Reduced Birth Weight Caused by Sextuple Drug-Resistant <i>Plasmodium falciparum</i> Infection in Early Second Trimester

Hansson, Helle; Minja, Daniel T. R.; Moeller, Sofie L; Lusingu, John; Bygbjerg, Ib Christian; Yde, Anna-Mathilde; Jensen, Rasmus Weisel; Nag, Sidsel; Msemo, Omari Abdul; Theander, Thor G.; Alifrangis, Michael; Schmiegelow, Christentze

doi:10.1093/infdis/jiab117

Cited by 4 publications

(6 citation statements)

References 31 publications

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“…A sixth mutant, dhps A581G, conveys high-grade resistance to sulfadoxine-pyrimethamine and appears to be increasing in prevalence. In Tanzania and Malawi, infection with parasites with the A581G mutation was associated with substantial decreases in birthweight compared to women with no malaria, or to women infected with parasites that lacked the mutation [52 ]. Sulfadoxine-pyrimethamine resistance has led to the search for alternative drugs or combinations.…”

Section: Malaria Prevention: Intermittent Preventive Treatmentmentioning

confidence: 99%

Pregnancy and malaria: the perfect storm

Rogerson

Unger

2022

Current Opinion in Infectious Diseases

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Purpose of reviewMalaria in pregnancy continues to exert a toll on pregnant women and their offspring.Recent findingsThe burden of Plasmodium falciparum infection is especially large in Africa, and new data show lasting effects of maternal infection on the infant's neurocognitive development. Elsewhere, P. vivax infection causes relapsing infections that are challenging to prevent. Infection in first trimester of pregnancy is an area of increasing focus, and its adverse effects on pregnancy outcome are increasingly recognised. First-trimester infection is common and frequently acquired prior to conception. Although newer rapid diagnostic tests still have limited sensitivity, they may be useful in detection of early pregnancy malaria for treatment. Artemisinin-based combination therapies are efficacious in later pregnancy but have yet to be recommended in first trimester because of limited safety data. In Africa, intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine improves pregnancy outcomes, but sulfadoxine-pyrimethamine resistance is worsening. The alternative, IPTp with dihydroartemisinin-piperaquine, has greater antimalarial efficacy, but does not appear to improve pregnancy outcomes, because sulfadoxine-pyrimethamine has poorly understood nonmalarial benefits on birthweight.SummaryNovel IPTp regimens must be combined with interventions to strengthen protection from malaria infection acquired before and in early pregnancy.

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Section: Malaria Prevention: Intermittent Preventive Treatmentmentioning

confidence: 99%

Pregnancy and malaria: the perfect storm

Rogerson

Unger

2022

Current Opinion in Infectious Diseases

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“…Before the advent of the Pfdhps 431V mutation in Nigeria, East Africa witnessed a similar scenario with the emergence of the quintuple ( IRN + 437 G + 540 E ) and sextuple ( IRN + 437 G + 540 E + 581 G ) mutant haplotypes. These were associated with a reduction in the mean birth weight and other metrics of SP-IPTp failure in Tanzania [ 13 , 56 ]. Although no 540E mutation was observed in the present study, it is possible that the emerging Pfdhps 431V and its co-occurrence with 581G and 613S could lead to a higher order mutant haplotype, and this alternative sextuple mutant might compromise the chemopreventive impact of SP-IPTp in West Africa.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicated that the prevalence of Pfdhps 431V varies across regions in Nigeria in clinical isolates collected at various respective study periods [ 13 – 15 ]. For instance, a low prevalence of Pfdhps 431V mutation was reported in Southwest Nigeria, whereas the prevalence in the parasite population is widespread in the Southeast and Northeast Nigeria among the samples collected about a decade ago [ 13 ]. Figures 2 and 3 give a view of the spatial distribution of Pfdhps -431V and -581G in Nigeria and neighbouring countries, using data reported in surveys conducted between 2007 and 2020.…”

Section: Discussionmentioning

confidence: 99%

“…This results in the ‘super resistant’ sextuple haplotype of Pfdhfr / Pfdhps (mainly the constructed haplotype: C IRN I-S GEG A). There is evidence that the C IRN I-S GEG A haplotype signals a loss of sensitivity of Plasmodium falciparum to SP and compromise the effectiveness of the SP-IPTp strategy including a reduction in its ability to prevent low birthweights [ 5 , 6 , 12 , 13 ]. In contrast, in West Africa, the absence of 540 and 581 genotypes was reassuring for the continuation of SP-IPTp efficacy.…”

Section: Introductionmentioning

confidence: 99%

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A snapshot of the prevalence of dihydropteroate synthase-431V mutation and other sulfadoxine-pyrimethamine resistance markers in Plasmodium falciparum isolates in Nigeria

