Intermittent Treatment for the Prevention of Malaria during Pregnancy in Benin: A Randomized, Open-Label Equivalence Trial Comparing Sulfadoxine-Pyrimethamine with Mefloquine
Intermittent Treatment for the Prevention of Malaria during Pregnancy in Benin: A Randomized, Open- Label Equivalence Trial Comparing Sulfadoxine- Pyrimethamine with Mefloquine
Val e´rie Briand 1 2
Julie Bottero 1 2
Harold Noe¨ l 1 2
Virginie Masse 1 2
Hugues Cordel 1 2
Jose´ Guerra 1 2
Hortense Kossou 0
Benjamin Fayomi 6
Paul Ayemonna 3
Nadine Fievet 5
Achille Massougbodji 4
Michel Cot 1 2
0 Programme National de Lutte contre le Paludisme
1 Universite ́ Paris-Descartes , Paris , France
2 Institut de Recherche pour le De ́veloppement, UR010
3 Hoˆpital de Zone , Ouidah, Be ́nin
4 Laboratoire de Parasitologie, Faculte ́ des Sciences de la Sante ́ , Cotonou
5 Institut de Recherche pour le De ́veloppement, UR010
6 Institut des Sciences Biome ́dicales Applique ́es
Background. In the context of the increasing resistance to sulfadoxine-pyrimethamine (SP), we evaluated the efficacy of mefloquine (MQ) for intermittent preventive treatment during pregnancy (IPTp). Methods. A multicenter, open-label equivalence trial was conducted in Benin from July 2005 through April 2008. Women of all gravidities were randomized to receive SP (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or 15 mg/kg MQ in a single intake twice during pregnancy. The primary end point was the proportion of lowbirth-weight (LBW) infants (body weight, !2500 g; equivalence margin, 5%). Results. A total of 1601 women were randomized to receive MQ (n p 802) or SP (n p 799). In the modified intention-to-treat analysis, which assessed only live singleton births, 59 (8%) of 735 women who were given MQ and 72 (9.8%) of 730 women who were given SP gave birth to LBW infants (difference between low birth weights in treatment groups, 1.8%; 95% confidence interval [CI], 4.8% to 1.1%]), establishing equivalence between the drugs. The per-protocol analysis showed consistent results. MQ was more efficacious than SP in preventing placental malaria (prevalence, 1.7% vs 4.4% of women; P p .005), clinical malaria (incidence rate, 26 cases/10,000 person-months vs. 68 cases/10,000 person-months; P p .007), and maternal anemia at delivery (as defined by a hemoglobin level !10 g/dL) (prevalence, 16% vs 20%; marginally significant at P p .09). Adverse events (mainly vomiting, dizziness, tiredness, and nausea) were more commonly associated with the use of MQ (prevalence, 78% vs 32%; P ! 10 3). One woman in the MQ group had severe neuropsychiatric symptoms. Conclusions. MQ proved to be highly efficacious-both clinically and parasitologically-for use as IPTp. However, its low tolerability might impair its effectiveness and requires further investigations. Clinical Trials Registration. NCT00274235.
In areas where there is high transmission of malaria
(mostly sub-Saharan Africa), malaria in pregnancy is
responsible for maternal anemia and low birth weight
(LBW) [1, 2], the latter of which is an important risk
factor for perinatal and infant death [3, 4].
The current recommendation of the World Health
Organization (WHO) for the prevention of malaria in
pregnancy is based on intermittent preventive
treatment during pregnancy (IPTp), insecticide-treated
bednets, and the effective management of malaria cases
. IPTp consists of administration of a single curative
dose of an antimalarial at predefined intervals during
pregnancy, regardless of whether women are infected. The
efficacy of 2 doses of the recommended drug
(sulfadoxine-pyrimethamine [SP]) for IPTp, compared with placebo or
chemoprophylaxis, has been demonstrated for the prevention of
LBW [6, 7], maternal anemia [6–9], and placental malaria
infection [6–8, 10, 11]. However, the spread of parasite resistance
to SP in sub-Saharan Africa raises important concerns about
the use of SP for IPTp and makes evaluation of alternative
antimalarials particularly urgent.
Mefloquine (MQ) is one of the most attractive options,
because it is immediately available and has the appropriate
properties for IPTp: a long half-life, safety, simplicity of
administration, and low associated rates of resistance in sub-Saharan
Africa [12, 13]. Although MQ proved to be efficacious in the
prevention of LBW  and peripheral [2, 14] and placental
malaria  when used as weekly prophylaxis (250 mg/week),
it has never been evaluated for use as IPTp.
