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Effect of Sulfadoxine-Pyrimethamine Resistance on the Efficacy of Intermittent Preventive Therapy for Malaria Control During Pregnancy A Systematic Review

Feiko O. ter Kuile, MD, PhD; Annemieke M. van Eijk, MD, PhD; Scott J. Filler, MD, DTMH
JAMA. 2007;297(23):2603-2616. doi:10.1001/jama.297.23.2603.
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Context In malaria-endemic regions, strategies to control malaria during pregnancy rely on case management of malaria illness and anemia, and preventive measures such as insecticide-treated nets and intermittent preventive therapy (IPT).

Objective To determine the effect of increasing resistance to sulfadoxine-pyrimethamine on the efficacy of IPT during pregnancy in Africa.

Data Sources and Study Selection The 6 databases of MEDLINE, EMBASE, SCOPUS, LILACS, Cochrane CENTRAL, and the trial register and bibliographic database of the Malaria in Pregnancy Library were searched for relevant studies regardless of language, published between 1966 and December 2006. The reference lists of all trials identified were searched and researchers were contacted about relevant data. Nine trials of IPT with sulfadoxine-pyrimethamine during pregnancy in Africa were identified and matched by year and location with treatment studies of sulfadoxine-pyrimethamine among symptomatic children.

Data Extraction Data on the efficacy of IPT with sulfadoxine-pyrimethamine on placental and peripheral malaria, birth weight, and hemoglobin level/anemia were independently abstracted by 2 investigators. Sulfadoxine-pyrimethamine resistance was defined as the proportion of total treatment failures in symptomatic children by day 14.

Data Synthesis Four trials compared 2-dose IPT with sulfadoxine-pyrimethamine to case management or placebo in women during their first or second pregnancy. The IPT reduced placental malaria (relative risk [RR], 0.48; 95% CI, 0.35-0.68), low birth weight (RR, 0.71; 95% CI, 0.55-0.92), and anemia (RR, 0.90; 95% CI, 0.81-0.99). The effect did not vary by sulfadoxine-pyrimethamine resistance levels (range, 19%-26%). Efficacy of IPT with sulfadoxine-pyrimethamine was lower among women using insecticide-treated nets. Three trials compared 2-dose with monthly IPT with sulfadoxine-pyrimethamine during pregnancy. Among HIV-positive women in their first or second pregnancy, monthly IPT resulted in less placental malaria (RR, 0.34; 95% CI, 0.18-0.64) and higher birth weight (mean difference, 112 g; 95% CI, 19-205 g) over the range of sulfadoxine-pyrimethamine resistance tested (8%-39%). Among HIV-negative women, there was no conclusive additional effect of monthly dosing (2 trials; 24% and 39% resistance).

Conclusions In areas in which 1 of 4 treatments with sulfadoxine-pyrimethamine fail in children by day 14, the 2-dose IPT with sulfadoxine-pyrimethamine regimen continues to provide substantial benefit to HIV-negative semi-immune pregnant women. However, more frequent dosing is required in HIV-positive women not using cotrimoxazole prophylaxis for opportunistic infections.

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Figures

Figure 1. Effect of 2-Dose Intermittent Preventive Therapy With Sulfadoxine-Pyrimethamine Among Women During Their First or Second Pregnancy vs Chloroquine Prophylaxis on Placental Malaria, Maternal Malaria, and Low Birth Weight
Graphic Jump Location

Both studies were conducted in areas of low to moderate sulfadoxine-pyrimethamine treatment failure among symptomatic children by day 14 (3% and 5%). However, chloroquine treatment failure in children was much lower in Mali (8.9% at day 7)36 than in Malawi (85.7% at day 7).37 The effect on mean birth weight, hemoglobin level, and anemia were reported only for the study in Mali (not shown). The size of the square data markers reflects the relative weight of each study. The diamonds represent summary effect estimates. CI indicates confidence interval; RR, relative risk.

*Indicates random-effects model was used.

†Indicates fixed-effects model was used.

Figure 2. Effect of 2-Dose Intermittent Preventive Therapy With Sulfadoxine-Pyrimethamine Among Women During Their First or Second Pregnancy vs Case Management or Placebo (Control) on Placental Malaria, Maternal Parasitemia, Low Birth Weight, and Maternal Anemia
Graphic Jump Location

In the study by Shulman et al,21 the number of sulfadoxine-pyrimethamine (or placebo) doses depended on gestational age at enrollment; the majority of women (64%) received 2 doses. The size of the square data markers reflects the relative weight of each study. The diamonds represent summary effect estimates. CI indicates confidence interval; RR, relative risk.

*Indicates random-effects model was used.

†Indicates fixed-effects model was used.

‡Hemoglobin level lower than 10 g/dL17,21 or lower than 11 g/dL.24

Figure 3. Effect of 2-Dose Intermittent Preventive Therapy With Sulfadoxine-Pyrimethamine Among Women During Their First or Second Pregnancy vs Case Management or Placebo (Control) on Mean Birth Weight and Hemoglobin Level
Graphic Jump Location

In the study by Shulman et al,21 the number of sulfadoxine-pyrimethamine (or placebo) doses depended on gestational age at enrollment; the majority of women (64%) received 2 doses. The size of the square data markers reflects the relative weight of each study. The diamonds represent summary effect estimates. CI indicates confidence interval.

*Indicates random-effects model was used.

†Indicates fixed-effects model was used.

Figure 4. Effect of Monthly vs 2-Dose Intermittent Preventive Therapy With Sulfadoxine-Pyrimethamine Among Women During Their First or Second Pregnancy by HIV Status and Level of Drug Resistance on Placental Malaria
Graphic Jump Location

Only data from women during their first or second pregnancy are presented from the study by Hamer et al (unpublished) to allow comparison with the other 2 studies. The size of the square data markers reflects the relative weight of each study. The diamonds represent summary effect estimates. CI indicates confidence interval; HIV, human immunodeficiency virus; RR, relative risk.

*Indicates fixed-effects model was used.

†Indicates random-effects model was used

Figure 5. Effect of Monthly vs 2-Dose Intermittent Preventive Therapy With Sulfadoxine-Pyrimethamine Among Women During Their First or Second Pregnancy by HIV Status and Level of Drug Resistance on Mean Birth Weight
Graphic Jump Location

Only data from women during their first or second pregnancy are presented from the study by Hamer et al (unpublished) to allow comparison with the other 2 studies. The size of the square data markers reflects the relative weight of each study. The diamonds represent summary effect estimates. CI indicates confidence interval; HIV, human immunodeficiency virus.

Figure 6. Relationship Between the Sulfadoxine-Pyrimethamine Treatment Response in Symptomatic Children at Day 14 and the Reduction in the Proportion of Women With Peripheral Parasitemia at Delivery vs Enrollment Among Women During Their First or Second Pregnancy
Graphic Jump Location

The reduction in the proportion of women with peripheral parasitemia is calculated as the percentage of women with peripheral parasitemia at enrollment minus the percentage with peripheral parasitemia at delivery divided by the percentage of peripheral parasitemia at enrollment divided by 100. The reference numbers in the figure indicate the reference of the trial (first number) and the reference of the matching study among children (numbers in parentheses). HIV indicates human immunodeficiency virus.

*The study population is pregnant women who are younger than 21 years during their first or second pregnancy.

†Women randomized to insecticide-treated nets were excluded.

‡Resistance to sulfadoxine-pyrimethamine was defined as the proportion of total treatment failure in symptomatic children by day 14.

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