MAJOR ARTICLE
Efficacy of Intermittent Preventive Treatment versus Chloroquine Prophylaxis to Prevent Malaria during Pregnancy in Benin Valérie Briand,1 Lise Denoeud,1 Achille Massougbodji,2 and Michel Cot1 1
Mother and Child Health in the Tropics, Development Research Institute, Paris, France; and 2Parasitology and Mycology Education and Research Unit, Science and Health Faculty, Cotonou, Benin
Background. In West Africa, treatment for the prevention of malaria during pregnancy has recently changed from chloroquine (CQ) prophylaxis to intermittent preventive treatment (IPTp). We assessed the benefits of IPTp with respect to those of CQ, using a before-after study. Methods. CQ efficacy was evaluated during a cross-sectional survey conducted in Benin between April 2004 and April 2005. IPTp efficacy was assessed using data from an ongoing clinical trial to compare sulfadoxinepyrimethamine with mefloquine that began in the same maternity clinics during July 2005; the present analysis is limited to women who delivered between November 2005 and November 2006. Treatment assignments were not unblinded. We compared the efficacy of the 2 strategies against low birth weight and placental infection by performing multiple logistic regressions. Results. A total of 1699 women (1090 in the CQ group and 609 in the IPTp group) who delivered live singletons were analyzed. Characteristics of women in the CQ group were similar to those of women in the IPTp group. We showed that women in the IPTp group had a significantly decreased risk of delivering an infant with a low birth weight (adjusted odds ratio [aOR], 0.54; 95% confidence interval [CI], 0.38 – 0.78) and placental infection (aOR, 0.15; 95% CI, 0.09 – 0.24). Conclusion. We clearly evidenced that IPTp is substantially more beneficial than CQ for the prevention of malaria during pregnancy. Trial registration. Clinicaltrials.gov identifier: NCT00274235. Malaria during pregnancy is associated with a range of deleterious effects in women and their offspring. In areas of high transmission, malaria is associated with maternal anemia and low birth weight [1], which is a high risk factor for perinatal death and for morbidity and mortality during infancy [2, 3]. A recent study in areas of malaria endemicity estimated that malaria may contribute
Received 21 September 2007; accepted 17 January 2008; electronically published 3 July 2008. Potential conflicts of interest: none reported. Financial support: Cross-sectional survey: Institut de Médecine et d’Epidémiologie Appliquée (grant 5714COT90), Fondation pour la Recherche Médicale (grant DEA20040701472); clinical trial: Fonds de Solidarite´ Prioritaire (Ministry of Foreign Affairs, project 2006-22); Fondation pour la Recherche Médicale (grant FDM20060907976 to V.B.); Fondation de France (to V.B.); Fondation Me´rieux (to V.B.). Reprints or correspondence: Dr. Valérie Briand, Development Research Institute, Mother and Child Health in the Tropics (UR010), Faculté de pharmacie, 4, avenue de l’Observatoire, 75270 Paris, cedex 06, France (
[email protected]). The Journal of Infectious Diseases 2008; 198:594 – 601 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19804-0019$15.00 DOI: 10.1086/590114
594
●
JID 2008:198 (15 August)
●
Briand et al.
to 3%–5% of maternal anemia cases, 8%–14% of low birth weight cases, and 3%– 8% of infant deaths [4]. In the 1950s, the World Health Organization (WHO) released its first recommendations on the prevention of malaria during pregnancy, which consisted of weekly or bimonthly chemoprophylaxis with chloroquine (CQ), sulfadoxine-pyrimethamine, or dapsone-pyrimethamine for the duration of pregnancy. A large number of clinical trials demonstrated the efficacy of these chemoprophylaxis regimens in preventing low birth weight, maternal anemia, and placental malaria [5, 6]. Unfortunately, because of the growing resistance of parasites to these drugs and the poor adherence to treatment among the women, the strategies ultimately showed a low efficacy and effectiveness [7–9]. In 2004, the WHO revised its recommendations, replacing chemoprophylaxis with intermittent preventive treatment (IPTp) [10]. IPTp involves the administration of a single curative dose of an antimalarial drug at least twice during pregnancy, regardless of whether the woman is infected with Plasmodium species. To ensure a greater rate of adher-
