Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali. The effects of malaria chemoprophylaxis given by traditional birth attendants on the course and outcome of pregnancy. Malaria chemoprophylaxis, infection of the placenta and birth weight in Gambian primigravidae. Malaria chemosuppression in pregnancy. I. The effect of chemosuppressive drugs on maternal parasitaemia. A community randomized controlled trial of insecticide-treated bednets for the prevention of malaria and anaemia among primigravid women on the Kenyan coast. Effect of chloroquine chemoprophylaxis during pregnancy on birth weight: results of a randomized trial. Impact of a double dose of sulphadoxine-pyrimethamine to reduce prevalence of pregnancy malaria in southern Mozambique. Two-dose versus monthly intermittent preventive treatment of malaria with sulfadoxine-pyrimethamine in HIV-seropositive pregnant Zambian women. Bed nets for the prevention of malaria and anaemia in pregnancy. Randomized trial of 2-dose versus monthly sulfadoxine-pyrimethamine intermittent preventive treatment for malaria in HIV-positive and HIV-negative pregnant women in Malawi. Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Reduction of malaria during pregnancy by permethrin-treated bed nets in an area of intense perennial malaria transmission in western Kenya. Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. The impact of insecticide-treated bednets on malaria and anaemia in pregnancy in Kassena-Nankana district, Ghana: a randomized controlled trial.
Malaria during pregnancy contributes to maternal anemia and low birth weight. In East Africa, several studies have demonstrated that intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) is more efficacious than weekly chloroquine (CQ) chemoprophylaxis in preventing these adverse consequences. To our knowledge, there are no published trials evaluating IPT in West Africa.
                We undertook a randomized controlled trial of weekly CQ chemoprophylaxis, 2-dose IPT with CQ, and 2-dose IPT with SP; 1163 women were enrolled.
                In multivariate analyses, when compared with weekly CQ, IPT/SP was associated with a reduction in third-trimester anemia (adjusted odds ratio [AOR], 0.49; P<.001), placental parasitemia (AOR, 0.69; P=.04), and low birth weight (<2500 g) (AOR, 0.69; P=.04). The prevalence of placental infection remained unexpectedly high, even in the IPT/SP group (24.5%), possibly because of the intensity of seasonal transmission. There were no significant differences in stillbirths, spontaneous abortions, or neonatal deaths among the 3 groups.
                In Mali, IPT with SP appears more efficacious than weekly chloroquine chemoprophylaxis in preventing malaria during pregnancy. These data support World Health Organization recommendations to administer at least 2 doses of IPT during pregnancy. In intensely seasonal transmission settings in Mali, >2 doses may be required to prevent placental reinfection prior to delivery. A trial of malaria chemoprophylaxis given by traditional birth attendants was undertaken in a rural area of The Gambia where access to antenatal clinics is difficult. Women received one or more doses of Maloprim or placebo from a traditional birth attendant during 1049 of 1208 pregnancies (87%) recorded in 16 villages over a 3-year period. Primigravidae who received Maloprim had a lower parasite rate and a significantly higher mean packed cell volume than primigravidae who received placebo, and their babies were significantly heavier (6% low birth weight vs 22%). In multigravidae chemoprophylaxis reduced malaria parasitaemia but it had no beneficial effect on haemoglobin level and much less effect on birth weight than was observed in primigravidae. However, the mean birth weight of babies born to grandemultigravidae who received chemoprophylaxis was significantly higher than that of babies born to grandemultigravidae who did not. A randomized, double blind, placebo-controlled community based trial of Maloprim (pyrimethamine 12.5 mg+dapsone 100 mg) administered to primigravid pregnant women by Traditional Birth Attendants was carried out in a rural area of The Gambia, West Africa. Placental histology showed less malaria infection in women who received chemoprophylaxis than in those who received placebo. The birth weight of children born to women who received chemoprophylaxis was increased by an average of 153 g. Within the treatment groups, there were no significant differences in the birthweights of babies born to women who had histological evidence of malaria infection of the placenta compared to those who had no malaria infection. This study confirms the beneficial effect of malaria prophylaxis for primigravid pregnant women but questions the mechanism by which malaria affects foetal development. A randomized prophylactic drug trial was conducted in a malaria holoendemic area, in the Muheza District of Tanzania. Of 327 pregnant women, 124 received proguanil (PROG), 113 chloroquine (CQ), 90 the proguanil and chloroquine combination (CQ+PROG). Prophylaxis was supervised. Chemosuppressive efficacy was measured through the incidence of malaria breakthrough parasitaemias and clinical episodes. Groups were comparable by age, parity, residential area, and enrollment gestational age. Compliance and drug bio-availability was good. The median breakthrough time of the first parasitaemia episode for primigravidae (PG) and multigravidae (MG) was significantly shorter for the CQ group (PG = 56, MG = 78 days) than in the PROG (PG = 97, MG = 112 days) and the CQ+PROG (PG = 138, MG = 140 days) groups. 