce the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (IPTp-SP). However, limited data exist on how IPTp regimens impact malaria risk during infancy. We conducted a double-blinded randomized controlled trial (RCT) to test the hypothesis that children born to mothers given IPTp-DP would have a lower incidence of malaria during infancy compared to children born to mothers who received IPTp-SP.

METHODS AND FINDINGS:

We compared malaria metrics among children in Tororo, Uganda, born to women randomized to IPTp-SP given every 8 weeks (SP8w, n = 100), IPTp-DP every 8 weeks (DP8w, n = 44), or IPTp-DP every 4 weeks (DP4w, n = 47). After birth, children were given chemoprevention with DP every 12 weeks from 8 weeks to 2 years of age. The primary outcome was incidence of malaria during the first 2 years of life. Secondary outcomes included time to malaria from birth and time to parasitemia following each dose of DP given during infancy. Results are reported after adjustment for clustering (twin gestation) and potential confounders (maternal age, gravidity, and maternal parasitemia status at enrolment).The study took place between June 2014 and May 2017. Compared to children whose mothers were randomized to IPTp-SP8w (0.24 episodes per person year [PPY]), the incidence of malaria was higher in children born to mothers who received IPTp-DP4w (0.42 episodes PPY, adjusted incidence rate ratio [aIRR] 1.92; 95% CI 1.00-3.65, p = 0.049) and nonsignificantly higher in children born to mothers who received IPT-DP8w (0.30 episodes PPY, aIRR 1.44; 95% CI 0.68-3.05, p = 0.34). However, these associations were modified by infant sex. Female children whose mothers were randomized to IPTp-DP4w had an apparently 4-fold higher incidence of malaria compared to female children whose mothers were randomized to IPTp-SP8w (0.65 versus 0.20 episodes PPY, aIRR 4.39, 95% CI 1.87-10.3, p = 0.001), but no significant association was observed in male children (0.20 versus 0.28 episodes PPY, aIRR 0.66, 95% CI 0.25-1.75, p = 0.42). Nonsignificant increases in malaria incidence were observed among female, but not male, children born to mothers who received DP8w versus SP8w. In exploratory analyses, levels of malaria-specific antibodies in cord blood were similar between IPTp groups and sex. However, female children whose mothers were randomized to IPTp-DP4w had lower mean piperaquine (PQ) levels during infancy compared to female children whose mothers received IPTp-SP8w (coef 0.81, 95% CI 0.65-1.00, p = 0.048) and male children whose mothers received IPTp-DP4w (coef 0.72, 95% CI 0.57-0.91, p = 0.006). There were no significant sex-specific differences in PQ levels among children whose mothers were randomized to IPTp-SP8w or IPTp-DP8w. The main limitations were small sample size and childhood provision of DP every 12 weeks in infancy.

CONCLUSIONS:

Contrary to our hypothesis, preventing malaria in pregnancy with IPTp-DP in the context of chemoprevention with DP during infancy does not lead to a reduced incidence of malaria in childhood; in this setting, it may be associated with an increased incidence of malaria in females. Future studies are needed to better understand the biological mechanisms of in utero drug exposure on drug metabolism and how this may affect the dosing of antimalarial drugs for treatment and prevention during infancy.

TRIAL REGISTRATION:

ClinicalTrials.gov number NCT02163447.

PMID:
30016328
PMCID:
PMC6049882
DOI:
10.1371/journal.pmed.1002606
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: (1) EC declared NIH research grants to institution; (2) DVH declared that they received grant funding from NIH. For studies outside of submitted work, they received antiretroviral therapy for NIH funded study from Gilead Sciences; (3) JB is a member of the Editorial Board of PLOS Medicine.

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center