Two-dose versus monthly intermittent preventive treatment of malaria with sulfadoxine-pyrimethamine in HIV-seropositive pregnant Zambian women

BACKGROUND: 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. METHODS: 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. RESULTS: 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.CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00270530.     

Effectiveness of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: An in silico pharmacological model

Objective: To explore the efficacy of intermittent preventive treatment in pregnancy(IPTp) with sulfadoxine and pyrimethamine(SP) against sensitive parasites. Methods: A pharmacological model was used to investigate the effectiveness of the previous recommended at least two-dose regimen, currently recommended three-dose regimen and 4, 6, 8-weekly regimens with specific focus on the impact of various nonadherence patterns in multiple transmission settings.Results: The effectiveness of the recommended three-dose regimen is high in all the transmission intensities, i.e. 99%, 98% and 92% in low, moderate and high transmission intensities respectively. The simulated 4 and 6 weekly IPTp-SP regimens were able to prevent new infections with sensitive parasites in almost all women(99%) regardless of transmission intensity. However, 8 weekly interval dose schedules were found to have 71% and 86% protective efficacies in high and moderate transmission areas, respectively. It highlights that patients are particularly vulnerable to acquiring new infections if IPTp-SP doses are missed.Conclusions: The pharmacological model predicts that full adherence to the currently recommended three-dose regimen should provide almost complete protection from malaria infection in moderate and high transmission regions. However, it also highlights that patients are particularly vulnerable to acquiring new infections if IPTp doses are spaced too widely or if doses are missed. Adherence to the recommended IPTp-SP schedules is recommended.     

Inferiority of single-dose sulfadoxine-pyrimethamine intermittent preventive therapy for malaria during pregnancy among HIV-positive Zambian women

BACKGROUND: The World Health Organization advocates 2-3 doses of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria (SP IPTp). The optimal number of doses and the consequences of single-dose therapy remain unclear.METHODS: Data were from a randomized, controlled study of human immunodeficiency virus-positive Zambian women comparing monthly versus 2-dose SP IPTp. We compared maternal and neonatal birth outcomes as a function of how many doses the mothers received (1 to > or =4 doses).RESULTS: Of 387 deliveries, 34 received 1 dose of SP. Single-dose SP was significantly associated with higher proportions of maternal anemia, peripheral and cord blood parasitemia, infant prematurity, and low birth weight. SP conferred dose-dependent benefits, particularly in the transition from 1 to 2 doses of SP. Women randomized to the standard 2-dose regimen were much more likely to receive only 1 dose than were women randomized to monthly IPT (relative risk, 16.4 [95% confidence interval, 4.0-68.3]).CONCLUSIONS: Single-dose SP was a common result of trying to implement the standard 2-dose regimen and was inferior to all other dosing regimens. At a programmatic level, this implies that monthly SP IPTp may ultimately be more effective than the standard regimen by reducing the risk of inadvertently underdosing mothers.     

Molecular markers of resistance to sulfadoxine-pyrimethamine during intermittent preventive treatment for malaria in Mozambican infants

BACKGROUND: Intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP) is a potential malaria control strategy. There is concern about the impact that increasing in vivo resistance to SP has on the efficacy of IPTi, as well as about the potential contribution of IPTi to increases in resistance. METHODS: We compared the frequency of clinical episodes of malaria caused by P. falciparum parasites with mutations in dhfr and dhps among sick children who received SP or placebo in the context of a randomized, double-blind, placebo-controlled IPTi trial in Mozambique. RESULTS: Half of the children who received placebo harbored quintuple-pure mutant parasites. Nevertheless, the protective efficacy of IPTi within the 35 days after the third dose was 70.8% (95% confidence interval [CI], 40.7%-85.6%). Between month 2 after the third IPTi dose and the end of the follow-up period, children receiving SP harbored more dhps codon 437 mixed infections (odds ratio [OR], 10.56 [95% CI, 1.30-86.14]) and fewer dhps double-pure mutant parasites (OR, 0.43 [95% CI, 0.22-0.84]) than did placebo recipients. CONCLUSIONS: IPTi appears to be associated with some changes in the prevalence of genotypes involved in SP resistance. In the face of a high prevalence of quintuple-mutant parasites, SP exhibited a high level of efficacy in the prevention of new episodes of malaria in infants.     

Community-based distribution of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy improved coverage but reduced antenatal attendance in southern Malawi

Objective  To evaluate the impact of a 2-year programme for community-based delivery of sulfadoxine-pyremethamine (SP) on intermittent preventive treatment during pregnancy coverage, antenatal clinic attendance and pregnancy outcome.
Methods  Fourteen intervention and 12 control villages in the catchment areas of Chikwawa and Ngabu Government Hospitals, southern Malawi, were selected. Village-based community health workers were trained in information, education and counselling on malaria control in pregnancy and the importance of attending antenatal clinics and promoted these messages to pregnant women. In the intervention group community health workers also distributed SP to pregnant women.
Results  In the control area, coverage of intermittent preventive treatment during pregnancy (>2 doses) was low before (44.1%) and during the intervention (46.1%). In the intervention area, coverage increased from 41.5% to 82.9% ( P  < 0.01). Antenatal clinic attendance (>2 visits) was maintained in control villages at above 90%, but fell in intervention villages from 87.3% to 51.5% ( P  < 0.01). Post-natal malaria parasitaemia prevalence fell in women from both study areas during the intervention phase ( P  < 0.05). Increasing the coverage of intermittent preventive treatment during pregnancy to >40% did not significantly improve maternal haemoglobin or reduce low birthweight prevalence.
Conclusions  Better coverage of community-based intermittent preventive treatment during pregnancy can lower attendance at antenatal clinics; thus its effect on pregnancy outcome and antenatal attendance need to be monitored.     

