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Review | Clinician's Corner

Intermittent Preventive Therapy for Malaria During Pregnancy Using 2 vs 3 or More Doses of Sulfadoxine-Pyrimethamine and Risk of Low Birth Weight in Africa:  Systematic Review and Meta-analysis FREE

Kassoum Kayentao, MD; Paul Garner, MD; Anne Maria van Eijk, PhD; Inbarani Naidoo, MSc; Cally Roper, PhD; Abdunoor Mulokozi, PhD; John R. MacArthur, MD; Mari Luntamo, MD; Per Ashorn, PhD; Ogobara K. Doumbo, PhD; Feiko O. ter Kuile, PhD
[+] Author Affiliations

Author Affiliations: Liverpool School of Tropical Medicine, Liverpool, United Kingdom (Drs Kayentao, Garner, van Eijk, and ter Kuile); Malaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Dentistry, University of Bamako, Bamako, Mali (Drs Kayentao and Doumbo); Malaria Research Unit, Medical Research Council, Overport, South Africa (Ms Naidoo); London School of Hygiene and Tropical Medicine, London, United Kingdom (Dr Roper); Ifakara Health Research and Development Centre, Dar es Salaam, Tanzania (Dr Mulokozi); Malaria Branch, Centers for Disease Control and Prevention, Atlanta, Georgia (Dr MacArthur); and the Department of International Health, University of Tampere School of Medicine, Tampere, Finland (Drs Luntamo and Ashorn).


JAMA. 2013;309(6):594-604. doi:10.1001/jama.2012.216231.
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Importance Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain.

Objective To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens.

Data Sources and Study Selection ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy.

Data Extraction Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models.

Results Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events.

Conclusions and Relevance Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.

Figures in this Article

Quiz Ref IDIn areas of stable malaria transmission in sub-Saharan Africa, Plasmodium falciparum infection in pregnant women is associated with maternal anemia and low birth weight (LBW) (<2500 g),13 especially among primigravida and secundigravida and human immunodeficiency virus (HIV)–infected women.1 The World Health Organization (WHO) recommended intermittent preventive therapy during pregnancy, consisting of at least 2 full treatment doses of sulfadoxine-pyrimethamine for HIV-negative women and at least 3 doses for HIV-positive women not receiving cotrimoxazole, administered presumptively in the second and third trimesters at least 1 month apart.4,5Quiz Ref IDEach dose suppresses or clears any existing asymptomatic infections from the placenta and provides up to 6 weeks of posttreatment prophylaxis.4,6 Although the standard 2-dose regimen provides at most 12 weeks of prophylaxis,6 it has been shown to be effective in reducing LBW713 and was adopted by 31 of 37 endemic countries in Africa with a policy for intermittent preventive therapy during pregnancy; the remaining countries use a 3-dose or monthly regimen.14 Nevertheless, reinfections are common with the 2-dose regimen, especially among women who complete their last dose early in the third trimester.8,9 A previous meta-analysis7 of 3 trials confirmed that additional doses of sulfadoxine-pyrimethamine may add benefit over 2 doses among HIV-infected primigravida plus secundigravida (G1-G2 women), but there was insufficient evidence on HIV-negative women or intermittent preventive therapy during pregnancy when used in combination with insecticide-treated nets. Furthermore, increasing sulfadoxine-pyrimethamine resistance, which results in a progressive decrease of the duration of the prophylactic effect,6 may also require more frequent dosing.7

The objective of this analysis was to evaluate whether 3 or more doses of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine are associated with higher birth weight or a lower risk of LBW than the current standard 2-dose regimen and to examine whether this is moderated by sulfadoxine-pyrimethamine resistance, HIV status, gravidity, or use of insecticide-treated nets.

Eligibility Criteria

Study inclusion criteria, outcomes, and methods for the analysis were prespecified in the protocol. Studies had to be quasi-randomized or randomized controlled trials conducted with pregnant women living in sub-Saharan Africa, comparing the standard 2-dose regimen with sulfadoxine-pyrimethamine with a regimen of intermittent preventive therapy during pregnancy consisting of 3 doses or monthly dosing. Studies or study groups that combined sulfadoxine-pyrimethamine with other antimalarial drugs, such as artemisinin derivatives or azithromycin, or other interventions, such as screening for malaria, were excluded. Use of mosquito nets was not an exclusion criterion. Trial inclusion was unrestricted by gravida group, HIV status, and type of outcomes reported.

Study Selection

Studies were identified by searching PubMed, SCOPUS, ISI Web of Knowledge, EMBASE, LILACS, Cochrane CENTRAL, the Malaria in Pregnancy Library,15 WHO's International Clinical Trials Registry Platform, and the Cochrane Central Register of Controlled Trials from their inception to December 11, 2012, without language restrictions; scanning reference lists of articles; and consultation with experts in the field (see eFigure 1 and eMethods). For trial selection, 2 authors (K.K. and A.M.v.E.) independently screened and assessed trials for eligibility and final inclusion in the analysis in a standardized manner. Disagreement between reviewers was resolved through consensus after discussion and consultation with the senior author (F.O.t.K.).

Data Collection and Analysis

Data extraction was conducted independently by 2 unblinded investigators (K.K. and A.M.v.E.) using pretested standardized data extraction forms. Authors of primary studies were contacted for missing information or if reported data did not fit the required format. For each study, the following information was extracted: first author, publication year, year of study start and end, study design, randomization procedures, inclusion criteria (eg, any restrictions by gravidity, age, or HIV status), insecticide-treated net or bed net use, folate supplementation and dosage, local malaria transmission, details of study groups, number of women enrolled, and outcomes assessed, including adverse events overall and stratified by subgroup. The Cochrane Collaboration's tool for assessing the risk of bias16 was used to determine the quality of included trials as low (high risk of bias), high (low risk of bias), or unclear. Uncertainties were resolved by consensus and by contacting the corresponding authors.17

Time- and location-matched data on molecular resistance to sulfadoxine-pyrimethamine were obtained from published articles, as described previously,18 and through correspondence with the authors of the trials. The prevalence of the K540E mutation in the dihydropteroate synthase (DHPS) gene was used as a proxy for the prevalence of the combined dihydrofolate reductase DHFR (N51I, C59R, and S108N) /DHPS (A437G, K540E) quintuple genotype that is strongly associated with treatment failure of sulfadoxine-pyrimethamine.19

Synthesis

The primary outcome measures were LBW and mean birth weight. Secondary outcomes included maternal hemoglobin level, maternal anemia (hemoglobin level <11 g/dL) and moderate to severe anemia (defined by the individual trials as hemoglobin level <6, 7, or 8 g/dL) at term or delivery, maternal malaria infection (peripheral blood) at delivery, placental malaria infection (all species), preterm delivery (<37 weeks' gestation), spontaneous miscarriage, stillbirth, and neonatal death (death within 0-27 days in live-born infants). All analyses were stratified a priori by HIV status and gravidity status (G1-G2 vs ≥G3 pregnancies [multigravida]), with the aim to provide independent subgroup estimates and overall estimates of the pooled data.

