Individual efficacy of intermittent preventive treatment with sulfadoxine–pyrimethamine in primi- and secundigravidae in rural Burkina Faso: impact on parasitaemia, anaemia and birth weight

Objective To assess the efficacy at individual level of intermittent preventive treatment with sulfadoxine–pyrimethamine (IPTp‐SP) in primi‐ and secundigravidae in rural Burkina Faso. Methods Data of 1441 women enrolled in a health centre randomized trial and delivering a live‐singleton between September 2004 and October 2006 were analysed at individual level. Prevalence of peripheral and placental parasitaemia, anaemia (PCV <33%), low‐birth weight (<2500 g; LBW), mean packed cell volume (PCV) and birth weight were compared in relation to the number of directly observed SP doses. Results Two or more doses of SP significantly reduced the risk of placental parasitaemia [adjusted odds ratio (AOR) = 0.04, 95%CI = 0.003–0.60, P = 0.023] and anaemia at delivery (AOR = 0.31, 95%CI = 0.18–0.52, P < 0.001). IPTp was associated with reduced risk of LBW in primigravidae (AOR = 0.11, 95%CI = 0.07–0.17, P < 0.001) but not secundigravidae (AOR = 0.70, 95%CI = 0.26–1.91, P = 0.452). For each increment in number of SP doses mean PCV increased by 1.0% (95%CI = 0.4–1.7, P = 0.005) at 32 weeks gestation, by 1.2% (95%CI = 0.2–2.2, P = 0.025) at delivery and mean birth weight by 220 g (95%CI = 134–306 P < 0.001) in primigravidae and by 102 g (95%CI = 55–148, P = 0.001) in secundigravidae. Conclusion The risk of malaria infection was significantly reduced by IPTp with SP in primi‐ and secundigravidae in rural Burkina Faso. The impact on clinical outcomes is lower and mainly limited to primigravidae for LBW. Incomplete uptake of IPTp‐SP and limited effect in low risk groups together may substantially dilute the measurable impact of effective interventions. This needs to be taken into account when evaluating interventions at community level.     

Mother-to-child transmission of HIV-1: association with malaria prevention, anaemia and placental malaria

Objectives

Malaria infection may impact on mother‐to‐child transmission (MTCT) of HIV‐1. Prevention of malaria in pregnancy could thus potentially affect MTCT of HIV. We studied the impact of intermittent preventive treatment during pregnancy (IPTp) on HIV‐1 MTCT in southern Mozambique.

Methods

A total of 207 HIV‐positive Mozambican pregnant women were enrolled in the study as part of a randomized placebo‐controlled trial of two‐dose sulfadoxine‐pyrimethamine (SP) IPTp in women receiving single‐dose nevirapine to prevent MTCT of HIV. HIV RNA viral load, maternal anaemia and peripheral and placental malaria were assessed at delivery. Infant HIV status was determined by DNA polymerase chain reaction (PCR) at 1 month of age.

Results

There were 19 transmissions of HIV in 153 mother–infant pairs. IPTp with SP did not have a significant impact on MTCT (11.8% in the SP group vs. 13.2% in the placebo group; P=0.784) or on maternal HIV RNA viral load [16 312 (interquartile range {IQR} 4076–69 296) HIV‐1 RNA copies/mL in the SP group vs. 18 274 (IQR 5471–74 104) copies/mL in the placebo group; P=0.715]. In multivariate analysis, maternal HIV RNA viral load [adjusted odds ratio (AOR) 19.9; 95% confidence interval (CI) 2.3–172; P=0.006] and anaemia (haematocrit <33%; AOR 7.5; 95% CI 1.7–32.4; P=0.007) were independent risk factors for MTCT. Placental malaria was associated with a decrease in MTCT (AOR 0.23; 95% CI 0.06–0.89; P=0.034).

Conclusions

IPTp with SP was not associated with a significant impact on MTCT of HIV. Maternal anaemia was an independent risk factor for MTCT.     

