Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant plasmodium falciparum: Clinical outcomes from the queerpam study

Clinical Infectious Diseases, Volume 55, No. 1, Year 2012

Interpretation

Background. Antenatal intermittent preventive therapy with 2 doses of sulfadoxine-pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads.Methods.We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes.Results.The prevalence of parasites with highly SP-resistant haplotypes increased from 17 to 100 (P <. 001), and the proportion of women receiving full IPTp (≥2 doses) increased from 25 to 82 (P <. 001). Women who received full IPTp with SP had lower peripheral (P =. 018) and placental (P <. 001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity.Conclusions.In this longitudinal study of malaria at delivery, the receipt of SP as IPTp did not potentiate PAM morbidity despite the increasing prevalence and fixation of SP-resistant P. falciparum haplotypes. Even when there is substantial resistance, SP may be used in modified IPTp regimens as a component of comprehensive antenatal care. © 2012 The Author. Ethical approval for this study was granted by the review boards of the Malawi Health Sciences Research Committee, the University of Malawi College of Medicine, and the University of North Carolina at Chapel Hill. Patient enrollment and sample collection have been described elsewhere [6, 8]. In brief, pregnant women delivering between July 1997 and August 2006 at Queen Elizabeth Central Hospital in Blantyre, Malawi, were invited to participate. Those who consented to participate were queried regarding demographic and clinical information. The receipt of SP antenatally was obtained from antenatal clinic cards; from 1999 onward, the date of the last dose of SP was available. Peripheral and placental blood was used to prepare thick blood smears, which were read by 2 microscopists for the presence and density of P. falciparum parasites. From 1998 onward, full-thickness placental biopsies were wax embedded, stained with modified Giemsa and/or hematoxylin and eosin, and assessed by 2 trained observers masked to other clinical data. Histologic indices included (1) density of parasitemia, expressed as percentage of all observed erythrocytes that were parasitized; (2) mononuclear cell infiltrate, expressed as percentage of all cells observed in the intervillous space; and (3) semiquantitative assessment of malaria pigment deposition in fibrin, as an indicator of chronic placental inflammation [9]. Maternal hemoglobin concentration was measured using HemoCue, and newborns were weighed within 1 day of birth. A subset of 25% of available samples from women with positive peripheral blood thick smears for P. falciparum parasites was manually selected at random by personnel blinded to all clinical information. From these specimens, genomic DNA was extracted and P. falciparum parasites were genotyped for mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes by direct sequencing [7]. To reduce contamination risk, separate work areas were maintained for molecular steps and filtered pipette tips were used for all procedures. Mutations were investigated at codons 51, 59, 108, and 164 of dhfr and codons 437, 540, 581, and 613 of dhps. Haplotypes were assigned based upon codons 51, 59, and 108 in dhfr and 437 and 540 in dhps [10]. The “quintuple mutant” haplotype consisted of mixed or mutant alleles at all 5 loci in dhfr and dhps; “partial wild-type” haplotypes were those with a wild-type allele at any locus. Recent antenatal SP receipt was defined as within 60 days prior to delivery, owing to the prolonged half-life and activity of SP [11]. Maternal anemia was defined as a hemoglobin concentration <11 g/dL (any) and <9 g/dL (moderate), and low birth weight was defined as <2500 g. Antenatal SP use was categorized as “full IPTp” (≥2 doses) or “suboptimal IPTp” (<2 doses). Antenatal indices and birth outcomes (parasite densities, placental histologic indices, maternal hemoglobin concentration, and birth weight) were compared between women who received suboptimal or full IPTp using the Kruskal-Wallis rank test, the Student t test, or the χ2 test. The prevalence of moderate anemia and low birth weight were compared between groups using the χ2 test. To assess for effect modification of the effect of IPTp upon birth outcomes, we stratified women into those harboring partial wild-type parasites and those with quintuple mutant parasites; after stratification, we repeated comparisons of birth outcomes between IPTp groups. To account for covariates (including the effect of the year of delivery and the effect of resistant P. falciparum) in the analysis of the association between IPTp-SP and birth outcomes, we first used linear or logistic regression to compare maternal peripheral parasite density, placental parasite density, maternal hemoglobin concentration, birth weight, and the dichotomized proportions of moderate anemia and low birth weight between women who received suboptimal and full IPTp. Parasite densities were natural log-transformed prior to regression modeling. Subsequently, adjusted comparisons were then computed by repeating regression models after the inclusion of covariates representing delivery year and P. falciparum haplotype, as well as reported mediators of placental pathology: human immunodeficiency virus (HIV) infection [12], gravidity (primigravid versus multigravid) [4], and the recent receipt of SP. Clinical data were initially entered into Epi Info or Microsoft Access; all statistical analyses were ultimately performed using Stata/IC, version 10.