We used both random-effects (primary method) and fixed-effects models to calculate the summary relative risks (RRs) for dichotomous outcomes (Mantel-Haenszel) or differences in means for continuous outcomes (inverse variance) and we prespecified that any heterogeneity would be investigated by subgroup analysis. To provide estimates of absolute risk and effect, values for the assumed control-group risk in 2-dose recipients and the corresponding intervention-group risk and 95% CI in ≥3-dose recipients were computed as assumed control-group risk = median risk (expressed per 1000 women) across the included trials in the 2-dose group; corresponding intervention-group risk = assumed control-group risk × RR (95% CI), where the RR was taken from random-effects models.20 The absolute risk reduction was calculated as the assumed control-group risk × (1 − RR) and expressed per 1000 women. Similar methods were used with the lower and upper CI of the RR to obtain the 95% CI of the absolute risk reduction. The number needed to treat (NNT) for LBW (the primary end point) was computed as NNT = 1/(assumed control-group risk × [1 − RR]).20 For the continuous end points, the observed median birth weight or hemoglobin concentration in the 2-dose group was reported as the assumed control-group median. The corresponding value in ≥3-dose recipients was expressed as the corresponding intervention-group median and 95% CI, which were computed as the assumed control-group median + mean difference (95% CI).

Heterogeneity was quantified with the I2 statistic and χ2 test.21 The Deeks and Higgens method was used to test for heterogeneity between the different summary estimates across subgroups.22 Publication and small-study bias was assessed by visual inspection of funnel plots and the Harbord test. To evaluate the change in pooled summary estimates for the RR with addition of new evidence, we created cumulative meta-analysis plots.23 Prespecified sensitivity analysis for the primary outcomes was performed by excluding all studies that were scored as low quality for allocation concealment or other sources of bias.16 Further sensitivity analysis was conducted to test the effect of each study on the pooled estimates and heterogeneity by removing one study at a time from the meta-analysis. We used P < .05 to indicate statistical significance (2-sided tests). Data were analyzed with Review Manager version 5.2, GradePro version 3.6, and Stata version 12.

Studies and Outcomes

A total of 241 studies were screened, and 7 trials including a total of 6281 pregnancies were included ( eFigure 1 ),9,12,2429 one of which was unpublished29 (Table 1). Authors of all primary studies provided further unpublished information where available. Five trials compared monthly sulfadoxine-pyrimethamine against the standard 2-dose regimen and the remaining 2 compared 3- vs 2-dose intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine.9,28 Sulfadoxine-pyrimethamine intake was supervised in all trials.

Table Graphic Jump LocationTable 1. Characteristics of Included Trials

Three trials in Kenya and Malawi involved both HIV-infected and uninfected women,12,24,26 and 1 trial in Zambia involved HIV-infected women only.25 In 3 other trials, the HIV status was unknown,9,28,29 2 of which were from areas with very low HIV prevalence among pregnant women (1% in Burkina Faso and 1.3% in Mali)9,28; results were therefore pooled with those of the HIV-negative women. The third trial from Tanzania29 was conducted in an area with high HIV prevalence and analyzed as a separate “HIV status unknown” stratum. Two of the 7 trials were considered of low quality (eFigure 2), including a trial in Burkina Faso, in which two-thirds of participants did not receive the intended regimen.28 The other study was a quasi-randomized trial12 conducted before the introduction of the Consolidated Standards of Reporting Trials (CONSORT) guidelines for clinical trials37 (Table 1).

Primary Outcomes: Birth Weight

Women in the ≥3-dose group had fewer infants with LBW (random-effects model RR = 0.80; 95% CI, 0.69-0.94; P = .006; I2 = 0%) (Figure 1), corresponding to an RR reduction (RR reduction = 100% × [1 − RR]) of 20% (95% CI, 6-31). Quiz Ref IDThe absolute risk reduction was 33 per 1000 women (95% CI, 10-52), from a median risk of 167 per 1000 in the 2-dose group (assumed control-group risk) to 134 per 1000 in the ≥3-dose recipients (NNT = 31). The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g (95% CI, 29-83 g) higher in the ≥3-dose group (Figure 2, Table 2). Analyses by gravida and HIV subgroup showed that the mean difference in birth weight was statistically significant in HIV-negative women (random-effects mean difference = 58 g; 95% CI, 26-90 g), HIV-positive women (mean difference = 97 g; 95% CI, 22-172) (Table 2), G1-G2 women (mean difference = 57 g; 95% CI, 22-93 g) (eTable 1), and multigravida (mean difference = 53 g; 95% CI, 11-95 g) (eTable 2) (between-subgroup difference, I2 = 0%; P = .53) (Figure 2). The RR estimates for LBW, however, were significant only in HIV-negative women (RR = 0.77 [95% CI, 0.63-0.94] [Table 2]; assumed control-group risk = 106 per 1000; absolute risk reduction = 24 per 1000 [95% CI, 6-39]; NNT = 42) and G1-G2 women (RR = 0.80 [95% CI, 0.68-0.95] [ eTable 1]; assumed control-group risk = 181 per 1000; absolute risk reduction = 36 per 1000 [95% CI, 9-58]; NNT = 28) but not in HIV-positive women (RR = 0.86 [95% CI, 0.53-1.39] [Table 2]; assumed control-group risk = 175 per 1000; absolute risk reduction = 24 per 1000 [95% CI, −68 to 82]; NNT = 42) or multigravida (RR = 0.79 [95% CI, 0.49-1.27] [ eTable 2]; assumed control-group risk = 78 per 1000; absolute risk reduction = 16 per 1000 [95% CI, −21 to 40]; NNT = 63). The difference in the RR estimates between the subgroups was not significant (between-subgroup difference I2 = 0%; P = .96) (Figure 1). The results of fixed-effects models overall and by gravidity or HIV groups were mostly identical or very similar (eTable 3).

Place holder to copy figure label and caption
Figure 1. Meta-analysis of the Risk of Low Birth Weight in Trials Comparing the Standard 2-Dose vs 3 or More Doses of Intermittent Preventive Therapy During Pregnancy With Sulfadoxine-Pyrimethamine
Graphic Jump Location

G1-G2 indicates first and second pregnancies; ≥G3, 2 or more previous pregnancies; HIV, human immunodeficiency virus; RR, relative risk. P values after the I2 statistics represent the χ2 test for heterogeneity. Dersimonian-Laird method used to calculate random-effects models; Mantel-Haenszel for fixed-effects models. Weights are from random-effects analysis. Data marker sizes indicate the weight applied to each study with random-effects meta-analysis. Test for subgroup differences: χ24 = 0.62, P = .96, l2 = 0.0%.