We report the results of what is, to our knowledge, the first
randomized clinical trial to evaluate the efficacy of MQ for
IPTp. This trial was conducted in Benin and was designed to
establish the equivalence of 2 doses of SP IPTp and 2 doses of
MQ IPTp for the prevention of LBW. Drugs were also compared
in terms of safety (in particular, the risk of stillbirth) and
tolerability, both of which might be a concern with MQ.
Study site. The trial was conducted from July 2005 through
April 2008 in Ouidah, a semirural town in Benin that is located
40 km west of Cotonou. Perennial malaria transmission with
seasonal peaks is mostly attributable to Plasmodium falciparum
. The average entomological inoculation rate was 5 infective
bites per person per year in the neighboring area of Tori Bossito
in 2007 (V. Corbel, personal communication). In 2005, rates
of SP and MQ resistance in vivo in children !5 years of age
were estimated to be 50% and 2.5% by day 28 of treatment,
respectively . Since 2003, insecticide-treated bednets have
been widely available in the area, and regular campaigns for
re-treatment have occurred. The prevalence of HIV in the
general population is ∼2% .
The study was initially conducted in the 2 main maternity
clinics, Kindji and the “H oˆpital de Zone.” Beginning in May
2006, to increase recruitment of subjects, a third center with
comparable characteristics, Kpasse´, was included in the study.
SP IPTp has been recommended by the Beninese Ministry
of Health since 2004 and has been applied since 2006.
Enrollment. Enrollment was done at antenatal care visits.
Women of all gravidities of 16–28 weeks’ gestation who had
no history of a neurologic or psychiatric disorder and who had
not either previously used SP or MQ or reported having adverse
reactions to medications containing sulfa were eligible to
participate. Eligible women were included in the study after they
provided signed, written informed consent. Beginning in May
2006, HIV screening was routinely undertaken in the study
area. Women who were known to be HIV infected before
enrollment were not recruited because, according to World Health
Organization (WHO)  and national recommendations, they
should receive 3 (rather than 2) IPTp doses.
Sociodemographic characteristics, obstetric history, and
measures for the prevention of malaria were collected.
Gestational age was estimated using the date of the last menstrual
period and/or by measurement of uterine fundal height. Venous
blood samples were collected for determination of the
hemoglobin (Hb) level, and thick and thin blood smears were
performed to detect malaria.
Follow-up. The second IPTp dose was administered from
30 weeks of gestation and at least 1 month after administration
of the first dose, and the same biological tests that were
performed at enrollment were performed again.
Adverse events (AEs) were recorded—using an open-labeled
questionnaire—during visits at home occurring within 1 week
after each IPTp intake. Symptomatic medications were given
If malaria was diagnosed at the time of IPTp administration,
no antimalarial drug other than SP or MQ was given. A smear
was made 5 days later, and quinine was given in case of
persistent parasitemia. Outside of their scheduled visits, women
received quinine treatment for 7 days after malaria was
confirmed by a thick blood smear. Women with anemia received
ferrous sulphate plus mebendazole and were referred to the
H oˆpital de Zone if they were symptomatic.
Intervention. Randomization of subjects was stratified
according to maternity clinic and gravidity (primigravidae vs
multigravidae), with subjects randomized in blocks of 4. The
allocation sequence was not concealed.
The treatment consisted of 2 doses of SP (1500 mg of
sulfadoxine and 75 mg of pyrimethamine per dose; Ajanta Pharma
and PharmaQuick) or MQ (15 mg/kg per dose; Mepha). Drugs
were controlled by the national reference laboratory.
Drugs were administered under observation. The dose was
readministered when vomiting occurred within 30 min after
intake. For the second IPTp dose, the treatment group was
changed (those in the SP group were switched to the MQ
group, and those in the MQ group were switched to the SP
group) in case of cutaneous reactions or severe
Women who were already enrolled in the study and who
were found to be HIV infected during the trial (8 of whom
were receiving MQ and 4 of whom were receiving SP) were
reassigned to the SP group if they originally had been
randomized to the MQ group; regardless of their randomization group,
they received a third dose of SP. They also were given
antiretroviral therapy for the prevention of mother-to-child
transmission of HIV, as well as cotrimoxazole prophylaxis if the
CD4 cell count was !500 cells/mL.
All women were prescribed daily ferrous (400 mg) and
folic (5 mg) supplementation (Beninese Ministry of Health
Delivery. During labor, venous blood samples were
collected for Hb dose determination and malaria diagnosis. After
delivery, blood smears were made from the maternal side of
the placenta and the umbilical cord. Newborns were weighed
using an electronic scale (Seca; accuracy of the scale, 100 g).
Gestational age was determined using the Ballard score ,
as assessed by a single specifically trained midwife (at a median
of 14 h after birth).