AI Digest

Study Justification:

The study aimed to investigate whether the use of sulfadoxine-pyrimethamine (SP) for preventing pregnancy-associated malaria (PAM) would exacerbate the condition due to the expansion of drug-resistant Plasmodium falciparum. This was an important question to address because recent studies had raised concerns that the current policy of using SP for preventing PAM may cause harm as resistance to the drug spreads.

Highlights:

– The study conducted a serial, cross-sectional analysis over a period of 9 years in Malawi.
– The prevalence of parasites with highly SP-resistant haplotypes increased significantly during the study period.
– The proportion of women receiving the recommended two doses of SP for intermittent preventive therapy increased substantially.
– Women who received the full recommended doses of SP had lower parasite densities in their peripheral blood and placenta compared to those who received suboptimal doses.
– The receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any measures of PAM morbidity.
– The study concluded that even in the presence of drug resistance, SP can still be used as part of comprehensive antenatal care.

Recommendations:

Based on the findings of the study, the following recommendations can be made:

1. Continue the use of sulfadoxine-pyrimethamine for intermittent preventive therapy to prevent pregnancy-associated malaria.
2. Monitor the prevalence of drug-resistant Plasmodium falciparum haplotypes to inform future treatment and prevention strategies.
3. Conduct further research to explore alternative drugs or combinations for preventing PAM in areas with high drug resistance.

Key Role Players:

1. Researchers and scientists specializing in malaria and antenatal care.
2. Healthcare providers and clinicians involved in antenatal care and malaria prevention programs.
3. Policy makers and government officials responsible for implementing and funding malaria prevention strategies.
4. Community health workers and educators who can disseminate information about the study findings and recommendations to pregnant women.

Cost Items for Planning Recommendations:

1. Research funding for further studies on alternative drugs or combinations for preventing PAM.
2. Training and capacity building for healthcare providers on the use of alternative drugs or combinations.
3. Monitoring and surveillance systems to track the prevalence of drug-resistant Plasmodium falciparum haplotypes.
4. Public health campaigns and education materials to raise awareness among pregnant women about the importance of antenatal care and malaria prevention.
5. Integration of malaria prevention programs into existing antenatal care services.
6. Infrastructure and equipment for diagnostic testing and treatment of malaria in antenatal clinics.

Strength of Evidence

The strength of evidence for this abstract is 8 out of 10.
The evidence in the abstract is strong because it is based on a longitudinal study with a large sample size conducted over a period of 9 years. The study analyzes the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity using various measures such as parasite densities, placental histology, and birth outcomes. The study also adjusts for covariates and includes a subset of samples for genotyping. To improve the evidence, the abstract could provide more information on the specific methods used for data collection and analysis, as well as the characteristics of the study population.