Place holder to copy figure label and caption
Figure 2. Meta-analysis of Mean Birth Weight in 7 Trials Comparing the Standard 2-Dose vs 3 or More Doses of Intermittent Preventive Therapy During Pregnancy With Sulfadoxine-Pyrimethamine
Graphic Jump Location

G1-G2 indicates first and second pregnancies; ≥G3, 2 or more previous pregnancies; HIV, human immunodeficiency virus status. P values after the I2 statistics represent the χ2 test for heterogeneity. Dersimonian-Laird method used for random-effects models; inverse-variance method used in the fixed-effects models. Weights are from random-effects analysis. Data marker sizes indicate the weight applied to each study with random-effects meta-analysis. Test for subgroup differences: χ24  = 3.14, P = .53, l2 = 0.0%.

Table Graphic Jump LocationTable 2. Random-Effects Meta-analysis of Trials Comparing the Standard 2-Dose vs ≥3 Doses of Sulfadoxine-Pyrimethamine for Intermittent Preventive Therapy During Pregnancy by HIV Status

There was no evidence for publication bias after visual inspection of funnel plots or with the Harbord modified test for small-study effects (P = .72) (eFigure 3). Cumulative meta-analysis, ordered by publication date, showed that a significant association with LBW emerged with the addition of new evidence from trials reported since 2010 (eFigures 4 and 5). Sensitivity analysis showed that after removal of both low-quality studies,12,28 the point estimates for LBW and mean birth weight were RR = 0.76 (95% CI, 0.61-0.93), I2 = 16%; and mean difference = 62 g (95% CI, 29-95 g), I2 = 0%. Removal of any individual trial also had relatively little effect and pooled results remained statistically significant at P < .05 for all 7 analyses with fixed-effects models and at P = .06 with random-effects models (eFigures 6 and 7).

Secondary Outcomes

The median maternal hemoglobin level at term in the 2-dose group was 10.9 g/dL (range, 9.7-11.6 g/dL), and this was on average 0.13 g/dL higher (95% CI, 0.03-0.22 g/dL) in the ≥3-dose group (Table 2, eFigure 8). This group had a lower risk of moderate to severe maternal anemia, but this was evident only in G1-G2 women (RR = 0.60 [95% CI, 0.36-0.99]; I2 = 20%) (eTable 1), not overall (RR = 0.73 [95% CI, 0.48-1.11]; I2 = 15%) (Table 2 and eFigure 9). Women in the ≥3-dose group were approximately half as likely to have placental malaria (6 studies) compared with those in the 2-dose group, regardless of HIV status (RR = 0.51 [95% CI, 0.38-0.68]; I2 = 0%) (Table 2, eFigure 10), but this was evident only in G1-G2 women (RR = 0.50 [95% CI, 0.35-0.70]; I2 = 0%) (eTable 1), not in multigravida (RR = 0.71 [95% CI, 0.26-1.95]; I2 = 21%) (eTable 2). Similarly, ≥3 doses were associated with less peripheral (maternal) malaria (RR = 0.68 [95% CI, 0.52-0.89]; I2 = 47%) (Table 2), but this was evident in G1-G2 women only (RR = 0.54 [95% CI, 0.37-0.80]; I2 = 56%) (eTable 1), not in multigravida (RR = 0.97 [95% CI, 0.75-1.24]; I2 = 0%) (eTable 2). No difference in preterm delivery was detected (RR = 0.95 [95% CI, 0.80-1.12]; I2 = 35%) or in the number of stillbirths (RR = 1.14 [95% CI, 0.85-1.55]; I2 = 0%), miscarriages (RR = 1.43 [95% CI, 0.88-2.33]; I2 = 0%), or neonatal deaths (RR = 0.88 [95% CI, 0.57-1.35]; I2 = 0%) (Table 2).

Stratified Analysis for LBW and Mean Birth Weight

There was no clear correlation between resistance level and the strength of the association between treatment regimen and LBW or mean birth weight; the point estimates were similar in areas with less than 50% DHPS -K540E mutations (5 trials) and areas with 50% or more DHPS -K540E (2 trials) (eFigures 11 and 12). There was also no evidence that intensity of malaria transmission or the median number of sulfadoxine-pyrimethamine doses in the ≥3-dose group modified the association (P > .17 for all tests for subgroup differences). There was no clear difference in the association between the dose group and the risk of LBW or mean birth weight in the 2 trials that used high-dose folate supplementation (5 mg/d)12,25 (which has since been contraindicated) vs the standard dose (0.25-0.5 mg/d). Three studies reported results stratified by insecticide-treated net use9,26,29; the associations with LBW and mean birth weight were statistically significant in the nonusers only. There was no evidence for an association with LBW in insecticide-treated net users (eFigures 11 and 12).

Adverse Events

The risks of neonatal icterus and congenital malformation were comparable between the groups, as were the number of adverse events in the mother. One study reported a case of Stevens-Johnson syndrome, which occurred in the 3 or more dose group, 3 weeks after the first dose (Table 3).25

Table Graphic Jump LocationTable 3. Summary of Adverse Events in Women and Neonates After Intermittent Preventive Therapy During Pregnancy With ≥3 Doses vs 2 Doses of Sulfadoxine-Pyrimethamine During Pregnancy

Quiz Ref IDThis meta-analysis of 7 trials demonstrated that regimens of intermittent preventive therapy during pregnancy consisting of ≥3 doses of sulfadoxine-pyrimethamine were well tolerated and, compared with the standard 2-dose regimen, were associated with higher mean birth weight, less LBW, and less placental and maternal malaria at delivery. The ≥3-dose regimen was also associated with slightly higher mean maternal hemoglobin levels at term overall, but a significant association with moderate to severe maternal anemia was observed only in G1-G2 women. The associations with birth weight were consistent across trials despite variations in study design, malaria endemicity, and the degree of sulfadoxine-pyrimethamine resistance. Although the number of trials was limited, there was no suggestion of publication or other small-study bias. There was also no suggestion that the results were affected by the weight of a single influential study. Two of the trials were classified as low quality, but sensitivity analysis indicated that their effect on the overall pooled estimate for LBW was minor. The consistency of these findings across the trials suggests the results are generalizable.

