Impact of maternal death reviews at a rural hospital in Zambia: a mixed methods study.

BACKGROUND: Maternal mortality in sub-Saharan Africa remains high despite programmatic efforts to improve maternal health. In 2007, the Zambian Ministry of Health mandated facility-based maternal death review (MDR) programs in line with World Health Organization recommendations. We assessed the impact of an [MDR program] at a district-level hospital in rural Zambia. METHODS: We conducted a mixed methods convergent study using hospital data on maternal mortality and audit reports of 106 maternal deaths from 2007 to 2011. To evaluate the overall impact of MDR on maternal mortality, we compared baseline (2007) to late (2010-11) post-intervention inpatient maternal mortality indicators. MDR committee reports were coded and dominant themes were extracted in a qualitative analysis. We assessed potential risk factors for maternal mortality in a before-and-after design comparing the periods 2008-09 and 2010-11. RESULTS: In-hospital maternal mortality declined from 23 per thousand live births in 2007 to 8 per thousand in 2010-11 (P < 0.01). Maternal case fatality for puerperal sepsis and uterine rupture decreased significantly from 63 and 32% in 2007 to 10 and 9% in 2010-11 (P < 0.01). No significant reduction was seen in case fatality due to postpartum hemorrhage. Qualitative analysis of risk factors for maternal mortality revealed four core themes: standards of practice, health systems, accessibility, and patient factors. Specific risk factors included delayed referral, missed diagnoses, intra-hospital delays in care, low medication inventory, and medical error. We found no statistically significant differences in the prevalence of risk factors between the before-and-after periods. CONCLUSIONS: Implementation of MDR was accompanied by a significant decrease in maternal mortality with reductions in maternal death from puerperal sepsis and uterine rupture, but not postpartum hemorrhage. Qualitative analysis of audit reports identified several modifiable risk factors within four core areas. Comparisons of potential explanatory factors did not show any differences over time. These results imply that MDR offers a means for hospitals to curtail maternal deaths, except deaths due to postpartum hemorrhage, suggesting additional interventions are needed. Documentation of MDR meetings provides an instrument to guide further quality improvements.

Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study.

BACKGROUND: The World Health Organization (WHO) recommendation of treating uncomplicated malaria during the second and third trimester of pregnancy with an artemisinin-based combination therapy (ACT) has already been implemented by all sub-Saharan African countries. However, there is limited knowledge on the effect of ACT on pregnancy outcomes, and on newborn and infant's health. METHODS: Pregnant women with malaria in four countries (Burkina Faso, Ghana, Malawi and Zambia) were treated with either artemether-lumefantrine (AL), amodiaquine-artesunate (ASAQ), mefloquine-artesunate (MQAS), or dihydroartemisinin-piperaquine (DHA-PQ); 3127 live new-borns (822 in the AL, 775 in the ASAQ, 765 in the MQAS and 765 in the DHAPQ arms) were followed-up until their first birthday. RESULTS: Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no significant differences between treatment arms. No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and infant mortality (p = 0.96) were found. CONCLUSIONS: Outcome of pregnancy and infant survival were similar between treatment arms indicating that any of the four artemisinin-based combinations could be safely used during the second and third trimester of pregnancy without any adverse effect on the baby. Nevertheless, smaller safety differences between artemisinin-based combinations cannot be excluded; country-wide post-marketing surveillance would be very helpful to confirm such findings. Trial registration ClinicalTrials.gov, NCT00852423, Registered on 27 February 2009, https://clinicaltrials.gov/ct2/show/NCT00852423.

The assessment of gestational age: a comparison of different methods from a malaria pregnancy cohort in sub-Saharan Africa.

BACKGROUND: Determining gestational age in resource-poor settings is challenging because of limited availability of ultrasound technology and late first presentation to antenatal clinic. Last menstrual period (LMP), symphysio-pubis fundal height (SFH) and Ballard Score (BS) at delivery are therefore often used. We assessed the accuracy of LMP, SFH, and BS to estimate gestational age at delivery and preterm birth compared to ultrasound (US) using a large dataset derived from a randomized controlled trial in pregnant malaria patients in four African countries. METHODS: Mean and median gestational age for US, LMP, SFH and BS were calculated for the entire study population and stratified by country. Correlation coefficients were calculated using Pearson's rho, and Bland Altman plots were used to calculate mean differences in findings with 95% limit of agreements. Sensitivity, specificity, positive predictive value and negative predictive value were calculated considering US as reference method to identify term and preterm babies. RESULTS: A total of 1630 women with P. falciparum infection and a gestational age > 24 weeks determined by ultrasound at enrolment were included in the analysis. The mean gestational age at delivery using US was 38.7 weeks (95%CI: 38.6-38.8), by LMP, 38.4 weeks (95%CI: 38.0-38.9), by SFH, 38.3 weeks (95%CI: 38.2-38.5), and by BS 38.0 weeks (95%CI: 37.9-38.1) (p < 0.001). Correlation between US and any of the other three methods was poor to moderate. Sensitivity and specificity to determine prematurity were 0.63 (95%CI 0.50-0.75) and 0.72 (95%CI, 0.66-0.76) for LMP, 0.80 (95%CI 0.74-0.85) and 0.74 (95%CI 0.72-0.76) for SFH and 0.42 (95%CI 0.35-0.49) and 0.77 (95%CI 0.74-0.79) for BS. CONCLUSIONS: In settings with limited access to ultrasound, and in women who had been treated with P. falciparum malaria, SFH may be the most useful antenatal tool to date a pregnancy when women present first in second and third trimester. The Ballard postnatal maturation assessment has a limited role and lacks precision. Improving ultrasound facilities and skills, and early attendance, together with the development of new technologies such as automated image analysis and new postnatal methods to assess gestational age, are essential for the study and management of preterm birth in low-income settings.

