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Background Four studies previously indicated that the effect of malaria infection during pregnancy on the risk of low birthweight (LBW, In a meta-analysis using individual participant data, Jordan Cates and colleagues explore potential interactions between malaria and nutrition during pregnancy and their associations with low birthweight., Author summary Why was this study done? More than 125 million pregnant women are at risk of malaria in pregnancy annually, producing detrimental effects on maternal, newborn, and infant health. Maternal undernutrition is estimated to be responsible for 800,000 newborn deaths annually. Prior evidence from 4 small studies indicated that the harmful impact of malaria on fetal growth and birthweight (BW) may depend upon the macronutrient nutritional status of the mother. If malaria and maternal undernutrition have synergistic negative impacts on pregnancy outcomes, interventions targeted to high-risk women might provide substantial public benefit. The present study provides a robust assessment of potential malaria–nutrition interactions in pregnancy and overcomes size and methodological limitations of earlier exploratory studies. What did the researchers do and find? We present a large, pooled analysis of individual participant data from 13 studies conducted in sub-Saharan Africa and the Western Pacific investigating the interaction between maternal malaria infection and malnutrition on the risk of low birthweight (LBW) and reduced mean BW. The findings suggest that women who are both infected with malaria and malnourished are at greater risk of LBW than their uninfected, well-nourished counterparts. However, the study found no conclusive evidence of interaction between the 2, i.e., the impact of malaria on BW was independent of the macronutrient nutritional status of the mother. Subgroup analyses did find that studies conducted just in Africa had slight evidence of interaction, but this was not consistent throughout all analyses. What do these findings mean? Although there was no overall evidence of malaria–nutrition interactions, more than 1 in 3 pregnant women suffered from malaria and/or undernutrition, emphasizing the importance of joint approaches to decrease maternal malaria and improve nutrition to minimize adverse pregnancy outcomes.

Purpose \ud The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria–nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists.\ud \ud Participants \ud Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015.\ud \ud Findings to date \ud Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort.\ud \ud Future plans \ud This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria–nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective.

Objective: To compare the frequency and etiology of diarrhea in children aged less than 2 years with known HIV status. Methods: This was a nested cohort study, whereby children were followed during monthly routine and unscheduled visits. The HIV status of children was determined with PCR. A stool culture was obtained from children with diarrhea. A subset of stool samples was examined for parasites and tested for rotavirus. Results: Between 1997 and 2001, 682 children (51.0% male) contributed observation periods with a mean of 47 weeks. Overall there were 198 episodes of diarrhea per 100 child-years of observation (CYO); diarrhea was more common among HIV-positive children than among HIV-negative children (321 vs. 183 episodes/100 CYO, respectively, p < 0.01) and was not statistically different for HIV-negative children born to HIV-positive compared with HIV-negative mothers (182 vs. 187 episodes/100 CYO, respectively, p = 0.36). For 66.5% of the acute episodes a stool culture was obtained; 27.8% of stool cultures yielded a bacterial pathogen. A positive stool culture was less likely among HIV-positive children compared to children of HIV-negative mothers (20.5% vs. 34.3%, p = 0.01). Susceptibility of Salmonella and Shigella to commonly used antibiotics was low. Rotavirus was detected in 13.9% of 202 examined stool samples, and a stool parasite in 3.8% of 394 samples. Diarrhea was associated with 37.8% of child deaths. Conclusions: Diarrhea was more common among HIV-infected children, but was not associated with specific bacterial pathogens. Measures that reduce diarrhea will benefit all children, but may benefit HIV-infected children in particular. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases

Background. Placental malaria (PM) and maternal infection with human immunodeficiency virus (HIV) type 1 have been shown to affect infant morbidity and immune responses to Plasmodium falciparum. We studied the effects of PM and HIV infection on the antimalarial antibody responses and morbidity outcomes of infants throughout the first year of life.Methods. A total of 411 Kenyan infants who were born to mothers who were singly or dually infected with PM and/or HIV had their levels of immunoglobulin G antibody to 6 P. falciparum antigens/epitopes (apical membrane antigen-1, erythrocyte-binding antigen-175; liver-stage antigen-1 [LSA-1], circumsporozoite protein [CSP], merozoite surface protein-2, and rhoptry-associated protein-1 [RAP-1]) and to tetanus toxoid (TT) tested using enzyme-linked immunosorbent assay.Results. PM had little effect on the antibody responses of infants, whereas maternal HIV infection resulted in decreased levels of antibody to LSA-1, CSP, and RAP-1 epitopes at birth, compared with the absence of PM and maternal HIV infection (P < .0063). Levels of antibodies to TT were significantly reduced in infants born to mothers coinfected with HIV and PM, compared with the levels noted in infants born to HIV-negative mothers (P < .0003). In HIV-infected infants, levels of antibody to TT were reduced, but levels of antibody to malarial antigens were not. Antimalarial antibody levels were positively associated with malaria-related morbidity outcomes.Conclusion. Infant HIV infection and maternal coinfection with HIV and PM negatively influence antibody responses to TT, but not those to malarial antigens, in infants. Antimalarial antibodies rarely showed protective associations with morbidity in infants and were more often a marker for malaria exposure and risk of infection.

OBJECTIVE To determine the prevalence of malaria and anaemia among urban and peri-urban women attending their first antenatal clinic (ANC) in an area of perennial malaria transmission. METHODS Between November 2003 and May 2004 we screened first ANC attenders for malaria and anaemia in a large urban hospital in Kisumu (western Kenya) and interviewed them to obtain demographic and medical information. RESULTS Among the 685 study participants, prevalence of malaria parasitaemia was 18.0%, prevalence of any anaemia (haemoglobin < 11 g/dl) was 69.1% and prevalence of moderate anaemia was (haemoglobin < 8 g/dl) 11.8%. Sixteen women were hospitalized during pregnancy, eight because of malaria. In multivariate analysis, young age, living in a house with mud walls, a visit to rural area, peri-urban residence, second trimester of pregnancy and Luo ethnicity were significant risk factors for malaria parasitaemia. Malaria was an important risk factor for any and moderate anaemia; use of an insecticide-treated net (ITN) was a protective factor for any anaemia. Married women with a higher level of education, better-quality housing and full-time employment were more likely to use an ITN. CONCLUSION Malaria and anaemia are established problems by the time of the first ANC visit. Mechanisms to deliver ITNs to women of child-bearing age before they become pregnant need to be explored. Early ANC visits are warranted in order for women to benefit from policies aimed at reducing the burden of malaria and anaemia.

Background. HIV and malaria in sub-Saharan Africa are associated with poor pregnancy outcome and infant survival. We studied the association of placental malaria, infant malaria and anemia, and infant HIV status with postneonatal infant mortality (PNIM) among infants of HIV-seropositive women. Methods. During 1996–2001, infants born to 570 HIV-seropositive mothers in Kisumu, Kenya were monitored monthly for malaria (parasitemia or clinical malaria) and anemia (hemoglobin level !8 g/dL) and vital status. Results. Thirty-nine deaths occurred among 112 HIV-positive infants (420/1000 live births [LBs] [95% confidence interval {CI}, 318–522 LBs]), and 36 occurred among 458 HIV-negative infants (99/1000 LBs [95% CI, 68–130 LBs]) ( ). In multivariate Cox regression analysis among HIV-negative infants, PNIM was associated P ! .001 with infant anemia (adjusted hazard ratio [AHR], 5.03 [95% CI, 1.97–12.81]) but not with placental malaria (AHR, 1.22 [95% CI, 0.50–2.95]) or infant malaria (AHR, 0.35 [95% CI, 0.10–1.21]). Among HIV-positive infants, neither placental malaria (AHR, 0.34 [95% CI, 0.10–1.10]) nor infant malaria (AHR, 0.31 [95% CI, 0.07–1.33]) or anemia (AHR, 1.07 [95% CI, 0.32–3.61]) was significantly associated with PNIM. Conclusion. In this study population, placental malaria and infant parasitemia were not risk factors for PNIM among infants of HIV-seropositive women. The prevention of infant anemia may decrease PNIM among HIVnegative infants of HIV-seropositive women.