If women delivered outside the study maternity clinics,
details of the delivery outcome were collected through antenatal
care cards. Hb level, malaria parasitemia, Ballard score, and
birth weight were assessed if the women attended the study
center immediately after delivery. Finally, mothers were seen 6
weeks postpartum, to check the health of the infant and to
search for AEs.
Laboratory investigations. Hemoglobin was measured
using a colorimeter (Anadeo; 540 nm). Thick and thin blood
Anemiad Hb level,d mean SD, g/dL HIV infectione
NOTE. Data are no. (%) of women with the characteristic, unless otherwise indicated. ANC, antenatal
care; BMI, body mass index; CI, confidence interval; Hb, hemoglobin; IPTp, intermittent preventive
treatment during pregnancy; SD, standard deviation.
a We did not collect information on whether bednets were treated with insecticide.
b Before the current pregnancy.
c Per microliter of blood.
d Determined for 735 and 726 of women in the MQ and SP groups, respectively; maternal anemia was
denoted by an Hb level of !10 g/dL.
e Determined for 430 and 448 of women in the MQ and SP groups, respectively, during their follow-up.
smears were stained with Giemsa stain. Parasite density was
determined according to the number of parasites per 500 or
200 leukocytes (with !10 or 10 parasites detected in the first
microscope fields, respectively) and under the assumption of
an average leukocyte count of 8000 cells/mL. All the placental
smears and a randomized sample of 15% of all other smears
were read independently by 2 microscopists. In case of
discrepancy, a third reading was done.
Blinding. The trial was open, because the 2 drugs were
different in look and taste. However, selection and
randomization were done independently, and the assessors of the
outcomes remained blind to the treatment arms.
Sample size. We calculated that 1610 women (805 per
treatment group) had to be recruited to establish the
equivalence between treatments for LBW (a prevalence of 12% was
expected in both groups, because the prevalence of LBW in the
study area was 16% before implementation of IPTp ),
using a 5% equivalence margin, 80% power, and a 2-sided a of
0.025 (NQuery). We chose 5% as the equivalence margin,
because it was the best compromise between the highest
difference in LBW that was acceptable for equivalence and
logistical and financial constraints.
Statistical analysis. We conducted a planned-interim
analysis of the first 150 deliveries. Because there were neither
relevant treatment differences with regard to LBW nor
unacceptable adverse events, no modifications were requested by
the data and safety monitoring board (DSMB).
The primary efficacy end point was the proportion of LBW
infants (those with a body weight of !2500 g). The secondary
end points were the proportions of women with placental
malaria infection (ie, presence of asexual-stage parasites in the
placental thick blood smear), maternal anemia (Hb, !10 g/dL),
and severe maternal anemia (Hb, !8 g/dL) at delivery. The
ancillary end points were the prevalence of maternal peripheral
malaria at delivery, cord blood malaria, stillbirth (delivery of
a dead child after 28 weeks’ gestation), spontaneous abortion
(expulsion of a fetus before 28 weeks’ gestation), and
prematurity (birth before 37 weeks’ gestation), as well as the mean
birth weight and mean maternal Hb level at delivery.
For assessment of LBW, only live singleton births were
analyzed. The analysis was performed on the modified
intentionto-treat (ITT) population of women who completed the study
(and for whose infants information on birth weight was
collected) and was based on the treatment randomization group.
The analysis was also conducted for the per-protocol (PP)
population, excluding women who were lost to follow-up, were
HIV infected (regardless of their randomization group),
received the second IPTp dose in 2 intakes, or changed treatment
group during follow-up. In addition, a second ITT analysis was
performed in which women who were lost to follow-up were
assumed to have a bad outcome (ie, a LBW infant). Because
gravidity is likely to be an important effect modifier (ie, there
are more deleterious effects of malaria in primigravidae), ITT
and PP analyses were also stratified according to gravidity.
MQ and SP were considered to be equivalent if the 2-sided
95% confidence interval for the difference in LBW between
treatments fell entirely within the interval ( 5% to 5%) in
both the modified ITT analysis and the PP analysis.
For secondary and ancillary end points, the analyses were
performed in both the ITT population (with missing data
excluded) and the PP population, and they included data on
twins, stillbirths, and miscarriages (except for the analysis of
prematurity). The treatment effect was estimated using the
relative risk for categorical variables and linear regression for
Only crude analyses are presented, because adjusted analyses
provided similar results. Differences between proportions were
compared using the x 2 test or Fisher’s exact test. Data analysis
was performed using Stata software (version 8.0; Stata).
Ethics. The Comite´ Consultatif de De´ontologie et
d’Ethique (France) and the ethics committee of the University of
Abomey-Calavi (Benin) approved the study protocol and its
Study population. Overall, 1609 women were randomized to
receive treatment (805 received MQ and 804 received SP). Eight
women were excluded a posteriori, 1 of whom was not pregnant
and 7 of whom had 2 consecutive pregnancies (only the first
pregnancy was considered in this analysis). A total of 1601
women (802 who received MQ and 799 who received SP) were
considered for analyses (figure 1). Characteristics at baseline
were similar for women in the 2 treatment groups (table 1).