Abstract

Ethical approval for this study was granted by the review boards of the Malawi Health Sciences Research Committee, the University of Malawi College of Medicine, and the University of North Carolina at Chapel Hill. Patient enrollment and sample collection have been described elsewhere [6, 8]. In brief, pregnant women delivering between July 1997 and August 2006 at Queen Elizabeth Central Hospital in Blantyre, Malawi, were invited to participate. Those who consented to participate were queried regarding demographic and clinical information. The receipt of SP antenatally was obtained from antenatal clinic cards; from 1999 onward, the date of the last dose of SP was available. Peripheral and placental blood was used to prepare thick blood smears, which were read by 2 microscopists for the presence and density of P. falciparum parasites. From 1998 onward, full-thickness placental biopsies were wax embedded, stained with modified Giemsa and/or hematoxylin and eosin, and assessed by 2 trained observers masked to other clinical data. Histologic indices included (1) density of parasitemia, expressed as percentage of all observed erythrocytes that were parasitized; (2) mononuclear cell infiltrate, expressed as percentage of all cells observed in the intervillous space; and (3) semiquantitative assessment of malaria pigment deposition in fibrin, as an indicator of chronic placental inflammation [9]. Maternal hemoglobin concentration was measured using HemoCue, and newborns were weighed within 1 day of birth. A subset of 25% of available samples from women with positive peripheral blood thick smears for P. falciparum parasites was manually selected at random by personnel blinded to all clinical information. From these specimens, genomic DNA was extracted and P. falciparum parasites were genotyped for mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes by direct sequencing [7]. To reduce contamination risk, separate work areas were maintained for molecular steps and filtered pipette tips were used for all procedures. Mutations were investigated at codons 51, 59, 108, and 164 of dhfr and codons 437, 540, 581, and 613 of dhps. Haplotypes were assigned based upon codons 51, 59, and 108 in dhfr and 437 and 540 in dhps [10]. The “quintuple mutant” haplotype consisted of mixed or mutant alleles at all 5 loci in dhfr and dhps; “partial wild-type” haplotypes were those with a wild-type allele at any locus. Recent antenatal SP receipt was defined as within 60 days prior to delivery, owing to the prolonged half-life and activity of SP [11]. Maternal anemia was defined as a hemoglobin concentration <11 g/dL (any) and <9 g/dL (moderate), and low birth weight was defined as <2500 g. Antenatal SP use was categorized as “full IPTp” (≥2 doses) or “suboptimal IPTp” (<2 doses). Antenatal indices and birth outcomes (parasite densities, placental histologic indices, maternal hemoglobin concentration, and birth weight) were compared between women who received suboptimal or full IPTp using the Kruskal-Wallis rank test, the Student t test, or the χ2 test. The prevalence of moderate anemia and low birth weight were compared between groups using the χ2 test. To assess for effect modification of the effect of IPTp upon birth outcomes, we stratified women into those harboring partial wild-type parasites and those with quintuple mutant parasites; after stratification, we repeated comparisons of birth outcomes between IPTp groups. To account for covariates (including the effect of the year of delivery and the effect of resistant P. falciparum) in the analysis of the association between IPTp-SP and birth outcomes, we first used linear or logistic regression to compare maternal peripheral parasite density, placental parasite density, maternal hemoglobin concentration, birth weight, and the dichotomized proportions of moderate anemia and low birth weight between women who received suboptimal and full IPTp. Parasite densities were natural log-transformed prior to regression modeling. Subsequently, adjusted comparisons were then computed by repeating regression models after the inclusion of covariates representing delivery year and P. falciparum haplotype, as well as reported mediators of placental pathology: human immunodeficiency virus (HIV) infection [12], gravidity (primigravid versus multigravid) [4], and the recent receipt of SP. Clinical data were initially entered into Epi Info or Microsoft Access; all statistical analyses were ultimately performed using Stata/IC, version 10.

Materials

Innovations

Based on the provided information, it is difficult to determine specific innovations for improving access to maternal health. The text describes a study on the use of sulfadoxine-pyrimethamine (SP) as intermittent preventive therapy for pregnancy-associated malaria (PAM). The study found that the receipt of SP did not exacerbate PAM morbidity, even in the presence of drug-resistant Plasmodium falciparum. The study also collected data on various maternal and birth outcomes.

To improve access to maternal health, some potential innovations could include:

1. Mobile health (mHealth) interventions: Using mobile phones and other digital technologies to provide information, reminders, and support to pregnant women, including reminders for antenatal care visits, medication adherence, and access to healthcare services.

2. Community health worker programs: Training and deploying community health workers to provide education, counseling, and basic healthcare services to pregnant women in remote or underserved areas.

3. Telemedicine: Using telecommunication technologies to connect pregnant women with healthcare providers for remote consultations, monitoring, and follow-up care.

4. Integrated antenatal care services: Ensuring that antenatal care services include comprehensive screening, prevention, and treatment for common maternal health issues, such as malaria, anemia, and HIV.

5. Task-shifting and task-sharing: Expanding the roles and responsibilities of healthcare workers, such as nurses and midwives, to provide a wider range of maternal health services, including antenatal care, delivery, and postnatal care.

