Abstract

BackgroundIn the context of the increasing resistance to sulfadoxine-pyrimethamine (SP), we evaluated the efficacy of mefloquine (MQ) for intermittent preventive treatment during pregnancy (IPTp)

MethodsA 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 low–birth-weight (LBW) infants (body weight, <2500 g; equivalence margin, 5%)

ResultsA total of 1601 women were randomized to receive MQ (n=802) or SP (n=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=.005), clinical malaria (incidence rate, 26 cases/10,000 person-months vs. 68 cases/10,000 person-months; P=.007), and maternal anemia at delivery (as defined by a hemoglobin level <10 g/dL) (prevalence, 16% vs 20%; marginally significant at 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

ConclusionsMQ 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 RegistrationNCT00274235

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 [5]. 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 [2] and peripheral [2, 14] and placental malaria [2] 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

Methods

Study siteThe 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 [15]. 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 [16]. 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% [17]

The study was initially conducted in the 2 main maternity clinics, Kindji and the “Hôpital de Zone.” Beginning in May 2006, to increase recruitment of subjects, a third center with comparable characteristics, Kpassé, was included in the study

SP IPTp has been recommended by the Beninese Ministry of Health since 2004 and has been applied since 2006

EnrollmentEnrollment 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) [5] 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-upThe 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 when needed

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 Hôpital de Zone if they were symptomatic

InterventionRandomization 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 neuropsychiatric symptoms

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/μL

All women were prescribed daily ferrous (400 mg) and folic (5 mg) supplementation (Beninese Ministry of Health recommendation)

DeliveryDuring 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 [18], 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 investigationsHemoglobin was measured using a colorimeter (Anadeo; 540 nm). Thick and thin blood 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/μL. 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

BlindingThe 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 sizeWe 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 [19]), using a 5% equivalence margin, 80% power, and a 2-sided α 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 analysisWe 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 intention-to-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 continuous variables

Only crude analyses are presented, because adjusted analyses provided similar results. Differences between proportions were compared using the χ2 test or Fisher’s exact test. Data analysis was performed using Stata software (version 8.0; Stata)

EthicsThe Comité Consultatif de Déontologie et d’Ethique (France) and the ethics committee of the University of Abomey-Calavi (Benin) approved the study protocol and its amendments

Results

Study populationOverall, 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)

Figure 1

Study profile. *Seven women were excluded because they were included twice (only their first pregnancy was considered for analyses); 1 woman (who was receiving sulfadoxine-pyrimethamine [SP]) was excluded because she was not pregnant. **Modified intention-to-treat (ITT) analysis from which women lost to follow-up, twins, and stillborn infants were excluded. †Forty-three women who had troublesome vomiting and dizziness after receiving the first dose of mefloquine (MQ) received the second dose in 2 supervised intakes on the same day. AE, adverse event; IPTp, intermittent preventive treatment during pregnancy; PP, per-protocol analysis

Figure 1

Study profile. *Seven women were excluded because they were included twice (only their first pregnancy was considered for analyses); 1 woman (who was receiving sulfadoxine-pyrimethamine [SP]) was excluded because she was not pregnant. **Modified intention-to-treat (ITT) analysis from which women lost to follow-up, twins, and stillborn infants were excluded. †Forty-three women who had troublesome vomiting and dizziness after receiving the first dose of mefloquine (MQ) received the second dose in 2 supervised intakes on the same day. AE, adverse event; IPTp, intermittent preventive treatment during pregnancy; PP, per-protocol analysis

Table 1

Characteristics of Randomized Women at Baseline, by Treatment Group

Table 1

Characteristics of Randomized Women at Baseline, by Treatment Group

Follow-upIn 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 regimensA 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%])

Table 2

Proportion of Women with Low–Birth-Weight (LBW) Infants (<2500 g), by Treatment Group, as Determined by Equivalence Analyses

Table 2

Proportion of Women with Low–Birth-Weight (LBW) Infants (<2500 g), by Treatment Group, as Determined by Equivalence Analyses

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=.005] and 1.5% vs 3.6% [P=.03]) (tables 3 and 4)

Table 3

Proportion of Placental Infection and Maternal Anemia at Delivery, by Treatment Group, According to Crude Analysis

Table 3

Proportion of Placental Infection and Maternal Anemia at Delivery, by Treatment Group, According to Crude Analysis

Table 4

Comparative Efficacy of Mefloquine (MQ) and Sulfadoxine-Pyrimethamine (SP) for Intermittent Preventive Treatment during Pregnancy (IPTp): Ancillary End Points in Crude Analysis

Table 4

Comparative Efficacy of Mefloquine (MQ) and Sulfadoxine-Pyrimethamine (SP) for Intermittent Preventive Treatment during Pregnancy (IPTp): Ancillary End Points in Crude Analysis