Follow-up. In both groups, the mean ( SD) gestational
age at the time of the first and second administrations of IPTp
was 24 2.8 and 33 2.3 weeks, respectively. Women in the
MQ group received a median dose of 812.5 mg (14.5 mg/kg)
(interquartile range [IQR], 750–1062.5 mg or 14–14.8 mg/kg).
The second dose was not administered to 9% of women
receiving MQ and 8% of women receiving SP. The main reasons
for failure to administer the second dose (MQ group vs SP
group) included travel (27% vs 34%), refusal because of the
occurrence of an AE after the first dose (26% vs 16%),
insufficient motivation (11% vs 29%), and delivery before
administration of the second dose (24% vs 11%).
Overall, 248 (15.5%) of 1601 women (the same proportions
in both treatment groups) delivered outside the study maternity
clinics. The main reasons included transfer in Cotonou for a
high-risk delivery, travel outside the study area, or
transportation difficulties. For those women, birth weights were
recorded from antenatal care cards, except for the 5% of women
who were considered to be lost to follow-up. Compared with
women who completed the study, women lost to follow-up
were significantly younger and were more likely to be
primigravid or to have parasitemia at enrollment (data not shown).
Efficacy of study regimens. A total of 1465 birth weights
were collected (with weights for stillborn or miscarried infants
and twins excluded). In the modified ITT analysis, LBW infants
were born to 8% of women receiving MQ and to 9.8% of
women receiving SP (difference between low birth weights in
the treatment groups, 1.8%; 95% CI, 4.8% to 1.1%]),
establishing equivalence between treatments. The PP analysis
showed consistent results (table 2). The second ITT analysis
(ie, LBW when lost to follow-up) did not show equivalence
but suggested that MQ was more efficacious than SP in
preventing LBW (for the MQ group vs the SP group, 88 [11.5%]
of 764 women vs 114 [14.8%] of 772 women; difference
between low birth weights in the treatment groups, 3.3% [95%
CI, 6.6% to 0.1%]).
By stratifying according to gravidity, we did not show any
significant difference between groups in terms of LBW either
in primigravidae or in multigravidae, but sample sizes had a
low power to detect a difference between groups (table 2).
Placental and peripheral parasitemia at delivery were detected
in 82% and 84% of the women. They were significantly less
prevalent in the MQ group than in the SP group (1.7% vs 4.4%
[P p .005] and 1.5% vs 3.6% [P p .03]) (tables 3 and 4).
At delivery, the Hb level was measured for 79% of cases.
Women in the MQ group were less likely to have anemia than
were women in the SP group, although the difference was only
marginally significant (16% vs 20%; P p .09) (table 3).
During follow-up (apart from the antenatal care visits for
IPTp administration and delivery), 8 women in the MQ group
and 21 women in the SP group were treated for 1
symptomatic malaria episodes with quinine (26 cases/10,000
personmonths vs 68 cases/10,000 person-months; P p .007). Three
Women assessed, analysis
RR (95% CI)
Difference between groups, % (95% CI)
1.8 ( 4.8 to 1.1)b
1.2 ( 4.0 to 1.8)b
3.0 ( 10.0 to 4.5)
0 ( 7.3 to 7.5)
1.4 ( 4.3 to 1.5)b
1.5 ( 4.5 to 1.4)b
NOTE. Data are no. of births for which LBW was detected/no. of live singleton births analyzed (% of births for
which LBW was detected). Mefloquine (MQ) and sulfadoxine-pyrimethamine (SP) were considered to be equivalent if
the 95% confidence interval (CI) for the difference in LBW between drug groups fell entirely within the equivalence
margin ( 5% to 5%). IPTp, intermittent preventive treatment during pregnancy; ITT, intention-to-treat analysis; PP,
perprotocol analysis; RR, relative risk.
a Women lost to follow-up, twins, and miscarriages were excluded.
b Data denote significant equivalences.
women had 2 episodes. In both groups, the mean (
abortion. The median (IQR) time between the events and the
between malaria cases and the last IPTp intake (first or second
last IPTp intake was 46 days (22–86 days) and 65 days (39–82
dose) was 52
days), in the MQ and SP groups, respectively.
The incidences of spontaneous
There were 5 maternal deaths in the MQ group. Of them,
tions, stillbirths, and congenital anomalies did not differ
sig4 were associated with obstetric causes (1 disseminated
intranificantly between groups, although they were higher in the
vascular coagulation with hyperfibrinogenolysis, 2 peripartum
MQ group than in the SP group (table 4).
hemorrhages, and 1 uterine rupture), and one remained
A cause for stillbirth or abortion was found for 38% of the
MQ group and 25% of the SP group, thus decreasing the
probAdverse events: mothers.
