Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ) is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women. A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1) SP, (2) single dose MQ (15 mg/kg), and (3) split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome) between groups (360/2,778 [13.0%]) for MQ group and 177/1,398 (12.7%) for SP group; risk ratio [RR], 1.02 (95% CI 0.86–1.22; p = 0.80 in the ITT analysis). Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51–0.96]; p = 0.03) and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85–0.99]; p = 0.03), and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52–0.88]; p = 0.004) and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78–0.95]; p = 0.003). There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP. The most frequently reported related adverse events were dizziness (ranging from 33.9% to 35.5% after dose 1; and 16.0% to 20.8% after dose 2) and vomiting (30.2% to 31.7%, after dose 1 and 15.3% to 17.4% after dose 2) with similar proportions in the full and split MQ arms. The open-label design is a limitation of the study that affects mainly the safety assessment. Women taking MQ IPTp (15 mg/kg) in the context of long lasting insecticide treated nets had similar prevalence rates of low birth weight as those taking SP IPTp. MQ recipients had less clinical malaria than SP recipients, and the pregnancy outcomes and safety profile were similar. MQ had poorer tolerability even when splitting the dose over two days. These results do not support a change in the current IPTp policy. ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001429343 Please see later in the article for the Editors' Summary Half the world's population is at risk of malaria, a mosquito-borne parasitic disease that kills about 600,000 people every year. Most of these deaths occur among young children in sub-Saharan Africa but pregnant women and their unborn children living in Africa are also very vulnerable to malaria. Infection with malaria during pregnancy can cause severe maternal anemia (reduced red blood cell numbers), stillbirths, and pre-term and low-birthweight babies, and is responsible for the deaths of many African babies and women. To prevent this loss of life, the World Health Organization (WHO) recommends a three-pronged approach—the delivery to pregnant women of the antimalarial drug sulfadoxine-pyrimethamine (SP) at each scheduled antenatal care visit given at least one month apart (intermittent preventive treatment in pregnancy; IPTp), the use of insecticide treated bed nets to protect pregnant women from the bites of infected mosquitoes, and effective case management of pregnant women with malarial illness. IPTp with SP reduces the delivery of low-birth-weight babies and neonatal deaths but malaria parasites are becoming resistant to SP. Thus, other antimalarial drugs need to be evaluated for use in IPTp. Suitable drugs need to remain in the body for a long time to maximize their prophylactic (preventative) effect, they need to be given as a single dose at antenatal clinic visits to ensure compliance, and they must not harm the unborn child. In this open-label, randomized controlled trial (RCT), the researchers compare the efficacy and safety of IPTp with SP and mefloquine (MQ, an antimalarial drug that matches these criteria) in HIV-negative women living in Africa. The study also compares the tolerability of two MQ regimens. RCTs compare outcomes in groups of people chosen to receive different interventions through the play of chance; in open-label RCTs, both the researchers and the study participants know which treatment is being administered. IPTp with SP is only recommended for HIV-negative women because SP interacts with cotrimoxazole, which is routinely given to HIV-positive individuals to prevent infections. The researchers assigned 4,749 pregnant women in Benin, Gabon, Mozambique, and Tanzania to one of three study groups. Participants in the SP and MQ groups received two doses of SP or MQ, respectively, administered at least one month apart. Participants in the split-dose MQ group received each MQ dose as half doses given on consecutive days. The prevalence of low-birth-weight deliveries (the study's primary outcome; the prevalence of a condition is the proportion of a population with that condition) was similar in the SP group and in the combined MQ groups. However, compared to women who received SP, women who received MQ had a lower risk of parasitemia (parasites in the blood), a lower risk of anemia at delivery, fewer episodes of clinical malaria, and fewer outpatient attendances. The prevalence of placental infection with malaria parasites and of adverse pregnancy outcomes such as stillbirth was similar in all the study groups. Finally, the tolerability of IPTp was poorer in the two MQ intervention groups than in the SP group, but similar proportions of adverse events (mainly dizziness and vomiting) were reported for the two MQ dosing regimens. These findings indicate that HIV-negative African women taking MQ for IPTp had a similar risk of a low-birth-weight delivery (the study's primary outcome) and lower risk of malaria illness during pregnancy than women taking SP for IPTp. Because the study did not have a no-IPTp arm (for ethical reasons), these findings provide no information about the efficacy or safety or either MQ or SP per se; these findings only indicate that MQ is no more efficacious than SP in the prevention of low-birth-weight babies. Moreover, because the study was open-label, the accuracy of the findings related to the tolerability and safety of MQ compared to SP may be limited because of biases in the assessment of safety outcomes. Given that the MQ dose used here for IPTp was associated with poorer tolerability than that of SP, these findings do not support the use of MQ instead of SP for IPTp. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001733.