56% of the CQ group experienced 2 or more clinical episodes compared to 19% (PROG) and 10% (CQ+PROG). PROG and CQ+PROG did not differ significantly. Parasite densities and in vitro tests suggested that CQ selected for more and highly resistant strain(s). Proguanil is suitable for prophylaxis. However, proguanil resistance should be monitored as well as controlled drug distribution and usage. Malaria control strategies other than chemoprophylaxis should be investigated. The effectiveness of insecticide-treated bednets (ITBN) in preventing malaria and anaemia among primigravidae living in Kilifi District, Kenya, was assessed by a randomized controlled trial between September 1994 and November 1995. All residents within 28 community clusters received ITBN in July 1993, whilst residents of another 28 clusters served as contemporaneous controls. All resident primigravid women with singleton pregnancies attending antenatal care at Kilifi District Hospital were eligible for recruitment. 503 primigravidae were recruited. 91.4% were anaemic antenatally (Hb < 11 g/dl): 91.0% from the intervention arm and 92.0% from the control arm. Severe anaemia (Hb < 7 g/dl) was found among 15.1% of intervention women and 20.1% of control women (P = 0.28). No significant differences were observed in reports of febrile illness or the presence of chloroquine in the serum or peripheral parasitaemia during the third trimester between the two groups. In the women delivering in hospital (n = 130), there was no association between placental malaria infection and the intervention: 77.4% of placentas from control women had evidence of past or active infection, compared with 72.0% of placentas from intervention women (P = 0.76). Similarly, in the women delivering in hospital, ITBN did not improve birth weight, and there were no differences in perinatal mortality between the two study groups. Despite ITBN having a great impact on paediatric severe malaria and mortality in this transmission setting, there was very little impact of ITBN on the morbidity associated with malaria infection in primigravidae. Alternative strategies are required to tackle this continued public health problem for pregnant women living in endemic areas similar to the Kenyan Coast. To determine the effect of chloroquine chemoprophylaxis during pregnancy on birth weights, a randomized trial was carried out in 1987 and 1988 in Banfora, Burkina Faso (West Africa). Seven hundred forty-five randomly selected women treated with chloroquine sulfate were compared to with 719 controls who received no treatment. In spite of an unquestionable effect of chloroquine in preventing placental infection (4.1% infected placentas in the treated group versus 19.0% in the controls), the mean difference in birth weights between the two groups (6 g) was not significant. The difference in the proportion of low birth weight (LBW) newborn babies in two groups (16.3% versus 16.4%) was also not significant. However, there was a strong relationship between placental infection and birth weight (the mean birth weight difference between infected and uninfected placentas was 113 g, and the proportion of LBW babies was 26.0% in infected placentas versus 14.8% in uninfected placentas). The small difference in birth weights observed between the two groups may be due to the fact that the prevalence rate of placental infection is low and that prophylaxis is effective only on a portion of the subjects in the treated group. It may also indicate that malaria is only one of several risk factors responsible for LBW. The relatively small increase in birth weight, the expected poor acceptance of mass prophylaxis, and the spreading of chloroquine-resistant Plasmodium strains should be considered before extending malaria chemoprophylaxis to all pregnant women. It might be worth considering to limit prophylaxis to primigravidae. Malarial infection during pregnancy increases the risks of severe sequelae for the pregnant woman and the risk of delivering a low birthweight baby. The aim of this intervention study was to reduce significantly the prevalence of malaria parasitaemia in adolescent parturients in Matola and Boane in Mozambique. The study was focused upon the most malaria-vulnerable group, adolescent nulliparous and primiparous women. After completing the usual antenatal clinic and giving informed consent, 600 pregnant women were randomly chosen in a double blind manner to one of two regimens comparing the prevailing routine (placebo) for malaria prevention with a two dose regimen of sulphadoxine-pyrimethamine (SP). The first dose was given at enrollment with a second dose at the beginning of the third trimester. At delivery maternal and placental malaria parasitaemia as well as birthweight and gestational duration were analysed. At booking the prevalence of malaria parasitaemia was 35.3% in the placebo group and 30.6% in the SP group. At the second dose, the prevalence of malaria parasitaemia in the placebo group and SP group was 19.7% and 8.7%, respectively. This implies a relative risk (RR) of 2.24 with 95% CI (1.34, 3.75). The corresponding figures at delivery were 13.6% and 6.3% with an RR of 2.22 (1.07, 4.60) and in placenta 13.3% and 2.4% with an RR of 4.87 (1.58, 15.0). Newborns with malaria within 7 days were significantly more frequent in the placebo group, 6.4% and 0.7% respectively, with an RR of 6.55 (1.20, 35.7). Almost all (approximately 98%) of the women studied had Plasmodium falciparum, the remainder had P. malariae and P. ovale. The mean birthweight in the SP group was 3077 g and in the placebo group 2926 g. The estimated mean difference between the two groups was 151 g with 95% CI (51, 252). The mean placental weight in the placebo group was 596 and 645 g in the SP group, implying a difference of 49 g with a 95% CI (11, 88). The mean gestational duration was 6.1 days longer in the SP group, 95% CI (1.5, 10.6). In the placebo group there were two cases of urticaria and one case of nausea; in the SP group there was one case of vomiting. No newborn showed any sign of serious SP side-effect. Two doses of SP were enough to significantly reduce the prevalence of peripheral and placental malaria parasitaemia among young nulliparous and primiparous pregnant women in Matola and Boane. Intermittent preventive treatment of malaria during pregnancy (IPTp) reduces placental infection, maternal anemia, and low birth weight (LBW). However, the optimal dosing regimen in settings in which human immunodeficiency virus (HIV) is highly prevalent among pregnant women remains controversial.
                We conducted a randomized, double-blind, placebo-controlled study of IPTp comparing the standard 2-dose sulfadoxine-pyrimethamine (SP) regimen with monthly IPTp among a cohort of HIV-positive pregnant Zambian women. Primary outcomes included placental malaria (by smear and histology) and maternal peripheral parasitemia at delivery.
                There were no differences between monthly IPTp (n=224) and standard IPTp (n=232) in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90 [95% confidence interval {CI}, 0.64-1.26]) or placental parasitemia (2% vs. 4%; RR, 0.55 [95% CI, 0.17-1.79]). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at 6 weeks.
                In an area of mesoendemicity in Zambia, monthly SP IPTp was not more efficacious than the standard 2-dose regimen for the prevention of placental malaria or adverse birth outcomes. IPTp policy recommendations need to take into account local malaria transmission patterns and the prevalence of HIV.
                ClinicalTrials.gov identifier: NCT00270530. A prospective comparison of the antimalarial efficacy of bed nets was conducted with 341 pregnant women living in a mesoendemic malarious area of the Thai-Burmese border. Women in 3 adjacent study sites were allocated at random to receive either a single size permethrin-impregnated bed net (PIB), a non-impregnated bed net (NIB), or to a control group who used either their own family size non-impregnated bed net (FNIB) or no net. In one study site, but not the other 2, PIB significantly reduced parasite densities and, together with FNIB, reduced the incidence of malaria in pregnancy from 56% to 33% (relative risk = 1.67, confidence interval = 1.07-2.61, P = 0.03, allowing for parity). Anaemia proved a more sensitive marker of bed net antimalarial efficacy than parasite rates. The incidence of anaemia (haematocrit < 30%) at all study sites was significantly lower at delivery in the PIB (27%) and FNIB groups (21%) than in the NIB group (41%) or those using no net (56%). This suggests that a significant proportion of the malaria in pregnancy in this mesoendemic area was sub-patent. Both patent Plasmodium falciparum parasitaemia and anaemia were associated with a reduction in birth weight. Infant mortality was high (16%) and strongly associated with prematurity, low birth weight and maternal anaemia. PIB were well tolerated and had no apparent adverse effect on the pregnancy or infant development. Although the overall effect of bed nets on patent parasitaemia was marginal, they were associated with a significant reduction in maternal malaria-associated anaemia.(ABSTRACT TRUNCATED AT 250 WORDS) Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) decreases placental malaria parasitemia and associated maternal anemia, premature delivery, and low birth weight. However, the optimal regimen in the setting of a high prevalence of human immunodeficiency virus (HIV) infection remains unclear.