ence to treatment, the drug is administered under supervision during an antenatal care visit. Sulfadoxine-pyrimethamine is the drug currently recommended by the WHO for IPTp. Since the mid-1990s, several studies have confirmed the efficacy of IPTp [11–21]. Most studies were observational (i.e., 0 doses of IPTp were compared with 肁1 doses of IPTp) or clinical trials in which IPTp was compared with placebo. On the basis of findings from these studies and the high prevalence of CQ resistance among parasites, many African countries followed the WHO recommendations and adopted the IPTp strategy [22]. Although IPTp replaced CQ prophylaxis, the benefits of IPTp versus those of CQ prophylaxis have not been thoroughly assessed [11, 19, 20]. In Benin, IPTp with sulfadoxine-pyrimethamine has been recommended since the end of 2004 and has been used in most parts of the country since 2006. This regimen replaced weekly prophylaxis with CQ. We previously evaluated the efficacy of CQ during a cross-sectional survey conducted in Benin between 15 April 2004 and 14 April 2005. In the same region, we are evaluating the efficacy of IPTp in an ongoing sulfadoxine-pyrimethamine/mefloquine clinical trial initiated in 2005 [23]; the present analysis is limited to women who delivered during 2005– 2006. In this article, we compared the efficacy of the 2 strategies, using a before-after comparison. SUBJECTS, MATERIALS, AND METHODS Study site, population, and design. The setting for the CQ study and the IPTp clinical trial is Ouidah, a semirural town situated 30 km from Cotonou, Benin. Women were evaluated at the 2 main maternity clinics in the city, Kindji and Hopital de Zone (the latter is also a tertiary care referral center). In the study area, malaria transmission occurs throughout the year, with 2 peaks corresponding with the 2 rainy seasons (April through July and September through November). In 2005, in vivo resistance to CQ, sulfadoxine-pyrimethamine, or mefloquine, defined as clinical failure of these agents by day 14 of treatment, was estimated to be present in 85.7%, 50%, and 2.5% of children ⬍5 years of age, respectively [24]. The prevalence of human immunodeficiency virus infection in the general population is ⬃2% [25]. In 2001, the percentages of pregnant women who attended 肁1 and 肁4 antenatal care visits was ⬃88% and ⬃61%, respectively, and the percentage of those who delivered in health facilities was ⬃78% [26]. Between 15 April 2004 and 14 April 2005, we conducted a cross-sectional study involving all women who delivered in the 2 maternity clinics. This survey aimed to provide accurate data on low birth weight and placental infection in the area while CQ prophylaxis was still recommended. The study design is described elsewhere [27]. Briefly, women were included at delivery. Sociodemographic indicators, parity, malaria prevention measures, number and dates of antenatal care visits, gestational age
at delivery, and infant characteristics were collected. We obtained information on CQ use by completing a questionnaire (which recorded the number of tablets taken per week, duration of prophylaxis, and date of the last drug intake) and checking antenatal care records. In case of discrepancies, we considered antenatal care records as the most reliable source of information. After delivery, blood was collected from the maternal side of the placenta for thick blood smears. Treatment adherence among the women was determined by quantifying CQ in urine in a subsample of the enrolled women. In July 2005, while the IPTp strategy was being implemented in the country, we started an equivalent trial to compare the efficacy of IPTp with sulfadoxine-pyrimethamine versus that of IPTp with mefloquine. At the present time, trial recruitment is ongoing. In this article, we only considered women who delivered in the 2 maternity clinics between 1 November 2005 and 30 November 2006 in order to compare an equivalent 1-year duration in both studies. Women were included in the trial if they were ⬎4 months pregnant, were living close to the maternity clinic, had not been using sulfadoxine-pyrimethamine or mefloquine within the 4 last weeks, and had not reported past adverse reactions to sulfa-containing medications or mefloquine or a history of neurological or psychiatric disorders. After they provided informed consent, participants were recruited and were randomized to receive sulfadoxine-pyrimethamine (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or mefloquine (15 mg/kg) twice during pregnancy. The first dose was administered between 16 and 28 weeks of gestation, and the second dose was administered after 30 weeks of gestation, with at least 1 month between the 2 intakes. Clinical and biological data similar to those collected in the cross-sectional survey were recorded. Gestational age at delivery was estimated using the Ballard criteria [28]. Both studies were approved by the ethics committees of the Development Research Institute in France and the University of Abomey-Calavi in Benin. Treatment of clinical malaria. During the cross-sectional survey, pregnant women who complained of malarial symptoms were generally treated with CQ. During the clinical trial, all symptomatic women were treated with quinine after laboratory confirmation of malaria. Laboratory investigations. Placental blood smears were stained with Giemsa stain. Samples were recorded as positive if an asexual-stage Plasmodium falciparum parasite was detected during examination of 400 microscope fields. Parasite densities were estimated using an assumed leukocyte count of 8000 leukocytes/L. Erythrocytes and/or circulating monocytes were evaluated for “malaria pigment” as an indirect indicator for active infection. During both studies, blood films were examined by the same laboratory assistants. Each slide was read independently by 2 microscopists. Their findings were generally concorIPTp vs. Chloroquine Chemoprophylaxis
