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Background: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) significantly reduces the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (SP), the current standard of care, but its impact on the incidence of malaria during infancy is unknown. Methods: We conducted a double-blind randomized trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomized to monthly IPTp with either DP or SP. Infants were followed for all their medical care in a dedicated study clinic, and routine assessments were conducted every 4 weeks. At all visits, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was malaria incidence during the first 12 months of life. All analyses were done by modified intention to treat. Results: Of the 782 women enrolled, 687 were followed through delivery from December 9, 2016, to December 5, 2017, resulting in 678 live births: 339 born to mothers randomized to SP and 339 born to those randomized to DP. Of these, 581 infants (85.7%) were followed up to 12 months of age. Overall, the incidence of malaria was lower among infants born to mothers randomized to DP compared to SP, but the difference was not statistically significant (1.71 vs 1.98 episodes per person-year, incidence rate ratio (IRR) 0.87, 95% confidence interval (CI) 0.73-1.03, p = 0.11). Stratifying by infant sex, IPTp with DP was associated with a lower incidence of malaria among male infants (IRR 0.75, 95% CI 0.58-0.98, p = 0.03) but not female infants (IRR 0.99, 95% CI 0.79-1.24, p = 0.93). Conclusion: Despite the superiority of DP for IPTp, there was no evidence of a difference in malaria incidence during infancy in infants born to mothers who received DP compared to those born to mothers who received SP. Only male infants appeared to benefit from IPTp-DP suggesting that IPTp-DP may provide additional benefits beyond birth. Further research is needed to further explore the benefits of DP versus SP for IPTp on the health outcomes of infants. Trial registration: ClinicalTrials.gov, NCT02793622. Registered on June 8, 2016.
This study was conducted from September 6, 2016, to December 4, 2018, in Busia district, south-eastern Uganda, an area of high malaria transmission intensity. The study was conducted in two phases: the pregnancy phase, which involved enrollment and follow-up of pregnant women through delivery, and the infancy phase, which involved follow-up of infants through 12 months of age. Details of the pregnancy phase of the study have been published elsewhere [9]. In brief, HIV-uninfected pregnant women were eligible for enrollment if they were 12–20 weeks of gestation, 16 years or older, agreed to come to the study clinic for any illness, had no history of taking IPTp-SP or any other antimalarial therapy during the current pregnancy, and provided written informed consent. Women were excluded if they had a history of serious adverse events to SP or DP. The infancy phase involved the follow-up of all live births among women enrolled in the pregnancy phase of the study. This was a double-blind randomized controlled trial designed to assess the impact of monthly IPTp with DP versus SP in HIV-uninfected pregnant women, on the incidence of malaria during infancy (trial registration, ClinicalTrials.gov; {“type”:”clinical-trial”,”attrs”:{“text”:”NCT02793622″,”term_id”:”NCT02793622″}}NCT02793622). At enrollment, pregnant women were randomly assigned in a 1:1 ratio to receive IPTp-DP or IPTp-SP. A randomization list was computer generated using permuted blocks of 4 or 8 by a staff member not directly involved in patient care. To achieve allocation concealment, sealed envelopes, each containing a treatment allocation number and treatment group assignment, were prepared following the sequence of the randomization list, prior to enrollment. Treatment allocation was done by a study pharmacist not involved in daily patient care by picking the next available sealed envelope, recording the participant’s identification number on the envelope, and opening it to reveal the assigned treatment. The treatment allocation number, the participant’s identification number, and the assigned treatment were then recorded on a treatment allocation log which was kept in a safe lockable place only accessible by the study pharmacist. Study drugs for each enrolled participant were pre-packaged by the study pharmacist and labeled with the participant’s identification number. Study drugs were administered every 4 weeks starting at 16 or 20 weeks of gestation. Each dose of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine; Duo-Cotexin, Holley-Cotec, Beijing, China) consisted of 3 tablets given once a day for 3 consecutive days. Each dose of SP (tablets of 500 mg of sulfadoxine and 25 mg of pyrimethamine; Kamsidar, Kampala Pharmaceutical Industries) consisted of 3 tablets given as a single dose. To achieve blinding, participants randomized to DP also received SP placebos, and participants randomized to SP received DP placebos every 4 weeks. The administration of all 1st daily doses of study drugs was directly observed in the study clinic. The 2nd and 3rd daily doses were dispensed to the mother for self-administration at home. Adherence to the 2nd and 3rd daily doses was assessed by self-reporting during the visits following routine visits. Study procedures for pregnant women have been previously described in detail [9]. Briefly, at enrollment, all participants received a long-lasting insecticide-treated net and