Prevention of malaria during pregnancy: assessing the effect of the distribution of IPTp through the national policy in Benin

The efficiency of malaria prevention during pregnancy was compared between three studies in Benin for malaria infection of the placenta (MIP) and low birth weight (LBW). The first was carried out when chloroquine prophylaxis was still recommended, the second was an intermittent preventive treatment in pregnancy (IPTp) clinical trial comparing sulfadoxine pyrimetamine (SP) versus mefloquine, and the third was an observational study after SP-IPTp national implementation. We showed an association between the use of IPTp and the reduction of LBW (10% with national IPTp and 8.7% in IPTp trial versus 15.7% in pre-trial study). The effect on MIP was better in the trial (2.9% versus 11.2% and 16.7% for national IPTp and pre-trial studies, respectively). In spite of a good overall compliance with the national IPTp (with 84% of women taking at least one dose of SP), there are still failures in adherence to the directly observed therapy (DOT) scheme and needs for better training of health staff.     

Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment

Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.     

Access and barriers to measures targeted to prevent malaria in pregnancy in rural Kenya

Objectives To evaluate barriers preventing pregnant women from using insecticide‐treated nets (ITN) and intermittent presumptive treatment (IPT) with sulphadoxine‐pyrimethamine (SP) 5 years after the launch of the national malaria strategy promoting these measures in Kenya. Methods All women aged 15–49 years were interviewed during a community survey in four districts between December 2006 and January 2007. Women pregnant in the last 12 months were asked about their age, parity, education, use of nets, ITN, antenatal care (ANC) services and sulphadoxine‐pyrimethamine (SP) (overall and for IPT) during pregnancy. Homestead assets were recorded and used to develop a wealth index. Travel time to ANC clinics was computed using a geographic information system algorithm. Predictors of net and IPT use were defined using multivariate logistic regression. Results Overall 68% of pregnant women used a net; 52% used an ITN; 84% attended an ANC clinic at least once and 74% at least twice. Fifty‐three percent of women took at least one dose of IPT‐SP, however only 22% took two or more doses. Women from the least poor homesteads (OR = 2.53, 1.36–4.68) and those who used IPT services (OR = 1.73, 1.24–2.42) were more likely to sleep under any net. Women who used IPT were more likely to use ITNs (OR = 1.35, 1.03–1.77), while those who lived more than an hour from an ANC clinic were less likely (OR = 0.61, 0.46–0.81) to use ITN. Women with formal education (1.47, 1.01–2.17) and those who used ITN (OR: 1.68, 1.20–2.36) were more likely to have received at least one dose of IPT‐SP. Conclusion Although the use of ITN had increased 10‐fold and the use of IPT fourfold since last measured in 2001, coverage remains low. Provider practices in the delivery of protective measures against malaria must change, supported by community awareness campaigns on the importance of mothers’ use of IPT.     

Short report: molecular markers associated with Plasmodium falciparum resistance to sulfadoxine-pyrimethamine in the Democratic Republic of Congo

Sulfadoxine-pyrimethamine (SP) is the first line antimalarial treatment in the Democratic Republic of Congo. Using polymerase chain reaction, we assessed the prevalence of mutations in the dihydrofolate reductase (dhfr) (codons 108, 51, 59) and dihydropteroate synthase (dhps) (codons 437, 540) genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulfadoxine, respectively. Four hundred seventy-four patients were sampled in Kilwa (N = 138), Kisangani (N = 112), Boende (N = 106), and Basankusu (N = 118). The proportion of triple mutations dhfr varied between sites but was always > 50%. The proportion of dhps double mutations was < 20%, with some sites as low as 0.9%. A quintuple mutation was present in 12.8% (16/125) samples in Kilwa; 11.9% (13/109) in Kisangani, 2.9% (3/102) in Boende, and 0.9% (1/112) in Basankusu. These results suggest high resistance to pyrimethamine alone or combined with sulfadoxine. Adding artesunate to SP does not seem a valid alternative to the current monotherapy.     