●
JID 2008:198 (15 August)
●
595
dant, but if results were discrepant the slide was read by a third microscopist. Definitions. Low birth weight was defined as a birth weight of ⬍2500 g. Women were considered to be fully adherent to the treatment if they took 300 mg of CQ per week or 2 IPTp doses during the course of pregnancy. Statistical analysis. Data were entered using Excel (for the CQ survey) and Epidata, version 3.1 (for the IPTp clinical trial). Data validation, cleaning, and statistical analysis were performed using Stata, version 8.0 (Stata). All women who delivered during the cross-sectional survey and women recruited for the clinical trial who delivered between November 2005 and November 2006 were included in the analysis. Because the clinical trial was still unfinished, it was not possible to unblind treatment assignments, and women in this group were considered to have received IPTp, regardless of the drug administered. Because women were randomized in blocks of 4, we can assume that half of the women we included in the IPTp group for the present analysis received mefloquine for IPTp. Also, only women who gave birth to live singletons were considered for the analysis. Characteristics of mothers and singletons were compared between the CQ prophylaxis and IPTp groups. Differences between means, medians, and proportions were compared using the Student t test, a K-sample test, and the 2 test, respectively. We used logistic regression models to compare the efficacy of CQ prophylaxis and IPTp for the prevention of low birth weight and placental malaria. Categorical variables were considered as dummy variables. For the multivariate analysis, all variables with a P value of 聿.20 in univariate analysis were initially introduced into the model, and those with a P value of ⬎.20 were removed following a backward-stepwise selection procedure, leaving only variables with a P value of ⬍.05 in the final model. Also, we compared the efficacy of CQ and IPTp for the prevention of birth weight, using a multiple linear regression and adjusting for factors significantly associated with low birth weight in the previous multivariate analysis. RESULTS Study populations. A total of 1180 women delivered during the cross-sectional survey, and 625 delivered during the 1-year follow-up of the clinical trial. Pregnancy resulted in a stillbirth for 62 women (3%; 55 [5%] in the CQ group and 7 [1%] in the IPTp group) and delivery of twins for 47 (3%; among the twins, 3 were stillborn). A total of 1699 women and their live singletons (1090 of each in the CQ group and 609 of each in the IPTp group) were analyzed. Characteristics of the mothers are summarized in table 1. Seventy-six percent were multigravidae. The mean number of antenatal care visits was 4.5 (median, 4 visits) [4]. Seventy-five percent of women reported use of bed nets. 596
●
JID 2008:198 (15 August)
●
Briand et al.
Table 1. Characteristics of women who delivered live singletons in Ouidah, Benin, during 2004 –2006, by treatment group. Characteristic Maternity clinic Kindji Hopital de Zone Maternal age, years 聿20 21–25 26–30 ⬎30 Education level None Primary Secondary, superior Residence setting Urban Rural Unknown Socioeconomic status Supplied latrines Supplied electricity Fon ethnicity Multigravidity Antenatal care visits, no. 聿3 ⬎3 Maternal hypertension Yes No Bed net use
CQ group
IPTp group
P
693/1090 (64) 397/1090 (36)
488/609 (80) 121/609 (20)
⬍.001
255/1072 (24) 373/1072 (35) 244/1072 (23) 200/1072 (18)
141/609 (23) 230/609 (38) 145/609 (24) 93/609 (15)
527/1051 (50) 359/1051 (34) 165/1051 (16)
289/609 (47) 231/609 (38) 89/609 (15)
.30
689/1090 (63) 205/1090 (19) 196/1090 (18)
533/609 (88) 75/609 (12) 1/609 (⬍1)
⬍.001
127/174 (73) 113/174 (65) 117/174 (67) 823/1090 (76)
477/609 (78) 357/609 (59) 421/609 (69) 464/609 (76)
.10 .13 .64 .75
400/1076 (37) 676/1076 (63)
157/609 (26) 440/609 (72)
⬍.001
56/1069 (5) 1013/1069 (95) 764/1010 (76)
38/609 (6) 571/609 (94) 454/609 (75)
.39 .62
.29
NOTE. Data are number of women with the characteristic/number for whom data were available (%). Women in the chloroquine prophylaxis (CQ) group delivered between April 2004 and April 2005, and women in the intermittent preventive treatment (IPTp) group delivered between November 2005 and November 2006. Socioeconomic status, marital status, and ethnicity were determined for all women during the IPTp clinical trial and for a subsample of women during the cross-sectional survey.
