Malaria, Folate, and Anemia during pregnancy

1. Malaria, Folate, and Anemia during pregnancy Division of Parasitic Diseases Centers for Disease Control and Prevention

2. Malaria, folate, and anemia in pregnancy Background • Humans are fully dependant on dietary folic acid • Plasmodium must synthesize their own folic acid • Folate is an essential nutrient for cell metabolism and purine/pyrimidine synthesis • Folate needs are increased in pregnancy • Folate deficiency in pregnancy is associated with: • Maternal megaloblastic anemia • Fetal neural tube defects (conception & 1st trimester) • Low birth weight

3. Malaria, folate, and anemia in pregnancy Prevention Recommendations for prevention of folate deficiency • For prevention of neural tube defects: • before conception through the 1st trimester -- supplement with 400 µg/day • To prevent folate deficiency: • Supplement throughout pregnancy with 600 µg/day • To prevent/manage anemia in pregnancy in settings with high anemia prevalence: • Supplement with 400 µg/day of folate and 60 mg/day of iron during 6 months of pregnancy and 3 months post-partum

4. Malaria, folate, and anemia in pregnancy Prevention Recommendations for prevention of folate deficiency • Practical considerations • in some countries, the lowest available dose/formulation of folate is 5 mg (approximately 10-fold higher than some suggested doses) • In conjunction with antifolate antimalarial drugs • WHO recommends delaying folic acid supplementation for one week after sulfadoxine-pyrimethamine (SP) to avoid potential inhibitory effect of folic acid (WHO expert committee, 2000)

5. Malaria, folate, and anemia in pregnancy Folate, antifolate drugs, and malaria • SP acts at sequential steps of the malaria parasite folate metabolism by inhibiting: • Dihydropteroate synthase (DHPS) -- sulfadoxine • Dihydrofolate reductase (DHFR) – pyrimethamine • Selective for parasite enzymes • Possible impact on human folic acid levels – but this may be unlikely at recommended dosing levels

6. Mammals Plasmodium sp. Guanosine monophosphate Para-aminobenzoic acid (PABA) Ingest folate Pteridine Dihydropteroate synthetase (DHPS) Sulfones and Sulfonamides compete with PABA for binding sites to DHPS Dihydropteroate DHFR Glutamate Dihydrofolate Dihydrofolate reductase (DHFR) Inhibited by pyrimethamine, trimethoprim, cycloguanil with higher affinity fro plasmodial enzyme than for human enzyme Action at or before schizont stage of parasite Tetrahydrofolate (folinic acid) Precursors Purine synthesis DNA & RNA synthesis

7. Malaria, folate, and anemia in pregnancy Folate and antimalarial activity • Gambian study: 9 children; no effect on antimalarial effect of pyrimethamine with folate supplementaion (10-30 mg per day of folate) (Hurley 1959) • Vietnam: 75 U.S. marines; pyrimethamine + sulfasoxazole and supplement with folic acid (5mg/d) or folinic acid (5mg/d) or placebo – no differences in antimalarial effect (Tong et al, 1970)

8. Malaria, folate, and anemia in pregnancy Folate and antimalarial activity • Plasmodia may be able to shift to using exogenous folate • Folic acid altered antimalarial activity of sulphonamide drugs in vitro (Watkins et al, 1985; Milhous et al, 1985) • Gambia study: children treated with SP+folic acid (5-10mg/d depending on weight) had higher treatment failure rate than children with SP or SP+iron: day 7 failure rates were 10.5% vs 3.1% (Boele van Hensbroek et al, 1995) • May be more complicated with parasites ability to synthesize folate versus utilize exogenous folate may depend on drug levels, drug resistance, and availability of exogenous folate (Wang et al, 1997, 1999)

9. Malaria, folate, and anemia in pregnancy Folate and antimalarial activity • The development of DHPS and DHFR mutants that, in combination, contribute to Plasmodia resistance to SP and SP-like drugs • Currently, it is unclear if this parasite resistance will or will not be further affected by folic acid supplementation • HIV infection may contribute further to this interaction • HIV-infected women may respond less well to SP (Parise et al, 1998) • HIV-infected women have lower serum folate levels (reduced intake and absorption and/or increased catabolism) (Friis et al, 2001)

10. Malaria, folate, and anemia in pregnancy Folate and antimalarial activity • What to do? • Further studies are under way • Follow current WHO guidance when possible – to delay start of folic acid supplementation when using SP for treatment of acute infection or for intermittent preventive treatment • However, it may have little overall effect to give low-dose supplementation with folic acid at the same time that SP is given for treatment.