Although the summary point estimates of the association with mean birth weight were modest (56-g difference overall and 67 g among HIV-negative G1-G2 women), these were associated with clinically relevant changes in the risk of LBW, particularly among HIV-negative G1-G2 women (RR reduction = 25%) (eTable 1). These estimates were comparable to that reported in previous studies for 2-dose intermittent preventive therapy during pregnancy relative to none (mean difference = 79 g; RR reduction = 29%) and for insecticide-treated nets alone (mean difference = 55 g; RR reduction = 23%).7,38 The magnitude of the observed association is remarkable, given that approximately 28% of women were protected by insecticide-treated nets in these 7 trials and considering that the control group benefited from protection of the 2-dose intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine. Quiz Ref IDThe association mainly reflects an association with fetal growth, rather than with preterm delivery, and indicates that more complete protection in the second and third trimesters, including the last 6 to 10 weeks of pregnancy, may be pivotal for fetal growth. This result is consistent with observations in healthy pregnancies, which show that of the total fetal weight gain, 28% and 55% of it occurs during the last 6 and 10 weeks of pregnancy, respectively.39

Although the lack of heterogeneity across the sulfadoxine-pyrimethamine resistance range is encouraging, it does not imply that sulfadoxine-pyrimethamine efficacy is unaffected at higher levels of resistance. A possible explanation is that the extra doses compensate for any reductions in efficacy of the 2-dose regimen resulting from a progressive decrease of the duration of posttreatment prophylaxis.

The association with placental infections is an expected outcome because the 3 or more dose group received their last dose on average 1 month closer to delivery and is likely to reflect clearance of existing infections near term and prevention of new infections by the extra period of prophylaxis. However, the association with mean birth weight among multigravida was unexpected because most multigravida in endemic countries have acquired a pregnancy-specific protective immunity during exposures in previous pregnancies. Overall, the evidence for a beneficial association in multigravida was weak, and the finding in this study may therefore reflect a chance observation (eg, because of multiple comparisons) or mechanisms other than the prevention of malaria. Although the point estimates for LBW (RR reduction 21%) and placental malaria (RR reduction 29%) were in the same direction as those observed in primigravida and secundigravida, none were statistically significant and there was no suggestion that ≥3 doses were associated with less maternal malaria or moderate to severe anemia. On the other hand, the lack of significant association with LBW may reflect lack of power because only 4 of the 7 studies included multigravida.

Our meta-analysis has some limitations. First, although all trials were designed to standardize the number of visits and antenatal care (eg, hematinic supplementation) between the 2 groups, in one trial in Tanzania the women in the ≥3-dose group had on average 1 extra visit compared with the 2-dose group and thus potentially better antenatal care.29 However, exclusion of this study in the sensitivity analysis did not change the conclusion (eFigures 6 and 7). Second, only 1 of the 7 trials was placebo controlled, which may have biased the results and affected some outcomes because of lack of expectations in a 2-dose group or differential behaviors across intervention groups. We did not use blinding in the selection, evaluation, and data abstraction phases, and because the authors were familiar with all included studies, this could have introduced bias.40 Third, none of the trials were conducted in regions where additional DHFR 164L or DHPS 581G mutations are prevalent, as reported from parts of Rwanda, Uganda, and northern Tanzania, conferring the highest level of sulfadoxine-pyrimethamine resistance.18,4143 Last, only 3 trials reported results stratified by insecticide-treated net use, limiting our evaluation of the potential modifying role of insecticide-treated nets. In this smaller subgroup of studies, significant associations with LBW and mean birth weight were observed among the nonusers of insecticide-treated nets only, consistent with results of previous evaluations of 2-dose intermittent preventive therapy during pregnancy against placebo.15,44,45

Only 1 serious cutaneous reaction was reported in the current meta-analysis involving 13 554 sulfadoxine-pyrimethamine treatments among 6281 pregnancies, and this occurred in an HIV-positive woman 3 weeks after she received her first dose of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy.25 We found no indication that more frequent dosing (ie, resulting in doses administered closer to delivery) was associated with increased risk of neonatal jaundice, the main safety signal of interest in neonates. Sulfonamides have the potential to displace unconjugated bilirubin from albumin, which could increase a newborn's risk of kernicterus if received near delivery. Our observations, combined with the evidence reviewed by Peters et al44 from the experience with sulfonamides for rheumatic fever prophylaxis, urinary tract infections, and congenital toxoplasmosis (which involve higher doses and prolonged use of sulfadoxine-pyrimethamine), suggest that concerns regarding kernicterus should not restrict the use of monthly sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy. There was no indication that ≥3-dose regimens increased or reduced the risk of stillbirth or neonatal death. The risk of spontaneous miscarriages in G1-G2 women was higher among the 3-dose group (RR = 1.78, P = .046 with fixed-effects models and RR = 1.75, P = .06 with random-effects models). These miscarriages, however, were not associated with the third dose because in 3 of the 4 trials that contributed 80% of the study weight, they occurred before 28 weeks of gestation when the third dose had not yet been provided.9,24,28 In the fourth trial, the risk of miscarriage was 2.0% with a monthly regimen, higher than the 1.1% in the 2-dose group but similar to the 2.3% in a third control group consisting of women randomized to passive case detection only instead of intermittent preventive therapy during pregnancy.12

Since the strategic framework for the control of malaria in pregnancy in sub-Saharan Africa was first developed, at least 3 doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy has been recommended by WHO for HIV-infected women or for all women in high-HIV-prevalence areas (>10%) where screening for HIV is not conducted. Some countries, such as Cameroon,45 Ghana, Zambia, and Zimbabwe, selected 3 doses of sulfadoxine-pyrimethamine in their policy for all pregnant women, but most other countries, including many high-HIV-prevalence countries, implemented the 2-dose regimen and use cotrimoxazole for HIV-infected women.14 However, more recently other countries, including Kenya and Malawi, implemented a monthly regimen among HIV-negative women mainly because of concerns about sulfadoxine-pyrimethamine resistance and for pragmatic reasons to minimize the risk for missed opportunities to deliver a second dose46 and to achieve better alignment with WHO's focused antenatal care schedule (a goal-oriented antenatal care approach consisting of 4 visits providing essential evidence-based interventions). In southern Malawi, this has resulted in a marked increase in the uptake of 2 or more doses of sulfadoxine-pyrimethamine.47

Our cumulative meta-analysis showed that, with the accumulation of results from the 4 most recent trials reported since 2010, evidence has emerged that 3-dose or monthly sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens among pregnant women in sub-Saharan Africa. These data provide support for the new WHO recommendation that intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine be provided at each scheduled focused antenatal-care visit in the second and third trimesters in all settings in which intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine is recommended.48 Future research should focus on how best to implement the updated WHO guidelines for intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine48 and specifically their integration with focused antenatal care. Continued monitoring of the association between population-level sulfadoxine-pyrimethamine resistance and the effectiveness of intermittent preventive therapy during pregnancy is required.

Corresponding Author: Feiko O. ter Kuile, PhD, Child and Reproductive Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom (terkuile@liv.ac.uk).