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. The objectives were 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. 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. 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. 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. (authors)

OBJECTIVE To evaluate the effect of routine antenatal haematinic supplementation programmes and intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) in Kenya. METHODS Anaemia [haemoglobin (Hb) < 11 g/dl), severe anaemia (Hb < 8 g/dl) and placental malaria were compared among women with known HIV status who delivered at a provincial hospital after study enrolment in the third trimester during three consecutive periods: period 1, no routine intervention (reference); period 2, routine haematinic supplementation (60 mg elementary iron three times/day, folic acid 5 mg once daily) and period 3, haematinics and IPT with SP. RESULTS Among 3108 participants, prevalence of placental malaria, anaemia and severe anaemia postpartum was 16.7%, 53.6% and 12.7%, respectively. Compared with period 1, women in period 2 were less anaemic [adjusted odds ratio (AOR), 95% confidence interval anaemia: 0.56, 0.47-0.67; severe anaemia 0.37, 0.28-0.49] and shared a similar prevalence of placental malaria (AOR 1.07, 0.86-1.32). Women in period 3 were also less anaemic (AOR anaemia: 0.43, 0.35-0.53 and severe anaemia: 0.43, 0.31-0.59), and had less placental malaria (AOR 0.56, 0.42-0.73). The effect of intervention did not differ significantly by HIV status. CONCLUSION The haematinic supplementation programme was associated with significant reductions in anaemia in HIV-seropositive and HIV-seronegative women. The subsequent introduction of IPT was associated with halving of malaria, but no additional haematological benefit over haematinics.

Background Genetic polymorphism of the Fc receptor IIa for immunoglobulin (Ig) G (Fc gamma RIIa) determines IgG subclass binding. Previous studies have shown that individuals with the IgG1/3-binding Fc gamma RIIa-Arg/Arg131 genotype are relatively protected against high-density malaria, whereas individuals with the IgG2-binding Fc gamma RIIa-His/His131 genotype are at increased risk for developing cerebral malaria. The present study was undertaken to examine the relationship between Fc gamma RIIa polymorphism and placental malaria (PM) in pregnant women of known human immunodeficiency virus (HIV)-1 status. Methods Fc gamma RIIa genotype was determined in 903 pregnant women who had participated in a study designed to assess the effect that PM has on vertical transmission of HIV-1. Fc gamma RIIa polymorphism was assessed in relation to PM. Results Among HIV-negative women, there was no difference in the distribution of the Fc gamma RIIa polymorphism by PM status. However, among HIV-positive women, the frequency of the Fc gamma RIIa-His/His131 genotype was significantly higher in women with PM than in women without PM (31% vs. 22%, respectively [P=.032]). In multivariate analysis, the adjusted odds ratio for PM in HIV-positive women with the Fc gamma RIIa-His/His131 genotype versus women in the Fc gamma RIIa-His/Arg131 reference group was 1.72 (95% confidence interval, 1.11-2.69 [P=.016]). Conclusions The present study suggests that the IgG2-binding Fc gamma RIIa-His/His131 genotype is associated with enhanced susceptibility to PM in HIV-positive women but not in HIV-negative women.

The high genetic diversity of HIV-1 continues to complicate effective vaccine development. To better understand the extent of genetic diversity, intersubtype recombinants and their relative contribution to the HIV epidemic in Kenya, we undertook a detailed molecular epidemiological investigation on HIV-1-infected women attending an antenatal clinic in Kisumu, Kenya. Analysis of gag-p24 region from 460 specimens indicated that 310 (67.4%) were A, 94 (20.4%) were D, 28 (6.1%) were C, 9 (2.0%) were A2, 8 (1.7%) were G, and 11 (2.4%) were unclassifiable. Analysis of the env -gp41 region revealed that 326 (70.9%) were A, 85 (18.5%) D, 26 (5.7%) C, 9 (2.0%) each of A2 and G, 4(0.9%) unclassifiable, and 1 (0.2%) CRF02_AG. Parallel analyses of the gag-p24 and env-gp41 regions indicated that 344 (74.8%) were concordant subtypes, while the remaining 116 (25.2%) were discordant subtypes. The most common discordant subtypes were D/A (40, 8.7%), A/D (27, 5.9%), C/A (11, 2.4%), and A/C (8, 1.7%). Further analysis of a 2.1-kb fragment spanning the gag-pol region from 38 selected specimens revealed that 19 were intersubtype recombinants and majority of them were unique recombinant forms. Distribution of concordant and discordant subtypes remained fairly stable over the 4-year period (1996-2000) studied. Comparison of amino acid sequences of gag-p24 and env-gp41 regions with the subtype A consensus sequence or Kenyan candidate vaccine antigen (HIVA) revealed minor variations in the immunodominant epitopes. These data provide further evidence of high genetic diversity, with subtype A as the predominant subtype and a high proportion of intersubtype recombinants in Kenya.

OBJECTIVE To evaluate the effect of polymorphism of the Fc gamma receptor IIa, which is associated with differential human IgG subclass binding, on perinatal HIV-1 transmission. METHODS Fc gamma RIIa genotype was tested in 448 HIV-seropositive mothers and their infants from a cohort study designed to assess the effect of placental malaria on HIV vertical transmission conducted from 1996 to 2001 in western Kenya. Fc gamma RIIa polymorphism was analyzed for associations with susceptibility to perinatal HIV infection and all-cause child mortality in HIV-positive children. RESULTS Overall, 20% of infants were perinatally infected with HIV. There was no statistically significant association between maternal genotype and perinatal HIV-1 transmission. However, frequency of the infant Fc gamma RIIa His/His131 genotype was higher in HIV-positive compared with HIV-negative infants (35% and 21%, respectively), whereas the distribution was reversed (15% and 28%, respectively) for infants with the Fc gamma RIIa Arg/Arg131 genotype. Multivariate logistic regression controlling for maternal and infant confounding factors demonstrated that the odds of perinatal HIV infection in infants with the Fc gamma RIIa His/His131 versus Fc gamma RIIa His/Arg131 genotypes were significantly higher (adjusted odds ratio, 2.22; 95% confidence interval, 1.23-4.02; P = 0.009). There was no evidence for an association between HIV-positive child all-cause mortality and Fc gamma RIIa genotype. CONCLUSIONS This study provides the first evidence that the infant Fc gamma RIIa His/His131 genotype is associated with susceptibility to perinatal HIV-1 transmission and further suggests that there is a dose-response relationship for the effect of the Fc gamma RIIa His131 gene on transmission.

To determine whether maternal placental malaria is associated with an increased risk for perinatal mother-to-child HIV transmission (MTCT), we studied HIV-positive women in western Kenya. We enrolled 512 mother-infant pairs; 128 (25.0%) women had placental malaria, and 102 (19.9%) infants acquired HIV perinatally. Log10 HIV viral load and episiotomy or perineal tear were associated with increased perinatal HIV transmission, whereas low-density placental malaria (10,000 parasites/mL) was associated with reduced risk (adjusted relative risk [ARR] 0.4). Among women dually infected with malaria and HIV, high-density placental malaria (10,000 parasites/mL) was associated with increased risk for perinatal MTCT (ARR 2.0), compared to low-density malaria. The interaction between placental malaria and MTCT appears to be variable and complex: placental malaria that is controlled at low density may cause an increase in broad-based immune responses that protect against MTCT; uncontrolled, high-density malaria may simultaneously disrupt placental architecture and generate substantial antigen stimulus to HIV replication and increase risk for MTCT.

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.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.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.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.

