Intermittent Preventive Treatment with Sulfadoxine–Pyrimethamine: More Than Just an Antimalarial?
Am. J. Trop. Med. Hyg.
Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine: More than Just an Antimalarial?
Julie Gutman 1 2
Laurence Slutsker 0 1
0 Malaria and Neglected Tropical Diseases, Center for Malaria Control and Elimination, PATH, Seattle , Washington
1 sion of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention , 1600 Clifton Road, NE Mailstop A06, Atlanta, GA 30322
2 Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention , Atlanta , Georgia
Malaria in pregnancy is associated with increased risk for
both maternal and neonatal adverse outcomes, notably low
birthweight and neonatal mortality.1 Since 2004, following
studies that showed that intermittent preventive treatment
with sulfadoxine–pyrimethamine (IPTp-SP) reduced the risk
of these adverse events,2 the World Health Organization
(WHO) recommended IPTp-SP for all areas in Africa with
moderate-to-high malaria transmission.3 IPTp-SP is
associated with significant reductions in low birthweight, with a
protective efficacy of approximately 26% in an analysis of
national survey data from 32 countries.4 This impact has
been presumed to be a result of the antimalarial effects of
SP. Because resistance to SP has increased, particularly in
eastern and southern Africa, SP is no longer recommended
for treatment of acute malaria illness, even in combination
with artemisinins. Despite this, even in areas where the
efficacy of SP to clear parasitemia has clearly decreased,
IPTp-SP has continued to show benefit for preventing low
birthweight.5 Moreover, no other antimalarials have yet been
shown to be an ideal replacement for SP for IPTp. Studies
evaluating potential alternative IPTp regimens have had
mixed outcomes on birthweight,6,7 leading to the hypothesis
that SP may exert some of its effect through antibacterial
or anti-inflammatory actions.6 In Lusaka, Zambia, where
malaria parasite prevalence is < 1%, Stoner and others
show that among human immunodeficiency virus (HIV)–
positive women, receipt of IPTp-SP was associated with a
dose-dependent reduction in the risk of low birthweight, as
well as an increase in gestational age, further suggesting a
mechanism other than antimalarial activity as an
explanation for a reduced risk of low birthweight among women
receiving IPTp-SP during pregnancy.8
The current WHO recommendation is for all HIV-positive
women to receive daily co-trimoxazole (an antifolate
antibiotic that is similar to, but shorter acting than SP) for
prevention of opportunistic infections. The co-administration
of co-trimoxazole and SP is contraindicated because of an
increased risk of adverse effects. Co-trimoxazole has
antimalarial activity; in one study, infant birthweight was
similar among HIV-positive women taking daily co-trimoxazole
and those taking IPTp-SP (3-dose goal).9 In a multicenter
trial assessing the benefit of adding IPTp with mefloquine
to daily co-trimoxazole in HIV-infected women, mefloquine
significantly reduced maternal peripheral and placental malaria
infection at delivery, but did not have a differential impact on
birthweight compared with women taking daily co-trimoxazole
alone, again suggesting an effect on birthweight
independent of antimalarial activity.10
That SP, which has antibacterial activity, could improve
birthweight independent of its antimalarial effect is perhaps
unsurprising. A non-malaria-related beneficial effect of SP
on birthweight could be due to several mechanisms,
including anti-inflammatory effects or alterations in the bacterial
flora of the gut or vagina leading to effects on maternal or
infant weight gain, indirect metabolic effects, or a reduction
in the impact of genitourinary tract organisms associated
with adverse pregnancy outcomes.11 Though the
mechanisms behind these benefits remain unclear, farmers have
long used low doses of antibiotics to fatten farm animals,
and a recent study in humans found an association between
early infant antibiotic use and increased body mass index.12
A study in mice found that antibiotic-induced changes in the
intestinal microbiome led to alterations in lipid and
cholesterol metabolism, with resulting increases in adiposity13;
whether this is the case in humans remains to be seen.
Alternately, as the authors hypothesize, SP could be treating
or preventing other infections,14 thus preventing preterm
delivery and associated low birthweight.
What is more surprising is that SP seemed to
counteract the effects of antiretrovirals on pregnancy outcomes.
Although administration of antiretroviral therapy (ART) to
pregnant women, compared with not treating mothers, is
associated with improved birthweight,15 and is clearly to the
benefit of both mothers and infants, concerns remain about
the safety of ART in pregnancy. As in other studies,16,17
Stoner and others found an association between ART and
increased risk for low birthweight and preterm delivery.8
The reasons for this remain unclear, but may include
modulation of the normal immune shift from Th1 to Th2 that
occurs during pregnancy, other alterations in inflammatory
cytokines, or possibly an increased risk of hypertension
with resultant placental insufficiency.16 The mechanisms
by which SP might counteract this effect are unclear, and
more research is needed to understand the underlying
mechanisms by which ART might increase risk for low
birthweight, and whether this occurs with all combinations
or only with specific drugs, combinations, or drug classes.
In this study, despite adjusting for CD4 count in the
analysis, the association between ART and low birthweight may
still have been simply related to the fact that women with
more advanced HIV were more likely to be on ART, as the
study used data from the era before widespread
implementation of the recommendation for all pregnant women
with HIV, regardless of CD4 count, to be started on
combination ART as soon as diagnosed, and continued for life
(Option B Plus).
In light of concerns about the decreasing antimalarial
efficacy of SP, recent studies have explored alternatives for
IPTp, including dihydroartemisinin–piperaquine (DP), with
demonstrated protection against malaria, but no clear
benefit compared with SP with respect to birthweight.6,7 Given
the inconsistent evidence of improved birth outcomes
with the use of IPTp-DP, the WHO recommended further
study into both the efficacy and feasibility of IPTp-DP
to inform a future recommendation (http://www.who.int/
findings of Stoner and others provide evidence that in a
setting where malaria was not likely an important factor
affecting pregnancy outcome, IPTp-SP still appeared to
confer benefit through as yet undefined pathways. Further
research is needed to elucidate these other mechanisms,
as well as to explore whether daily co-trimoxazole confers
Disclaimer: The findings and conclusions presented in this
manuscript are those of the authors and do not necessarily
reflect the official position of the U.S. Centers for Disease
Control and Prevention.
Authors’ addresses: Julie Gutman, Malaria Branch, Division of
Parasitic Diseases and Malaria, Centers for Disease Control and
Prevention, Atlanta, GA, E-mail: . Laurence Slutsker,
Malaria and Neglected Tropical Diseases, Center for Malaria
Control and Elimination, PATH, Seattle, WA, E-mail: .
This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the
original author and source are credited.
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