6. Strengthening health systems: Improving infrastructure, supply chains, and healthcare workforce capacity to ensure that pregnant women have access to quality maternal health services, including skilled birth attendants, emergency obstetric care, and essential medications.

These are just a few examples of potential innovations that could improve access to maternal health. It is important to note that the specific context and needs of each community or country should be considered when implementing these innovations.

AI Innovations Description

The recommendation based on the study is to continue using sulfadoxine-pyrimethamine (SP) as part of antenatal intermittent preventive therapy (IPTp) to prevent pregnancy-associated malaria (PAM) in sub-Saharan Africa. The study found that despite the increasing prevalence of SP-resistant Plasmodium falciparum, the receipt of SP did not exacerbate PAM morbidity. Women who received full IPTp with SP had lower parasite densities compared to those who received suboptimal IPTp. The study suggests that even with resistance, SP can still be used in modified IPTp regimens as part of comprehensive antenatal care.

AI Innovations Methodology

Based on the provided description, here are some potential recommendations to improve access to maternal health:

1. Strengthen Antenatal Care Services: Enhance antenatal care services by ensuring that pregnant women have access to regular check-ups, screenings, and necessary interventions. This can be achieved by increasing the number of trained healthcare providers, improving infrastructure, and implementing effective referral systems.

2. Community-Based Interventions: Implement community-based interventions to reach pregnant women in remote or underserved areas. This can include mobile clinics, community health workers, and outreach programs to provide essential maternal health services closer to where women live.

3. Health Education and Awareness: Increase health education and awareness programs to empower women with knowledge about maternal health, including the importance of antenatal care, nutrition, and hygiene practices. This can be done through community workshops, radio campaigns, and the use of informational materials.

4. Telemedicine and Digital Solutions: Utilize telemedicine and digital solutions to provide remote consultations, monitoring, and support for pregnant women. This can help overcome geographical barriers and improve access to specialized care, especially in areas with limited healthcare facilities.

To simulate the impact of these recommendations on improving access to maternal health, a methodology could include the following steps:

1. Define the Objectives: Clearly define the objectives of the simulation study, such as assessing the potential increase in antenatal care coverage, reduction in maternal mortality rates, or improvement in birth outcomes.

2. Data Collection: Gather relevant data on the current state of maternal health access, including the number of healthcare facilities, healthcare providers, antenatal care coverage, and maternal health indicators. This data can be obtained from national health surveys, health facility records, and other relevant sources.

3. Model Development: Develop a simulation model that represents the current maternal health system and incorporates the proposed recommendations. This model should consider factors such as population demographics, geographical distribution, healthcare infrastructure, and resource availability.

4. Parameter Estimation: Estimate the parameters of the simulation model based on available data and expert knowledge. This may involve conducting surveys, interviews, or literature reviews to gather information on factors such as healthcare provider capacity, community preferences, and resource allocation.

5. Scenario Testing: Simulate different scenarios by varying the implementation of the recommendations. This can involve increasing the number of healthcare providers, improving infrastructure, or implementing community-based interventions. Evaluate the impact of each scenario on the defined objectives, comparing them to the baseline scenario.

6. Sensitivity Analysis: Perform sensitivity analysis to assess the robustness of the results and identify key factors that influence the outcomes. This can involve varying input parameters within plausible ranges to determine their impact on the results.

7. Interpretation and Reporting: Analyze the simulation results and interpret the findings in relation to the defined objectives. Prepare a comprehensive report summarizing the methodology, results, and recommendations for improving access to maternal health based on the simulation outcomes.

It is important to note that the methodology described above is a general framework and may require customization based on the specific context and available data.

Author

Dima Health

Statistics:

Citations: 30

Identifiers:

DOI: 10.1093/cid/cis301

ISSN: 10584838

Research Areas:

Genetics and Genomics, Health System and Policy, Infectious Diseases, Maternal Access, Maternal and Child Health, Quality of Care, Sexual and Reproductive Health, Social Determinants

Study Countries:

Malawi

Study Design:

Cohort Study, Cross Sectional Study

Study Approach:

Quantitative

Participants Gender:

Female