dhfr and dhps genotype and sulfadoxine‐pyrimethamine treatment failure in children with falciparum malaria in the Democratic Republic of Congo

Objective To determine the relationship between mutations in dhfr and dhps and SP treatment failure in Plasmodium falciparum malaria in the Democratic Republic of the Congo (DRC). Methods Therapeutic efficacy trial was conducted in Rutshuru, Eastern DRC, between June and September 2002, comparing sulfadoxine‐pyrimethamine (SP), SP plus amodiaquine (AQSP) and artesunate plus SP (ASSP) regimens for treating malaria in children under 5 years old. We genotyped 212 samples for mutations associated with SP resistance and investigated their association with treatment failure. Results In the SP arm, 61% of the subjects experienced treatment failure after 14 days. The failure rate was lower in the combination arms (AQSP: 32%, ASSP: 21%). The dhfr‐108 and dhfr‐51 mutations were nearly universal while 89% of the samples had at least one additional mutation at dhfr‐59, dhps‐437 or dhps‐540. Dhps mutations had a bigger impact on treatment failure in children with high parasite density: for children with a parasite density <45 000 parasites/μl, the risk of treatment failure was 37% for mutations at dhps‐437 and dhps‐540 mutation and 21% for neither mutation [risk difference (RD) = 17%, 95% CI: ?3%, 36%]. In children with a parasite density >45 000 parasites/μl, the treatment failure risk was 58% and 8% for children with both mutations or neither mutation, respectively (RD = 51%, 95% CI: 34%, 67%). Conclusions Dhps‐437 and dhps‐540 are strongly associated with SP treatment failure and should be evaluated further as a method for surveillance of SP‐based therapy in DRC.     

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.     

Malaria prevention during pregnancy: assessing the disease burden one year after implementing a program of intermittent preventive treatment in Koupela District, Burkina Faso

The World Health Organization recommends that pregnant women in malaria-endemic areas receive >or= 2 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp/SP) in the second and third trimesters of pregnancy to prevent maternal anemia, placental parasitemia, and low birth weight (LBW). In 2001, a program evaluation in Koupéla District, Burkina Faso demonstrated that despite widespread use of chloroquine chemoprophylaxis, the burden of malaria during pregnancy remained high. In 2003, the Burkina Faso Ministry of Health piloted a program of IPTp/SP (three doses) and accelerated distribution of insecticide-treated nets (ITN) to pregnant women in Koupéla District. In 2004, a follow-up program evaluation was conducted. Coverage with >or= 1 doses of IPTp/SP was high among women attending antenatal clinics (ANCs) (96.2%) and delivery units (DUs) (93.5%); ITN ownership was moderately high (ANC = 53.9%, DU = 61.6%). In multivariate analysis, >or= 1 dose of IPTp/SP was associated with a significant reduction in the prevalence of peripheral parasitemia at ANCs (risk ratio [RR] = 0.49, P = 0.008), >or= 2 doses of IPTp/SP were associated with a reduction in the prevalence of placental parasitemia (RR = 0.56, P = 0.02), and three doses of IPTp/SP were associated with a reduced risk of LBW (RR = 0.51, P = 0.04). The proportions of women at ANCs with peripheral parasitemia and anemia were significantly lower in 2004 than in 2001 (RR = 0.53, P = 0.001 and RR = 0.78, P = 0.003, respectively). The proportions of women at DUs with peripheral and placental parasitemia were also significantly lower in 2004 than in 2001 (RR = 0.66, P < 0.0001 and RR = 0.71, P = 0.0002, respectively). These data suggest that a package of IPTp/SP and ITNs is effective in reducing the burden of malaria during pregnancy in Burkina Faso.     

