The Impact of Antenatal Azithromycin and Monthly Sulfadoxine-Pyrimethamine on Maternal Malaria during Pregnancy and Fetal Growth: A Randomized Controlled Trial

Abstract

Maternal malaria and infections during pregnancy are risk factors for fetal growth restriction. We assessed the impact of preventive treatment in pregnancy on maternal malaria and fetal growth. Between 2003 and 2006, we enrolled 1,320 pregnant Malawian women, 14–26 gestation weeks, in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (SP, control) at enrollment and between 28–34 gestation weeks; with monthly SP from enrollment until 37 gestation weeks; or with monthly SP and azithromycin twice, at enrollment and between 28 and 34 gestation weeks (AZI-SP). Participants were seen at 4-week intervals until 36 completed gestation weeks and weekly thereafter. At each visit, we collected dried blood spots for real-time polymerase chain reaction diagnosing of malaria parasitemia and, in a random subgroup of 341 women, we measured fetal biparietal diameter and femur length with ultrasound. For the monthly SP versus the control group, the odds ratios (OR) (95% CI) of malaria parasitemia during the second, third, and both trimesters combined were 0.79 (0.46–1.37), 0.58 (0.37–0.92), and 0.64 (0.42–0.98), respectively. The corresponding ORs for the AZI-SP versus control group were 0.47 (0.26–0.84), 0.51 (0.32–0.81), and 0.50 (0.32–0.76), respectively. Differences between the AZI-SP and the monthly SP groups were not statistically significant. The interventions did not affect fetal biparietal diameter and femur length growth velocity. The results suggest that preventive maternal treatment with monthly SP reduced malaria parasitemia during pregnancy in Malawi and that the addition of azithromycin did not provide much additional antimalarial effect.

PeRinatal, neOnatal, and Maternal OuTcomEs with azithromycin prophylaxis in pregnancy and labour (PROMOTE-PROPHYLAXIS): systematic review and meta-analysis

“…We have identified 20 RCTs with 56,381 participants 8 , 10 , 11 , 13 , 15 , 16 , 24 , 25 , 26 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 [ Fig. 1 ].…”

“…Subsequent trials from high-income countries where the prevalence of untreated RTIs and malaria was low in pregnancy failed to show beneficial effects on foetal and neonatal well-being. 15 , 16 , 24 Instead, they consistently showed that single-dose intrapartum azithromycin prophylaxis was associated with reduced SSIs, endometritis, and maternal mortality. 10 , 13 , 15 Hence, recently, the focus has shifted from neonatal to maternal outcomes.…”

“…We critically appraised the existing evidence syntheses on this topic and have several concerns [ Table S1 ]. Several recent RCTs have been conducted, 13 , 15 , 16 , 24 , 25 , 26 including some large multicentric ones. 13 , 15 , 16 Thus, we have almost four times more participants than the most comprehensive evidence synthesis on this topic.…”

Malaria in Pregnancy, Current Challenges, and Emerging Prevention Strategies in a Warming Climate

“…33 Chloroquine was not well tolerated in pregnancy trials nor were attempts at substituting SP with mefloquine, amodiaquine or azithromycin. [34][35][36] IPTp with dihydroartemisin-piperaquine (DP) is the most promising alternative to IpTP-SP perhaps because of the long half-life of piperaquine that may serve as prophylaxis against future mosquito bites as well as clearing any parasites sequestered in the placenta at the time of administration. Compared with IPTp-SP, IPTp-DP was associated with a lower risk of clinical malaria, peripheral parasitemia during pregnancy, and placental malaria at delivery.…”

“…SP resistance has led researchers to evaluate alternative antimalarials for chemoprophylaxis in pregnancy, including the reintroduction of chloroquine, an early antimalarial with widespread resistance whose efficacy in Africa reappeared after years of not recommending its use 33 . Chloroquine was not well tolerated in pregnancy trials nor were attempts at substituting SP with mefloquine, amodiaquine or azithromycin 34–36 . IPTp with dihydroartemisin-piperaquine (DP) is the most promising alternative to IpTP-SP perhaps because of the long half-life of piperaquine that may serve as prophylaxis against future mosquito bites as well as clearing any parasites sequestered in the placenta at the time of administration.…”