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=.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 person-months vs 68 cases/10,000 person-months; P=.007). Three women had 2 episodes. In both groups, the mean (±SD) time between malaria cases and the last IPTp intake (first or second dose) was 52 ±19 days

Delivery outcomesThe incidences of spontaneous abortions, stillbirths, and congenital anomalies did not differ significantly between groups, although they were higher in the MQ group than in the SP group (table 4)

A cause for stillbirth or abortion was found for 38% of the MQ group and 25% of the SP group, thus decreasing the probability of an effect due to the drug (table 5). Malaria at delivery was diagnosed for 1 of 19 women who had a stillbirth or abortion. The median (IQR) time between the events and the last IPTp intake was 46 days (22–86 days) and 65 days (39–82 days), in the MQ and SP groups, respectively

Table 5

Possible Causes of Stillbirths and Spontaneous Abortions and Types of Congenital Anomalies, by Treatment Group

Table 5

Possible Causes of Stillbirths and Spontaneous Abortions and Types of Congenital Anomalies, by Treatment Group

There were 5 maternal deaths in the MQ group. Of them, 4 were associated with obstetric causes (1 disseminated intravascular coagulation with hyperfibrinogenolysis, 2 peripartum hemorrhages, and 1 uterine rupture), and one remained unexplained

Adverse events: mothersThe proportion of women who reported an AE was significantly higher in the MQ group than in the SP group (78% vs 32%; P<10-3) (figure 2). The most 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

Figure 2

Proportion and type of adverse events, by treatment group. Data are proportions (95% confidence interval [CI]) of women with the symptom on the occasion of at least one treatment. In all but 19 women, symptoms occurred (96% of cases) or increased (4% of cases) after drug intake. Six women had a cutaneous reaction (1 and 5 women in the mefloquine [MQ] and sulfadoxine-pyrimethamine [SP] groups, respectively). One woman (in the MQ group) had a severe neurologic reaction. *P<10-3. **Defined as vomiting occurring within 30 min after drug intake. IPTp, intermittent preventive treatment during pregnancy

Figure 2

Proportion and type of adverse events, by treatment group. Data are proportions (95% confidence interval [CI]) of women with the symptom on the occasion of at least one treatment. In all but 19 women, symptoms occurred (96% of cases) or increased (4% of cases) after drug intake. Six women had a cutaneous reaction (1 and 5 women in the mefloquine [MQ] and sulfadoxine-pyrimethamine [SP] groups, respectively). One woman (in the MQ group) had a severe neurologic reaction. *P<10-3. **Defined as vomiting occurring within 30 min after drug intake. IPTp, intermittent preventive treatment during pregnancy

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 hospitalization

Adverse events: neonates and infantsNeonatal 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, >75% of deaths were explained; they were related to prematurity, infection, or malformation

Discussion

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 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 [19]

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 [16], 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 [22]. 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 [7]

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 chemoprophylaxis [19]

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 [25], 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 semi-immune women or only suppression of parasitemia to low-grade 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 [26]. In contrast, it could theoretically increase the risk for selection of resistance

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 [31]. 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 [34]. This finding had not been reported in a larger prospective trial of MQ prophylaxis (250 mg per week) in Malawian pregnant women [35] 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 [16], 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) [19]. These results are consistent with the findings of ter Kuile et al [7], 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 children

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 better tolerated

Acknowledgments

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, Hôpital de Zone, and Kpassé for their valuable contribution to this trial. We would particularly like to thank Gildas Gbaguidi, Carine Akplogan, Jacqueline Affedjou, Jean-Claude Sagbo, Clémence Azon, and Séverin Tossou-Vignibé, who were the field investigators, for their hard work and dedication to this study. We also thank Ossenatou Taïrou, Ghislain Koura Kobto, Agnès Le Port, André Garcia, Agnès Aubouy, and Florence Migot-Nabias, who helped supervise the study; and Justin Dorichamou, who performed quality control of blood smear reading. We thank Richard Kiniffo and Yolaine Glélé-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