Mefloquine versus Sulfadoxine–Pyrimethamine for Intermittent Preventive Treatment in Pregnancy: A Joint Analysis on Efficacy and Tolerability

Since there is no ideal candidate to replace sulfadoxine–pyrimethamine (SP) for intermittent preventive treatment (IPTp), alternatives need to be evaluated on basis of their benefit–risk ratio. We reanalyzed the first Beninese trial on mefloquine (MQ) versus SP for IPTp using a multiple outcome approach, which allowed the joint assessment of efficacy and tolerability. Overall superiority of MQ to SP was defined as superiority on at least one efficacy outcome (low birth weight [LBW], placental malaria, or maternal anemia), non-inferiority on all of them as well as on tolerability defined as cutaneous or neuropsychiatric adverse events (AEs) or low compliance with the treatment. The analysis included 1,601 women. MQ was found to be overall superior to SP (P = 0.004). Performing several sensitivity analyses to handle both missing data and stillbirths provided similar results. Using MQ for IPTp as an example, we show that a multiple outcome analysis is a pragmatic way to assess the benefits/disadvantages of one drug compared with another. In the current context of a lack of antimalarials that could be used for IPTp, such a statistical approach could be widely used by institutional policy makers for future recommendations regarding the prevention of malaria in pregnancy (MiP).     

Lack of inhibition of the anti-malarial action of sulfadoxine-pyrimethamine by folic acid supplementation when used for intermittent preventive treatment in Gambian primigravidae

Folic acid is frequently given to pregnant women at the same time as intermittent preventive treatment (IPTp) with sulfadoxine/pyrimethamine (SP), but it is not known if it interferes with the anti-malarial activity of SP. To investigate this concern, 1,035 Gambian primigravidae were randomized to receive either folic acid (500-1,500 microg/day) together with oral iron (522) or oral iron alone (513) for 14 days at the same time as they received IPTp with SP. On presentation, 261 women (25%) had Plasmodium falciparum asexual parasitemia. Prevalences of parasitemia on day 14 after treatment were similar in both groups: 5.7% (26 of 458) in the iron plus folic acid group and 4.9% (22 of 446) in the iron alone group (risk difference = 0.74%, 95% confidence interval [CI] = -2.2% to 3.7%). Parasitologic cure was observed in 116 (91%) of 128 of women who were parasitemic on presentation and who received iron and folic acid and in 122 (92%) of 133 women who received iron alone (difference = 1.1%, 95% CI = -5.6% to 8.0%). Women who received folic acid and iron had a slightly higher mean hemoglobin concentration at day 14 than women who had received iron alone (difference = 0.14 g/dL, 95% CI = 0.01-0.27 g/dL). The results of this study suggest that in an area of low SP resistance, administration of folic acid to pregnant women in a dose of 500-1,500 mug/day will not interfere with the protective effect of SP when used for IPTp.     

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.     

A randomized, placebo-controlled trial of intermittent preventive treatment with sulphadoxine-pyrimethamine in Gambian multigravidae

We investigated the ability of intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine/pyrimethamine to prevent anaemia and low birthweight in Gambian multigravidae. Between July 2002 and February 2004, 2688 multigravidae living in a rural area of The Gambia received SP (1346 women) or placebo (1342 women) up to four times during pregnancy and were followed until 6-weeks post-partum. Shortly after delivery, 10.7% of women in the intervention group and 8.8% in the control group were severely anaemic [Hb < 7 g/dl, risk difference = 0.02 (95% CI -0.01, 0.04), P = 0.17]. The overall mean birthweight of infants born to women who had received SP (3103 g) was very similar to that observed in infants born to women in the control group [3075 g; difference = 28 g (95% CI -11 g, 67 g), P = 0.16]. However, among women who did not use a bednet (either insecticide treated or untreated), infants born to women who had received SP weighed more than infants born to women in the control group [3147 g vs. 3044 g; difference 143 g (95% CI 53 g, 232 g), interaction test P < 0.001]. This study did not show that IPTp with SP benefited Gambian multigravidae overall but that it may benefit a sub-group of women who do not use a bednet. In areas such as The Gambia, provision of insecticide-treated bednets to multigravidae may provide an adequate means of protection against malaria in pregnancy without the need for additional IPTp.     