                In Malawi, where the efficacy of SP for the treatment of malaria in children is decreasing, we conducted a randomized, nonblinded study to compare the efficacy of monthly SP IPTp with a 2-dose regimen for the prevention of placental parasitemia in HIV-positive and -negative primigravid and secundigravid women.
                Of HIV-positive women, 7.8% who received monthly SP had placental malaria, compared with 21.5% of those who received 2-dose SP (relative risk [RR], 0.36 [95% confidence interval {CI}, 0.17-0.79]). Of HIV-negative women, 2.3% who received monthly SP and 6.3% who received 2-dose SP had placental malaria (RR, 0.37 [95% CI, 0.11-1.19]). Less than 1% of women reported adverse drug reactions, with no increase in HIV-positive women or those who received monthly SP.
                In HIV-positive pregnant women, monthly SP IPTp is more efficacious than a 2-dose regimen in preventing placental malaria. The study also demonstrates the continued efficacy of SP for the prevention of placental malaria, even in the face of its decreasing efficacy for the treatment of malaria in children. In areas with intense transmission of falciparum malaria and a high prevalence of HIV infection, monthly SP IPTp should be adopted. Malaria and anaemia, especially that due to iron deficiency, are two leading causes of morbidity worldwide. Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas. We undertook a randomised comparison of different strategies for control of anaemia and malaria in infants, including an assessment of the effect of iron supplementation on malaria susceptibility.
                832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October, 1995, were randomly assigned to group DI, receiving daily oral iron (2 mg/kg daily) plus weekly Deltaprim (3.125 mg pyrimethamine plus 25 mg dapsone); group IP, receiving iron plus weekly placebo; group DP, receiving daily placebo plus weekly Deltaprim; or group PP. supplementation was given from 8 to 24 weeks of age, and the weekly chemoprophylaxis from 8 to 48 weeks. The frequency of severe anaemia (packed-cell volume < 25%) and malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys.
                The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron (0.62 vs 0.87 cases per person-year; protective efficacy 28.8% [95% CI 6.3-45.8). Iron supplementation had no effect on the frequency of malaria (0.87 vs 1.00 cases per person-year; protective efficacy 12.8% [-12.8 to 32.5]). The groups that received malaria prophylaxis had lower frequencies of both severe anaemia (0.45 vs 1.04 episodes per person-year; protective efficacy 57.3% [43.0-67.9]) and malaria (0.53 vs 1.34 episodes per person-year; protective efficacy 60.5% [48.2-69.9]) than the groups that did not receive prophylaxis. After the end of the intervention period, children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups (relative risks 2.2 [1.3-3.7] and 1.8 [1.3-2.6]).
                Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity. Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria. Our findings support iron supplementation of infants to prevent iron-deficiency anaemia, even in malaria-endemic areas. The impact of insecticide (permethrin)-treated bed nets (ITNs) on malaria in pregnancy was studied in a rural area in western Kenya with intense perennial malaria transmission. All households in 40 of 79 villages were randomized to receive ITNs by January 1997. The ITNs were distributed in control villages two years later. Complete data on birth outcome were available on 2,754 (89.6%) of 3,072 deliveries. Women (n = 780) were followed monthly throughout pregnancy in 19 of 79 villages. Among gravidae 1-4, ITNs were associated with reductions of 38% (95% confidence interval [CI] = 17-54%) in the incidence of malaria parasitemia and 47% (95% CI = 6-71%) in the incidence of severe malarial anemia (hemoglobin level < 8 g/dL with parasitemia) during pregnancy. At the time of delivery, mean hemoglobin levels were 0.6 g/dL (95% CI = 0.01-1.2 g/dL) higher, the prevalence of placental or maternal malaria was reduced by 35% (95% CI = 20-47%), and the prevalence of low birth weight was reduced by 28% (95% CI = 2-47%) in gravidae 1-4 from ITN villages. No beneficial impact was observed in gravidae five or higher. In areas of intense perennial malaria transmission, permethrin-treated bed nets reduce the adverse effect of malaria during the first four pregnancies. In areas of endemic transmission, malaria in pregnancy is associated with severe maternal anaemia and low-birthweight babies. We studied the efficacy of intermittent treatment doses of sulphadoxine-pyrimethamine in preventing malaria and severe anaemia in pregnancy in a double-blind placebo-controlled trial among primigravid women living in Kilifi District, Kenya.