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 greater than or equal to2, 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

Objective: To study the importance of HIV infection for malaria in pregnancy in Kisumu, Kenya. Subjects and methods: Healthy women with an uncomplicated pregnancy of 32 weeks or more attending the prenatal clinic in the Provincial Hospital between June 1996 and March 1999 were tested for HIV and malaria after consent had been obtained. For participating women who delivered in the same hospital, a blood smear of the mother and the placenta were obtained. Results: In the third trimester, 5093 women consented to testing: the prevalence of malaria and HIV was 20.1 and 24.9%, respectively. Among the 2502 screened women who delivered in the hospital, the prevalence of HIV, peripheral parasitaemia and placental malaria was 24.5, 15.2, and 19.0%, respectively. Compared with HIV-seronegative women, HIV-seropositive women were more likely to be parasitaemic, to have higher parasite densities, and to be febrile when parasitaemic. Placental infections in HIV-seropositive women were more likely to be chronic, as indicated by the presence of moderate to heavy pigment depositions. When adjusted by age, the typical gravid ity-specific pattern of malaria in pregnancy disappeared in HIV-seropositive women; HIV-seropositive primigravidae had a similar risk of malaria as HIV-seropositive multigravidae. The excess malaria attributable to HIV in the third trimester increased from 34.6% among HIV-seropositive primigravidae, to 41.5% among HIV-seropositive secundigravidae, and 50.7% among HIV-seropositive gravidae with three or more pregnancies. Conclusion: HIV infection alters patterns of malaria in pregnant women; in areas with both infections, all pregnant women should use malaria prevention. (C) 2003 Lippincott Williams Wilkins

To assess risk factors for malaria in pregnancy in Kisumu, western Kenya, we studied healthy women with an uncomplicated pregnancy of greater than or equal to 32 weeks attending the antenatal clinic in the Provincial Hospital. Between June 1996 and March 1999, malaria and human immunodeficiency virus (HIV) infection were examined in 5093 pregnant women: 20.1% of the women were parasitaemic and 24.9% were HPV-seropositive. 2502 women delivered in the hospital and a smear was obtained: the prevalence of placental malaria, maternal peripheral parasitaemia, and HIV infection was respectively 19.0%, 15.2% and 24.5%. HIV infection (risk ratio [RR] 1.58, 95% confidence interval [95% CI] 1.32-1.89), young age (

To assess risk factors for anemia in late pregnancy, we studied healthy pregnant women with a singleton uncomplicated pregnancy of > or = 32 weeks attending the prenatal clinic in the Provincial Hospital in Kisumu, Kenya. Between June 1996 and December 1998, 4,608 pregnant women had a blood sample collected for hemoglobin (Hb) measurement, malaria smear, and testing for human immunodeficiency virus (HIV). The mean +/- standard deviation of Hb was 9.58 +/- 1.8 g/dL; 21% had malaria in their blood; and 25% of the women were HIV seropositive. Plasmodium falciparum parasitemia was more common among HIV-seropositive women in all gravidities compared with HIV-seronegative women (risk ratio, 1.71; 95% confidence interval, 1.53-1.92). In a multivariate analysis, for primi- and secundigravidae women, the factors malaria, belonging to the Luo tribe, and HIV seropositivity were significantly associated with any anemia (Hb < 11 g/dL), and HIV seropositivity and documented fever were associated with severe anemia (Hb < 7 g/dL). In women of higher gravidities, HIV seropositivity was the only statistically significant factor associated with any anemia or with severe anemia. Asymptomatic HIV seropositivity is an important risk factor to be considered in the differential diagnosis of maternal anemia, independent of P. falciparum parasitemia.

Our objective was to evaluate HIV prevalence and identify risk factors for HIV infection among women attending the antenatal clinic (ANC) at a large public hospital in Kisumu town, western Kenya. Between June 1996 and November 1997, in the context of a study to determine the effect of placental malaria on mother-to-child transmission of HIV in western Kenya, HIV-1 antibody testing was offered to women with a singleton uncomplicated pregnancy ofor =32 weeks' gestation attending the ANC. Women were interviewed using a structured questionnaire and had a fingerstick blood sample collected for haemoglobin (Hb), malaria smears, and HIV antibody testing. Overall HIV seroprevalence was 26.1% (743/2844) (95% confidence interval (CI): 24.5-27.7) and in bivariate evaluation was significantly associated with anaemia (Hb11 g/dl) (risk ratio (RR) 1.8), malarial parasitaemia (RR 1.6), fever (axillary temperatureor =37.5 degrees C at screening) (RR 1.6), a history of being treated for either vaginal discharge (RR 1.5) or tuberculosis (RR 1.6), reported alcohol consumption (RR 1.6), being an unmarried multigravida (RR 2.2) or a history of the most recent child having died (RR 2.0). Poisson regression analysis for all women identified 5 significant factors independently associated with HIV seropositivity: anaemia (adjusted RR 1.7; 95% CI 1.3-2.0), malarial parasitaemia (adjusted RR 1.7; 95% CI 1.4-2.0), a history of being treated for vaginal discharge (adjusted RR 1.5; 95% CI 1.1-2.0), fever (adjusted RR 2.0; 95% CI 1.3-3.2) and reported alcohol consumption (adjusted RR 1.6; 95% CI 1.1-2.5). Multigravidae women whose most recent child had died were also more likely to be HIV seropositive (adjusted RR 1.9; 95% CI 1.7-2.8). Only 5.5% (156/2844) of the women had none of these risk factors, of whom 12% (18/156) were HIV(+). Even though the model containing the 5 identified factors fitted the data well (goodness-of-fit chi2=18.41, P=0.10), its collective capacity to predict HIV infection was poor; while 74% of the truly positive women were correctly predicted positive by the model, 52% of the truly negative women were misclassified. Among pregnant women attending the ANC in western Kenya, we were unable to identify a subgroup at risk of HIV infection using non-serological information, indicating that wherever possible universal access to voluntary HIV counselling and testing would be preferable to targeted screening.This study evaluated the HIV prevalence and identified the risk factors for HIV infection among women attending the antenatal clinic at a public hospital in Kisumu, western Kenya. Also, the effect of placental malaria on vertical HIV transmission were determined using structured interviews and HIV-1 antibody testing and hemoglobin malaria smears were offered to the respondents. Overall, HIV seroprevalence was 26.1% (743/2844) (95% confidence interval [CI]: 24.5-27.7) and in bivariate evaluation was significantly associated with anemia (risk ratio [RR] 1.8), malarial parasitemia (RR 1.6), fever (RR 1.6), a history of being treated for either vaginal discharge (RR 1.5) or tuberculosis (RR 1.6), alcohol consumption (RR 1.6), being an unmarried multigravida (RR 2.2), or a history of the most recent child having died (RR 2.0). Using the Poisson regression analysis, 5 significant factors associated with HIV seropositivity were identified: anemia, malarial parasitemia, and history of being treated for vaginal discharge, fever, and reported alcohol consumption. Among the pregnant women, the researchers were unable to identify a subgroup at risk of HIV infection using nonserological information, indicating that universal access to voluntary HIV counseling and testing would be preferable to targeted screening.

A large-scale longitudinal cohort project was initiated in western Kenya in June 1992. The primary purpose of the project was to study Plasmodium falciparum malaria in a highly endemic area using a comprehensive and multidisciplinary approach, which included epidemiology, entomology, and immunology. Between June 1992 and July 1994, pregnant women living in 15 rural villages were identified during a monthly census and 1,164 were enrolled. The women were followed-up throughout their pregnancy and they, along with their newborn infants and direct siblings of the infants' less than 15 years of age, were monitored over time. As of May 1995, 1,017 infants had been born to these women. This paper presents the design and general methodology used in this study and describes the initial experience with intense monitoring of a large population over a prolonged period.

Background The findings of a prevalence survey conducted in western Kenya, in a population with 14.9% HIV prevalence suggested inadequate case finding. We found a high burden of infectious and largely undiagnosed pulmonary tuberculosis (PTB), that a quarter of the prevalent cases had not yet sought care, and a low case detection rate. Objective and methods We aimed to identify factors associated with inadequate case finding among adults with PTB in this population by comparing characteristics of 194 PTB patients diagnosed in a health facility after self-report, i.e., through passive case detection, with 88 patients identified through active case detection during the prevalence survey. We examined associations between method of case detection and patient characteristics, including HIV-status, socio-demographic variables and disease severity in univariable and multivariable logistic regression analyses. Findings HIV-infection was associated with faster passive case detection in univariable analysis (crude OR 3.5, 95% confidence interval (CI) 2.0–5.9), but in multivariable logistic regression this was largely explained by the presence of cough, illness and clinically diagnosed smear-negative TB (adjusted OR (aOR) HIV 1.8, 95% CI 0.85–3.7). Among the HIV-uninfected passive case detection was less successful in older patients aOR 0.76, 95%CI 0.60–0.97 per 10 years increase), and women (aOR 0.27, 95%CI 0.10–0.73). Reported current or past alcohol use reduced passive case detection in both groups (0.42, 95% CI 0.23–0.79). Among smear-positive patients median durations of cough were 4.0 and 6.9 months in HIV-infected and uninfected patients, respectively. Conclusion HIV-uninfected patients with infectious TB who were older, female, relatively less ill, or had a cough of a shorter duration were less likely found through passive case detection. In addition to intensified case finding in HIV-infected persons, increasing the suspicion of TB among HIV-uninfected women and the elderly are needed to improve TB case detection in Kenya.

