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Chloroquine as prophylaxis may offer pregnant women protection from malaria
When comparing chloroquine and sulfadoxine-pyrimethamine as intermittent therapy for the treatment of malaria in pregnant women — in a setting of high resistance to sulfadoxine-pyrimethamine — intermittent chloroquine did not provide improved protection from malaria and related adverse events, but chloroquine as prophylaxis may offer protection and its use warrants further study, according to finding published in The Lancet Infectious Diseases.
“In most malaria-endemic countries, intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine is recommended during the second and third trimesters,” Titus H. Divala, MBBS, PhD, MPH, a Malawi-based researcher, and colleagues wrote. “An intermittent regimen of sulfadoxine-pyrimethamine diminishes the risk of malaria-associated poor pregnancy outcomes, but emergence of malaria resistant to sulfadoxine-pyrimethamine is threatening the efficacy of this strategy; hence, there is an urgent need to find a replacement drug for pregnant women.”
Findings suggest role for chloroquine prophylaxis
Divala and colleagues noted that there are challenges in diagnosing malaria in pregnant women because not only is it “typically asymptomatic,” but point-of-care diagnostic methods have difficulty detecting the infection.
Divala and colleagues conducted a phase 3 open-label, single-center, randomized controlled trial at Ndirande Health Centre in Blantyre, southern Malawi. Between February 2012 and May 2014, they enrolled HIV-negative pregnant women in their first or second pregnancy who were at 20 to 28 weeks’ gestation and randomly assigned them to receive intermittent sulfadoxine-pyrimethamine, intermittent chloroquine or chloroquine prophylaxis.
Women in the intermittent sulfadoxine-pyrimethamine group received two doses of 1,500 mg sulfadoxine and 75 mg pyrimethamine, 4 weeks apart. Women in the intermittent chloroquine group received two doses of 600 mg on day 1,600 mg on day 2 and 300 mg on day 3. Women in the chloroquine prophylaxis arm received 600 mg on day 1, then 300 mg every week until delivery, according to the study.
The primary endpoint was placental malaria in the modified intent-to-treat population, defined as study participants who “contributed placental histopathology data at birth.” Secondary outcomes were clinical malaria, maternal anemia, low birth weight and safety.
The final study population consisted of 765 eligible women who had histopathological data. Divala and colleagues observed what they classified as a lower-than-expected prevalence of placental malaria infection of 14% (n = 108). Neither chloroquine as intermittent therapy nor as prophylaxis improved protection from placental malaria compared with intermittent sulfadoxine-pyrimethamine, according to the study. Of the 259 women who received chloroquine as prophylaxis, 12% (n = 30) had positive histopathology (RR = 0.75; 95% CI, 0.48-1.17). Of the 253 women in the intermittent chloroquine group, 15% (n = 39) had positive histopathology (RR = 1; 95% CI, 0.67-1.50). Of the 253 women who received intermittent sulfadoxine-pyrimethamine, 15% (n = 39) had positive histopathology.
Divala and colleagues also compared chloroquine as prophylaxis with intermittent sulfadoxine-pyrimethamine in a protocol-specified analyses that adjusted for maternal age, gestational age at enrollment, bed net use the night before enrollment, anemia at enrollment and malaria infection at enrollment. They found that placental infections were 34% lower in women taking chloroquine as prophylaxis (RR = 0.66; 95% CI, 0.46-0.95).
According to the study, in the intermittent sulfadoxine-pyrimethamine arm, nine women were reported with clinical malaria and five with maternal anemia. The intermittent chloroquine arm and the chloroquine prophylaxis arm included four (P = .26) and two (P = .063) women with reported clinical malaria, respectively. In the intermittent chloroquine arm, 15 women (P = .038) were reported with maternal anemia compared with six (P > .99) in the chloroquine prophylaxis arm.
The researchers observed 31, 29 (P = .78) and 41 (P = .28) babies with low birth weight in the intermittent sulfadoxine-pyrimethamine, intermittent chloroquine and chloroquine prophylaxis arms, respectively. Four women receiving intermittent sulfadoxine-pyrimethamine experienced adverse events, whereas the intermittent chloroquine arm and the chloroquine prophylaxis arm reported adverse events for 94 and 26 women, respectively (P < .0001). According to the study, severe or life-threatening adverse events were reported from three women who were allocated to the intermittent chloroquine arm (P = .25).
“The findings of our open-label randomized controlled trial suggest that chloroquine prophylaxis could be an option for reducing malaria in HIV-negative pregnant women in Malawi,” Divala and colleagues wrote. “Because the findings from our stratified model were unanticipated and based on an exploratory analysis, we recommend their validation through confirmatory studies that investigate explicitly the effectiveness of a chloroquine prophylaxis regimen and whether this effect is modified by baseline malaria infection.”
‘Unlikely to swing the pendulum back’
Also writing in The Lancet Infectious Diseases, R. Matthew Chico, PhD, MPH, assistant professor of public health at the London School of Hygiene & Tropical Medicine, and Feiko O ter Kuile, MD, PhD, professor of tropical epidemiology at the Liverpool School of Tropical Medicine, noted that Malawi withdrew the use of chloroquine in 1993 in favor of sulfadoxine-pyrimethamine, then was the first country in Africa to report renewed parasite sensitivity to the agent about 8 years later.
However, they said the findings in the current study are “unlikely to swing the pendulum back in favor of chloroquine prophylaxis.”
“Nevertheless, with the return of chloroquine susceptibility in many parts of Africa, use of chloroquine in the first trimester might be worth investigating further,” they wrote. “Future studies are needed to ascertain if intermittent preventive treatment in pregnancy with dihydroartemisinin-piperaquine in the second and third trimesters is better than sulfadoxine-pyrimethamine at reducing adverse pregnancy outcomes. If we can learn anything from this study and other trials, it is to temper our expectations.” – by Marley Ghizzone
Disclosures: The authors report no relevant financial disclosures.