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Sulfadoxine/Pyrimethamine Intermittent Preventive Treatment for Malaria During Pregnancy

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Sulfadoxine/Pyrimethamine Intermittent Preventive Treatment for Malaria During Pregnancy SYNOPSIS Sulfadoxine/Pyrimethamine Intermittent Preventive Treatment for Malaria during Pregnancy Philippe Deloron, Gwladys Bertin, Valérie Briand, Achille Massougbodji, and Michel Cot MedscapeCME ACTIVITY Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infec- tious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit com- mensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certifi cate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the educa- tion content; (3) take the post-test and/or complete the evaluation at www.medscapecme.com/journal/eid; (4) view/print certifi cate. Learning Objectives Upon completion of this activity, participants will be able to: • Identify pregnant women who are most susceptible to pregnancy-associated malaria and the current recommendations for intermittent preventive treatment in pregnancy for malaria prophylaxis. • Examine adverse events resulting from malaria during pregnancy and the effi cacy of varying chemoprophylactic regimens in prevention. Editor Thomas J. Gryczan, MS, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Thomas J. Gryczan, MS, has disclosed no relevant fi nancial relationships. CME Author Desiree Lie, MD, MSED, Clinical Professor of Family Medicine, Director of Research and Faculty Development, University of Cali- fornia, Irvine at Orange, California. Désirée Lie, MD, MSEd, has disclosed the following relevant fi nancial relationship: served as a nonproduct speaker for: “Topics in Health” for Merck Speaker Services. Authors Disclosure: Philippe Deloron, MD, PhD; Gwladys Bertin, MSc; Valérie Briand, MD, PhD, MPH; Achille Massougbodji, MD; and Michel Cot, MD, PhD, have disclosed no relevant fi nancial relationships. For monitoring effi cacy of sulfadoxine/pyrimethamine ing pregnancy appears questionable. The World Health intermittent preventive treatment for malaria during preg- Organization recently proposed conducting in vivo studies nancy, data obtained from studies of children seemed inad- in pregnant women to evaluate molecular markers for de- equate. High prevalence of triple and quadruple mutants in tecting resistance precociously. Other possible alternative the dihydropteroate synthase and dihydrofolate reductase strategies are considered. genes of Plasmodium falciparum parasites contrasts with the effi cacy of sulfadoxine/pyrimethamine in reducing low birthweights and placental infection rates. In light of this alaria during pregnancy is a major cause of anemia discrepancy, emphasis on using molecular markers for Mand maternal death and one of the main causes of low monitoring effi cacy of intermittent preventive treatment dur- birthweight (1,2). Consequently, the World Health Organi- zation (WHO) recommends protection for women during Author affi liations: Institut de Recherche pour le Développement, pregnancy. Until recently, prevention consisted of weekly Paris, France (P. Deloron, G. Bertin, V. Briand, M. Cot); Université chemoprophylaxis with either chloroquine or sulfadoxine/ Paris Descartes, Paris (P. Deloron, G. Bertin, V. Briand, M. Cot); pyrimethamine. Because of poor patient compliance with and Faculté des Sciences de la Santé, Cotonou, Benin (A. Mas- prophylaxis and increasing resistance of parasite strains to sougbodji) chloroquine, administration of intermittent preventive treat- ment in pregnancy (IPTp) with sulfadoxine/pyrimethamine DOI: 10.3201/eid1611.101064 1666 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 16, No. 11, November 2010 Treatment for Malaria during Pregnancy is now recommended for all pregnant women living in proportion of placental infection by 75% compared with areas with stable malaria transmission (3). Sulfadoxine/ the effi cacy of chloroquine prophylaxis administered the pyrimethamine is given during antenatal visits at curative previous year (15). However, a recent study in an area of doses (1,500 mg sulfadoxine and 75 mg pyrimethamine; high drug resistance in Tanzania demonstrated no clinical i.e., 3× the prophylactic dosage previously used) at least benefi t of IPTp with sulfadoxine/pyrimethamine, in addi- twice during pregnancy, once at the second trimester and tion to a worse outcome (16). once at least 1 month after the fi rst treatment. An additional rationale for not extrapolating sulfa- IPTp with sulfadoxine/pyrimethamine has proven effi - doxine/pyrimethamine effi cacy data obtained in studies of cacious in reducing the incidence of pregnancy-associated young children to the effi cacy of IPTp is that the primary malaria (4,5) and is currently part of the national malaria outcome of interest differs. In children, the main outcome prevention program in most countries in Africa. However, of the in vivo test is parasite clearance. Although parasite resistance to sulfadoxine/pyrimethamine is increasing in clearance is always highly desirable, the main rationale for Africa (6,7). In many countries, sulfadoxine/pyrimethamine administering IPTp is to avoid birthweight reduction as now demonstrates inadequate therapeutic effi cacy in chil- a consequence of massive placenta infection. How IPTp dren <5 years of age (8–10) and is no longer the drug of achieves such results is unknown. However, parasite clear- choice for treatment, having been replaced by artemisinin ance may not be required. A high reduction in parasite load combination therapy, according to WHO guidelines. Thus, in blood is likely to be paralleled in the placenta and may this drug will soon be compromised, and an urgent need restore transplacental exchanges. exists to assess alternative drug regimens for IPTp. Overall, these fi ndings have led the WHO technical report group to recommend that the protective effi cacy of Monitoring Drug Effi cacy during IPTp sulfadoxine/pyrimethamine be evaluated in asymptomatic with Sulfadoxine/Pyrimethamine pregnant women instead of in children, in parallel with WHO has recently stressed the inadequacy of sulfa- constant monitoring of the effectiveness of IPTp with sul- doxine/pyrimethamine effi cacy data obtained from studies fadoxine/pyrimethamine at sentinel sites. Another priority of children <5 years of age with symptomatic malaria as identifi ed by the WHO technical group is urgent evalua- a reliable indicator for pregnant women (11). Antimalar- tion of the prevalence of molecular markers associated with ial immunity and pregnancy-specifi c differences in phar- drug resistance as a surrogate to the protective effi cacy of macokinetics explain that in vivo data obtained for these IPTp (11). children cannot be extrapolated to adult women (12,13). Therapeutic effi cacy of sulfadoxine/pyrimethamine in chil- Usefulness of Molecular Methods dren with clinical Plasmodium falciparum malaria largely The WHO technical report group recommended geno- underestimates its effi cacy during IPTp because sulfadox- typing of Plasmodium spp. dihydrofolate reductase (dhfr) ine/pyrimethamine effi cacy in pregnant women may likely and dihydropteroate synthase (dhps) genes, a method com- depend on their previous immunity. Furthermore, primi- monly used in molecular epidemiology, to monitor the gravidae, who are the most vulnerable to the effects of protective effi cacy of sulfadoxine/pyrimethamine. Numer- pregnancy-associated malaria, are also the least protected ous molecular epidemiologic studies showed that resis- among pregnant women who are given sulfadoxine/py- tance to pyrimethamine is associated with the acquisition rimethamine in areas where resistance is increasing (13). of mutations in dhfr; the most common mutations related In Tanzania, 28 days after treatment with sulfadoxine/ to pyrimethamine resistance are Ser108Asn, Asn51Ile, pyrimethamine, the rate of treatment failure was 16% in Cys59Arg, and Ile164Leu (17,18). Similarly, resistance pregnant women and 80% in children <5 years of age 2 to sulfadoxine is associated with 3 mutations in dhps: years earlier (14). A recent systematic review indicated that Ala437Gly, Ser436Phe, and Lys540Glu (19,20). Each mu- 2 doses of IPTp with sulfadoxine/pyrimethamine retained tation leads to a decrease in sensitivity to pyrimethamine activity to reduce placental malaria and low birthweight (dhfr gene) and sulfadoxine (dhps gene). in areas with 19%–26% in vivo resistance in children (5). Molecular markers are useful for tracking the emer- Also, the proportional reduction of peripheral parasitemia gence and spread of drug resistance where resistance is at delivery compared with that at enrollment with 2 doses low or moderate. However, even for markers with virtu- of IPTp with sulfadoxine/pyrimethamine remained >60%, ally absolute correlations between genotype and in vitro even at in vivo resistance rates <39%. In southern Be- phenotype (such as those for sulfadoxine/pyrimethamine), nin, where the in vivo resistance rate to sulfadoxine/py- other factors (including acquired immunity and pharma- rimethamine reached 72% in children
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