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Background:Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is widely recommended in sub-Saharan Africa to reduce the risk of malaria and improve birth outcomes. However, there are reports that the efficacy of IPTp with SP is waning, especially in parts of Africa where antimalarial resistance to this drug has become widespread.Methodology/Principal Findings:We conducted a cross-sectional study of 565 HIV-uninfected women giving birth at Tororo District Hospital in southeastern Uganda. The primary objective of the study was to measure associations between use of SP during pregnancy from antenatal records and the risk of adverse outcomes including placental malaria, low birth weight, maternal parasitemia and maternal anemia. The proportion of women who reported taking 0, 1, 2, and 3 doses of SP during pregnancy was 5.7%, 35.8%, 56.6% and 2.0% respectively. Overall, the prevalence of placental malaria was 17.5%, 28.1%, and 66.2% by placental smear, PCR, and histopathology, respectively. In multivariate analyses controlling for potential confounders, ≥2 doses of SP was associated with non-significant trends towards lower odds of placental malaria by placental smear (OR = 0.75, p = 0.25), placental malaria by PCR (OR = 0.93, p = 0.71), placental malaria by histopathology (OR = 0.75, p = 0.16), low birth weight (OR = 0.63, p = 0.11), maternal parasitemia (OR = 0.88, p = 0.60) and maternal anemia (OR = 0.88, p = 0.48). Using a composite outcome, ≥2doses of SP was associated with a significantly lower odds of placental malaria, low birth weight, maternal parasitemia, or maternal anemia (OR = 0.52, p = 0.01).Conclusions/Significance:In this area of Uganda with intense malaria transmission, the prevalence of placental malaria by histopathology was high even among women who reported taking at least 2 doses of SP during pregnancy. The reported use of ≥2 doses of SP was not associated with protection against individual birth and maternal outcome measures but did protect against a composite measure of any adverse outcome. © 2013.
The study protocol was approved by the Uganda National Council of Science and Technology and the institutional review boards of the University of California, San Francisco, Makerere University, and the U.S. Centers for Disease Control and Prevention. Written informed consent was sought from all participants before being enrolled in the study. This study was conducted in Tororo, an area of southeastern Uganda with high malaria transmission intensity and an entomological inoculation rate recently estimated to be 125 infectious bites per person per year in 2011–12 (Grant Dorsey, personal communication). Study participants were women giving birth at Tororo District Hospital (TDH), a government hospital that provides antenatal services and free HIV testing to all pregnant women. Using a cross-sectional study design, all pregnant women with singleton births delivering at TDH who were known to be HIV-uninfected were screened for enrollment if they delivered between Monday 8∶00 am through Friday 4∶00 pm from February 28th through July 4th, 2011. Women were enrolled if they fulfilled the following selection criteria: 1) SP use documented from antenatal card if attended antenatal care, 2) HIV status known and negative, 3) absence of reported antimalarial therapy other than SP in the previous 1 month, and 4) provision of informed consent. A standardized questionnaire was administered to all enrolled women including review of their government issued antenatal card. Information collected as part of the questionnaire included demographics, previous pregnancies, bednet use, education level, ownership of household items, and the number and timing of doses of SP (for which administration is directly observed in the antenatal clinic) and other medications. Delivery outcomes were assessed and birth weight obtained using a digital scale (Seca, Birmingham, U.K.). Data on gestational age was not collected because information on last menstrual period was often missing and if present thought to be inaccurate. Biological samples collected included maternal finger prick for blood smear and hemoglobin measurement and placental blood and tissue biopsy. Hemoglobin measurements from maternal blood were made using a portable spectrophotometer (HemoCue, Ängelholm, Sweden). Maternal and placental thick blood smears were stained with 2% Giemsa for 30 minutes and examined for malaria parasites by standard microscopy. Parasite density was estimated by counting the number of asexual parasites per 200 white blood cells and calculating parasites per µL, assuming a white blood cell count of 8,000 cells per µL. A smear was judged to be negative if no parasites were seen after review of 500 high-powered fields. Final microscopy results were based on a rigorous quality control system with re-reading all blood smears by a second microscopist and resolution of any discrepancies by a third microscopist. PCR for the detection of malaria parasites were performed on placental blood stored on filter paper using nested PCR as previously described [12]. Placental biopsies of approximately 1–2 cm×1–2 cm from the maternal side were collected using scissors and placed in 10% neutral buffered formalin. After 24 hours, biopsies were trimmed with a razor blade to 1×1 cm size and formalin replaced with fresh neutral buffered formalin. Following 1–3 months of storage, placental tissue was embedded in paraffin wax, microtome sectioned and stained with 2% Giemsa, and hematoxylin and eosin. Histopathological slides were examined using standard and polarized light microscopy for hemozoin pigment in intervillous fibrin, malaria parasites, and macrophages with hemozoin pigment using standardized criteria as previously described [13]. Data were double entered in Access (Microsoft Corporation, Redmond, Washington, USA), and analyses performed using STATA (Stata Corp., College Station, Texas, USA). The primary exposure variable of interest was IPTp use with SP as indicated on the participant’s antenatal card. Given the distribution of the number of SP doses reported taken, SP usage was dichotomized into <2 doses vs. ≥2 doses of IPTp. Comparisons of characteristics between the two SP usage groups were made using the chi-squared or t-test. Three definitions of placenta malaria were used: 1) any parasitemia by placental blood smear, 2) detection of parasites by PCR, and 3) any evidence of placental malaria by histopathology. Maternal peripheral parasitemia was defined as a positive blood smear and maternal anemia defined as a hemoglobin level <11 gm/dL. Low birth weight was defined as <2500 gm. Univariate and multivariate analyses of associations between SP usage and outcomes of interest were performed using logistic regression. Covariates adjusted for in multivariate analyses included maternal age, gravidity, bednet use, level of education, transmission season, and a wealth index generated using principal component analysis as previously described [14]. Characteristics used to calculate the wealth index included number of people sleeping in room with participant, and household ownership of electricity, television, mobile phone, radio, bicycle, motorcycle, refrigerator and toilet. A p-value of <0.05 was considered statistically significant.
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