Intermittent preventive treatment against malaria during pregnancy in HIV-positive women: what is the best dosing frequency?

Monthly intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is comparable to the standard two-dose SP IPTp in protection against malaria in HIV-positive Zambian women, according to the findings of a study published in the December 1st edition of the Journal of Infectious Diseases.

However, the two-dose IPTp is fraught with the risk of under-dosing with some women receiving only a single dose leading to poor pregnancy outcomes according to an accompanying paper by the authors in the same issue of the journal.

About twelve million pregnant women in sub-Saharan Africa will suffer malaria attacks during 2007. Poor pregnancy outcomes attributed to placental malaria include anemia, still-births, miscarriages, abortions, low birth weight (LBW) infants, and maternal death. LBW infants are vulnerable to many childhood diseases.

This public health problem is compounded by malaria and HIV co-infections which are common in many sub-Saharan African countries. HIV-positive pregnant women are more vulnerable to malaria attacks than HIV-negative pregnant women. Malaria attacks on the other hand increase HIV viral loads and the risk of mother-to-child transmission of HIV.

IPTp is an effective intervention which reduces placental infection, maternal anemia, and LBW in HIV-negative women. However, there are no clear guidelines for the best SP dosing frequency in HIV-positive pregnant women who are not yet on cotrimoxazole (CTX) prophylaxis.

Two previous studies in Kenya and Malawi demonstrated that monthly IPTp was more effective than two-dose IPTp in HIV–infected and HIV-seronegative pregnant women. These findings must be confirmed in other African settings with different levels of malaria transmission.

In order to address this issue, a team of Zambian and US investigators compared monthly IPTp and two-dose IPTp in a region of low malaria transmission. The study took place between January 2003 and October 2004 at three district health clinics in Ndola, Zambia. Malaria SP treatment failure rate increased over 2.5-fold during this period.

The study subjects were all HIV-1-seropositive pregnant women between 16 and 28 weeks of gestation. After voluntary counselling and testing (VCT), HIV-positive women were offered nevirapine (NVP) and recruited into the study. The study was a randomised, double-blind, placebo-controlled study of IPTp comparing the standard two-dose SP regimen with monthly IPTp in HIV-positive pregnant Zambian women. Baseline demographic information was obtained and a blood sample was collected for haemoglobin determination and malaria microscopy.

Mothers were de-wormed and provided with monthly supplements of iron and folate. SP IPTp was administered under direct observation until 36 weeks of gestation. At monthly follow-up visits, all mothers completed a questionnaire and underwent an obstetrical examination and laboratory examination for anemia and malaria.

At delivery, maternal and infant haemoglobin levels were determined, placental, cord, and maternal peripheral blood was collected for malaria microscopy, and placental biopsies were taken for histology. Infant weight was measured and gestational age was estimated. Mothers and infants returned at one and six weeks after delivery for clinical check-up.

Of the 456 HIV-positive women enrolled, 224 received monthly IPTp and 232 received the standard two-dose IPTp. The baseline demographic and clinical characteristics, bednet (ITN) use, recent antimalarial treatment, and peripheral parasitemia were comparable between the two treatment arms.

There were no differences between monthly IPTp and standard two-dose IPTp in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90) or placental parasitemia (2% vs. 4%; RR, 0.55). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at six weeks.

Women in the monthly IPTp received a median of four doses of SP with only 1 % receiving one dose. By contrast, 16 % of women on two-dose IPTp received one dose of SP. Maternal and birth outcomes were compared between women who received a single dose and those who received 2-4 or more doses. Single-dose SP was significantly associated with a higher risk of maternal anemia, peripheral and cord blood parasitemia, infant prematurity, and LBW.

In conclusion, the Zambian study demonstrated that in an area of low malaria transmission, monthly SP IPTp was comparable to the standard two-dose regimen for the prevention of placental malaria or adverse birth outcomes. However, the risk of under-dosing was significantly increased in the two-dose regimen.

These findings reinforce the earlier Kenyan and Malawian studies on the usefulness of monthly SP IPTp in pregnant HIV-positive African women. They also demonstrate the significant dose-effect of SP and underscore the inferiority of single-dose SP treatment.

The policy implication of these findings is that monthly SP IPTp remains a better option for controlling malaria in HIV-positive pregnant women since the women are more likely to receive more than one dose of SP. However, enthusiasm about SP IPTp in general must be tempered with caution.

There are concerns about possible sulfonamide toxicity. In this Zambian study although the rates of mild adverse events were similar for both treatment arms, there was one case of neonatal jaundice and one case of fatal Stevens-Johnson syndrome (SJS). Since the risk of SJS increases disproportionately in HIV-infected subjects, SP IPTp in these subjects is risky despite the low incidence of toxicity so far reported for SP IPTp.

SP resistance is also increasing in many African countries and an IPTp policy based on SP might soon become obsolete in many countries. The accompanying editorial recommends that alternative antimalarial drug combinations be evaluated for IPTp in the context of ITN use since ITNs are an integral component of malaria control in pregnant women. Such trials are on-going in Africa.