Author Contributions: Drs Kayentao and ter Kuile had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kayentao, Garner, ter Kuile.

Acquisition of data: Kayentao, Garner, van Eijk, Naidoo, Roper, Mulokozi, MacArthur, Luntamo, Ashorn, Doumbo, ter Kuile.

Analysis and interpretation of data: Kayentao, Garner, van Eijk.

Drafting of the manuscript: Kayentao, Garner, ter Kuile.

Critical revision of the manuscript for important intellectual content: Kayentao, Garner, van Eijk, Naidoo, Roper, Mulokozi, MacArthur, Luntamo, Ashorn, Doumbo, ter Kuile.

Statistical analysis: Kayentao, Garner, ter Kuile.

Obtained funding: MacArthur, ter Kuile.

Administrative, technical, or material support: van Eijk, MacArthur, Doumbo, ter Kuile.

Study supervision: Garner, ter Kuile.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr ter Kuile reports receiving reimbursement for meeting presentation expenses from Pfizer. Drs Luntamo and Ashorn report institutional support from Pfizer in the form of active drug and placebo for a trial of preterm delivery.

Funding/Support: This review was funded by a grant from the Centers for Disease Control and Prevention for salary support through a cooperative agreement between the Division of Parasitic Diseases and Malaria (Centers for Disease Control and Prevention, USA) and the Malaria Epidemiology Unit of the Child and Reproductive Health Group, Liverpool School of Tropical Medicine (LSTM), held by Dr ter Kuile. Dr Ashorn and Dr Luntamo were supported by grants from the Academy of Finland and the Finnish Cultural Foundation. Dr Kayentao was supported by a PhD training grant from the European and Developing Countries Clinical Trials Partnership, The Hague, the Netherlands. Drs ter Kuile and van Eijk are partly funded by the Malaria in Pregnancy Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the LSTM. Dr Doumbo reports receiving support from National Institute of Allergy and Infectious Diseases (NIH).

Role of the Sponsor: The funding institutions had no role in the protocol development; the design and conduct of the review; data collection, analysis, and interpretation; or preparation, review, or approval of the manuscript.

Additional Contributions: We thank Vittoria Lutje, PhD, information specialist, Cochrane Infectious Diseases Group, LSTM, for helping with the search strategy; Alison Reynolds, MA, and Helen Wong, BA, Child and Reproductive Health Group, LSTM, for invaluable administrative support; the authors of the other studies who provided results in addition to the published data to allow stratification of the results by gravidity and HIV groups (Monica Parise, MD, and Scott Filler, MD, Centers for Disease Control and Prevention, Atlanta, Georgia; Davidson Hamer, MD, Boston University Schools of Public Health and Medicine; Innocent Valea, MD, and Halidou Tinto, PharmD, PhD, Laboratory of Parasitology and Entomology, Centre Muraz, Bobo-Dioulasso, and Institut de Recherche en Sciences de la santé, Direction Régionale de l'Ouest, Bobo-Dioulasso, Burkina Faso; and Umberto d’ Alessandro, MD, PhD, Medical Research Council, Gambia Unit, Banjul, The Gambia, and the Institute of Tropical Medicine, Antwerp, Belgium); Brian Greenwood, MD, London School of Hygiene and Tropical Medicine, and Stephen Rogerson, FRACP, PhD, Department of Medicine, University of Melbourne, for useful comments on the manuscript; and Sarah Donegan, MSc, Cochrane Infectious Disease Group, Liverpool School of Tropical Medicine, for statistical advice. No one received financial compensation for his or her contributions.