The effects of malaria and intermittent preventive treatment during pregnancy on fetal anemia in Malawi

Background.?Fetal anemia is common in malarious areas and is a risk factor for infant morbidity and mortality. Malaria during pregnancy may cause decreased cord hemoglobin (Hb) and fetal anemia among newborns. Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is protective against malaria but may also affect hematopoiesis and contribute to fetal anemia. Methods.?Peripheral, placental, and cord blood were examined for malaria parasitemia and Hb concentration in a cross-section of 3848 mothers and infants delivered at Queen Elizabeth Central Hospital in Blantyre, Malawi between 1997 and 2006. Unconditional linear and logistic regressions were performed with multiple imputation for missing covariates to assess the associations between malaria, IPTp with SP, and fetal anemia. Results.?The overall prevalence of fetal anemia was 7.9% (n?=?304). Malaria parasitemia at delivery was associated with an adjusted decrease in cord Hb of -0.24?g/dL (95% confidence interval [CI], -.42 to -.05). The adjusted prevalence odds ratio for the effect of malaria on fetal anemia was 1.41 (95% CI, 1.05-1.90). Primigravidae who did not take IPTp had infants at highest risk for fetal anemia, and density of parasitemia was correlated with the decrease in cord Hb. There was no significant association between SP use and cord Hb or fetal anemia. Conclusions.?Malaria during pregnancy, but not IPTp, decreases cord Hb and is a risk factor for fetal anemia in Malawi. Intermittent preventive treatment during pregnancy with SP may continue to be safe and effective in preventing malaria during pregnancy and fetal anemia despite development of SP resistance.     

Intermittent preventive treatment with sulfadoxine-pyrimethamine against malaria and anemia in pregnant women

The effectiveness of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) against malaria and anemia is unclear because of the spread of SP-resistant Plasmodium falciparum. This study evaluates the effectiveness of IPTp-SP among pregnant women attending the antenatal clinic at Korle-Bu Teaching Hospital in Accra, Ghana. A cross-sectional study comparing malaria and anemia prevalence among pregnant women using IPTp-SP with non-IPTp-SP users was conducted during June-August 2009. A total of 363 pregnant women (202 of IPTp users and 161 non-IPTp users) were recruited. A total of 15.3% of IPTp users had malaria compared with 44.7% of non-IPTp users (P < 0.001). A total of 58.4% of non-IPTp users were anemic compared with 22.8% of IPTp users (P < 0.001). When we controlled for other variables, the difference in the prevalence of malaria (odds ratio = 0.18, 95% confidence interval = 0.08-0.37) and anemia (odds ratio = 0.20, 95% confidence interval = 0.12-0.34) remained significant. The recommended IPTp-SP regimen is useful in preventing malaria and anemia among pregnant women in Ghana.     

Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Efficacy of intermittent preventive treatment versus chloroquine prophylaxis to prevent malaria during pregnancy in Benin

BACKGROUND: In West Africa, treatment for the prevention of malaria during pregnancy has recently changed from chloroquine (CQ) prophylaxis to intermittent preventive treatment (IPTp). We assessed the benefits of IPTp with respect to those of CQ, using a before-after study. METHODS: CQ efficacy was evaluated during a cross-sectional survey conducted in Benin between April 2004 and April 2005. IPTp efficacy was assessed using data from an ongoing clinical trial to compare sulfadoxine-pyrimethamine with mefloquine that began in the same maternity clinics during July 2005; the present analysis is limited to women who delivered between November 2005 and November 2006. Treatment assignments were not unblinded. We compared the efficacy of the 2 strategies against low birth weight and placental infection by performing multiple logistic regressions. RESULTS: A total of 1699 women (1090 in the CQ group and 609 in the IPTp group) who delivered live singletons were analyzed. Characteristics of women in the CQ group were similar to those of women in the IPTp group. We showed that women in the IPTp group had a significantly decreased risk of delivering an infant with a low birth weight (adjusted odds ratio [aOR], 0.54; 95% confidence interval [CI], 0.38-0.78) and placental infection (aOR, 0.15; 95% CI, 0.09-0.24). CONCLUSION: We clearly evidenced that IPTp is substantially more beneficial than CQ for the prevention of malaria during pregnancy.     