Immunoglobulin (Ig) GM and KM allotypes, genetic markers of γ and κ chains, are associated with humoral immune responsiveness. Previous studies have shown the relationships between GM6-carrying haplotypes and susceptibility to malaria infection in children and adults; however, the role of the genetic markers in placental malaria (PM) infection and PM with HIV co-infection during pregnancy has not been investigated. We examined the relationship between the gene polymorphisms of Ig GM6 and KM allotypes and the risk of PM infection in pregnant women with known HIV status. DNA samples from 728 pregnant women were genotyped for GM6 and KM alleles using polymerase chain reaction-restriction fragment length polymorphism method. Individual GM6 and KM genotypes and the combined GM6 and KM genotypes were assessed in relation to PM in HIV-1 negative and positive women, respectively. There was no significant effect of individual GM6 and KM genotypes on the risk of PM infection in HIV-1 negative and positive women. However, the combination of homozygosity for GM6(+) and KM3 was associated with decreased risk of PM (adjusted OR, 0.25; 95% CI, 0.08-0.8; P = 0.019) in HIV-1 negative women while in HIV-1 positive women the combination of GM6(+/-) with either KM1-3 or KM1 was associated with increased risk of PM infection (adjusted OR, 2.10; 95% CI, 1.18-3.73; P = 0.011). Hardy-Weinberg Equilibrium (HWE) tests further showed an overall significant positive F(is) (indication of deficit in heterozygotes) for GM6 while there was no deviation for KM genotype frequency from HWE in the same population. These findings suggest that the combination of homozygous GM6(+) and KM3 may protect against PM in HIV-1 negative women while the HIV-1 positive women with heterozygous GM6(+/-) combined with KM1-3 or KM1 may be more susceptible to PM infection. The deficit in heterozygotes for GM6 further suggests that GM6 could be under selection likely by malaria infection.

Background Schistosome and soil-transmitted helminth (STH) infections are recognized as major global public health problems, causing severe and subtle morbidity, including significant educational and nutritional effects in children. Although effective and safe drugs are available, ensuring access to these drugs by all those at risk of schistosomiasis and STHs is still a challenge. Community-directed intervention (CDI) has been used successfully for mass distribution of drugs for other diseases such as onchocerciasis and lymphatic filariasis. A national control programme is yet to be instituted in Kenya and evidence for cost-effective strategies for reaching most affected communities is needed. This study evaluated the effectiveness and feasibility of the CDI strategy in the control of schistosomiasis and STHs, in East Uyoma location, Rarieda district, a community of western Kenya that is highly endemic for both infections. Results Pre-treatment prevalence of S. mansoni averaged 17.4% (range 5-43%) in the entire location. Treatment coverage in different villages ranged from 54.19 to 96.6% by community drug distributor (CDD) records. Assessment from a household survey showed coverage of 52.3 -91.9% while the proportion of homesteads (home compounds) covered ranged from 54.9-98.5%. Six months after one round of drug distribution, the prevalence levels of S. mansoni, hookworm and Trichuris trichura infections were reduced by 33.2%, 69.4% and 42.6% respectively. Conclusions This study shows that CDI is an accepted and effective strategy in the mass treatment of schistosomiasis and STH infections in resource constrained communities in Kenya and may be useful in similar communities elsewhere. A controlled trial comparing CDI and school based mass drug administration to demonstarte their relative advantages is ongoing.

Pregnant women have abundant natural killer (NK) cells in their placenta, and NK cell function is regulated by polymorphisms of killer cell immunoglobulin-like receptors (KIRs). Previous studies report different roles of NK cells in the immune responses to placental malaria (PM) and human immunodeficiency virus (HIV-1) infections. Given these references, the aim of this study was to determine the association between KIR gene content polymorphism and PM infection in pregnant women of known HIV-1 status. Sixteen genes in the KIR family were analyzed in 688 pregnant Kenyan women. Gene content polymorphisms were assessed in relation to PM in HIV-1 negative and HIV-1 positive women, respectively. Results showed that in HIV-1 negative women, the presence of the individual genes KIR2DL1 and KIR2DL3 increased the odds of having PM, and the KIR2DL2/KIR2DL2 homozygotes were associated with protection from PM. However, the reverse relationship was observed in HIV-1 positive women, where the presence of individual KIR2DL3 was associated with protection from PM, and KIR2DL2/KIR2DL2 homozygotes increased the odds for susceptibility to PM. Further analysis of the HIV-1 positive women stratified by CD4 counts showed that this reverse association between KIR genes and PM remained only in the individuals with high CD4 cell counts but not in those with low CD4 cell counts. Collectively, these results suggest that inhibitory KIR2DL2 and KIR2DL3, which are alleles of the same locus, play a role in the inverse effects on PM and PM/HIV co-infection and the effect of KIR genes on PM in HIV positive women is dependent on high CD4 cell counts. In addition, analysis of linkage disequilibrium (LD) of the PM relevant KIR genes showed strong LD in women without PM regardless of their HIV status while LD was broken in those with PM, indicating possible selection pressure by malaria infection on the KIR genes.

Background The two issues mostly affecting the success of tuberculosis (TB) control programmes are delay in presentation and non-adherence to treatment. It is important to understand the factors that contribute to these issues, particularly in resource limited settings, where rates of tuberculosis are high. The objective of this study is to assess health-seeking behaviour and health care experiences among persons with pulmonary tuberculosis, and identify the reasons patients might not complete their treatment. Methods We performed qualitative one-on-one in-depth interviews with pulmonary tuberculosis patients in nine health facilities in rural western Kenya. Thirty-one patients, 18 women and 13 men, participated in the study. All reside in an area of western Kenya with a Health and Demographic Surveillance System (HDSS). They had attended treatment for up to 4 weeks on scheduled TB clinic days in September and October 2005. The nine sites all provide diagnostic and treatment services. Eight of the facilities were public (3 hospitals and 5 health centres) and one was a mission health centre. Results Most patients initially self-treated with herbal remedies or drugs purchased from kiosks or pharmacies before seeking professional care. The reported time from initial symptoms to TB diagnosis ranged from 3 weeks to 9 years. Misinterpretation of early symptoms and financial constraints were the most common reasons reported for the delay. We also explored potential reasons that patients might discontinue their treatment before completing it. Reasons included being unaware of the duration of TB treatment, stopping treatment once symptoms subsided, and lack of family support. Conclusions This qualitative study highlighted important challenges to TB control in rural western Kenya, and provided useful information that was further validated in a quantitative study in the same area.

Background Maternal mortality remains high in developing countries and data to monitor indicators of progress in maternal care is needed. We examined the status of maternal care before and after health care worker (HCW) training in WHO recommended Focused Antenatal Care. Methods An initial cross-sectional survey was conducted in 2002 in Asembo and Gem in western Kenya among a representative sample of women with a recent birth. HCW training was performed in 2003 in Asembo, and a repeat survey was conducted in 2005 in both areas. Results Antenatal clinic (ANC) attendance was similar in both areas (86%) in 2005 and not significantly different from 2002 (90%). There was no difference in place of delivery between the areas or over time. However, in 2005, more women in Asembo were delivered by a skilled assistant compared to Gem (30% vs.23%, P = 0.04), and this proportion increased compared to 2002 (17.6% and 16.1%, respectively). Provision of iron (82.4%), folic acid (72.0%), sulfadoxine-pyrimethamine (61.7%), and anthelminths (12.7%) had increased in Asembo compared to 2002 (2002: 53.3%, 52.8%, 20.3%, and 4.6%, respectively), and was significantly higher than in Gem in 2005 (Gem 2005: 69.7%, 47.8%, 19.8%, and 4.1%, respectively) (P < 0.05 for all). Offering of tests for sexually transmitted diseases and providing information related to maternal health was overall low ( Conclusions We observed improvements in some ANC services in the area where HCWs were trained. However, since our evaluation was carried out 2 years after three-day training, we consider any significant, sustained improvement to be remarkable.