Desai M, ter Kuile FO, Nosten F,  et al.  Epidemiology and burden of malaria in pregnancy.  Lancet Infect Dis. 2007;7(2):93-104
PubMed   |  Link to Article
Steketee RW, Nahlen BL, Parise ME, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas.  Am J Trop Med Hyg. 2001;64(1-2):(Suppl)  28-35
PubMed
World Health Organization.  Malaria and HIV Interactions and Their Implications for Public Health Policy: Report of a Technical Consultation Geneva, Switzerland, 23-25 June 2004. Geneva, Switzerland: World Health Organization; 2004
World Health Organization.  A Strategic Framework for Malaria Prevention and Control During Pregnancy in the African RegionBrazzaville, Africa: World Health Organization: Regional Office for Africa; 2004. AFR/MAL/04/01
World Health Organization.  Recommendations on the Use of Sulfadoxine-Pyrimethamine (SP) for Intermittent Preventive Treatment During Pregnancy (IPT) in Areas of Moderate to High Resistance to SP in the African Region; October 2005http://www.who.int/malaria/publications/atoz/who_sp_statement.pdf. 2006
White NJ. Intermittent presumptive treatment for malaria.  PLoS Med. 2005;2(1):e3
PubMed   |  Link to Article
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(23):2603-2616
PubMed   |  Link to Article
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(1):109-116
PubMed   |  Link to Article
Diakite OS, Kayentao K, Traoré BT,  et al.  Superiority of 3 over 2 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria during pregnancy in mali: a randomized controlled trial.  Clin Infect Dis. 2011;53(3):215-223
PubMed   |  Link to Article
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(3):277-282
PubMed   |  Link to Article
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;353(9153):632-636
PubMed   |  Link to Article
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(5):813-822
PubMed
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;11(7):992-1002
PubMed   |  Link to Article
van Eijk AM, Hill J, Alegana VA,  et al.  Coverage of malaria protection in pregnant women in sub-Saharan Africa: a synthesis and analysis of national survey data.  Lancet Infect Dis. 2011;11(3):190-207
PubMed   |  Link to Article
van Eijk AM, Hill J, Povall S, Reynolds A, Wong H, Ter Kuile FO. The “Malaria in Pregnancy” library: a bibliometric review.  Malar J. 2012;11:362
PubMed   |  Link to Article
Higgins JP, Altman DG, Gøtzsche PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.  BMJ. 2011;343:d5928
PubMed   |  Link to Article
Cochrane Collaboration.  Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1.  Chichester, England: John Wiley & Sons; 2008. Updated September 2008
Naidoo I, Roper C. Drug resistance maps to guide intermittent preventive treatment of malaria in African infants.  Parasitology. 2011;138(12):1469-1479
PubMed   |  Link to Article
Picot S, Olliaro P, de Monbrison F, Bienvenu AL, Price RN, Ringwald P. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria.  Malar J. 2009;8:89
PubMed   |  Link to Article
Schünemann HJ, Oxman AD, Higgins JPT,  et al.  Presenting results and “Summary of Findings” tables. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. Cochrane Collaboration, John Wiley & Sons; 2008. Updated September 2008
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Deeks JJ, Higgins JPT. Statistical Algorithms in Review Manager 5. Cochrane Collaboration; 2010. http://ims.cochrane.org/revman/documentation/Statistical-methods-in-RevMan-5.pdf
Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis.  JAMA. 2011;306(24):2704-2714
PubMed   |  Link to Article
Filler SJ, Kazembe P, Thigpen M,  et al.  Randomized trial of 2-dose versus monthly sulfadoxine-pyrimethamine intermittent preventive treatment for malaria in HIV-positive and HIV-negative pregnant women in Malawi.  J Infect Dis. 2006;194(3):286-293
PubMed   |  Link to Article
Hamer DH, Mwanakasale V, Macleod WB,  et al.  Two-dose versus monthly intermittent preventive treatment of malaria with sulfadoxine-pyrimethamine in HIV-seropositive pregnant Zambian women.  J Infect Dis. 2007;196(11):1585-1594
PubMed   |  Link to Article
Luntamo M, Kulmala T, Mbewe B, Cheung YB, Maleta K, Ashorn P. Effect of repeated treatment of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in Malawi: a randomized controlled trial.  Am J Trop Med Hyg. 2010;83(6):1212-1220
PubMed   |  Link to Article
Luntamo M, Rantala AM, Meshnick SR,  et al.  The effect of monthly sulfadoxine-pyrimethamine, alone or with azithromycin, on PCR-diagnosed malaria at delivery: a randomized controlled trial.  PLoS One. 2012;7(7):e41123
PubMed   |  Link to Article
Valea I, Tinto H, Drabo MK,  et al.  Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso.  Malar J. 2010;9:324
MacArthur JR, Kabanywanyi AM, Baja A,  et al.  Abstract 830: efficacy of intermittent treatment with sulfadoxine-pyrimethamine alone or sulfadoxine-pyrimethamine plus artesunate for prevention of placental malaria in Tanzania. Paper presented at: 56th Annual Meeting of the American Society of Tropical Medicine and Hygiene; November 4-8, 2007; Philadelphia, PA
Iriemenam NC, Shah M, Gatei W,  et al.  Temporal trends of sulphadoxine-pyrimethamine (SP) drug-resistance molecular markers in Plasmodium falciparum parasites from pregnant women in western Kenya.  Malar J. 2012;11(1):134
PubMed   |  Link to Article
Dzinjalamala FK, Macheso A, Kublin JG,  et al.  Association between the pharmacokinetics and in vivo therapeutic efficacy of sulfadoxine-pyrimethamine in Malawian children.  Antimicrob Agents Chemother. 2005;49(9):3601-3606
PubMed   |  Link to Article
Pearce RJ, Pota H, Evehe MS,  et al.  Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.  PLoS Med. 2009;6(4):e1000055
PubMed   |  Link to Article
Lin JT, Mbewe B, Taylor SM, Luntamo M, Meshnick SR, Ashorn P. Increased prevalence of dhfr and dhps mutants at delivery in Malawian pregnant women receiving intermittent preventive treatment for malaria.  Trop Med Int Health. 2012;
PubMed
Dokomajilar C, Lankoande ZM, Dorsey G, Zongo I, Ouedraogo JB, Rosenthal PJ. Roles of specific Plasmodium falciparum mutations in resistance to amodiaquine and sulfadoxine-pyrimethamine in Burkina Faso.  Am J Trop Med Hyg. 2006;75(1):162-165
PubMed
Mbugi EV, Mutayoba BM, Malisa AL, Balthazary ST, Nyambo TB, Mshinda H. Drug resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum malaria in Mlimba, Tanzania.  Malar J. 2006;5:94
PubMed   |  Link to Article
Coulibaly SO, Gies S, D’Alessandro U. Malaria burden among pregnant women living in the rural district of Boromo, Burkina Faso.  Am J Trop Med Hyg. 2007;77(6):(Suppl)  56-60
PubMed
Begg C, Cho M, Eastwood S,  et al.  Improving the quality of reporting of randomized controlled trials. The CONSORT statement.  JAMA. 1996;276(8):637-639
PubMed   |  Link to Article
Gamble C, Ekwaru PJ, Garner P, ter Kuile FO. Insecticide-treated nets for the prevention of malaria in pregnancy: a systematic review of randomised controlled trials.  PLoS Med. 2007;4(3):e107
PubMed   |  Link to Article
Mikolajczyk RT, Zhang J, Betran AP,  et al.  A global reference for fetal-weight and birthweight percentiles.  Lancet. 2011;377(9780):1855-1861
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Gesase S, Gosling RD, Hashim R,  et al.  High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581.  PLoS One. 2009;4(2):e4569
PubMed   |  Link to Article
Harrington WE, Mutabingwa TK, Muehlenbachs A,  et al.  Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment.  Proc Natl Acad Sci U S A. 2009;106(22):9027-9032
PubMed   |  Link to Article
Harrington WE, Mutabingwa TK, Kabyemela E, Fried M, Duffy PE. Intermittent treatment to prevent pregnancy malaria does not confer benefit in an area of widespread drug resistance.  Clin Infect Dis. 2011;53(3):224-230
PubMed   |  Link to Article
Peters PJ, Thigpen MC, Parise ME, Newman RD. Safety and toxicity of sulfadoxine/pyrimethamine: implications for malaria prevention in pregnancy using intermittent preventive treatment.  Drug Saf. 2007;30(6):481-501
PubMed   |  Link to Article
Leke RG, Taylor DW. The use of intermittent preventive treatment with sulfadoxine-pyrimethamine for preventing malaria in pregnant women.  Clin Infect Dis. 2011;53(3):231-233
PubMed   |  Link to Article
Gill CJ, Macleod WB, Mwanakasale V,  et al.  Inferiority of single-dose sulfadoxine-pyrimethamine intermittent preventive therapy for malaria during pregnancy among HIV-positive Zambian women.  J Infect Dis. 2007;196(11):1577-1584
PubMed   |  Link to Article
Kalilani L, Taylor S, Madanitsa M,  et al.  Waning effectiveness of intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) in the presence of high SP resistance in Malawi. Abstract 1179. Paper presented at: 60th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Abstract Book; December 4–8, 2011; Philadelphia, PA
World Health Organization; Global Malaria Program.  Updated WHO Policy Recommendation (October 2012): Intermittent Preventive Treatment of Malaria in Pregnancy Using Sulfadoxine-Pyrimethamine (IPTp-SP)Geneva, Switzerland: World Health Organization; 2012

Figures

Place holder to copy figure label and caption
Figure 1. Meta-analysis of the Risk of Low Birth Weight in Trials Comparing the Standard 2-Dose vs 3 or More Doses of Intermittent Preventive Therapy During Pregnancy With Sulfadoxine-Pyrimethamine
Graphic Jump Location

G1-G2 indicates first and second pregnancies; ≥G3, 2 or more previous pregnancies; HIV, human immunodeficiency virus; RR, relative risk. P values after the I2 statistics represent the χ2 test for heterogeneity. Dersimonian-Laird method used to calculate random-effects models; Mantel-Haenszel for fixed-effects models. Weights are from random-effects analysis. Data marker sizes indicate the weight applied to each study with random-effects meta-analysis. Test for subgroup differences: χ24 = 0.62, P = .96, l2 = 0.0%.