                Between January, 1996, and April, 1997, 1264 primigravid women were recruited when they attended for antenatal care, and randomly assigned sulphadoxine-pyrimethamine (640) or placebo (624). Women received one, two, or three doses of study medication depending on the duration of gestation at enrolment. Primary outcome measures were severe anaemia (haemoglobin <8 g/dL) and malaria parasitaemia, assessed at 34 weeks of gestation. Analyses were based on intention to treat among women who had study blood tests at 34 weeks.
                30 (5.3%) of 567 women in the sulphadoxine-pyrimethamine group and 199 (35.3%) of 564 in the placebo group had peripheral parasitaemia (protective efficacy 85% [95% CI 78-90], p<0.0001). 82 (14.5%) and 134 (23.7%) had severe anaemia (protective efficacy 39% [22-52], p<0.0001). Even women who booked late and received only one dose of sulphadoxine-pyrimethamine benefited significantly from the intervention. The effects were seen both in women who owned insecticide-treated bednets and in women who did not.
                Intermittent presumptive treatment with sulphadoxine-pyrimethamine is an effective, practicable strategy to decrease the risk of severe anaemia in primigravidae living in malarious areas. A fever case management (CM) approach using sulfadoxine-pyrimethamine (SP) was compared with two presumptive intertmittent SP treatment regimens in the second and third trimesters in pregnant primigravidae and secundigravidae in an area of intense Plasmodium falciparum malaria transmission in western Kenya. The investigation evaluated efficacy of the antimalarial regimens for prevention of placental malaria and examined the effect of human immunodeficiency virus (HIV) infection on antimalarial drug efficacy and adverse drug reactions. Twenty-seven percent (93 of 343) of pregnant women in the CM group had placental malaria compared with 12% (38 of 330; P < 0.001) of women who received two doses of SP and compared with 9% (28 of 316; P < 0.001) of women who received monthly SP. Fourteen percent (49 of 341) of women in the CM group delivered low birth weight (LBW) infants compared with 8% (27 of 325; P=0.118) of women who received two doses of SP and compared with 8% (26 of 331; P=0.078) of women who received monthly SP. Seven percent (7 of 99) of the HIV-negative women on the two-dose SP regimen had placental malaria compared with 25% (10 of 39; P=0.007) of HIV-positive women on the same regimen; the rate of placental malaria in HIV-positive women was reduced to 7% (2 of 28; P=-0.051) for women on the monthly SP regimen. Less than 2% of women reported adverse drug reactions, with no statistically significant differences between HIV-positive and HIV-negative women. Intermittent treatment with SP is safe and efficacious for the prevention of placental malaria in pregnant primigravidae and secundigravidae in sub-Saharan Africa. While a two-dose SP regimen may be effective in areas with low HIV seroprevalence, administration of SP monthly during the second and third trimesters of pregnancy should be considered in areas of high HIV seroprevalence to prevent the effects of maternal malaria on the newborn. The impact of insecticide-treated bednet use on malaria and anaemia in pregnancy was assessed, as a supplementary study, in a major WHO/TDR-supported bednet trial in northern Ghana between July 1994 and April 1995. The study area was divided into 96 clusters of compounds, with 48 clusters being randomly allocated to intervention. All pregnant women were included in the study but the focus was on primigravidae and secundigravidae. 1961 pregnant women were recruited into the study--1033 (52.7%) in the treated bednet group and 928 (47.3%) in the no net group. 1806 (92.1%) had blood taken for malaria microscopy and haemoglobin determination in the third trimester. Pregnancy outcomes were reported for 847 women. The characteristics of women in intervention and control groups were comparable. The odds ratios, with 95% confidence interval (CI), for different study endpoints were, for Plasmodium falciparum parasitaemia--0.89 (0.73, 1.08), for anaemia--0.88 (0.70, 1.09), for low birthweight (LBW)--0.87 (0.63, 1.19), indicating no benefit for treated bednet use. Effective net use by parity varied from 42% in primigravidae to 63% in multigravidae, in spite of free nets and insecticide impregnation. The main reasons for not using a net were warm weather and perceived absence of mosquito biting. Chloroquine use in pregnancy was low and comparable in both groups. Implications of findings for malaria control in pregnancy and further research are discussed.
Chemoprophylaxis or IPT reduces antenatal parasite prevalence and placental malaria when given to women in all parity groups. They also have positive effects on birthweight and possibly on perinatal death in low-parity women.