Implementation of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in Kisumu, western Kenya

OBJECTIVE: In 1998, the Kenyan Ministry of Health introduced intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP), one treatment dose in the second trimester (16-27 weeks) and one treatment dose between 28 and 34 weeks of gestational age, for the control of malaria in pregnancy. We evaluated the coverage and determinants of receipt of IPT after its introduction in the Provincial Hospital in Kisumu, western Kenya. METHODS: Information on the use of IPT in pregnancy was collected from women who attended the antenatal clinic (ANC) and delivered in the same hospital. In exit interviews, we assessed patterns of IPT use in the ANC. RESULTS: Of 1498 women who delivered between June 1999 and June 2000, 23.7%, 43.4% and 32.9% received > or =2, 1 or no dose of SP, respectively. Late first ANC attendance was the most important factor contributing to incomplete IPT; 45% of the women started attending ANC in the third trimester. More women received at least one tetanus toxoid immunization than at least one dose of IPT (94%vs. 67%, P < 0.05). In exit interviews, 74% correctly associated IPT with treatment of malaria; however, knowledge on the need for the second dose was poor. Three per cent of the administrations were given despite contraindications. The agreement between gestational age by date of last menstrual period and by palpation was low (kappa = 0.1). CONCLUSIONS: Education of pregnant women and ANC staff to increase earlier attendance for ANC has the potential to substantially increase the proportion of women receiving two doses of IPT with SP.     

Follow-up survey of children who received sulfadoxine-pyrimethamine for intermittent preventive antimalarial treatment in infants

Recently, the World Health Organization emphasized the potential benefit of intermittent preventive treatment in infants (IPTi) to control malaria and officially recommended implementation of IPTi with sulfadoxine-pyrimethamine (SP) in areas with moderate and high transmission, where SP resistance is not high. As reported rebound effects make further observation mandatory, we performed a survey of participants of a former IPTi trial. Malariometric parameters were similar in the SP and the placebo group. In contrast, anti-Plasmodium falciparum lysate immunoglobulin G antibody levels, a proxy measure for preceding malaria episodes, remained lower in the SP arm. The most likely explanation is a lower overall exposure to parasitic antigens after IPTi.     

The effect of health care worker training on the use of intermittent preventive treatment for malaria in pregnancy in rural western Kenya

BACKGROUND: In 1998, Kenya adopted intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) for malaria prevention during pregnancy. We conducted a survey in 2002 among women who had recently delivered in the rural neighbouring areas Asembo and Gem and reported coverage of 19% of at least one dose and 7% of two or more doses of SP. Health care workers (HCW) in Asembo were retrained on IPTp in 2003. OBJECTIVES: To evaluate if IPTp coverage increased and if the training in Asembo led to better coverage than in Gem, and to identify barriers to the effective implementation of IPTp. METHODS: Community-based cross-sectional survey among a simple random sample of women who had recently delivered in April 2005, interviews with HCW of antenatal clinics (ANC) in Asembo and Gem. RESULTS: Of the 724 women interviewed, 626 (86.5%) attended the ANC once and 516 (71.3%) attended two or more times. Overall IPTp coverage was 41% for at least one dose, and 21% for at least two doses of SP. In Asembo, coverage increased from 19% in 2002 to 61% in 2005 for at least one dose and from 7% to 17% for two doses of SP. In Gem, coverage increased from 17% to 28% and 7% to 11%, respectively. Interviews of HCW in both Asembo and Gem revealed confusion about appropriate timing, and lack of direct observation of IPTp. CONCLUSION: Training of HCW and use of simplified IPTp messages may be a key strategy in achieving Roll Back Malaria targets for malaria prevention in pregnancy in Kenya.     

Effectiveness of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in western Kenya: a hospital-based study

OBJECTIVE: To monitor the effectiveness of intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) for the control of malaria in pregnancy at delivery in the Provincial Hospital in Kisumu, Kenya, and to assess the effect of IPT in participants in a cohort study. METHODS: Between June 1999 and June 2000, information on IPT and birth outcome was collected in 2302 consecutive deliveries. A group of 889 women, who were enrolled in a cohort to assess the interaction between malaria and HIV, were analysed separately because of the enrollment criteria and different access to health care. RESULTS: The prevalence of placental malaria was 13.8% and of low birthweight (LBW) was 12.2%. In multivariable analysis, IPT (> or =1 dose of SP) was associated with a reduction in placental malaria and LBW [adjusted odds ratio (OR) 0.56, 95% confidence interval (CI) 0.39-0.83 and OR 0.65, 95% CI 0.45-0.95, respectively]. An adjusted mean increase in birthweight of 61 g was seen (95% CI 22-101 g) for each increment in number of SP doses (> or =2 doses grouped together). IPT was associated with a reduction in placental malaria in HIV-seronegative women (OR 0.49, 95% CI 0.28-0.86) but this was not significant among HIV-seropositive women (OR 0.45, 95% CI 0.20-1.05). A significant effect on birthweight could not be detected among participants in the HIV-cohort. CONCLUSIONS: This evaluation confirms that IPT with SP is effective in reducing placental malaria and LBW. It will be important to increase coverage of IPT and to extend IPT to antenatal clinics in peri-urban and rural areas.