The proportion of women who
ability of an effect due to the drug (table 5). Malaria at
delivreported an AE was significantly higher in the MQ group than
ery was diagnosed for 1 of 19 women who had a stillbirth or
in the SP group (78% vs 32%; P ! 10 3) (figure 2). The most
Anemiac at delivery
Severe anemiad at delivery
RR (95% CI)
NOTE. Data are no. of deliveries for which placental malaria, anemia, or severe anemia was
detected/no. of deliveries analyzed (% of deliveries for which placental malaria, anemia, or severe anemia
was detected). CI, confidence interval; IPTp, intermittent preventive treatment during pregnancy; ITT,
intention-to-treat analysis (missing data excluded); MQ, mefloquine; PP, per-protocol analysis; RR, relative
risk; SP, sulfadoxine-pyrimethamine.
a Defined as the presence of asexual-stage parasites in the placental thick blood smear.
b Statistically significant result (P ! .05).
c Denoted by an Hb level of !10 g/dL.
d Denoted by an Hb level of !8 g/dL.
Finding, by analysis
MQ IPTp group
SP IPTp group
RR or b coefficient
+17 ( 27 to 61)
+15 ( 30 to 60)
+0.13 ( 0.05 to 0.31)
+0.12 ( 0.07 to 0.31)
NOTE. Data are no. of outcomes detected/no. of deliveries analyzed (% of outcomes detected), unless otherwise indicated.
CI, confidence interval; ITT, intention-to-treat analysis (missing data excluded); NA, not applicable; PP, per-protocol analysis; RR,
a Statistically significant result (P ! .05).
b Defined as birth at !37 weeks’ gestation, according to the Ballard score. Rates were calculated only for live singleton
births. When all children (ie, twins and stillbirths included) were considered, 11 (0.9%) of 1282 were premature.
c Spontaneous abortion was defined as the expulsion of a fetus before 28 weeks’ gestation, and stillbirth was defined as
the delivery of a dead child after 28 weeks’ gestation. Spontaneous abortions and stillbirths were pooled for the estimation
of the RRs.
common complaints were vomiting, dizziness, tiredness, and
nausea. They lasted a median of 24–48 h. There were less AEs
after the second IPTp dose than after the first IPTp dose (72%
and 39%, respectively, in the MQ group vs 27% and 13%,
respectively, in the SP group). Of the women who received 2
IPTp doses, 33% of the MQ group and 8% of the SP group
reported an AE after both intakes.
A total of 28% of the women in the MQ group and 5% of
the women in the SP group received medical care at the
maternity clinic because of an AE (mainly vomiting and dizziness).
One woman (without a personal or familial history) had a
severe neurologic AE consisting of confusion, anxiety, dizziness,
and insomnia 4 h after intake of 750 mg of MQ (17 mg/kg).
The symptoms resolved spontaneously within 3 days, without
Adverse events: neonates and infants. Neonatal icterus was
noted in 5 of 747 children in the MQ group and in 7 of 753
children in the SP group. None had neurologic symptoms. A
total of 10 (1.4%) of 738 and 12 (1.7%) of 721 neonates in
the MQ and SP groups, respectively, died during the 6-week
follow-up. In both groups, 175% of deaths were explained;
they were related to prematurity, infection, or malformation.
In the context of the increasing resistance of P. falciparum to
SP and questioning its useful lifespan for IPTp, we showed, for
the first time, that 2 doses of MQ IPTp were equivalent to 2
doses of SP IPTp in the prevention of LBW. Also, MQ was
found to be more efficacious than SP in the prevention of
symptomatic malaria, placental and peripheral malaria
infections at delivery, and maternal anemia, although it was only
marginally significant for the latter.
During the trial, almost all women received 5 mg of folate
Outcome, cause or type
MQ IPTp group
SP IPTp group
NOTE. Data are the no. of women with the outcome OR the no. of women with the
outcome/no. of women assessed (% of women with the outcome).
a Defined as the delivery of a dead child after 28 weeks’ gestation.
b Corresponding to a twin pregnancy.
c Defined as the expulsion of a fetus before 28 weeks’ gestation.
d Major congenital anomalies were 2 anencephalies and 1 microcephaly; minor
congenital anomalies were 7 surplus fingers, 1 branchial cyst, and 1 hooded penis.
daily, which could have impaired the efficacy of SP against
malaria [20, 21]. Although the parasitologic efficacy of SP IPTp
may have been decreased, at least partly, it retains a substantial
clinical efficacy to prevent LBW, as is shown by the
preinvestigation study, when chloroquine prophylaxis was used .