The overall characteristics of women were similar between the 2 groups. However, in the IPTp study, more women delivered at the Kindji maternity ward, the number of antenatal care visits was greater, and more women lived in an urban setting. In the cross-sectional survey, the mean self-reported duration of CQ use, which began at 4 months of gestation, was 5 months for ⬎95% of the women. Among 162 women for whom a urine specimen was tested for CQ, 100% had a detectable concentration of CQ, and 72% had a high concentration of CQ. Women with a high level of CQ were less likely than women with a low level to have a placental infection (7% vs. 17%; P ⫽ .06). Also, there was a significant association between delivery of an infant with low birth weight and both self-reported duration of CQ prophylaxis (P ⬍ .001, by the 2 test for linear trend) and selfreported CQ use during the last trimester of pregnancy (aOR, 0.24; 95% CI, 0.11– 0.56; P ⬍ .001) [27]. In the clinical trial,
Table 2. Characteristics of live singletons born to women in Ouidah, Benin, during 2004 –2006, by maternal treatment group. Characteristic Born during rainy season Sex Female Male Birth weight, mean (95% CI), g Low birth weight (⬍2500 g) Placental malaria Placental parasitemiaa Malformationb
CQ group
IPTp group
P
435/1090 (40)
264/609 (43)
.17
522/1090 (48) 568/1090 (52) 2876 (2847–2905) 171/1087 (16) 176/1052 (17) 1391 12/909 (1)
323/608 (53) 285/608 (47) 3060 (3025–3094) 53/609 (9) 17/585 (3) 16,904 7/608 (1)
.04 ⬍.001 ⬍.001 ⬍.001 .04 .77
NOTE. Data are number (%) of infants, unless otherwise indicated. Infants born to mothers in the chloroquine prophylaxis (CQ) group were delivered between April 2004 and April 2005, and infants born to mothers in the intermittent preventive treatment (IPTp) group were delivered between November 2005 and November 2006. CI, confidence interval. a
Data are median number of parasites per mm3 among infected mothers. In the CQ group, 4 had a surplus finger, 1 had a palate malformation, 1 had hydrocephaly, 1 had microcephaly, and 5 had other polymalformative syndromes. In the IPTp group, 4 had a surplus finger, 1 had microcephaly, and 2 had other polymalformative syndromes. b
95% of the women received 2 IPTp doses. The median gestational ages at the time of the first and second doses of IPTp were 24 weeks (range, 16 –29 weeks) and 33 weeks (range, 30 – 42 weeks), respectively. In the cross-sectional survey, 72% of women complained of malarial symptoms during pregnancy [27]. Most were treated with CQ without laboratory confirmation. During the clinical trial, 10 women had a symptomatic malarial infection (confirmed by the laboratory) and were treated with quinine. Before their inclusion in the survey, 44% of women had received CQ as chemoprophylaxis. Effectiveness of CQ and IPTp on low birth weight and placental infection. The mean birth weight was 2876 g in the CQ group and 3060 g in the IPTp group (P ⬍ .001) (table 2). The percentage of infants with a low birth weight in the IPTp group was significantly less than that in the CQ group (9% vs. 16%; P ⬍ .001). The prevalence of placental malaria was much higher in the CQ group (17% vs. 3%; P ⬍ .001), with a significantly lower level of placental parasitemia. On a broader definition of placental infection (i.e., detection of malaria pigments), 25% of women in the CQ group and 4% in the IPTp group had this condition. In univariate analysis, the risk for low birth weight was significantly lower in the IPTp group and for the following factors: multigravidity, older maternal age, absence of maternal hypertension during pregnancy, large number of antenatal care visits, use of bed nets, no placental infection, and male sex of the infant (table 3). In multivariate analysis, all of these factors remained significantly associated with low birth weight except for maternal age and use of bed nets, which were highly correlated with gravidity. Women in the IPTp group had a 2-fold decreased risk for low birth weight, compared with women in the CQ group
(OR, 0.54; 95% CI, 0.38 – 0.78; P ⫽ .001). After restriction of the analysis to women with a good adherence to treatment, we found an even more marked protective effect of IPTp (OR, 0.48; 95% CI, 0.33– 0.71). We showed that the mean weight for newborns delivered by women in the IPTp group was 170 g (95% CI, 127–219 g) greater than that for newborns in the CQ group (P ⬍ .001). Singletons delivered to primigravidae in the IPTp group weighed a mean of 148 g (95% CI, 55–241 g) more than those delivered to primigravidae in the CQ group (P ⫽ .002), and singletons delivered to multigravidae in the IPTp group weighed a mean of 182 g (95% CI, 129 –235 g) more than those delivered to multigravidae in the CQ group (P ⬍ .001). In univariate analysis, the risk for placental infection was significantly lower for IPTp use, delivery at Kindji, multigravidity, and older maternal age (table 4). In multivariate analysis, the risk of placental infection for women in the IPTp group remained significantly lower than that for women in the CQ group (OR, 0.15; 95% CI, 0.09 – 0.24; P ⬍ .001), and the risk for multigravidae was significantly lower than that for primigravidae. When we stratified the analysis on the basis of gravidity, we found a lower risk for placental infection in the IPTp group for both primigravidae (OR, 0.13; 95% CI, 0.05– 0.30) and multigravidae (OR, 0.16; 95% CI, 0.08 – 0.30). There was no significant association between placental infection and maternal age after adjustment for gravidity, because both variables were highly correlated. DISCUSSION Although the IPTp strategy has replaced CQ prophylaxis in areas with high rates of malaria transmission, its benefits have not IPTp vs. Chloroquine Chemoprophylaxis
●
JID 2008:198 (15 August)
●
597
Table 3. Logistic regression analysis of factors possibly significantly associated with delivery of an infant with a low birth weight in Ouidah, Benin, during 2004 –2006. Univariate analysis Variable
Multivariate analysisa
Deliveries, proportion (%)
Crude OR (95% CI)b
Adjusted OR (95% CI)b
P
171/1087 (16) 53/609 (9)
1.00 0.51 (0.37–0.71)
1.00 0.54 (0.38–0.78)
.001
157/1179 (13) 67/517 (13)
1.00 0.97 (0.71–1.32)
... ...
