Dataset Information

Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study.

ABSTRACT:

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.

SUBMITTER: Taylor SM

PROVIDER: S-EPMC3520448 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Publications

Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study.

Taylor Steve M SM Antonia Alejandro L AL Chaluluka Ebbie E Mwapasa Victor V Feng Gaoqian G Molyneux Malcolm E ME ter Kuile Feiko O FO Meshnick Steven R SR Rogerson Stephen J SJ

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20120322 1

<h4>Background</h4>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.<h4>Methods</h4>We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plas ...[more]

PMID: 22441649

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Project description:Malaria is a major parasitic disease, affecting millions of people in endemic areas. Plasmodium falciparum parasites are responsible for the most severe cases and its resistance to anti-malarial drugs is notorious. This is a possible obstacle to the effectiveness of intermittent preventive treatment (IPT) based on sulfadoxine-pyrimethamine (SP) cures administrated to pregnant women (IPTp) during their pregnancy. As this intervention is recommended in Angola since 2006, it has assessed, in this country, the molecular profiles in P. falciparum dhfr and dhps, two polymorphic genes associated to pyrimethamine and sulfadoxine resistance, respectively.Blood samples from 52 falciparum patients were collected in Lubango, Angola and pfdhfr and pfdhps polymorphisms were analysed using nested-PCR and DNA sequencing.In the pfdhfr gene, the 108N mutation was almost fixed (98 %), followed by 59R (63 %), 51I (46 %), 50R and 164L (2 %, respectively). No 16V/S mutations were found. The most common double mutant genotype was CNRN (59 + 108; 46 %), followed by CICN (51 + 108; 29 %) whereas IRN (51 + 59 + 108; 15 %), CNRNVL (59 + 108 + 164; 2 %) and RICN (50 + 51 + 108; 2 %) triple mutant genotypes were detected. Investigations of the pfdhps gene showed that the 437G mutation was the most prevalent (97 %). Only two and one samples disclosed the 540E (7 %) and the 436A (3 %), respectively. Single mutant SGKAA (437; 86 %) was higher than SGEAA (437 + 540; 7 %) or AGKAA (436 + 437; 3 %) double mutants genotypes. No polymorphism was detected at codons 581G and 613T/S. Combining pfdhfr and pfdhps alleles two triple mutant haplotypes (double mutant in dhfr and single mutant in dhps) were observed: the ACICNVI/SGKAA in 14 (56 %) samples and the ACNRNVI/SGKAA in five (20 %) samples. One quadruple mutant haplotype was detected (ACIRNVI/SGKAA) in six (24 %) P. falciparum samples. No quintuple pfdhfr-pfdhps mutant was noted.pfdhfr and pfdhps gene mutations in isolates from Lubango are suggestive of a low-grade SP resistance and IPT for pregnant women and infant based on SP treatment could be effective. Routine molecular studies targeting polymorphism in these two genes need to be routinely conducted at country level.

Project description:BACKGROUND:In Pakistan, artesunate (AS) in combination with sulfadoxine-pyrimethamine (SP) is the recommended treatment for uncomplicated Plasmodium falciparum malaria. Monitoring molecular markers of anti-malarial drug resistance is crucial for early detection and containment of parasite resistance to treatment. Currently, no data are available on molecular markers of artemisinin resistance (K13 mutations) in P. falciparum isolates from Pakistan. In this study, the prevalence of mutations associated with SP and artemisinin resistance was estimated in different regions of Pakistan. METHODS:A total of 845 blood samples that were positive for malaria parasites by microscopy or rapid diagnostic test were collected from January 2016 to February 2017 from 16 different sites in Pakistan. Of these samples, 300 were positive for P. falciparum by PCR. Polymorphisms in the P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes were identified by pyrosequencing while polymorphisms in the propeller domain of the pfk13 gene were identified by Sanger sequencing. RESULTS:The prevalence of the PfDHFR 108N and 59R mutations was 100% and 98.8%, respectively, while the prevalence of PfDHFR 50R and 51I mutations was 8.6%. No mutation was observed at PfDHFR position 164. In PfDHPS, the prevalence of mutations at positions 436, 437, and 613 was 9.9%, 45.2%, and 0.4%, respectively. No mutations were found at PfDHPS positions 540 and 581. The prevalence of double PfDHFR mutants (59R?+?108N) ranged from 93.8% to 100%, while the prevalence of parasites having the PfDHFR 59R?+?108N mutations in addition to the PfDHPS 437G mutation ranged from 9.5% to 83.3% across different regions of Pakistan. Nine non-synonymous and four synonymous mutations were observed in the PfK13 propeller domain, none of which correspond to mutations validated to contribute to artemisinin resistance. CONCLUSION:The absence of the highly resistant PfDHFR/PfDHPS quintuple mutant parasites and the lack of PfK13 mutations associated with artemisinin resistance is consistent with AS?+?SP being effective in Pakistan.