We tested the equivalence, rather than the superiority, of MQ
and SP regarding LBW, because we postulated that, despite a
significant rate of failure of SP in children living in the same
study area , the drug remained efficacious in protecting
semi-immune pregnant women. A similar finding had been
shown with the use of chloroquine chemoprophylaxis in the
same area . Also, a recent meta-analysis confirmed that SP
IPTp continued to benefit pregnant women in areas of up to
39% resistance to SP by day 14 in children !5 years of age .
We used birth weight as the primary end point, because it
is a good public health indicator of the consequences of malaria
in pregnancy, and it was correlated with the efficacy of IPTp
in several studies [6, 23, 24]. Recently, in the same study area,
we showed that the risk of LBW was 2.5-fold lower with IPTp
(either SP or MQ) than with chloroquine
There were very few losses to follow-up with regard to LBW,
and we made sure that the proportions and baseline
characteristics of those women were comparable between groups.
Secondary end points were not determined for ∼20% of women,
who mainly had delivered outside the study centers. Because
the reasons why they delivered in another center, as well as
their characteristics at baseline, were comparable between
groups, it is unlikely that it could have biased our results.
Finally, HIV status was determined for only 50% of the women.
Because HIV infection is associated with both higher risks for
malaria and LBW and a lower efficacy of IPTp, it may have
acted as a confounder. However, the prevalence of HIV was
low (2%) in the study area.
Although a curative dose of 25 mg/kg has been recommended
in Southeast Asia, where resistance to MQ is high, a lower dose
(15 mg/kg) has been shown to be efficacious in areas of low
resistance , as in most parts of Africa. In our study, 15 mg/
kg MQ proved to be efficacious enough for IPTp, even if it is
unclear whether either full protection from infection in
semiimmune women or only suppression of parasitemia to
lowgrade controlled levels is required to prevent malaria-associated
LBW. Also, this dosage allowed administration in a single
supervised intake, with the expectation of lower AEs . In
contrast, it could theoretically increase the risk for selection of
Despite having fair tolerance of MQ at prophylactic doses,
78% of the women in the MQ group reported experiencing
AEs. However, the decreased proportion of AEs that we
observed in both groups after the second IPTp dose suggests a
possible overexpectation of AEs in the community where
discussions had been organized before the first administration of
IPTp. Most of the symptoms were mild and resolved fast and
spontaneously, although 5.5% of the women in the MQ group
were unwilling to receive the second dose and 2% refused it
(the corresponding values for women in the SP group were 2%
and 1%). Also, 1 in 802 women in the MQ group had a serious
neuropsychiatric episode (consistent with the literature [27–
29]), which may cause concern regarding the acceptability of
MQ for routine programmatic use in pregnancy. A split dose
of 10 mg/kg and 5 mg/kg given over 2 days or 6–8 h apart
may be better tolerated—as has been shown for a dose of 25
mg/kg [26, 30]—without lowering the total dose . Finally,
to determine the optimal mefloquine dosage regimen for IPTp
in Africa, pharmacokinetic data need to be collected for
asymptomatic African pregnant women, who may well have
pharmacogenetic differences from symptomatic Asian women, for
whom pharmacokinetic parameters have already been reported
elsewhere [32, 33].
In our trial, the proportion of both stillbirths and
spontaneous abortions was not statistically different between groups,
although it was slightly higher in the MQ group. However, the
sample size was sufficient to detect a 70% increased risk of
stillbirths in the MQ group, as was previously suggested in a
study of Karen women treated with 25 mg/kg MQ . This
finding had not been reported in a larger prospective trial of
MQ prophylaxis (250 mg per week) in Malawian pregnant
women  or during postmarketing monitoring by the
manufacturer of MQ [36, 37]. Also, the proportion of congenital
anomalies did not differ significantly between groups. Because
women received IPTp late during pregnancy, it is most unlikely
that MQ was responsible for the 3 major anomalies that were
reported. However, to be definitively sure of the safety of MQ
during pregnancy, larger studies are needed because stillbirths
and congenital anomalies are rare outcomes.
Although it is likely that SP will soon have to be replaced
by a more effective antimalarial drug, it is not clear when this
change becomes necessary. In our study area, where the rate
of SP treatment failure by day 28 was estimated to be 50% in
children , the protection that SP IPTp provided to pregnant
women receiving SP for IPTp (10% of whom had LBW infants
and 4.4% of whom had placental malaria) was higher than that
provided by chloroquine chemoprophylaxis, particularly
against placental malaria (16% and 17%, respectively) .