Background Geohelminth infections are common in rural western Kenya, but risk factors and effects among pregnant women are not clear. Methodology During a community-based cross-sectional survey, pregnant women were interviewed and asked to provide a blood sample and a single fecal sample. Hemoglobin was measured and a blood slide examined for malaria. Geohelminth infections were identified using the concentration and Kato-Katz method. Results Among 390 participants who provided a stool sample, 76.2% were infected with at least one geohelminth: 52.3% with Ascaris lumbricoides, 39.5% with hookworm, and 29.0% with Trichuris trichiura. Infection with at least one geohelminth species was associated with the use of an unprotected water source (adjusted odds ratio [AOR] 1.8, 95% confidence interval [CI] 1.1–3.0) and the lack of treatment of drinking water (AOR 1.8, 95% CI 1.1–3.1). Geohelminth infections were not associated with clinical symptoms, or low body mass index. A hookworm infection was associated with a lower mid upper arm circumference (adjusted mean decrease 0.7 cm, 95% CI 0.3–1.2 cm). Hookworm infections with an egg count ≥1000/gram feces (11 women) were associated with lower hemoglobin (adjusted mean decrease 1.5 g/dl, 95% CI 0.3–2.7). Among gravidae 2 and 3, women with A. lumbricoides were less likely to have malaria parasitemia (OR 0.4, 95% CI 0.2–0.8) compared to women without A. lumbricoides, unlike other gravidity groups. Conclusion Geohelminth infections are common in this pregnant population; however, there were few observed detrimental effects. Routine provision of antihelminth treatment during an antenatal clinic visit is recommended, but in this area an evaluation of the impact on pregnancy, malaria, and birth outcome is useful., Author Summary In rural western Kenya, both malaria and intestinal infections with worms are common. Pregnant women are particularly vulnerable to infection with malaria, but the effect on pregnancy of intestinal infections with worms is not clear and may depend both on how heavy the worm infection is and on the type of worm. Additionally, it is not clear whether infections with worms may affect malaria infections. In this article, we begin to disentangle some of these issues. Intestinal infections with worms were diagnosed in three-quarters of 390 pregnant women in western Kenya who provided a stool sample. In these women, intestinal worm infections caused a modest decrease both in haemoglobin levels and indicators of nutritional status. Women in their second and third pregnancies who were diagnosed with one particular type of worm infection (Ascaris lumbricoides) were less likely to have malaria than other women in their second or third pregnancies who did not have this type of worm infection. Although our results suggest that it would be good advice to treat women with drugs for intestinal worm infections during their pregnancy in this area, the effect on maternal and infant health and malaria infection needs further study.

Sulfadoxine-pyrimethamine (SP) inhibits folate metabolism by the malaria parasite. We investigated the association between folate levels and SP failure in pregnant women. Data from a trial to assess the effect that folate supplementation has on SP failure in 467 pregnant women were analyzed. Plasma folate levels were determined at enrollment and at day 7. High baseline folate levels, high parasite densities, and age20 years were risk factors for SP failure. High-dose (5 mg daily) folate supplementation or high folate levels at day 7 were independent risk factors. Therefore, pregnant women receiving SP should receive low-/moderate-dose folate supplementation.http://www.clinicaltrials.gov identifier: NCT00130065.

To determine the prevalence of malaria and anaemia among urban and peri-urban women attending their first antenatal clinic (ANC) in an area of perennial malaria transmission.Between November 2003 and May 2004 we screened first ANC attenders for malaria and anaemia in a large urban hospital in Kisumu (western Kenya) and interviewed them to obtain demographic and medical information.Among the 685 study participants, prevalence of malaria parasitaemia was 18.0%, prevalence of any anaemia (haemoglobin11 g/dl) was 69.1% and prevalence of moderate anaemia was (haemoglobin8 g/dl) 11.8%. Sixteen women were hospitalized during pregnancy, eight because of malaria. In multivariate analysis, young age, living in a house with mud walls, a visit to rural area, peri-urban residence, second trimester of pregnancy and Luo ethnicity were significant risk factors for malaria parasitaemia. Malaria was an important risk factor for any and moderate anaemia; use of an insecticide-treated net (ITN) was a protective factor for any anaemia. Married women with a higher level of education, better-quality housing and full-time employment were more likely to use an ITN.Malaria and anaemia are established problems by the time of the first ANC visit. Mechanisms to deliver ITNs to women of child-bearing age before they become pregnant need to be explored. Early ANC visits are warranted in order for women to benefit from policies aimed at reducing the burden of malaria and anaemia.

To the Editor: Studies indicate that Plasmodium falciparum infection increases HIV replication in adults (1,2). Although malaria-related illness and death are more common in children, and HIV-1 generally progresses faster in children than in adults (3,4), to our knowledge the effect of intermittent malaria on HIV-1 viral load has not been directly explored in children. To investigate this issue, we monitored HIV-positive infants from a 1996–2001 birth cohort study in Kisumu, Kenya, a P. falciparum–holoendemic area. Study design and methods have been described elsewhere (5,6). Twenty-four children that were perinatally infected with HIV were included in this substudy. During monthly visits during the child’s first 2 years of life, malaria and HIV incidence were recorded (5,6). Both children with malaria-positive blood smears and those with fever but no smear result available were treated with sulfadoxine-pyrimethamine according to national guidelines. At the time of this substudy, none of the study participants were taking antiretroviral drugs. HIV and malaria diagnoses were determined by using standard methods (5–7). To reduce the chance of including infants infected through breast-feeding, perinatal infection was defined as >2 consecutive HIV-positive tests, with the first positive PCR results by 4 months of age (7). The so-called baseline viral load was the premalaria value measured 1 month before the first observation in the analysis. To be included in the analysis, follow-up visits had to have data available on the current and previous months’ viral load and malaria status and occur at roughly monthly intervals at >4 months of age. Malaria parasites were found at 53 of 146 visits in the month before viral load measurement, although at 89% of visits in which children were malaria-positive, the children’s samples had