165/1220 (14) 29/280 (10) 30/196 (15)
1.00 0.74 (0.49–1.12) 1.16 (0.76–1.76)
... ... ...
90/411 (22) 134/1285 (10)
1.00 0.42 (0.31–0.56)
1.00 0.39 (0.28–0.54)
79/395 (20) 78/602 (13) 37/388 (10) 26/293 (9)
1.00 0.60 (0.42–0.84) 0.42 (0.28–0.64) 0.39 (0.24–0.62)
... ... ... ...
198/1582 (13) 24/93 (26)
1.00 2.43 (1.49–3.96)
1.00 2.45 (1.45–4.16)
.001
98/557 (18) 120/1113 (11)
1.00 0.57 (0.42–0.76)
1.00 0.61 (0.44–0.83)
.002
66/400 (17) 144/1216 (12)
1.00 0.68 (0.50–0.93)
... ...
136/1000 (14) 88/696 (13)
1.00 0.92 (0.69–1.22)
... ...
172/1442 (12) 45/192 (23)
1.00 2.26 (1.56–3.27)
1.00 1.54 (1.01–2.35)
.04
86/851 (10) 137/855 (16)
1.00 1.72 (1.29–2.30)
1.00 1.75 (1.28–2.40)
.001
Treatment group Chloroquine IPTp Maternity clinic Kindji Hopital de Zone Residence setting Urban Rural Unknown Gravidity status Primigravidity Multigravidity Maternal age, years 聿20 21–25 26–30 ⬎30 Maternal hypertension No Yes Antenatal care visits, no. 聿3 ⬎3 Bed net use No Yes Delivery season Dry Rainy Placental malaria No Yes Infant sex Male Female
⬍.001
NOTE. Data are number of deliveries in which low birth weight was detected/number of deliveries analyzed (%), unless otherwise indicated. Infants born to mothers in the chloroquine prophylaxis group were delivered between April 2004 and April 2005, and infants born to mothers in the intermittent preventive treatment (IPTp) group were delivered between November 2005 and November 2006. CI, confidence interval; IPTp, intermittent preventive treatment. a Multivariate analysis was performed for 1511 women for whom all variables that were initially included in the model (i.e., those with a P value of ⬍.20 in the univariate analysis) were filled in. Season, maternity clinic and place of living were not selected for the multivariate analysis (P ⬎ .20 in the univariate analysis). After a backward-stepwise selection procedure, maternal age and use of bed nets were removed from the final model. R2 ⫽ 0.07. b For variables with ⬎2 categories, the P value of the global test is given.
been fully assessed. In this article, we show clear evidence that IPTp is more efficacious than CQ for preventing low birth weight and placental infection. Our results are in agreement with those of the few studies that have been published about this subject [11, 19, 20]. In particular, 598
●
JID 2008:198 (15 August)
●
Briand et al.
a clinical trial conducted in Mali when the prevalence of CQ resistance was still moderate found that IPTp with sulfadoxinepyrimethamine had 1.5 times the efficacy of CQ prophylaxis in reducing the incidences of low birth weight and placental malaria [19]. In our study, the benefit of IPTp was remarkably sub-
Table 4. Logistic regression analysis of factors possibly significantly associated with having a mother with placental malaria in Ouidah, Benin, during 2004 –2006. Univariate analysis Factor Treatment group Chloroquine IPTp Maternity clinic Kindji Hopital de Zone Gravidity status Primigravidity Multigravidity Maternal age, years 聿20 21–25 26–30 ⬎30 Bed net use No Yes Residence setting Urban Rural Unknown Delivery season Dry Rainy
Multivariate analysisa
Deliveries, proportion (%)
Crude OR (95% CI)b
Adjusted OR (95% CI)b
P
176/1052 (17) 17/585 (3)
1.00 0.15 (0.09–0.25)
1.00 0.15 (0.09–0.24)
⬍.001
117/1150 (10) 76/487 (16)
1.00 1.63 (1.20–2.23)
... ...