Adegbola

Ijarotimi

Ubom

et al. 2023

Malar J

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Background Malaria is a major public health issue with substantial risks among vulnerable populations. Currently, the World Health Organization (WHO) recommends SP-IPTp in the second and third trimesters. However, the efficacy of SP-IPTp is threatened by the emergence of sulfadoxine-pyrimethamine resistant malaria parasites due to single nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. This study aimed to assess the current prevalence of Pfdhfr/Pfdhps mutations in P. falciparum isolates collected from individuals residing in Ile-Ife, Nigeria, and also present maps of the prevalence of Pfdhps 431V and 581G within Nigeria and surrounding countries. Methods Between October 2020 and April 2021, samples were collected as dried blood spots among 188 participants who showed malaria positivity with a histidine-rich-protein-based rapid diagnostic test (RDT). Nested PCR assays were used to confirm falciparum in the samples with RDT positivity, and to amplify fragments of the Pfdhfr/Pfdhps genes followed by targeted amplicon sequencing. Published data since 2007 on the prevalence of the Pfdhps genotypes in Nigeria and the neighbouring countries were used to produce maps to show the distribution of the mutant genotypes. Results Only 74 and 61 samples were successfully amplified for the Pfdhfr and Pfdhps genes, respectively. At codons resulting in N51I, C59R, and S108N, Pfdhfr carried mutant alleles of 97.3% (72/74), 97.3% (72/74) and 98.6% (73/74), respectively. The Pfdhps gene carried mutations at codons resulting in amino acid changes at 431–436-437–540-581–613; I431V [45.9%, (28/61)], A581G [31.1% (19/61)] and A613S [49.2% (30/61)]. Constructed haplotypes were mainly the triple Pfdhfr mutant 51I-59R-108N (95.9%), and the most common haplotypes observed for the Pfdhps gene were the ISGKAA (32.8%), ISGKGS (8.2%), VAGKAA (14.8%), VAGKAS (9.8%) and VAGKGS (14.8%). In the context of the previously published data, a high prevalence of 431V/581G mutations was found in the study population. It seems quite evident that the Pfdhps 431V, 581G and 613S often co-occur as Pfdhps-VAGKGS haplotype. Conclusion This study showed that the prevalence of VAGKGS haplotype seems to be increasing in prevalence. If this is similar in effect to the emergence of 581G in East Africa, the efficacy of SP-IPTp in the presence of these novel Pfdhps mutants should be re-assessed.

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“…Women were screened for malaria using malaria rapid diagnostic test kit (ParaHIT, Span Diagnostics or CareStart Malaria Pf, ACCESS BIO). Microscopy were performed on all samples, and PCR on a subset, to confirm malaria positivity [ 32 ]. Malaria patients were offered oral artemether-lumefantrine (Lumartem 20 mg/120 mg, Cipla Ltd), quinine, or artesunate injections depending on severity and GA [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

Cord Blood FGF-21 and GDF-15 Levels Are Affected by Maternal Exposure to Moderate to Severe Anemia and Malaria

Hjort,

Wewer Albrechtsen,

Minja

et al. 2023

Journal of the Endocrine Society

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Introduction Anemia and malaria are global health problems affecting >50% of pregnant women in Sub-Saharan Africa and are associated with intrauterine growth restriction. The hormones fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) are involved in metabolic regulation, and expressed in the placenta. No studies exist on FGF-21 and GDF-15 responses to exposures of malaria and anemia in pregnancy. Aims and Methods Using a prospective, longitudinal pregnancy and birth cohort of women with an average age of 26 years from a rural region in northeastern Tanzania, we examined if FGF-21 and GDF-15 levels in maternal blood at week 33±2 (n=301) and in cord blood at birth (n=353), were associated with anemia and malaria exposure at different time points in pregnancy and with neonatal anthropometry. Results Among mothers at gestation week 33±2, lower FGF-21 levels were observed after exposure to malaria in the 1st trimester, but not anemia, whereas GDF-15 levels at week 33±2 were not associated with malaria nor anemia. In cord blood, moderate-severe anemia at any time point in pregnancy was associated with higher levels of FGF-21, whereas malaria exposure in the 3rd trimester was associated with lower FGF-21 levels in cord blood. Negative associations were observed between cord blood FGF-21 and GDF-15 levels and neonatal skinfold thicknesses and birthweight. Conclusions Our results suggest that moderate-severe anemia throughout pregnancy associate with higher FGF-21 levels, and malaria in last trimester associate with lower FGF-21 levels, in the neonates, thereby potentially affecting the future cardio-metabolic health of the child.

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Reduced Birth Weight Caused by Sextuple Drug-Resistant Plasmodium falciparum Infection in Early Second Trimester

Cited by 4 publications

References 31 publications

Pregnancy and malaria: the perfect storm

Pregnancy and malaria: the perfect storm

A snapshot of the prevalence of dihydropteroate synthase-431V mutation and other sulfadoxine-pyrimethamine resistance markers in Plasmodium falciparum isolates in Nigeria

Cord Blood FGF-21 and GDF-15 Levels Are Affected by Maternal Exposure to Moderate to Severe Anemia and Malaria

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