In vivo efficacy study of amodiaquine and sulfadoxine/ pyrimethamine in Kibwezi, Kenya and Kigoma, Tanzania

We conducted two randomized clinical trials to determine the in vivo efficacy of amodiaquine and sulfadoxine/pyrimethamine in treating Plasmodium falciparum malaria. Seventy-five patients under the age of 10 years in Kibwezi, Kenya, and 171 patients in Kigoma, Tanzania, were enrolled for treatment. Due to loss of eight patients in Kibwezi and 37 in Kigoma to follow-up, we used best and worst case scenarios for the parasitological response. The in vivo sensitivity of Plasmodium falciparum to amodiaquine was 75% (no loss to follow-up) in Kibwezi and ranged from 85% in the best to 65% in the worst case scenario in Kigoma. The sensitivity to sulfadoxine/pyrimethamine was 70% to 88% in Kibwezi and 65% to 89% in Kigoma. R1 resistance to amodiaquine was 22% in Kibwezi and varied from 6% in the best to 26% for the worst case scenario in Kigoma. The R1 resistance to sulfadoxine/pyrimethamine was 5% to 23% in Kibwezi and 2% to 26% in Kigoma. R2 resistance was 3% for amodiaquine and 7% for sulfadoxine/pyrimethamine in Kibwezi and 9% in Kigoma for each treatment group. There was no statistically significant difference between treatment groups at either study site, except for a slight difference in R1 resistance in the best case scenario, Kibwezi, in favour of S/P. Although both amodiaquine and sulfadoxine/pyrimethamine resistance seems to be increasing, these antimalarials are still effective in parasite clearance.     

The effects of a pre-season treatment with effective antimalarials on subsequent malaria morbidity in under five-year-old children living in high and seasonal malaria transmission area of Burkina Faso

Objectives To evaluate the effects of pre‐season treatment with single dose of sulfadoxine‐pyrimethamine (SP) or artemether‐lumefantrine (AL) on subsequent malaria morbidity in under‐fives. Methods A cohort of 156 children was enrolled for longitudinal follow‐up. Children received curative therapy with SP or AL, and a third group received no treatment. Participants were home‐visited twice a week with blood smears taken from children with fever (axillary T°≥37.5 °C) or history of fever. To assess the time to re‐infection, a blood film was also systematically obtained from pre‐treated children every 2 weeks. Results The mean time to the first malaria infection was 36 days in the SP arm and 26 days in the AL arm (P = 0.006). The incidence density of malaria infection was similar in both groups (86.5%vs. 92.3%, P = 0.52). The mean time to the first malaria episode was 47 days in the SP arm and 32 days in the AL arm (P < 0.001). The incidence of malaria episodes was significantly higher in the group pre‐treated with AL (45.7 per 1000 child days‐at‐risk CI 95% [35–56]) than in the control group (10.7 per 1000 child days‐at‐risk CI 95% [7–15]); P < 0.001). Conclusions Our findings suggest that the radical clearance of parasitemia with AL may increase susceptibility to malaria infection and clinical malaria episodes.     

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.     

Intermittent preventive treatment of malaria in pregnancy: at the crossroads of public health policy

The intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) has been a key component of the focused antenatal care package for nearly a decade, reducing the burden of low birthweight attributable to malaria in sub-Saharan Africa. However, SP has lost parasite sensitivity in many sub-Saharan locations during the same period, rendering its beneficial effect in IPTp debatable. Malaria transmission has also declined in some epidemiological settings. There is no evidence to suggest, however, that the risk of malaria in pregnancy without preventive measures has declined in the same locations. Thus, the urgency to identify efficacious drugs and/or new strategies to prevent malaria in pregnancy remains as great as ever. We summarise the results of recently published SP-IPTp studies from areas of high drug resistance and/or low malaria transmission. We also present the evidence for mefloquine and azithromycin-based combinations (ABCs), two leading drug options to replace SP in IPTp. We discuss optimal dosing for ABCs and their likely protection against several sexually transmitted and reproductive tract infections. We also summarise data from a diagnosis-based alternative to IPTp known as the intermittent screening and treatment (IST) for malaria. Clinical and operational research is urgently needed to compare birth outcomes achieved by IPTp with ABCs vs. IST using an efficacious antimalarial therapy.     