These results are consistent with the findings of ter Kuile et al
, which showed that SP IPTp can be continued in areas of
SP resistance and suggested that the in vivo efficacy of SP should
be monitored specifically in pregnant women and not in young
MQ proved to be an interesting option for IPTp in terms
of efficacy (resulting in equivalent proportions of LBW, lower
risk of placental and peripheral parasitemia, and fewer episodes
of malaria than were noted for SP). However, its moderate
tolerability raises some concerns about its acceptability in a
pragmatic context and may limit its use for IPTp. MQ remains
a very efficacious drug for use in IPTp, and, at present, it is
the only alternative to SP. However, further data on its
tolerability and safety should be gathered before it is recommended
systematically. Also, pharmacokinetics studies are needed to
determine the best dose regimen for MQ IPTp. A split dose of
15 mg/kg may be an interesting option, because it could be
We are grateful to all the women and children who participated in the
trial. We thank all the medical, laboratory, and administrative staffs of
Kindji, Hoˆ pital de Zone, and Kpasse´ for their valuable contribution to this
trial. We would particularly like to thank Gildas Gbaguidi, Carine Akplogan,
Jacqueline Affedjou, Jean-Claude Sagbo, Cle´mence Azon, and Se´verin
Tossou-Vignibe´, who were the field investigators, for their hard work and
dedication to this study. We also thank Ossenatou Ta¨ırou, Ghislain Koura
Kobto, Agne`s Le Port, Andre´ Garcia, Agne`s Aubouy, and Florence
MigotNabias, who helped supervise the study; and Justin Dorichamou, who
performed quality control of blood smear reading. We thank Richard
Kiniffo and Yolaine Gle´le´-Ahanhanzo, who are the regional health coordinators,
for their support in this trial. We are grateful to Muriel Vray, Elisabeth
Elefant, and Olivier Bouchaud (members of the data safety monitoring
board) for their valuable advice.
1. Brabin BJ . An analysis of malaria in pregnancy in Africa . Bull World Health Organ 1983 ; 61 : 1005 - 16 .
2. Steketee RW , Wirima JJ , Hightower AW , Slutsker L , Heymann DL , Breman JG . The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi . Am J Trop Med Hyg 1996 ; 55 : 33 - 41 .
3. Bloland P , Slutsker L , Steketee RW , Wirima JJ , Heymann DL , Breman JG . Rates and risk factors for mortality during the first two years of life in rural Malawi . Am J Trop Med Hyg 1996 ; 55 : 82 - 6 .
4. Steketee RW , Wirima JJ , Campbell CC . Developing effective strategies for malaria prevention programs for pregnant African women . Am J Trop Med Hyg 1996 ; 55 : 95 - 100 .
5. World Health Organization (WHO). A strategic framework for malaria prevention and control during pregnancy in the Africa region . AFR/ MAL/04/01. Brazzaville, Republic of the Congo: WHO Regional Office for Africa , 2004 .
6. Kayentao K , Kodio M , Newman RD , et al. Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali . J Infect Dis 2005 ; 191 : 109 - 16 .
7. ter Kuile FO , van Eijk AM , Filler SJ . Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review . JAMA 2007 ; 297 : 2603 - 16 .
8. Shulman CE , Dorman EK , Cutts F , et al. Intermittent sulphadoxinepyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial . Lancet 1999 ; 353 : 632 - 6 .
9. Njagi JK , Magnussen P , Estambale B , Ouma J , Mugo B. Prevention of anaemia in pregnancy using insecticide-treated bednets and sulfadoxine-pyrimethamine in a highly malarious area of Kenya: a randomized controlled trial . Trans R Soc Trop Med Hyg 2003 ; 97 : 277 - 82 .
10. Schultz LJ , Steketee RW , Macheso A , Kazembe P , Chitsulo L , Wirima JJ . The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi . Am J Trop Med Hyg 1994 ; 51 : 515 - 22 .
11. Mene´ndez C , Bardajı´ A, Sigauque B , et al. A randomized placebocontrolled trial of intermittent preventive treatment in pregnant women in the context of insecticide treated nets delivered through the antenatal clinic . PLoS ONE 2008 ; 3 : e1934 .
12. World Health Organization (WHO). Report of the technical expert group meeting on intermittent preventive treatment in pregnancy (IPTp). 11-13 July . Geneva: WHO, 2007 .
13. Menendez C , D'Alessandro U , ter Kuile FO. Reducing the burden of malaria in pregnancy by preventive strategies . Lancet Infect Dis 2007 ; 7 : 126 - 35 .
14. Nosten F , ter Kuile F , Maelankiri L , et al. Mefloquine prophylaxis prevents malaria during pregnancy: a double-blind, placebo-controlled study . J Infect Dis 1994 ; 169 : 595 - 603 .
15. Akogbeto M , Modiano D , Bosman A. Malaria transmission in the lagoon area of Cotonou , Benin. Parassitologia 1992 ; 34 : 147 - 54 .
