Menu
Menu
Menu
Menu
Background. Antenatal intermittent preventive therapy with 2 doses of sulfadoxine-pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads.Methods.We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes.Results.The prevalence of parasites with highly SP-resistant haplotypes increased from 17 to 100 (P <. 001), and the proportion of women receiving full IPTp (≥2 doses) increased from 25 to 82 (P <. 001). Women who received full IPTp with SP had lower peripheral (P =. 018) and placental (P <. 001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity.Conclusions.In this longitudinal study of malaria at delivery, the receipt of SP as IPTp did not potentiate PAM morbidity despite the increasing prevalence and fixation of SP-resistant P. falciparum haplotypes. Even when there is substantial resistance, SP may be used in modified IPTp regimens as a component of comprehensive antenatal care. © 2012 The Author.
Ethical approval for this study was granted by the review boards of the Malawi Health Sciences Research Committee, the University of Malawi College of Medicine, and the University of North Carolina at Chapel Hill. Patient enrollment and sample collection have been described elsewhere [6, 8]. In brief, pregnant women delivering between July 1997 and August 2006 at Queen Elizabeth Central Hospital in Blantyre, Malawi, were invited to participate. Those who consented to participate were queried regarding demographic and clinical information. The receipt of SP antenatally was obtained from antenatal clinic cards; from 1999 onward, the date of the last dose of SP was available. Peripheral and placental blood was used to prepare thick blood smears, which were read by 2 microscopists for the presence and density of P. falciparum parasites. From 1998 onward, full-thickness placental biopsies were wax embedded, stained with modified Giemsa and/or hematoxylin and eosin, and assessed by 2 trained observers masked to other clinical data. Histologic indices included (1) density of parasitemia, expressed as percentage of all observed erythrocytes that were parasitized; (2) mononuclear cell infiltrate, expressed as percentage of all cells observed in the intervillous space; and (3) semiquantitative assessment of malaria pigment deposition in fibrin, as an indicator of chronic placental inflammation [9]. Maternal hemoglobin concentration was measured using HemoCue, and newborns were weighed within 1 day of birth. A subset of 25% of available samples from women with positive peripheral blood thick smears for P. falciparum parasites was manually selected at random by personnel blinded to all clinical information. From these specimens, genomic DNA was extracted and P. falciparum parasites were genotyped for mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes by direct sequencing [7]. To reduce contamination risk, separate work areas were maintained for molecular steps and filtered pipette tips were used for all procedures. Mutations were investigated at codons 51, 59, 108, and 164 of dhfr and codons 437, 540, 581, and 613 of dhps. Haplotypes were assigned based upon codons 51, 59, and 108 in dhfr and 437 and 540 in dhps [10]. The “quintuple mutant” haplotype consisted of mixed or mutant alleles at all 5 loci in dhfr and dhps; “partial wild-type” haplotypes were those with a wild-type allele at any locus. Recent antenatal SP receipt was defined as within 60 days prior to delivery, owing to the prolonged half-life and activity of SP [11]. Maternal anemia was defined as a hemoglobin concentration <11 g/dL (any) and <9 g/dL (moderate), and low birth weight was defined as <2500 g. Antenatal SP use was categorized as “full IPTp” (≥2 doses) or “suboptimal IPTp” (<2 doses). Antenatal indices and birth outcomes (parasite densities, placental histologic indices, maternal hemoglobin concentration, and birth weight) were compared between women who received suboptimal or full IPTp using the Kruskal-Wallis rank test, the Student t test, or the χ2 test. The prevalence of moderate anemia and low birth weight were compared between groups using the χ2 test. To assess for effect modification of the effect of IPTp upon birth outcomes, we stratified women into those harboring partial wild-type parasites and those with quintuple mutant parasites; after stratification, we repeated comparisons of birth outcomes between IPTp groups. To account for covariates (including the effect of the year of delivery and the effect of resistant P. falciparum) in the analysis of the association between IPTp-SP and birth outcomes, we first used linear or logistic regression to compare maternal peripheral parasite density, placental parasite density, maternal hemoglobin concentration, birth weight, and the dichotomized proportions of moderate anemia and low birth weight between women who received suboptimal and full IPTp. Parasite densities were natural log-transformed prior to regression modeling. Subsequently, adjusted comparisons were then computed by repeating regression models after the inclusion of covariates representing delivery year and P. falciparum haplotype, as well as reported mediators of placental pathology: human immunodeficiency virus (HIV) infection [12], gravidity (primigravid versus multigravid) [4], and the recent receipt of SP. Clinical data were initially entered into Epi Info or Microsoft Access; all statistical analyses were ultimately performed using Stata/IC, version 10.