Pharmacokinetics of sulfadoxine-pyrimethamine in HIV-infected and uninfected pregnant women in Western Kenya

BACKGROUND: Sulfadoxine-pyrimethamine (SP) is among the most commonly used antimalarial drugs during pregnancy, yet the pharmacokinetics of SP are unknown in pregnant women. HIV-infected (HIV(+)) women require more frequent doses of intermittent preventive therapy with SP than do HIV-uninfected (HIV(-)) women. We investigated whether this reflects their impaired immunity or an HIV-associated alteration in the disposition of SP. METHODS: Seventeen pregnant HIV(-) women and 16 pregnant HIV(+) women received a dose of 1500 mg of sulfadoxine and 75 mg of pyrimethamine. Five HIV(-) and 6 HIV(+) postpartum women returned 2-3 months after delivery for another dose. The pharmacokinetics of sulfadoxine and pyrimethamine were compared between these groups. RESULTS: HIV status did not affect the area under the curve (AUC(0-->infinity)) or the half-lives of sulfadoxine or pyrimethamine in prepartum or postpartum women, although partum status did have a significant affect on sulfadoxine pharmacokinetics. Among prepartum women, the median half-life for sulfadoxine was significantly shorter than that observed in postpartum women (148 vs 256 h; P<.001), and the median AUC(0-->infinity) was ~40% lower (22,816 vs 40,106 microg/mL/h, P<.001). HIV status and partum status did not show any significant influence on pyrimethamine pharmacokinetics. CONCLUSION: Pregnancy significantly modifies the disposition of SP, whereas HIV status has little influence on pharmacokinetic parameters in pregnant women.     

Translation of artemether-lumefantrine treatment policy into paediatric clinical practice: an early experience from Kenya

Objective To describe the quality of outpatient paediatric malaria case‐management approximately 4–6 months after artemether–lumefantrine (AL) replaced sulfadoxine–pyrimethamine (SP) as the nationally recommended first‐line therapy in Kenya. Methods Cross‐sectional survey at all government facilities in four Kenyan districts. Main outcome measures were health facility and health worker readiness to implement AL policy; quality of antimalarial prescribing, counselling and drug dispensing in comparison with national guidelines; and factors influencing AL prescribing for treatment of uncomplicated malaria in under‐fives. Results We evaluated 193 facilities, 227 health workers and 1533 sick‐child consultations. Health facility and health worker readiness was variable: 89% of facilities stocked AL, 55% of health workers had access to guidelines, 46% received in‐service training on AL and only 1% of facilities had AL wall charts. Of 940 children who needed AL treatment, AL was prescribed for 26%, amodiaquine for 39%, SP for 4%, various other antimalarials for 8% and 23% of children left the facility without any antimalarial prescribed. When AL was prescribed, 92% of children were prescribed correct weight‐specific dose. AL dispensing and counselling tasks were variably performed. Higher health worker’s cadre, in‐service training including AL use, positive malaria test, main complaint of fever and high temperature were associated with better prescribing. Conclusions Changes in clinical practices at the point of care might take longer than anticipated. Delivery of successful interventions and their scaling up to increase coverage are important during this process; however, this should be accompanied by rigorous research evaluations, corrective actions on existing interventions and testing cost‐effectiveness of novel interventions capable of improving and maintaining health worker performance and health systems to deliver artemisinin‐based combination therapy in Africa.     

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.