16. Aubouy A , Fievet N , Bertin G , et al. Dramatically decreased therapeutic efficacy of chloroquine and sulfadoxine-pyrimethamine, but not mefloquine , in southern Benin. Trop Med Int Health 2007 ; 12 : 886 - 94 .
17. Benin: demographic and health surveys, 2006-final report [in French]. 2006 . Available at: http://www.measuredhs.com/pubs/pub_details .cfm? IDp733&srchTpptype . Accessed 28 July 2008 .
18. Ballard JL , Khoury JC , Wedig K , Wang L , Eilers-Walsman BL , Lipp R. New Ballard score, expanded to include extremely premature infants . J Pediatr 1991 ; 119 : 417 - 23 .
19. Briand V , Denoeud L , Massougbodji A , Cot M. Efficacy of intermittent preventive treatment versus chloroquine prophylaxis to prevent malaria during pregnancy in Benin . J Infect Dis 2008 ; 198 : 594 - 601 .
20. Ouma P , Parise ME , Hamel MJ , et al. A randomized controlled trial of folate supplementation when treating malaria in pregnancy with sulfadoxine-pyrimethamine . PLoS Clin Trials 2006 ; 1 : e28 .
21. van Eijk AM , Ouma PO , Williamson J , et al. Plasma folate level and high-dose folate supplementation predict sulfadoxine-pyrimethamine treatment failure in pregnant women in Western Kenya who have uncomplicated malaria . J Infect Dis 2008 ; 198 : 1550 - 3 .
22. Denoeud L , Fievet N , Aubouy A , et al. Is chloroquine chemoprophylaxis still effective to prevent low birth weight? Results of a study in Benin . Malar J 2007 ; 6 : 27 .
23. Parise ME , Ayisi JG , Nahlen BL , et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection . Am J Trop Med Hyg 1998 ; 59 : 813 - 22 .
24. Mbaye A , Richardson K , Balajo B , et al. A randomized, placebo-controlled trial of intermittent preventive treatment with sulphadoxinepyrimethamine in Gambian multigravidae . Trop Med Int Health 2006 ; 11 : 992 - 1002 .
25. Bosman A , Delacollette C , Olumese P , et al. The use of antimalarial drugs: report of an informal consultation . Geneva: World Health Organization , 2001 .
26. ter Kuile FO , Nosten F , Luxemburger C , et al. Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients . Bull World Health Organ 1995 ; 73 : 631 - 42 .
27. Weinke T , Trautmann M , Held T , et al. Neuropsychiatric side effects after the use of mefloquine . Am J Trop Med Hyg 1991 ; 45 : 86 - 91 .
28. Luxemburger C , Nosten F , ter Kuiile F , Frejacques L , Chongsuphajaisiddhi T , White NJ . Mefloquine for multidrug-resistant malaria . Lancet 1991 ; 338 : 1268 .
29. Phillips-Howard PA , ter Kuile FO. CNS adverse events associated with antimalarial agents . Fact or fiction? Drug Saf 1995 ; 12 : 370 - 83 .
30. Ashley EA , Lwin KM , McGready R , et al. An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new coformulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand . Trop Med Int Health 2006 ; 11 : 1653 - 60 .
31. Simpson JA , Price R , ter Kuile F , et al. Population pharmacokinetics of mefloquine in patients with acute falciparum malaria . Clin Pharmacol Ther 1999 ; 66 : 472 - 84 .
32. Na Bangchang K , Davis TM , Looareesuwan S , White NJ , Bunnag D , Karbwang J. Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria . Trans R Soc Trop Med Hyg 1994 ; 88 : 321 - 3 .
33. Nosten F , Karbwang J , White NJ , et al. Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study . Br J Clin Pharmacol 1990 ; 30 : 79 - 85 .
34. Nosten F , Vincenti M , Simpson J , et al. The effects of mefloquine treatment in pregnancy . Clin Infect Dis 1999 ; 28 : 808 - 15 .
35. Steketee RW , Wirima JJ , Slutsker L , Khoromana CO , Heymann DL , Breman JG . Malaria treatment and prevention in pregnancy: indications for use and adverse events associated with use of chloroquine or mefloquine . Am J Trop Med Hyg 1996 ; 55 : 50 - 6 .
36. Vanhauwere B , Maradit H , Kerr L. Post-marketing surveillance of prophylactic mefloquine (Lariam) use in pregnancy . Am J Trop Med Hyg 1998 ; 58 : 17 - 21 .
37. Phillips-Howard PA , Steffen R , Kerr L , et al. Safety of mefloquine and other antimalarial agents in the first trimester of pregnancy . J Travel Med 1998 ; 5 : 121 - 6 .