Chloroquine for Malaria in Pregnancy

• Incidence of placental malaria infection based on histology. [ Time Frame: At delivery: Approximately 12-36 weeks after enrollment ] [ Designated as safety issue: No ]
  

• Incidence of infection in the fetal circulation based on the results of the thick smear and polymerase chain reaction (PCR) from the cord blood sample. [ Time Frame: After childbirth (approximately 13-19 weeks after randomization) ] [ Designated as safety issue: No ]
  
• Incidence of maternal anemia (hemoglobin < 10gm/dl) [ Time Frame: From enrollment until delivery, approximately 12-36 weeks ] [ Designated as safety issue: Yes ]
  
• Incidence of maternal severe anemia (hemoglobin < 7gm/dl) [ Time Frame: From enrollment until delivery, approximately 12-36 weeks ] [ Designated as safety issue: Yes ]
  
• Incidence of stillbirth [ Time Frame: At delivery: Approximately 12-36 weeks after enrollment ] [ Designated as safety issue: Yes ]
  
• Incidence of miscarriage (estimated gestational age <28 weeks) [ Time Frame: At delivery: Approximately 12-36 weeks after enrollment ] [ Designated as safety issue: Yes ]
  
• Incidence of placental malaria infection diagnosed by placental impression smear. [ Time Frame: After childbirth (approximately 13-19 weeks after randomization) ] [ Designated as safety issue: No ]
  
• Infant mortality rate to 14 weeks of age [ Time Frame: For 14 weeks after delivery. ] [ Designated as safety issue: Yes ]
  
• Incidence of low birth weight (LBW) (birthweight < 2500 grams) [ Time Frame: At delivery: Approximately 12-36 weeks after enrollment ] [ Designated as safety issue: Yes ]
  
• Incidence of intrauterine growth restriction (IUGR) (weight <10th percentile gestational age based on the World Health Organization (WHO) fetal growth curve) [ Time Frame: At delivery: Approximately 12-36 weeks after enrollment ] [ Designated as safety issue: Yes ]
  
• Incidence of active placental malaria infection diagnosed by the presence of parasites and/or pigment on histological section. [ Time Frame: After childbirth (approximately 13-19 weeks after randomization) ] [ Designated as safety issue: No ]
  
• Per arm: Incidence of malaria infection, all species. [ Time Frame: Enrollment to delivery (approximately 12-36 weeks) ] [ Designated as safety issue: No ]
  
• Per arm: Incidence of clinical malaria, all species. [ Time Frame: Enrollment to delivery (approximately 12-36 weeks) ] [ Designated as safety issue: No ]
  
• Incidence of preterm delivery [ Time Frame: At delivery: Approximately 12-36 weeks after enrollment ] [ Designated as safety issue: Yes ]
  

In areas of high malaria endemicity, typical of much of sub-Saharan Africa, despite having achieved semi-immunity to malaria in adulthood, women become vulnerable to malaria infection during pregnancy, especially during their first or second pregnancy. They have increased rates of infection in the peripheral blood and high concentrations of parasites can be found in the placenta. On histological examination, mature asexual parasites, forms that are not usually detected in the peripheral blood, accumulate in the placenta. Pregnancy-specific variant surface antigens are responsible for the increased vulnerability of pregnant women to malaria because they are unrecognized by the immune systems of women who encounter them for the first time in their first pregnancy. In subsequent pregnancies, women develop immunity to these parasite surface antigens and the parasites are cleared by the host response. Plasmodium (P) falciparum infection during pregnancy has important health consequences for both pregnant women and their newborns. Adverse outcomes of pregnancy-associated malaria that have been documented in Malawi include maternal anemia, low birth weight (LBW), and increased infant mortality. The primary objective of the study is to compare weekly chloroquine prophylaxis and chloroquine intermittent preventative therapy (IPT) for malaria in pregnancy (IPTp) to the standard practice [IPTp with sulfadoxine-pyrimethamine (SP)] with respect to prevention of placental malaria. The secondary objectives are: to compare weekly chloroquine prophylaxis and chloroquine IPTp to the standard practice (IPTp with SP) with respect to prevention of malaria during pregnancy; to compare weekly chloroquine prophylaxis and chloroquine IPTp to the standard practice (IPTp with SP) with respect to prevention of the adverse maternal and newborn effects of pregnancy-associated malaria; to compare the effect of IPTp and chemoprophylaxis on the selection of drug-resistant malaria parasites; to identify the vulnerable periods during pregnancy when malaria infection is more likely to cause placental infection, maternal anemia, and low infant birth weight; and to compare the effects of new versus recurrent malaria infections during pregnancy on the risk of developing adverse outcomes in the mother and the infant. This is a randomized controlled trial to compare chloroquine as IPT or chloroquine as chemoprophylaxis to IPTp with SP. Women will be randomized after Screening and enrollment, and they begin the assigned treatment between Week 20 and Week 28 gestation. Specimens will be collected at every prenatal visit and any time the participant is ill to determine if malaria is present. Pregnant women will be monitored during pregnancy, and newborns will be assessed at birth and followed until they are approximately 14 weeks of age. Participants will be randomized to one of the following regimens: Chloroquine approximately 1,500 mg base over 3 days, twice during pregnancy (2 tablets on Day 0, 2 tablets on Day 1, 1 tablet on Day 2); Chloroquine base 600 mg (2 tablets) loading dose followed by 300 mg (1 tablet) orally once per week; SP 1500 mg/75 mg twice during pregnancy.