75/398 (19) 118/1239 (10)
1.00 0.45 (0.33–0.62)
1.00 0.46 (0.33-0.65)
71/384 (18) 68/582 (12) 32/375 (9) 20/280 (7)
1.00 0.58 (0.41–0.84) 0.41 (0.26–0.64) 0.34 (0.20–0.57)
... ... ... ...
53/381 (14) 128/1178 (11)
1.00 0.75 (0.54–1.06)
... ...
123/1179 (10) 39/264 (15) 31/194 (16)
1.00 1.49 (1.00–2.19) 1.63 (1.06–2.50)
... ... ...
120/958 (13) 73/679 (11)
1.00 0.84 (0.62–1.15)
... ...
⬍.001
NOTE. Data are number of deliveries in which placental infection was detected/number of deliveries analyzed (%), unless otherwise indicated. Infants born to mothers in the chloroquine prophylaxis group were delivered between April 2004 and April 2005, and infants born to mothers in the intermittent preventive treatment (IPTp) group were delivered between November 2005 and November 2006. CI, confidence interval; IPTp, intermittent preventive treatment. a Multivariate analysis was performed for 1544 women for whom all variables that were initially included in the model (i.e., those with a P value of ⬍.20 in the univariate analysis) were filled in. Season was not selected for the multivariate analysis (P ⬎ .20 in the univariate analysis). After a backward-stepwise selection procedure, maternity clinic, residential setting, use of bed nets, and maternal age were removed from the final model. R2 ⫽ 0.10. b For variables with ⬎2 categories, the P value of the global test is given.
stantial, as singletons delivered by women who received IPTp had a 2-fold decreased risk for low birth weight. As reported in all published studies, the risk for delivering an infant with a low birth weight approximately doubles for women with placental infection [29]. Therefore, the protective effect we measured could not have been greater. The effect of IPTp on low birth weight was found to be independent of the presence of placental infection. This certainly reflects the preventive and/or curative effect of IPTp on malarial infection during pregnancy, in addition to its effect near delivery. The reduction in the risk of placental infection was greater than the reduction in the risk of low birth weight. This is not surprising, because unlike placental infection, malaria is only one of the factors responsible for low birth weight. Moreover, in the same population, despite the high level of CQ resistance
among parasites in the study area [24], CQ was shown to be still effective at preventing low birth weight but not placental infection [27]. Because CQ is no longer recommended in areas where the rate of malaria transmission is high, it is not ethical to compare the efficacy of CQ and IPTp by use of a clinical trial design. In this article, we performed a before-after comparison of CQ prophylaxis in one study with IPTp from a successive study. These studies were conducted in 2 large populations of women recruited in the same maternity clinics. Each population of women was followed during a 1-year period, to cover the different malaria transmission seasons. Despite similar study sites and intervals, the 2 sample sizes were different. Indeed, during the IPTp clinical trial, specific selection criteria (e.g., place of living and gestational age) were used for recruitment. However, even if the women selected for the trial represented a subsample of all IPTp vs. Chloroquine Chemoprophylaxis
●
JID 2008:198 (15 August)
●
599
women who delivered in Kindji and Hopital de Zone, we think it is unlikely that selection bias was a serious problem in this study because all other characteristics of the subjects were similar in the 2 study groups (table 1). We performed another analysis that was restricted to women in the CQ group who attended at least 2 antenatal care visits and were living in the same areas as women from the IPTp group, and similar results were obtained (data not shown). Although our comparison was not a rigorous clinical trial, we are confident that the new antimalarial strategy of IPTp was responsible for the reduction in low birth weight observed between 2005 and 2006. There have been no other known changes in the malaria control strategy or in malaria transmission in the area that could account for the observed reduction. Each regimen was correctly used by the women; adherence to CQ prophylaxis was particularly good. We made sure that women in the CQ and IPTp groups were comparable for several risk factors for delivery of an infant with a low birth weight, such as gravidity, maternal age, and socioeconomic status. In addition, the use of bed nets, which may also play a role in the outcome of pregnancy, was similar in both groups. During the 2 study periods, the vast majority of women used insecticide-treated nets (ITNs). Because ITNs have been widely available in the area since 2003, maternity clinics were regularly supplied with ITNs, and there were several campaigns to reimpregnate bed nets with insecticide. It was not possible, given the scope of these studies, to collect nutritional data. However, no factor that was likely to influence the nutritional status of the women, such as socioeconomic level, supply of foodstuffs, or quality of harvests, was subject to modification during the 2 years of observation. Maternal weight was recorded for women in the IPTp group only; thus, we could not compare this factor between groups. We did not adjust for gestational age, because the accuracy of these data was unreliable during the cross-sectional study. Gestational age might have been a confounding factor for the association between IPTp and low birth weight because of its association with better management of anemia, hypertension, and infectious diseases and because it is also potentially responsible for low birth weight. We took into account the difference in follow-up duration between the 2 groups by adjusting for the number of antenatal care visits. The different study designs probably resulted in some other differences between the groups that we could not adjust for. In particular, we cannot exclude the possibility that women from the IPTp group had better motivation than the women observed through the cross-sectional CQ survey or that they benefited from better treatment when they had symptomatic malaria. Concerning the latter point, it is important to note that only 10 women in the IPTp trial reported clinical malaria symptoms and were subsequently treated with quinine. Should there have been a difference in the quality of clinical management of malaria between the 2 groups, it would have only marginally affected the results because of the small number of individuals who were treated for 600
●
JID 2008:198 (15 August)
●
Briand et al.