Background Primigravid (PG) women are at risk for pregnancy-associated malaria (PAM). Multigravid (MG) women acquire protection against PAM; however, HIV infection impairs this protective response. Protection against PAM is associated with the production of IgG specific for variant surface antigens (VSA-PAM) expressed by chondroitin sulfate A (CSA)-adhering parasitized erythrocytes (PEs). We hypothesized that VSA-PAM-specific IgG confers protection by promoting opsonic phagocytosis of PAM isolates and that HIV infection impairs this response. Methods and Findings We assessed the ability of VSA-PAM-specific IgG to promote opsonic phagocytosis of CSA-adhering PEs and the impact of HIV infection on this process. Opsonic phagocytosis assays were performed using the CSA-adherent parasite line CS2 and human and murine macrophages. CS2 PEs were opsonized with plasma or purified IgG subclasses from HIV-negative or HIV-infected PG and MG Kenyan women or sympatric men. Levels of IgG subclasses specific for VSA-PAM were compared in HIV-negative and HIV-infected women by flow cytometry. Plasma from HIV-negative MG women, but not PG women or men, promoted the opsonic phagocytosis of CSA-binding PEs (p < 0.001). This function depended on VSA-PAM-specific plasma IgG1 and IgG3. HIV-infected MG women had significantly lower plasma opsonizing activity (median phagocytic index 46 [interquartile range (IQR) 18–195] versus 251 [IQR 93–397], p = 0.006) and levels of VSA-PAM-specific IgG1 (mean fluorescence intensity [MFI] 13 [IQR 11–20] versus 30 [IQR 23–41], p < 0.001) and IgG3 (MFI 17 [IQR 14–23] versus 28 [IQR 23–37], p < 0.001) than their HIV-negative MG counterparts. Conclusions Opsonic phagocytosis may represent a novel correlate of protection against PAM. HIV infection may increase the susceptibility of multigravid women to PAM by impairing this clearance mechanism., Based on a comparison of HIV-negative or HIV-infected primigravid and multigravid women, Kevin Kain and colleagues suggest that opsonic phagocytosis might protect against pregnancy-associated malaria, and that HIV infection might impair this parasite clearance mechanism., Editors' Summary Background. Every year, malaria kills more than one million people—mostly young children. Among adults, pregnant women are most affected by malaria, a parasitic disease spread by mosquitos. In areas of Africa where malaria is widespread, about 10,000 women die because of pregnancy-associated malaria (PAM) each year. In PAM, red blood cells containing parasites (parasitized erythrocytes or PEs) collect in the woman's placenta. These PEs, which stick to a placental molecule called chondroitin sulfate A (CSA), are covered with parasitic proteins known as variant surface antigens of PAM (VSA-PAM). Women in their first pregnancy (primigravid women) are particularly susceptible to PAM, but multigravid women are more resistant unless they are also infected with HIV (the virus that causes AIDS), in which case they are extremely susceptible to PAM. Protection against PAM in multigravid women is associated with the production of immunoglobulins (proteins made by the immune system that circulate in the blood and bind to foreign proteins or antigens) that recognize VSA-PAM. These immunoglobulins or antibodies are called VSA-PAM-specific IgG and their production increases with each pregnancy Why Was This Study Done? It is unclear how VSA-PAM-specific IgG protects multigravid women against PAM or how HIV infection impairs this protective response. One possibility is that VSA-PAM-specific IgG coats the PEs in the placenta to enable immune system cells called macrophages to recognize and ingest them, a process called opsonic phagocytosis. In this study, the researchers have investigated whether opsonic phagocytosis provides multigravid women with protection against PAM and whether a failure of this form of protective immunity underlies the susceptibility of HIV-infected multigravid women to PAM. What Did the Researchers Do and Find? The researchers collected plasma (the fluid part of blood) from primigravid and multigravid women (some of whom were infected with HIV) living in a Kenyan region where malaria is common soon after they gave birth and from men living in the same area. They then purified IgG1, IgG2, IgG3, and IgG4 from the plasma samples. These four IgG subclasses have different immune functions—only IgG1 and IgG3 participate in opsonic phagocytosis. To measure the ability of the plasma samples and purified IgGs to promote opsonic phagocytosis, the researchers mixed each sample with a laboratory isolate of CSA-binding PEs and macrophages and counted how many PEs the macrophages ingested. Plasma from HIV-negative multigravid women but not primigravid women or men promoted opsonic phagocytosis and, in the plasma from multigravid women, this activity depended on IgG1 and IgG3. HIV-infected multigravid women, however, had less opsonizing activity in their plasma than HIV-negative multigravid women and the level of this activity correlated with the levels of VSA-PAM-specific IgG1 and IgG3 (measured using a technique called flow cytometry) in the plasma samples of these two groups of women. What Do These Findings Mean? These findings support the hypothesis that VSA-PAM-specific IgG1 and IgG3 promote opsonic clearance of CSA-binding PEs. Thus, opsonic immune mechanisms may be involved in the protective response to PAM seen in multigravid women. However, because all the measurements of opsonic phagocytosis in this study used a laboratory isolate of PEs, these findings need to be confirmed using PEs isolated from placentas to check that they are generalizable. Other findings reported here suggest that HIV-positive multigravid women are more susceptible to PAM than HIV-negative multigravid women because reduced amounts of VSA-PAM-specific IgG in their plasma reduce the ability of opsonic phagocytosis to clear PEs from their placenta. Overall, these results may have implications for the development of vaccines against PAM. For example, they suggest that vaccines should be designed to stimulate the production of VSA-PAM-specific antibodies of the IgG1 and IgG3 subclasses. They also suggest that, provided the link between opsonic phagocytosis and protection against PAM can be confirmed in population-based studies, new vaccines could be evaluated for their potential to protect women against PAM by seeing whether the plasma of vaccinees promotes opsonic phagocytosis of CSA-binding PEs. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040181. US Centers for Disease Control and Prevention information on malaria and malaria during pregnancy (in English and Spanish) World Health Organization information on malaria, including a feature on malaria in pregnancy (in English, Spanish, French, Arabic, Chinese and Russian) Special Program for Research and Training in Tropical Diseases (TDR) information on malaria and research into the disease Roll Back Malaria Partnership fact sheets on all aspects of malaria, including malaria in pregnancy (in English, French and Portuguese) HIV Insite, information from the University of California at San Francisco on malaria and HIV

To evaluate the effect of routine antenatal haematinic supplementation programmes and intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) in Kenya.Anaemia [haemoglobin (Hb)11 g/dl), severe anaemia (Hb8 g/dl) and placental malaria were compared among women with known HIV status who delivered at a provincial hospital after study enrolment in the third trimester during three consecutive periods: period 1, no routine intervention (reference); period 2, routine haematinic supplementation (60 mg elementary iron three times/day, folic acid 5 mg once daily) and period 3, haematinics and IPT with SP.Among 3108 participants, prevalence of placental malaria, anaemia and severe anaemia postpartum was 16.7%, 53.6% and 12.7%, respectively. Compared with period 1, women in period 2 were less anaemic [adjusted odds ratio (AOR), 95% confidence interval anaemia: 0.56, 0.47-0.67; severe anaemia 0.37, 0.28-0.49] and shared a similar prevalence of placental malaria (AOR 1.07, 0.86-1.32). Women in period 3 were also less anaemic (AOR anaemia: 0.43, 0.35-0.53 and severe anaemia: 0.43, 0.31-0.59), and had less placental malaria (AOR 0.56, 0.42-0.73). The effect of intervention did not differ significantly by HIV status.The haematinic supplementation programme was associated with significant reductions in anaemia in HIV-seropositive and HIV-seronegative women. The subsequent introduction of IPT was associated with halving of malaria, but no additional haematological benefit over haematinics.

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 infinity) was ~40% lower (22,816 vs 40,106 microg/mL/h, P

Kenya established intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) for malaria in pregnancy as national policy in 1998. We assessed the coverage of IPT among women who had recently delivered in a rural area of western Kenya with perennial malaria transmission and high coverage with insecticide treated nets (ITNs) through a cross-sectional, community-based survey in December 2002. Antenatal clinic (ANC) attendance was high (89.9% of the 635 participating women); 77.5% of attendees visited an ANC before the third trimester and 91.9% made more than one visit. Delivery of SP by the ANC was reported by 19.1% of all women but only 6.8% reported receiving more than one dose. Given the high rate of use of ANC services, if SP were given at each visit after the first trimester, the potential coverage of IPT (two doses of SP) would be 80.3% in this study population. ITNs were used by 82.4% of women during pregnancy, and almost all mothers (98.5%) who slept under an ITN shared the nets with their newborns after delivery. Women who thought malaria in pregnancy caused foetal problems were more likely to have used an ITN (adjusted odds ratio [AOR] 1.6, 95% confidence interval [CI] 1.0-2.4), and to have visited ANC more than once (AOR 2.4, 95% CI 1.2-4.7) compared to women who thought malaria in pregnancy was either not a problem or caused problems for the mother only. These findings illustrate the need for improved IPT coverage in this rural area. Identification and removal of the barriers to provision of IPT during ANC visits can help to increase coverage. In this area of Kenya, health messages stressing that foetal complications of malaria in pregnancy may occur in the absence of maternal illness may improve the demand for IPT.

To determine the effect of placental malaria (PM) infection on the development of antibody responses to malaria in infants, we measured immunoglobulin G levels to seven different Plasmodium falciparum epitopes by using plasma samples collected at monthly intervals from infants born to mothers with and without PM. Overall, PM was associated with diminished antibody levels to all of the epitopes tested, especially with infants aged ≥4 to 12 months, and the difference was statistically significant for four of the seven epitopes ( P < 0.0035). These findings suggest that PM can negatively influence the development of immune responses to malaria in infants.

