Lack of effect of intermittent preventive treatment for malaria in pregnancy and intense drug resistance in western Uganda

Abstract

BackgroundIntermittent preventive treatment in pregnancy (IPTp) with sulfadoxine–pyrimethamine (SP) is widely implemented in sub-Saharan Africa for the prevention of malaria in pregnancy and adverse birth outcomes. However, in areas of intense SP resistance, the efficacy of IPTp may be compromised.MethodsA cross-sectional study among 915 delivering women (728 analysable live singleton deliveries) was conducted in Fort Portal, western Uganda, to assess associations of reported IPTp use, Plasmodium falciparum infection, maternal anaemia, low birth weight, and preterm delivery, and to estimate the degree of SP resistance as reflected by pfdhfr/pfdhps mutations.ResultsPlasmodium falciparum infection was detected by PCR in 8.9 % and by microscopy of placental blood samples in 4.0 %. Infection was significantly associated with stillbirth, early neonatal death, anaemia, low birth weight, and pre-term delivery. Eighty percent of the women had taken at least one dose of IPTp, and more than half had taken two doses. As compared to women without chemoprophylaxis against malaria, IPTp had no significant influence on the presence of P. falciparum infection (13.8 vs. 9.6 %, P = 0.31). Nor was it associated with reductions in anaemia, low birth weight or preterm delivery. P. falciparum with intense SP resistance (pfdhfr/pfdhps quintuple or sextuple mutations) were observed in 93 % (pfdhps 581G, 36 %), and the additional high resistance allele pfhdr 164L in 36 %.ConclusionsIn Fort Portal, Uganda, reported use of IPTp with SP does not provide an observable benefit. The molecular markers of P. falciparum indicate high grade SP resistance reaching the threshold set by WHO for the discontinuation of IPTp with SP. Alternative approaches for the prevention of malaria in pregnancy are urgently needed.

Pharmacokinetics of Sulfadoxine and Pyrimethamine for Intermittent Preventive Treatment of Malaria During Pregnancy and After Delivery

“…Sulfadoxine/pyrimethamine (SP) is recommended by the WHO as intermittent preventative treatment (IPTp) for the prevention of malaria in pregnancy in sub‐Saharan Africa 6. IPTp with SP is administered in at least two doses, starting in the second trimester of pregnancy after quickening, with an interval of at least 4 weeks 4.…”

Prevalence of <em>Plasmodium falciparum</em> antimalarial drug resistance genes in Southeastern Gabon from 2011 to 2014

“…The triple Pfdhfr mutation N51I, C59R, and S108N in combination with the double A437G and K540E Pfdhps mutant formed a quintuple mutant haplotype, which confers a high risk of treatment failure with SP 6. Recent studies have shown an increase in Pfdhps mutations at A581G, thus further escalating the risk for even higher levels of resistance and significant decreases in the effectiveness of SP as IPTp 7,8…”

Burden of Placental Malaria among Pregnant Women Who Use or Do Not Use Intermittent Preventive Treatment at Mulago Hospital, Kampala

“…This scenario contrasts with a previous study in which up to 25% of pregnant women reporting nonuse of SP were found to have residual drug when tested [34]. Many previous studies reporting ineffectiveness of SP-IPTp have relied on self-reports and ANC records as proof of SP use [14, 15, 19]. Where no effort is made to ascertain actual user compliance, such findings remain questionable, especially coming from resource-constrained settings where unsupervised administration of SP is the norm, contrary to guidelines.…”

“…These concerns have been largely driven by the rising prevalence of higher-level SP resistance mutations. To this end, recent studies from areas with high prevalence of resistance mutations have reported reduced efficacy of SP-IPTp [14, 15, 19, 20]. However, such findings in most cases are hampered by the exclusive reliance on self-reports and antenatal records to ascertain SP use.…”