this condition. Finally, because we found a large reduction in the risk of low birth weight and because we adjusted for several relevant confounding factors for low birth weight, we are confident in our final results, even if the difference in the efficacy of IPTp versus that of CQ may somehow have been overestimated. It is interesting to note that, if poor compliance was, in addition to an increasing prevalence of chemoresistance of P. falciparum, one of the reasons for the replacement of CQ chemoprophylaxis by IPTp with sulfadoxine-pyrimethamine, in our study area the adherence of pregnant women to chemoprophylaxis was remarkably high (72% of the women had high CQ concentrations in urine specimens). This observation was also pointed out in Benin by the WHO in its 2003 malaria report [30]. The lower rates of low birth weight and placental infection that we observed among women who reported taking CQ and/or who had high concentrations of CQ in urine specimens suggest that women were well-adherent to treatment—for probably ⬎1 week—and they validate self-reported CQ use by the women. In most African settings, compliance is notably lower (1%–18%) [31], and one could expect even better results for IPTp than were found in the present analysis. This article clearly evidenced that IPTp was of greater benefit to women during pregnancy than CQ prophylaxis. Even though IPTp with sulfadoxine-pyrimethamine, as currently recommended by the WHO, is presently an efficacious and adequate treatment strategy, there are concerns about its future efficacy, particularly because of the increasing prevalence of sulfadoxinepyrimethamine resistance among parasites. Although it is likely that sulfadoxine-pyrimethamine will soon be replaced by a more effective antimalarial drug, it is not clear when this change will become necessary. Recent data indicate that IPTp with sulfadoxine-pyrimethamine remains beneficial even when up to 39% of children ⬍5 years of age do not respond to sulfadoxinepyrimethamine treatment by day 14 [32]. Furthermore, in the clinical trial we are conducting, IPTp with sulfadoxinepyrimethamine seems to retain some efficacy, despite an in vivo resistance rate of 50% among children from the same area [24] and despite the fact that the protective effect we observed could be attributed to mefloquine only. In the future, it will be necessary to base the decision to switch to more-efficacious antimalarials than sulfadoxine-pyrimethamine on the association between several indicators, some clinical (such as birth weight, placental infection, and maternal anemia) and others more directly related to the drug (such as the in vivo efficacy of sulfadoxine-pyrimethamine in pregnant women rather than in children and the molecular markers of sulfadoxine-pyrimethamine resistance). Because the relation between the protective efficacy of IPTp and the clinical and molecular markers of resistance is not yet established, there is a need for continuous monitoring of the efficacy and effectiveness of IPTp with sulfadoxinepyrimethamine in pregnant women. There is also a need to evaluate alternative antimalarial drugs for future use in IPTp. As
suggested by our initial findings, mefloquine might be one of the most attractive options. Finally, one has to keep in mind that changes in prevention policy are difficult to make because they substantially affect programs to educate the target population, health care organizations, and the drug supply network. Such changes also have a considerable economical and political cost that should be carefully weighed. Acknowledgments We thank the women who participated in these studies, as well as the midwives, nurses, and assistants, for their valuable contributions.