In areas endemic for malaria, pregnant women frequently present with a placenta that has been parasitized by Plasmodium falciparum, an infection associated with a reduction in the birth weight of the offspring. However, the impact of placental infection on malaria-related morbidity during the infant's first years of life has not been investigated. Between 1993 and 1995, 197 children in southern Cameroon were followed weekly clinically and monthly parasltologically. The dates of first positive blood smear and the evolution of the parasite prevalence rates were compared between infants bom to mothers presenting with (n = 42) and without (n = 155) P. falciparum infection of the placenta. Infants born to placenta-infected mothers were more likely to develop a malaria infection between 4 and 6 months of age; then the difference progressively disappeared. Similarly, parasite prevalence rates were higher in placenta-infected infants from 5 to 8 months of age. Thus, malarial infection of the placenta seems to result in a higher susceptibility of infants to the parasite. This was not related to maternally transmitted antibodies, as specific antibody levels were similar in both groups of infants. A better understanding of the involved mechanisms may have important implications for the development of malaria control strategies.

Background. Molecular, as opposed to microscopic, detection measures the real prevalence of Plasmodium falciparum infections. Such occult infections are common during pregnancy but their impact on pregnancy outcomes is unclear. We performed a longitudinal study to describe that impact. Methods. In a cohort of 1037 Beninese pregnant women, we used ultrasound to accurately estimate gestational ages. Infection with P. falciparum, hemoglobin concentration, use of intermittent preventive treatment during pregnancy (IPTp) for malaria, and other parameters were recorded during pregnancy. Using multivariate analyses, we evaluated the impact of submicroscopic infections on maternal anemia, premature birth, and low birth weight. Results. At inclusion, polymerase chain reaction (PCR) and microscopy detected infection in 40% and 16% of women, respectively. The proportion infected declined markedly after 2 doses of IPTp but rebounded to 34% (by PCR) at delivery. Submicroscopic infections during pregnancy were associated with lower mean hemoglobin irrespective of gravidity, and with increased anemia risk in primigravidae (odds ratio [OR], 2.23; 95% confidence interval [CI], .98–5.07). Prospectively, submicroscopic infections at inclusion were associated with significantly increased risks of low birth weight in primigravidae (OR, 6.09; 95% CI, 1.16–31.95) and premature births in multigravidae (OR, 2.25; 95% CI, 1.13–4.46). Conclusions. In this detailed longitudinal study, we document the deleterious impact of submicroscopic P. falciparum parasitemia during pregnancy on multiple pregnancy outcomes. Parasitemia occurs frequently during pregnancy, but routine microscopic and rapid diagnostic tests fail to detect the vast majority of episodes. Our findings imply caution in any revision of the current strategies for prevention of pregnancy-associated malaria.

Although consequences of malaria in pregnancy are well known, the period of pregnancy in which infection has the highest impact is still unclear. In Benin, we followed up a cohort of 1,037 women through pregnancy until delivery. The objective was to evaluate the relationship between the timing of infection and birth weight, and maternal anemia at delivery. At the beginning of pregnancy, peripheral infections were associated with a decrease in mean birth weight (−98.5 g; P = 0.03) and an increase in the risk of anemia at delivery (adjusted odds ratio [aOR] = 1.6; P = 0.03). Infections in late pregnancy were related to a higher risk of maternal anemia at delivery (aOR = 1.7; P = 0.001). To fully protect the women during the whole pregnancy, already implemented measures (insecticide-treated nets and intermittent preventive treatment) should be reinforced. In the future, a vaccine against pregnancy-associated malaria parasites could protect the women in early pregnancy, which seems to be a high-risk period.

Studies with animal models have suggested the possibility of interactions between parasites during concurrent infections and have raised the question of a similar phenomenon in humans. The present survey was undertaken to assess the impact of urinary schistosomiasis on the susceptibility of children to malaria. It was carried out in Senegal between September 2001 and March 2002 among 523 children 3–15 years of age. We tested the association between Plasmodium falciparum densities and the load of Schistosoma haematobium egg excretion using a linear mixed model because data were not independent. After controlling for age, sex, and season, we showed that children lightly infected with S. haematobium (1–9 eggs/10 mL of urine) had lower P. falciparum densities than those not infected (β = −0.34, 95% confidence interval = −0.85, −0.10), suggesting a negative interaction between both parasites.

BackgroundIn the context of the increasing resistance to sulfadoxine-pyrimethamine (SP), we evaluated the efficacy of mefloquine (MQ) for intermitten