underwent a standard history and physical examination. Pregnant women were encouraged to come to a dedicated study clinic any time they were ill and to attend routine visits conducted every 4 weeks for study drug dispensing and laboratory testing. Pregnant women diagnosed with symptomatic malaria detected by microscopy at any visit were treated with artemether-lumefantrine. Asymptomatic parasitemia detected during routine visits was not treated. At delivery, a standardized assessment was completed including evaluation of birth weight, gestation age based on ultrasound dating, and collection of biological specimens including placental tissue and placental blood. Following delivery, all live births were followed up to 12 months of age. Mothers were encouraged to bring their infants to a dedicated study clinic open every day for all their medical care and were provided a transport refund. Routine assessments were conducted every 4 weeks including the collection of blood for the detection of parasites by microscopy. Infants who presented with a history of fever in the past 24 h or with a documented tympanic temperature > 38.0 °C had blood collected for a thick blood smear. If the thick blood smear was positive, infants were treated for malaria according to the Uganda Ministry of Health guidelines which consisted of artemether-lumefantrine for uncomplicated malaria and intravenous artesunate for complicated malaria. Non-malarial illnesses were treated according to the integrated management of childhood illnesses guidelines. At 12, 28, and 52 weeks of age, blood was collected for hemoglobin measurement. The presence of malaria parasites in dried placental blood spots was detected by loop-mediated isothermal amplification as previously described [18]. Placental malaria by histology defined as the presence of malaria parasites or malaria pigment was detected from placental tissue as previously described [19]. Blood smears were stained with 2% Giemsa and read by experienced microscopists. A blood smear was considered negative when the examination of 100 high-power fields did not reveal asexual parasites. All blood smears were read by two independent microscopists. Blood smears with discrepant results between the first and the second readers were read by a third reader as a tiebreaker. Hemoglobin measurements were made using a portable spectrophotometer (Hemocue, Angelholm, Sweden). The primary outcome was the incidence of malaria from birth to 12 months of age. An incident episode of malaria was defined as the presence of fever (history of fever in the past 24 h or a tympanic temperature ≥ 38.0 °C) with a positive thick blood smear not preceded by another malaria episode in the last 14 days. Secondary outcomes included time to the first episode of malaria, incidence of complicated malaria defined as an episode of malaria with danger signs (any of the following, less than 3 convulsions over 24 h, inability to sit or stand, vomiting everything, unable to breastfeed or drink) or the meeting standardized criteria for severe malaria, incidence of all-cause hospitalizations, infant mortality, incidence of non-malarial febrile illnesses, prevalence of malaria parasitemia during routine visits, and prevalence of anemia (hemoglobin < 10 g/dL) at 12, 28, and 52 weeks of age. To test the hypothesis that infants born to mothers randomized to IPTp-DP would have a lower incidence of malaria during the first 12 months of life compared to infants born to mothers randomized to IPTp-SP, it was estimated that the incidence of malaria in infants born to mothers randomized to IPTp-SP would be 3–5 episodes per person-year (using data from a prior study conducted in the adjacent district of Tororo [20] and a loss of 5% of follow-up time per year). With these assumptions, the study had 80% power to detect an 18–23% difference in the incidence of malaria (incidence rate ratio of 0.77–0.82) among infants born to mothers randomized to IPTp-DP compared to those born to mothers randomized to IPTp-SP with a two-sided significance level of 0.05. Data were double entered and verified in Microsoft Access by two independent data entrants. Using Stata, version 14.2, statistical analyses were done in the modified intention-to-treat population, which included all live births followed until they reached 12 months of age or premature study withdrawal. Comparisons of simple proportions were made using the chi-square test or Fisher’s exact test. Comparisons of continuous variables were made using the t test. Comparisons of proportions with repeated measures were made with generalized estimating equations, with the use of log-binomial regression and robust standard errors to adjust for clustering. Comparisons of incidence measures were made using a negative binomial regression model. Incidence rate ratios (IRRs) were defined as the incidence in the IPTp-DP arm divided by the incidence in the IPTp-SP arm. Prevalence ratios were defined as the prevalence in the IPTp-DP arm divided by the prevalence in the IPTp-SP arm. Stratified analyses of our primary outcome according to infant sex and age, and maternal gravidity were planned a priori in the statistical analysis plan. The cumulative risk of the first episode of malaria was compared using a Cox proportional hazards model with the association expressed as the hazard ratio (HR). In all analyses, two-sided p values of < 0.05 were considered statistically significant.
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