In vivo Efficacy of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Malaria in Pregnancy — Mansa, Zambia

People continue to question the efficacy of Sulfadoxine-Pyrimethamine for intermittent preventive treatment of malaria during pregnancy as a preventive measure. Kathrine R. Tan, Bonnie R. Katalenich, Kimberly E. Mace, Michael Nambozi, Steve M. Taylor, Steven R. Meshnick, Ryan E. Wiegand, Victor Chalwe, Scott J. Filler, Mulakwa Kamuliwo, and Allen S. Craig presented information at the recent American Society of Tropical medicine and Hygiene 62nd Annual meeting that should allay these concerns.  Below are the main points from their poster.

Fig 1Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) decreases adverse effects of malaria during pregnancy SP resistance threatens IPTp–SP strategy.  Mutations on the P. falciparum genes for dhfr and dhps are associated with SP drug resistance. Quintuple mutant haplotype (substitutions in N51I, C59R, S108N in dhfr and A437G and K540E in dhps) is a marker for SP treatment failure in non-pregnant patients.  Prevalence of molecular markers for SP resistance among pregnant women and how this translates into efficacy of IPTp-SP is unknown.

Fig 2The study objectives were 1) To determine the efficacy of IPTp-SP in clearing peripheral parasitemia in asymptomatic pregnant women , 2) To estimate prevalence of molecular markers for SP resistance among pregnant women in Mansa and 3) To describe the relationship of therapeutic efficacy of IPTp-SP with prevalence of molecular markers for SP resistance.

Tab 1Setting and population focused on Pregnant women attending two antenatal clinics in Mansa, Zambia, an area with high malaria transmission between January 2010 – March 2011 . Inclusion criteria were Pregnant women in their second trimester (by last menstrual period), HIV negative, no prior antimalarials or IPTp-SP in the current pregnancy, and asymptomatic parasitemia. The In vivo therapeutic efficacy study  looked for

  • Asymptomatic parasitemia determined by fever history, temperature measurement, and rapid diagnostic test (confirmed with malaria smear)
  • Follow up weekly for five weeks to assess for fever, parasitemia by blood smear, and hemoglobin
  • Polymerase chain reaction (PCR) of parasites on follow up to determine reinfection or recrudescence
  • Main Outcomes observed were –
  1. Adequate parasitic response — no parasitemia on follow up
  2. Parasitological failure — recrudescence
  3. Survival analysis done to describe time to failure and included those with incomplete follow up

Fig 3Molecular markers include PCR of Day 0 specimens to detect mutations on genes for dhps and dhfr.

Figure 1 shows Enrollment and disposition of study participants with Molecular Markers on 84. Quintuple mutant was seen in 51 (61%). There was No association between quintuple mutation and in vivo therapeutic efficacy outcome. Triple mutant only was 20 (24%) ; Double mutant only 7 (8%); and  Sextuple mutant (quintuple mutation plus mutation at codon 581 of dhps) 2 (2%). Table 1 shows the Characteristics of the study 92 participants.

Figure 2 provides Outcomes of in vivo therapeutic efficacy study. A Summary of outcomes found Parasitological failure in 7 (14%)  and Adequate parasitological response in 44 (86%). Figure 3 depicts the Kaplan-Meier survival estimates. Time to failure for all study participants (n=92, top panel) was 33.6 days, and did not significantly differ by gravidity (bottom pannel).

The study had some limitations including Small sample size — underpowered. There were No refusals for participation, but high rates for incomplete and loss to follow up — women may have enrolled as a socially desirable response, then later dropped out. Efficacy of IPTp-SP was examined in terms of parasite clearance. Care must be taken in extrapolating these results to effectiveness of IPTp-SP to prevent outcomes such as low birthweight and neonatal mortality.

IPTp-SP in Zambia still has in vivo efficacy and should be continued especially since there are no other drug alternatives for IPTp. Low in vivo failure rate relative to the moderate prevalence of molecular markers in Mansa was observed. There was No association between presence of the quintuple mutant and parasitologic failure, This is the First time the sextuple mutant has been described in Zambia. This study contributes to the paucity of data on in vivo efficacy of IPTp-SP in the setting of intermediate prevalence of SP resistance markers. Zambian IPTp-SP guidelines have been updated to reflect current WHO guidelines stressing IPTp at each ANC visit after quickening.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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