Place holder to copy figure label and caption
Figure 2. Meta-analysis of Mean Birth Weight in 7 Trials Comparing the Standard 2-Dose vs 3 or More Doses of Intermittent Preventive Therapy During Pregnancy With Sulfadoxine-Pyrimethamine
Graphic Jump Location

G1-G2 indicates first and second pregnancies; ≥G3, 2 or more previous pregnancies; HIV, human immunodeficiency virus status. P values after the I2 statistics represent the χ2 test for heterogeneity. Dersimonian-Laird method used for random-effects models; inverse-variance method used in the fixed-effects models. Weights are from random-effects analysis. Data marker sizes indicate the weight applied to each study with random-effects meta-analysis. Test for subgroup differences: χ24  = 3.14, P = .53, l2 = 0.0%.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Included Trials
Table Graphic Jump LocationTable 2. Random-Effects Meta-analysis of Trials Comparing the Standard 2-Dose vs ≥3 Doses of Sulfadoxine-Pyrimethamine for Intermittent Preventive Therapy During Pregnancy by HIV Status
Table Graphic Jump LocationTable 3. Summary of Adverse Events in Women and Neonates After Intermittent Preventive Therapy During Pregnancy With ≥3 Doses vs 2 Doses of Sulfadoxine-Pyrimethamine During Pregnancy

References

Desai M, ter Kuile FO, Nosten F,  et al.  Epidemiology and burden of malaria in pregnancy.  Lancet Infect Dis. 2007;7(2):93-104
PubMed   |  Link to Article
Steketee RW, Nahlen BL, Parise ME, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas.  Am J Trop Med Hyg. 2001;64(1-2):(Suppl)  28-35
PubMed
World Health Organization.  Malaria and HIV Interactions and Their Implications for Public Health Policy: Report of a Technical Consultation Geneva, Switzerland, 23-25 June 2004. Geneva, Switzerland: World Health Organization; 2004
World Health Organization.  A Strategic Framework for Malaria Prevention and Control During Pregnancy in the African RegionBrazzaville, Africa: World Health Organization: Regional Office for Africa; 2004. AFR/MAL/04/01
World Health Organization.  Recommendations on the Use of Sulfadoxine-Pyrimethamine (SP) for Intermittent Preventive Treatment During Pregnancy (IPT) in Areas of Moderate to High Resistance to SP in the African Region; October 2005http://www.who.int/malaria/publications/atoz/who_sp_statement.pdf. 2006
White NJ. Intermittent presumptive treatment for malaria.  PLoS Med. 2005;2(1):e3
PubMed   |  Link to Article
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(23):2603-2616
PubMed   |  Link to Article
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(1):109-116
PubMed   |  Link to Article
Diakite OS, Kayentao K, Traoré BT,  et al.  Superiority of 3 over 2 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria during pregnancy in mali: a randomized controlled trial.  Clin Infect Dis. 2011;53(3):215-223
PubMed   |  Link to Article
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(3):277-282
PubMed   |  Link to Article
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;353(9153):632-636
PubMed   |  Link to Article
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(5):813-822
PubMed
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;11(7):992-1002
PubMed   |  Link to Article
van Eijk AM, Hill J, Alegana VA,  et al.  Coverage of malaria protection in pregnant women in sub-Saharan Africa: a synthesis and analysis of national survey data.  Lancet Infect Dis. 2011;11(3):190-207
PubMed   |  Link to Article
van Eijk AM, Hill J, Povall S, Reynolds A, Wong H, Ter Kuile FO. The “Malaria in Pregnancy” library: a bibliometric review.  Malar J. 2012;11:362
PubMed   |  Link to Article
Higgins JP, Altman DG, Gøtzsche PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.  BMJ. 2011;343:d5928
PubMed   |  Link to Article
Cochrane Collaboration.  Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1.  Chichester, England: John Wiley & Sons; 2008. Updated September 2008
Naidoo I, Roper C. Drug resistance maps to guide intermittent preventive treatment of malaria in African infants.  Parasitology. 2011;138(12):1469-1479
PubMed   |  Link to Article
Picot S, Olliaro P, de Monbrison F, Bienvenu AL, Price RN, Ringwald P. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria.  Malar J. 2009;8:89
PubMed   |  Link to Article
Schünemann HJ, Oxman AD, Higgins JPT,  et al.  Presenting results and “Summary of Findings” tables. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. Cochrane Collaboration, John Wiley & Sons; 2008. Updated September 2008
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Deeks JJ, Higgins JPT. Statistical Algorithms in Review Manager 5. Cochrane Collaboration; 2010. http://ims.cochrane.org/revman/documentation/Statistical-methods-in-RevMan-5.pdf
Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis.  JAMA. 2011;306(24):2704-2714
PubMed   |  Link to Article
Filler SJ, Kazembe P, Thigpen M,  et al.  Randomized trial of 2-dose versus monthly sulfadoxine-pyrimethamine intermittent preventive treatment for malaria in HIV-positive and HIV-negative pregnant women in Malawi.  J Infect Dis. 2006;194(3):286-293
PubMed   |  Link to Article
Hamer DH, Mwanakasale V, Macleod WB,  et al.  Two-dose versus monthly intermittent preventive treatment of malaria with sulfadoxine-pyrimethamine in HIV-seropositive pregnant Zambian women.  J Infect Dis. 2007;196(11):1585-1594
PubMed   |  Link to Article
Luntamo M, Kulmala T, Mbewe B, Cheung YB, Maleta K, Ashorn P. Effect of repeated treatment of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in Malawi: a randomized controlled trial.  Am J Trop Med Hyg. 2010;83(6):1212-1220
PubMed   |  Link to Article
Luntamo M, Rantala AM, Meshnick SR,  et al.  The effect of monthly sulfadoxine-pyrimethamine, alone or with azithromycin, on PCR-diagnosed malaria at delivery: a randomized controlled trial.  PLoS One. 2012;7(7):e41123
PubMed   |  Link to Article
Valea I, Tinto H, Drabo MK,  et al.  Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso.  Malar J. 2010;9:324
MacArthur JR, Kabanywanyi AM, Baja A,  et al.  Abstract 830: efficacy of intermittent treatment with sulfadoxine-pyrimethamine alone or sulfadoxine-pyrimethamine plus artesunate for prevention of placental malaria in Tanzania. Paper presented at: 56th Annual Meeting of the American Society of Tropical Medicine and Hygiene; November 4-8, 2007; Philadelphia, PA
Iriemenam NC, Shah M, Gatei W,  et al.  Temporal trends of sulphadoxine-pyrimethamine (SP) drug-resistance molecular markers in Plasmodium falciparum parasites from pregnant women in western Kenya.  Malar J. 2012;11(1):134
PubMed   |  Link to Article
Dzinjalamala FK, Macheso A, Kublin JG,  et al.  Association between the pharmacokinetics and in vivo therapeutic efficacy of sulfadoxine-pyrimethamine in Malawian children.  Antimicrob Agents Chemother. 2005;49(9):3601-3606
PubMed   |  Link to Article
Pearce RJ, Pota H, Evehe MS,  et al.  Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.  PLoS Med. 2009;6(4):e1000055
PubMed   |  Link to Article
Lin JT, Mbewe B, Taylor SM, Luntamo M, Meshnick SR, Ashorn P. Increased prevalence of dhfr and dhps mutants at delivery in Malawian pregnant women receiving intermittent preventive treatment for malaria.  Trop Med Int Health. 2012;
PubMed
Dokomajilar C, Lankoande ZM, Dorsey G, Zongo I, Ouedraogo JB, Rosenthal PJ. Roles of specific Plasmodium falciparum mutations in resistance to amodiaquine and sulfadoxine-pyrimethamine in Burkina Faso.  Am J Trop Med Hyg. 2006;75(1):162-165
PubMed
Mbugi EV, Mutayoba BM, Malisa AL, Balthazary ST, Nyambo TB, Mshinda H. Drug resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum malaria in Mlimba, Tanzania.  Malar J. 2006;5:94
PubMed   |  Link to Article
Coulibaly SO, Gies S, D’Alessandro U. Malaria burden among pregnant women living in the rural district of Boromo, Burkina Faso.  Am J Trop Med Hyg. 2007;77(6):(Suppl)  56-60
PubMed
Begg C, Cho M, Eastwood S,  et al.  Improving the quality of reporting of randomized controlled trials. The CONSORT statement.  JAMA. 1996;276(8):637-639
PubMed   |  Link to Article
Gamble C, Ekwaru PJ, Garner P, ter Kuile FO. Insecticide-treated nets for the prevention of malaria in pregnancy: a systematic review of randomised controlled trials.  PLoS Med. 2007;4(3):e107
PubMed   |  Link to Article
Mikolajczyk RT, Zhang J, Betran AP,  et al.  A global reference for fetal-weight and birthweight percentiles.  Lancet. 2011;377(9780):1855-1861
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Gesase S, Gosling RD, Hashim R,  et al.  High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581.  PLoS One. 2009;4(2):e4569
PubMed   |  Link to Article
Harrington WE, Mutabingwa TK, Muehlenbachs A,  et al.  Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment.  Proc Natl Acad Sci U S A. 2009;106(22):9027-9032
PubMed   |  Link to Article
Harrington WE, Mutabingwa TK, Kabyemela E, Fried M, Duffy PE. Intermittent treatment to prevent pregnancy malaria does not confer benefit in an area of widespread drug resistance.  Clin Infect Dis. 2011;53(3):224-230
PubMed   |  Link to Article
Peters PJ, Thigpen MC, Parise ME, Newman RD. Safety and toxicity of sulfadoxine/pyrimethamine: implications for malaria prevention in pregnancy using intermittent preventive treatment.  Drug Saf. 2007;30(6):481-501
PubMed   |  Link to Article
Leke RG, Taylor DW. The use of intermittent preventive treatment with sulfadoxine-pyrimethamine for preventing malaria in pregnant women.  Clin Infect Dis. 2011;53(3):231-233
PubMed   |  Link to Article
Gill CJ, Macleod WB, Mwanakasale V,  et al.  Inferiority of single-dose sulfadoxine-pyrimethamine intermittent preventive therapy for malaria during pregnancy among HIV-positive Zambian women.  J Infect Dis. 2007;196(11):1577-1584
PubMed   |  Link to Article
Kalilani L, Taylor S, Madanitsa M,  et al.  Waning effectiveness of intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) in the presence of high SP resistance in Malawi. Abstract 1179. Paper presented at: 60th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Abstract Book; December 4–8, 2011; Philadelphia, PA
World Health Organization; Global Malaria Program.  Updated WHO Policy Recommendation (October 2012): Intermittent Preventive Treatment of Malaria in Pregnancy Using Sulfadoxine-Pyrimethamine (IPTp-SP)Geneva, Switzerland: World Health Organization; 2012