References 1. Steketee R, Wirima J, Hightower A, Slutsker L, Heymann D, Breman J. 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. 2. McCormick M. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312:82–90. 3. Bloland P, Slutsker L, Steketee R, Wirima J, Heymann D, Breman J. 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 R, Nahlen B, Parise M, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg 2001; 64:28 – 35. 5. Garner P, Gulmezoglu A. Drugs for preventing malaria-related illness in pregnant women and death in the newborn. Cochrane Database Syst Rev 2003; 1:CD000169. 6. Cot M, Deloron P. Malaria prevention strategies. Br Med Bull 2003; 67: 137– 48. 7. Heymann D, Steketee R, Wirima J, McFarland D, Khoromana C, Campbell C. Antenatal chloroquine chemoprophylaxis in Malawi: chloroquine resistance, compliance, protective efficacy and cost. Trans R Soc Trop Med Hyg 1990; 84:496 – 8. 8. Sirima S, Sawadogo R, Moran A, et al. Failure of a chloroquine chemoprophylaxis program to adequately prevent malaria during pregnancy in Koupela district, Burkina Faso. Clin Infect Dis 2003; 36:1374 – 82. 9. Nahlen B, Akintunde A, Alakija T, et al. Lack of efficacy of pyrimethamine prophylaxis in pregnant Nigerian women. Lancet 1989; 2: 830 – 4. 10. World Health Organization (WHO). A strategic framework for malaria prevention and control during pregnancy in the Africa Region. Document AFR/MAL/04/01. Geneva, Switzerland: WHO, 2004. 11. Shultz L, Steketee R, Macheso A, Kazembe P, Chitsulo L, Wirima J. 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. 12. Shulman C, Dorman E, 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. 13. Parise M, Ayisi J, Nahlen B, 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. 14. Verhoeff F, Brabin B, Chimsuku L, Kazembe P, Russell W, Broadhead R. An evaluation of the effects of intermittent sulfadoxine-pyrimethamine treatment in pregnancy on parasite clearance and risk of low birthweight in rural Malawi. Ann Trop Med Parasitol 1998; 92:141–50.
15. Rogerson S, Chaluluka E, Kanjala M, Mkundika P, Mhango C, Molyneux M. Intermittent sulfadoxine-pyrimethamine in pregnancy: effectiveness against malaria morbidity in Blantyre, Malawi, in 1997–99. Trans R Soc Trop Med Hyg 2000; 94:549 –53. 16. Njagi J, 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. 17. Challis K, Osman N, Cotiro M, Nordahl G, Dgedge M, Bergstrom S. Impact of a double dose of sulphadoxine-pyrimethamine to reduce prevalence of pregnancy malaria in southern Mozambique. Trop Med Int Health 2004; 9:1066 –73. 18. Van Eijk A, Ayisi J, ter Kuile F, et al. Effectiveness of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in western Kenya: a hospital-based study. Trop Med Int Health 2004; 9:351– 60. 19. Kayentao K, Kodio M, Newman R, 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. 20. Sirima S, Cotte A, Konate A, et al. Malaria prevention during pregnancy: assessing the disease burden one year after implementing a program of intermittent preventive treatment in Koupela district, Burkina Faso. Am J Trop Med Hyg 2006; 75:205–11. 21. Falade C, Yusuf B, Fadero F, Mokuolu O, Hamer D, Salako L. Intermittent preventive treatment with sulfadoxine-pyrimethamine is effective in preventing maternal and placental malaria in Ibadan, south-western Nigeria. Malar J 2007; 6:88. 22. Hill J, Kazembe P. Reaching the Abuja target for intermittent preventive treatment of malaria in pregnancy in African women: a review of progress and operational challenges. Trop Med Int Health 2006 11:409 –18. 23. National Institutes of Health. Intermittent preventive treatment during pregnancy in Benin: a randomized, open, and equivalent trial comparing sulfadoxine-pyrimethamine with mefloquine. Available at: http:// www.measuredhs.com/pubs/pdf/FR197/16Chapitre16.pdf. Accessed 16 June 2008. 24. 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. 25. Joint United Nations Programme on HIV/AIDS. Report on the global HIV/AIDS epidemic: 4th global report 2004. Available at: http://www. unaids.org/bangkok2004/GAR2004_html/GAR2004_00_en.html. Accessed 20 August 2007. 26. World Health Organization. The world health report 2005. Available at: http://www.who.int/whr/2005/annex/indicators_country_a-f.pdf. Accessed 19 December 2007. 27. 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 2006; 6:27. 28. Ballard J, Khoury JC, Wedig K, Wang L, Eilers-Walsman B, Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr 1991; 119:417–23. 29. Guyatt H, Snow R. Impact of malaria during pregnancy on low birth weight in sub-Saharan Africa. Clin Microbiol Rev 2004; 17:760 –9. 30. World Health Organization (WHO), United Nations Children’s Fund. The Africa Malaria Report 2003. Document WHO/CDS/MAL/ 2003.1093. Available at: http://rbm.who.int/amd2003/amr2003/pdf/ amr2003.pdf. Accessed 20 August 2007. 31. Steketee R, Wirima JJ, Campbell C. Developing effective strategies for malaria prevention programs for pregnant African women. Am J Trop Med Hyg 1996; 55(1 Suppl):95–100. 32. ter Kuile F, van Eijk A, Filler S. Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy. JAMA 2007; 297:2603–16.
IPTp vs. Chloroquine Chemoprophylaxis
●
JID 2008:198 (15 August)
●
601
