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Safety and Toxicity of Sulfadoxine/Pyrimethamine

Implications for Malaria Prevention in Pregnancy using Intermittent Preventive Treatment

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Abstract

Plasmodium falciparum infection during pregnancy is strongly associated with maternal anaemia and low birth weight, contributing to substantial morbidity and mortality in sub-Saharan Africa. Intermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine (IPTp-SP) has been one of the most effective approaches to reduce the burden of malaria during pregnancy in Africa. IPTp-SP is based on administering ≥2 treatment doses of sulfadoxine/pyrimethamine to pregnant women at predefined intervals after quickening (around 18–20 weeks). Randomised, controlled trials have demonstrated decreased rates of maternal anaemia and low birth weight with this approach. The WHO currently recommends IPTp-SP in malaria-endemic areas of sub-Saharan Africa. However, implementation has been suboptimal in part because of concerns of potential drug toxicities. This review evaluates the toxicity data of sulfadoxine/pyrimethamine, including severe cutaneous adverse reactions, teratogenicity and alterations in bilirubin metabolism. Weekly sulfadoxine/pyrimethamine prophylaxis is associated with rare but potentially fatal cutaneous reactions. Fortunately, sulfadoxine/pyrimethamine use in IPTp programmes in Africa, with 2–4 treatment doses over 6 months, has been well tolerated in multiple IPTp trials. However, sulfadoxine/pyrimethamine should not be administered concurrently with cotrimoxazole given their redundant mechanisms of action and synergistic worsening of adverse drug reactions. Therefore, HIV-infected pregnant women in malaria endemic areas who are already receiving cotrimoxazole prophylaxis should not also receive IPTp-SP. Although folate antagonist use in the first trimester is associated with neural tube defects, large case-control studies have demonstrated that sulfadoxine/pyrimethamine administered as IPTp (exclusively in the second and third trimesters and after organogenesis) does not result in an increased risk of teratogenesis. Folic acid supplementation is recommended for all pregnant women to reduce the rate of congenital anomalies but high doses of folic acid (5 mg/day) may interfere with the antimalarial efficacy of sulfadoxine/pyrimethamine. However, the recommended standard dose of folic acid supplementation (0.4 mg/day) does not affect antimalarial efficacy and may provide the optimal balance to prevent neural tube defects and maintain the effectiveness of IPTp-SP. No clinical association between sulfadoxine/pyrimethamine use and kernicterus has been reported despite the extensive use of sulfadoxine/pyrimethamine and related compounds to treat maternal malaria and congenital toxoplasmosis in near-term pregnant women and newborns. Although few drugs in pregnancy can be considered completely safe, sulfadoxine/pyrimethamine — when delivered as IPTp — has a favourable safety profile. Improved pharmacovigilance programmes throughout Africa are now needed to confirm its safety as access to IPTp-SP increases. Given the documented benefits of IPTp-SP in malaria endemic areas of Africa, access to this treatment for pregnant women should continue to expand.

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  1. 1The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

The authors have no conflicts of interest that are directly relevant to the content of this manuscript. No sources of funding were used in the preparation of this review. The findings and conclusions in this publication are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. The authors are grateful to Dr Laurence Slutsker for helpful comments on drafts of this review.

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  1. Division of Infectious Diseases, Emory University School of Medicine, 69 Jesse Hill Jr. Drive S.E., Atlanta, Georgia, 30303, USA

    Philip J. Peters & Michael C. Thigpen

  2. Malaria Branch, Atlanta, Georgia, USA

    Michael C. Thigpen, Monica E. Parise & Robert D. Newman

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Peters, P.J., Thigpen, M.C., Parise, M.E. et al. Safety and Toxicity of Sulfadoxine/Pyrimethamine. Drug-Safety 30, 481–501 (2007). https://doi.org/10.2165/00002018-200730060-00003

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