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Kayentao K, Garner P, van Eijk A, et al. Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis. JAMA. doi: 10.1001/jama.2012.216231

eMethods

eFigure 1. PRISMA flow diagram for systematic review of 3+ versus 2-dose of intermittent preventive treatment with sulfadoxine-pyrimethamine in Africa

eFigure 2. Risk of bias assessment representing the authors' judgements about each risk of bias item for each included study across the domains

eTable 1. Random effects meta-analysis of trials comparing the standard 2-dose vs 3+ doses of IPTp with sulfadoxine-pyrimethamine by HIV status among first and second pregnancies

eTable 2. Random effects meta-analysis of trials comparing the standard 2-dose vs 3+ doses of IPTp with sulfadoxine-pyrimethamine by HIV status among multigravidae (G3+)

eTable 3. Fixed effects meta-analysis of trials comparing the standard 2-dose vs 3+ doses of IPTp with sulfadoxine-pyrimethamine by HIV status and gravidity groups

eFigure 3. Funnel plot of standard error by log relative risk

eFigure 4. Cumulative meta-analysis of the association with low birth weight, ranked by year of publication, overall and by HIV status

eFigure 5. Cumulative meta-analysis of the association with mean birth weight, ranked by year of publication, overall and by HIV status

eFigure 6. Influence of removing 1 study at a time on the meta-analysis summary estimates for low birth weight

eFigure 7. Influence of removing 1 study at a time on the meta-analysis summary estimates for differences in mean birth weight

eFigure 8. Meta-analysis of mean maternal haemoglobin at birth in trials comparing the standard 2- dose vs 3+ doses of IPTp with sulfadoxine-pyrimethamine

eFigure 9. Meta-analysis of moderate-severe maternal anemia at birth in trials comparing the standard 2-dose vs 3+ doses of IPTp with sulfadoxine-pyrimethamine

eFigure 10. Meta-analysis of placental malaria in trials comparing the standard 2-dose vs 3+ doses of IPTp with sulfadoxine-pyrimethamine

eFigure 11. Subgroup analysis and analysis of determinants of the association with low birth weight

eFigure 12. Subgroup analysis and analysis of determinants of the association with mean birth weight

eReferences

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