References

1
Brabin
BJ
An analysis of malaria in pregnancy in Africa
Bull World Health Organ
 , 
1983
, vol. 
61
 (pg. 
1005
-
16
)
2
Steketee
RW
Wirima
JJ
Hightower
AW
Slutsker
L
Heymann
DL
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
, vol. 
55
 (pg. 
33
-
41
)
3
Bloland
P
Slutsker
L
Steketee
RW
Wirima
JJ
Heymann
DL
Rates and risk factors for mortality during the first two years of life in rural Malawi
Am J Trop Med Hyg
 , 
1996
, vol. 
55
 (pg. 
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
, vol. 
55
 (pg. 
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
 , 
2004
Brazzaville, Republic of the Congo
WHO Regional Office for Africa
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
, vol. 
191
 (pg. 
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
, vol. 
297
 (pg. 
2603
-
16
)
8
Shulman
CE
Dorman
EK
Cutts
F
, et al.  . 
Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial
Lancet
 , 
1999
, vol. 
353
 (pg. 
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
, vol. 
97
 (pg. 
277
-
82
)
10
Schultz
LJ
Steketee
RW
Macheso
A
Kazembe
P
Chitsulo
L
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
, vol. 
51
 (pg. 
515
-
22
)
11
Menéndez
C
Bardají
A
Sigauque
B
, et al.  . 
A randomized placebo-controlled trial of intermittent preventive treatment in pregnant women in the context of insecticide treated nets delivered through the antenatal clinic
PLoS ONE
 , 
2008
, vol. 
3
 (pg. 
e1934
-
e1934
)
12
World Health Organization (WHO)
Report of the technical expert group meeting on intermittent preventive treatment in pregnancy (IPTp). 11–13 July
2007
Geneva
WHO
13
Menendez
C
D’Alessandro
U
ter Kuile
FO
Reducing the burden of malaria in pregnancy by preventive strategies
Lancet Infect Dis
 , 
2007
, vol. 
7
 (pg. 
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
, vol. 
169
 (pg. 
595
-
603
)
15
Akogbeto
M
Modiano
D
Bosman
A
Malaria transmission in the lagoon area of Cotonou, Benin
Parassitologia
 , 
1992
, vol. 
34
 (pg. 
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
, vol. 
12
 (pg. 
886
-
94
)
17
Benin: demographic and health surveys 2006–final report [in French]
2006
 
Available at: http://www.measuredhs.com/pubs/pub_details.cfm?ID=733&srchTp=type. Accessed 28 July 2008
18
Ballard
JL
Khoury
JC
Wedig
K
Wang
L
Eilers-Walsman
BL
New Ballard score, expanded to include extremely premature infants
J Pediatr
 , 
1991
, vol. 
119
 (pg. 
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
, vol. 
198
 (pg. 
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
, vol. 
1
 (pg. 
e28
-
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
, vol. 
198
 (pg. 
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
, vol. 
6
 pg. 
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
, vol. 
59
 (pg. 
813
-
22
)
24
Mbaye
A
Richardson
K
Balajo
B
, et al.  . 
A randomized, placebo-controlled trial of intermittent preventive treatment with sulphadoxine-pyrimethamine in Gambian multigravidae
Trop Med Int Health
 , 
2006
, vol. 
11
 (pg. 
992
-
1002
)
25
Bosman
A
Delacollette
C
Olumese
P
, et al.  . 
The use of antimalarial drugs: report of an informal consultation
2001
Geneva
World Health Organization
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
, vol. 
73
 (pg. 
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
, vol. 
45
 (pg. 
86
-
91
)
28
Luxemburger
C
Nosten
F
ter Kuiile
F
Frejacques
L
Chongsuphajaisiddhi
T
Mefloquine for multidrug-resistant malaria
Lancet
 , 
1991
, vol. 
338
 pg. 
1268
 
29
Phillips-Howard
PA
ter Kuile
FO
CNS adverse events associated with antimalarial agents. Fact or fiction
Drug Saf
 , 
1995
, vol. 
12
 (pg. 
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 co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand
Trop Med Int Health
 , 
2006
, vol. 
11
 (pg. 
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
, vol. 
66
 (pg. 
472
-
84
)
32
Na Bangchang
K
Davis
TM
Looareesuwan
S
White
NJ
Bunnag
D
Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria
Trans R Soc Trop Med Hyg
 , 
1994
, vol. 
88
 (pg. 
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
, vol. 
30
 (pg. 
79
-
85
)
34
Nosten
F
Vincenti
M
Simpson
J
, et al.  . 
The effects of mefloquine treatment in pregnancy
Clin Infect Dis
 , 
1999
, vol. 
28
 (pg. 
808
-
15
)
35
Steketee
RW
Wirima
JJ
Slutsker
L
Khoromana
CO
Heymann
DL
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
, vol. 
55
 (pg. 
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
, vol. 
58
 (pg. 
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
, vol. 
5
 (pg. 
121
-
6
)
Potential conflicts of interest: none reported
Presented in part: 57th meeting of the American Society of Tropical Medicine and Hygiene, New Orleans, 7–11 December 2008 (abstract 210)
Financial support: Fonds de Solidarité Prioritaire (French Ministry of Foreign Affairs; project no. 2006–22); Institut de Recherche pour le Développement; Fondation pour la Recherche Médicale (grant FDM20060907976 to V.B.); Fondation de France; and Fondation Mérieux
The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit the data for publication
J.B., H.N., V.M., H.C., and J.G. contributed equally to this work