OBJECTIVE A short pregnancy interval (PI) has been associated with increased child mortality, but mechanisms are unclear. We studied factors associated with PI and the effect of PI on birthweight and haemoglobin. METHODS Information was analysed from 2218 multigravidae who were recruited at the prenatal clinic (1758) or in the labour ward (460) of the Provincial Hospital in Kisumu between June 1996 and July 2000 for a study to assess the interaction between placental malaria and vertical HIV transmission. RESULTS The HIV prevalence was 28.9%. HIV seropositivity, older age, being unmarried, and

Objectives: HIV-seropositive pregnant women are more susceptible to malaria than HIV-seronegative women. We assessed whether HIV infection alters maternal and cord plasma malarial antibody responses and the mother-to-infant transfer of malaria antibodies. Methods: We determined plasma levels of maternal and cord antibodies [Immunoglobulin (IgG)] to recombinant malarial proteins [merozoite surface protein 1 (MSP-1 19kD ), the erythrocyte binding antigen (EBA-175)], the synthetic peptides [MSP-2, MSP-3, rhoptry associated protein 1 (RAP-1), and the pre-erythrocytic stage, circumsporozoite protein (NANP) 5 ] antigenic determinants of Plasmodium falciparum ; and tetanus toxoid (TT) by ELISA among samples of 99 HIV-seropositive mothers, 69 of their infants, 102 HIV-seronegative mothers and 62 of their infants. Results: The prevalence of maternal antibodies to the malarial antigenic determinants ranged from 18% on MSP3 to 91% on EBA-175; in cord plasma it ranged from 13% to 91%, respectively. More than 97% of maternal and cord samples had antibodies to TT. In multivariate analysis, HIV infection was only associated with reduced antibodies to (NANP) 5 in maternal ( P =0.001) and cord plasma ( P =0.001); and reduced mother-to-infant antibody transfer to (NANP) 5 ( P =0.012). This effect of HIV was independent of maternal age, gravidity and placental malaria. No consistent HIV-associated differences were observed for other antigenic determinants. Conclusion: An effect of HIV infection was only observed on one malarial antigenic determinant, suggesting that the increased susceptibility to malaria among HIV-infected pregnant women may not be explained on the basis of their reduced antibody response to malaria antigens.

The role of maternal and pediatric infection with human immunodeficiency virus type 1 (HIV-1) and malaria as risk factors for anemia was determined in a birth cohort of infants born to mothers participating in a study of the interaction between placental malaria and HIV infection, in Kisumu, Kenya. Between June 1996 and April 2000, 661 infants born to 467 HIV-seropositive and 194 HIV-seronegative mothers were monitored monthly from birth. At each visit a questionnaire was completed and a blood sample was collected for the determination of hemoglobin levels and detection of malaria and HIV. Anemia was common and increased from 13.6% at one month to 75% at six months and remained high throughout the second half of infancy. Placental malaria, infant malaria, and HIV infection of the infant were all associated with infant anemia in a multivariate model, adjusting for other co-variates found to be associated with infant anemia. The HIV-infected infants with malaria parasitemia had lower mean hemoglobin levels compared with HIV-uninfected infants, or HIV-infected infants without malaria, suggesting that HIV-infected infants are particularly vulnerable to the adverse consequences of malaria at this age. Early detection and prompt treatment of infant malaria and treatment of anemia as part of the study protocol failed to prevent most of the infants from becoming anemic. Although not proven effective in this study, micronutrient supplementation should be prospectively assessed in HIV-infected infants as a means of preventing anemia.

Prevention of placental malaria through administration of antimalarial medications to pregnant women in disease-endemic areas decreases the risk of delivery of low birth weight (LBW) infants. In areas of high Plasmodium falciparum transmission, two intermittent presumptive treatment doses of sulfadoxine-pyrimethamine (SP) during the second and third trimesters of pregnancy are effective in decreasing the prevalence of placental malaria in human immunodeficiency virus (HlV)-negative women, while HIV-positive women may require a monthly SP regimen to reduce their prevalence of placental parasitemia. A decision-analysis model was used to compare the cost-effectiveness of three different presumptive SP treatment regimens with febrile case management with SP in terms of incremental cost per case LBW prevented. Factors considered included HIV seroprevalence, placental malaria prevalence, LBW incidence, the cost of SP, medical care for LBW infants, and HIV testing. For a hypothetical cohort of 10,000 pregnant women, the monthly SP regimen would always be the most effective strategy for reducing LBW associated with malaria. The two-dose SP and monthly SP regimens would prevent 172 and 229 cases of LBW, respectively, compared with the case management approach. At HIV seroprevalence rates greater than 10%, the monthly SP regimen is the least expensive strategy. At HIV seroprevalence rates less than 10%, the two-dose SP regimen would be the less expensive option. When only antenatal clinic costs are considered, the two-dose and monthly SP strategies cost US $11 and $14, respectively, well within the range considered cost effective. Presumptive treatment regimens to prevent LBW associated with malaria and the subsequent increased risk of mortality during the first year of life are effective and cost effective strategies in areas with both elevated HIV prevalence and malaria transmission rates.

An association was demonstrated recently between elevated in vitro production of interferon (IFN)-gamma by intervillous blood mononuclear cells (IVBMCs) and protection against placental malaria (PM). Because human immunodeficiency virus (HIV)-infected pregnant women have increased susceptibility to PM, loss of the IFN-gamma response in these women may impair their ability to control PM. Measurement of cytokines in culture supernatants by ELISA revealed that IFN-gamma responses by HIV-positive IVBMCs were impaired, especially after malarial antigen stimulation. Interleukin (IL)-4 and IL-10 responses also were reduced in HIV-positive persons, the latter more so in HIV-positive, PM-positive persons. In contrast, tumor necrosis factor-alpha production generally was enhanced in PM-positive and HIV-positive persons. Overall, cytokine production was reduced in HIV-positive persons with CD4 T cell counts

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.

A noninvasive perfusion method for the recovery of maternal placental (intervillous) blood for use in immunologic assays is described. 60% of the perfused blood samples tested for fetal red blood cell (RBC) contamination were found to be pure maternal blood; in the remainder, fetal RBC contamination, with a single exception, was less than 6%. The intervillous mononuclear cells (IVBMC) isolated from this blood were of predominantly maternal origin as demonstrated by a polymerase chain reaction-based DNA typing technique. The number of IVBMC obtained was within the range of 9 to 55×10 6 cells. Phenotypic analysis of IVBMC surface antigens revealed that 61% of the cells were CD3+ T-cells and 18% were CD19+ B-cells. The CD4+ and CD8+ T-lymphocyte subsets accounted for 28 and 26% of the IVBMC, respectively. The IVBMC were functionally competent as evidenced by in vitro lymphoproliferation and cytokine production in response to mitogen and PPD stimulation. This technique allows for rapid and safe isolation of large numbers of IVBMC which are functionally active up to 12 h post-delivery, thus representing a significant improvement over previously described methods. It should facilitate more vigorous research in the study of uteroplacental immunity and infectious disease research, particularly in field settings where sample collection and laboratory facilities are distant.