Project description:BackgroundSulfadoxine-pyrimethamine (SP) is recommended in Africa in several antimalarial preventive regimens including Intermittent Preventive Treatment in pregnant women (IPTp), Intermittent Preventive Treatment in infants (IPTi) and Seasonal Malaria Chemoprevention (SMC). The effectiveness of SP-based preventive treatments are threatened in areas where Plasmodium falciparum resistance to SP is high. The prevalence of mutations in the dihydropteroate synthase gene (pfdhps) can be used to monitor SP effectiveness. IPTi-SP is recommended only in areas where the prevalence of the pfdhps540E mutation is below 50%. It has also been suggested that IPTp-SP does not have a protective effect in areas where the pfdhps581G mutation, exceeds 10%. However, pfdhps mutation prevalence data in Africa are extremely heterogenous and scattered, with data completely missing from many areas.Methods and findingsThe WWARN SP Molecular Surveyor database was designed to summarize dihydrofolate reductase (pfdhfr) and pfdhps gene mutation prevalence data. In this paper, pfdhps mutation prevalence data was used to generate continuous spatiotemporal surface maps of the estimated prevalence of the SP resistance markers pfdhps437G, pfdhps540E, and pfdhps581G in Africa from 1990 to 2020 using a geostatistical model, with a Bayesian inference framework to estimate uncertainty. The maps of estimated prevalence show an expansion of the pfdhps437G mutations across the entire continent over the last three decades. The pfdhps540E mutation emerged from limited foci in East Africa to currently exceeding 50% estimated prevalence in most of East and South East Africa. pfdhps540E distribution is expanding at low or moderate prevalence in central Africa and a predicted focus in West Africa. Although the pfdhps581G mutation spread from one focus in East Africa in 2000, to exceeding 10% estimated prevalence in several foci in 2010, the predicted distribution of the marker did not expand in 2020, however our analysis indicated high uncertainty in areas where pfdhps581G is present. Uncertainty was higher in spatial regions where the prevalence of a marker is intermediate or where prevalence is changing over time.ConclusionsThe WWARN SP Molecular Surveyor database and a set of continuous spatiotemporal surface maps were built to provide users with standardized, current information on resistance marker distribution and prevalence estimates. According to the maps, the high prevalence of pfdhps540E mutation was to date restricted to East and South East Africa, which is reassuring for continued use of IPTi and SMC in West Africa, but continuous monitoring is needed as the pfdhps540E distribution is expanding. Several foci where pfdhps581G prevalence exceeded 10% were identified. More data on the pfdhps581G distribution in these areas needs to be collected to guide IPTp-SP recommendations. Prevalence and uncertainty maps can be utilized together to strategically identify sites where increased surveillance can be most informative. This study combines a molecular marker database and predictive modelling to highlight areas of concern, which can be used to support decisions in public health, highlight knowledge gaps in certain regions, and guide future research.

Dataset Information

Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study.

Background

Methods

Results

Conclusions

Publications

Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study.

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