Objectives: Sulfadoxine-pyrimethamine (SP) is an antimalarial drug that acts on the folate metabolism of the malaria parasite. We investigated whether folate (FA) supplementation in a high or a low dose affects the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. Design: This was a randomized, placebo-controlled, double-blind trial. Setting: The trial was carried out at three hospitals in western Kenya. Participants: The participants were 488 pregnant women presenting at their first antenatal visit with uncomplicated malaria parasitaemia (density of ≥ 500 parasites/μl), a haemoglobin level higher than 7 g/dl, a gestational age between 17 and 34 weeks, and no history of antimalarial or FA use, or sulfa allergy. A total of 415 women completed the study. Interventions: All participants received SP and iron supplementation. They were randomized to the following arms: FA 5 mg, FA 0.4 mg, or FA placebo. After 14 days, all participants continued with FA 5 mg daily as per national guidelines. Participants were followed at days 2, 3, 7, 14, 21, and 28 or until treatment failure. Outcome Measures: The outcomes were SP failure rate and change in haemoglobin at day 14. Results: The proportion of treatment failure at day 14 was 13.9% (19/137) in the placebo group, 14.5% (20/138) in the FA 0.4 mg arm (adjusted hazard ratio [AHR], 1.07; 98.7% confidence interval [CI], 0.48 to 2.37; p = 0.8), and 27.1% (38/140) in the FA 5 mg arm (AHR, 2.19; 98.7% CI, 1.09 to 4.40; p = 0.005). The haemoglobin levels at day 14 were not different relative to placebo (mean difference for FA 5 mg, 0.17 g/dl; 98.7% CI, −0.19 to 0.52; and for FA 0.4 mg, 0.14 g/dl; 98.7% CI, −0.21 to 0.49). Conclusions: Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. Countries that use SP for treatment or prevention of malaria in pregnancy need to evaluate their antenatal policy on timing or dose of FA supplementation., Editorial Commentary Background: Health authorities worldwide recommend that pregnant women supplement their diet with folate (one of the B-vitamins), normally 0.4 mg per day. There is good evidence from systematic reviews of controlled trials that folate supplementation around conception and early in pregnancy is effective in protecting against neural tube (spine and brain) defects; continued supplementation throughout pregnancy reduces the chance of anemia in the mother. In many African countries, including Kenya, the dose of folate used is 5 mg per day, because this dose is more easily available there. In Kenya, as well as elsewhere in Africa, sulfadoxine-pyrimethamine is also given twice or more after the first trimester to treat and/or prevent malaria infection (which is more likely, and can have serious consequences, when a woman is pregnant). However, there is some evidence from laboratory experiments and clinical studies, none of which were done in pregnant women, suggesting that folate supplementation might reduce the effectiveness of sulfadoxine-pyrimethamine. Therefore, these researchers conducted a trial to test this hypothesis in 415 pregnant Kenyan women with malaria parasites in the blood but no severe symptoms. All were given standard sulfadoxine-pyrimethamine treatment. The women were randomized to receive either folate 5 mg daily, folate 0.4 mg daily, or placebo tablets for 14 days, after which all women reverted to the standard folate 5 mg tablets. The women were followed up for 28 days after the initial sulfadoxine-pyrimethamine dose and the principal outcome the researchers were interested in was the failure of sulfadoxine-pyrimethamine treatment, defined as fever and the presence of parasites in the blood (clinical failure) or the failure of parasites to clear from the blood or to reappear too soon (parasitological failure). What this trial shows: In this trial, women receiving folate 5 mg daily were approximately twice as likely to fail treatment with sulfadoxine-pyrimethamine than women receiving folate 0.4 mg or placebo. (Overall, around 27% of the women receiving folate 5 mg had treatment failure during the follow-up period.) All the treatment groups had similar levels of blood hemoglobin at the end of the study. There did not seem to be any major differences in adverse events (such as premature deliveries, stillbirths, or neonatal deaths) among women taking part in the different study groups. Strengths and limitations: The randomization procedures were appropriate and procedures were used to blind participants and researchers to the different interventions, therefore reducing the risk of bias. Since the trial had a placebo arm, it was possible to conclude that the lower dose of folate (0.4 mg) did not significantly affect efficacy of sulfadoxine-pyrimethamine as compared with placebo. A limitation of the study is that the length of the intervention was short, since all women reverted to standard 5 mg folate after 14 days. It is therefore not clear whether a longer trial would have shown additional risks or benefits of the different doses of folate. Finally, PCR genotyping was not done on the parasites infecting women in the trial; this procedure could have distinguished between true treatment failures and new infections (but which would have been unlikely within 14 days). Contribution to the evidence: Other trials and observational studies have suggested that high doses of folate can reduce the efficacy of sulfadoxine-pyrimethamine in children and adults. However these studies have not examined the effect in pregnant women, for whom most national bodies recommend regular folate supplementation. The results from this trial supports the findings from previous studies and enables the evidence to be generalized to pregnant women. The study also found no evidence that 0.4 mg folate compromises the efficacy of sulfadoxine-pyrimethamine. The findings suggest that the lower level of folate dosing should be used in pregnancy, or that antimalarial treatments other than sulfadoxine-pyrimethamine be used.

Background We describe reproductive health issues among pregnant women in a rural area of Kenya with a high coverage of insecticide treated nets (ITNs) and high prevalence of HIV (15%). Methods We conducted a community-based cross-sectional survey among rural pregnant women in western Kenya. A medical, obstetric and reproductive history was obtained. Blood was obtained for a malaria smear and haemoglobin level, and stool was examined for geohelminths. Height and weight were measured. Results Of 673 participants, 87% were multigravidae and 50% were in their third trimester; 41% had started antenatal clinic visits at the time of interview and 69% reported ITN-use. Malaria parasitemia and anaemia (haemoglobin < 11 g/dl) were detected among 36% and 53% of the women, respectively. Geohelminth infections were detected among 76% of the 390 women who gave a stool sample. Twenty percent of women were underweight, and sixteen percent reported symptoms of herpes zoster or oral thrush in the last two months. Nineteen percent of all women reported using a contraceptive method to delay or prevent pregnancy before the current pregnancy (injection 10%, pill 8%, condom 0.4%). Twenty-three percent of multigravidae conceived their current pregnancy within a year of the previous pregnancy. More than half of the multigravidae (55%) had ever lost a live born child and 21% had lost their last singleton live born child at the time of interview. Conclusion In this rural area with a high HIV prevalence, the reported use of condoms before pregnancy was extremely low. Pregnancy health was not optimal with a high prevalence of malaria, geohelminth infections, anaemia and underweight. Chances of losing a child after birth were high. Multiple interventions are needed to improve reproductive health in this area.

Background Improving maternal health is one of the UN Millennium Development Goals. We assessed provision and use of antenatal services and delivery care among women in rural Kenya to determine whether women were receiving appropriate care. Methods Population-based cross-sectional survey among women who had recently delivered. Results Of 635 participants, 90% visited the antenatal clinic (ANC) at least once during their last pregnancy (median number of visits 4). Most women (64%) first visited the ANC in the third trimester; a perceived lack of quality in the ANC was associated with a late first ANC visit (Odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0–2.4). Women who did not visit an ANC were more likely to have < 8 years of education (adjusted OR [AOR] 3.0, 95% CI 1.5–6.0), and a low socio-economic status (SES) (AOR 2.8, 95% CI 1.5–5.3). The ANC provision of abdominal palpation, tetanus vaccination and weight measurement were high (>90%), but provision of other services was low, e.g. malaria prevention (21%), iron (53%) and folate (44%) supplementation, syphilis testing (19.4%) and health talks (14.4%). Eighty percent of women delivered outside a health facility; among these, traditional birth attendants assisted 42%, laypersons assisted 36%, while 22% received no assistance. Factors significantly associated with giving birth outside a health facility included: age ≥ 30 years, parity ≥ 5, low SES, < 8 years of education, and > 1 hour walking distance from the health facility. Women who delivered unassisted were more likely to be of parity ≥ 5 (AOR 5.7, 95% CI 2.8–11.6). Conclusion In this rural area, usage of the ANC was high, but this opportunity to deliver important health services was not fully utilized. Use of professional delivery services was low, and almost 1 out of 5 women delivered unassisted. There is an urgent need to improve this dangerous situation.

Background Resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum parasites is associated with mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes and has spread worldwide. SP remains the recommended drug for intermittent preventive treatment for malaria in pregnancy (IPTp) and information on population prevalence of the SP resistance molecular markers in pregnant women is limited. Methods Temporal trends of SP resistance molecular markers were investigated in 489 parasite samples collected from pregnant women at delivery from three different observational studies between 1996 and 2009 in Kenya, where SP was adopted for both IPTp and case treatment policies in 1998. Using real-time polymerase chain reaction, pyrosequencing and direct sequencing, 10 single-nucleotide polymorphisms (SNPs) of SP resistance molecular markers were assayed. Results The prevalence of quintuple mutant (dhfr N51I/C59R/S108N and dhps A437G/K540E combined genotype) increased from 7 % in the first study (1996–2000) to 88 % in the third study (2008–2009). When further stratified by sample collection year and adoption of IPTp policy, the prevalence of the quintuple mutant increased from 2.4 % in 1998 to 44.4 % three years after IPTp policy adoption, seemingly in parallel with the increase in percentage of SP use in pregnancy. However, in the 1996–2000 study, more mutations in the combined dhfr/dhps genotype were associated with SP use during pregnancy only in univariable analysis and no associations were detected in the 2002–2008 and 2008–2009 studies. In addition, in the 2008–2009 study, 5.3 % of the parasite samples carried the dhps triple mutant (A437G/K540E/A581G). There were no differences in the prevalence of SP mutant genotypes between the parasite samples from HIV + and HIV- women over time and between paired peripheral and placental samples. Conclusions There was a significant increase in dhfr/dhps quintuple mutant and the emergence of new genotype containing dhps 581 in the parasites from pregnant women in western Kenya over 13 years. IPTp adoption and SP use in pregnancy only played a minor role in the increased drug-resistant parasites in the pregnant women over time. Most likely, other major factors, such as the high prevalence of resistant parasites selected by the use of SP for case management in large non-pregnant population, might have contributed to the temporally increased prevalence of SP resistant parasites in pregnant women. Further investigations are needed to determine the linkage between SP drug resistance markers and efficacy of IPTp-SP.