Artemisinin-based combination therapy in pregnant women in Zambia: efficacy, safety and risk of recurrent malaria.

BACKGROUND: In Zambia, malaria is one of the leading causes of morbidity and mortality, especially among under five children and pregnant women. For the latter, the World Health Organization recommends the use of artemisinin-based combination therapy (ACT) in the second and third trimester of pregnancy. In a context of limited information on ACT, the safety and efficacy of three combinations, namely artemether-lumefantrine (AL), mefloquine-artesunate (MQAS) and dihydroartemisinin-piperaquine (DHAPQ) were assessed in pregnant women with malaria. METHODS: The trial was carried out between July 2010 and August 2013 in Nchelenge district, Luapula Province, an area of high transmission, as part of a multi-centre trial. Women in the second or third trimester of pregnancy and with malaria were recruited and randomized to one of the three study arms. Women were actively followed up for 63 days, and then at delivery and 1 year post-delivery. RESULTS: Nine hundred pregnant women were included, 300 per arm. PCR-adjusted treatment failure was 4.7% (12/258) (95% CI 2.7-8.0) for AL, 1.3% (3/235) (95% CI 0.4-3.7) for MQAS and 0.8% (2/236) (95% CI 0.2-3.0) for DHAPQ, with significant risk difference between AL and DHAPQ (p = 0.01) and between AL and MQAS (p = 0.03) treatments. Re-infections during follow up were more frequent in the AL (HR: 4.71; 95% CI 3.10-7.2; p < 0.01) and MQAS (HR: 1.59; 95% CI 1.02-2.46; p = 0.04) arms compared to the DHAPQ arm. PCR-adjusted treatment failure was significantly associated with women under 20 years [Hazard Ratio (HR) 5.35 (95% CI 1.07-26.73; p = 0.04)] and higher malaria parasite density [3.23 (95% CI 1.03-10.10; p = 0.04)], and still women under 20 years [1.78, (95% CI 1.26-2.52; p < 0.01)] had a significantly higher risk of re-infection. The three treatments were generally well tolerated. Dizziness, nausea, vomiting, headache and asthenia as adverse events (AEs) were more common in MQAS than in AL or DHAPQ (p < 0.001). Birth outcomes were not significantly different between treatment arms. CONCLUSION: As new infections can be prevented by a long acting partner drug to the artemisinins, DHAPQ should be preferred in places as Nchelenge district where transmission is intense while in areas of low transmission intensity AL or MQAS may be used.

The return of chloroquine-susceptible Plasmodium falciparum malaria in Zambia.

BACKGROUND: Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to malaria control and elimination. The parasite has developed resistance to every anti-malarial drug introduced for wide-scale treatment. However, the spread of resistance may be reversible. Malawi was the first country to discontinue chloroquine use due to widespread resistance. Within a decade of the removal of drug pressure, the molecular marker of chloroquine-resistant malaria had disappeared and the drug was shown to have excellent clinical efficacy. Many countries have observed decreases in the prevalence of chloroquine resistance with the discontinuation of chloroquine use. In Zambia, chloroquine was used as first-line treatment for uncomplicated malaria until treatment failures led the Ministry of Health to replace it with artemether-lumefantrine in 2003. Specimens from a recent study were analysed to evaluate prevalence of chloroquine-resistant malaria in Nchelenge district a decade after chloroquine use was discontinued. METHODS: Parasite DNA was extracted from dried blood spots collected by finger-prick in pregnant women who were enrolling in a clinical trial. The specimens underwent pyrosequencing to determine the genotype of the P. falciparum chloroquine resistance transporter, the gene that is associated with CQ resistance. RESULTS: Three-hundred and two specimens were successfully analysed. No chloroquine-resistant genotypes were detected. CONCLUSION: The study found the disappearance of chloroquine-resistant malaria after the removal of chloroquine drug pressure. Chloroquine may have a role for malaria prevention or treatment in Zambia and throughout the region in the future.

Antimalarial Drug Resistance and Implications for the WHO Global Technical Strategy.

PURPOSE OF REVIEW: Five years have passed since the World Health Organization released its Global Technical Strategy for Malaria (GTS). In that time, progress against malaria has plateaued. This review focuses on the implications of antimalarial drug resistance for the GTS and how interim progress in parasite genomics and antimalarial pharmacology offer a bulwark against it. RECENT FINDINGS: For the first time, drug resistance-conferring genes have been identified and validated before their global expansion in malaria parasite populations. More efficient methods for their detection and elaboration have been developed, although low-density infections and polyclonality remain a nuisance to be solved. Clinical trials of alternative regimens for multidrug-resistant malaria have delivered promising results. New agents continue down the development pipeline, while a nascent infrastructure in sub-Saharan Africa for conducting phase I trials and trials of transmission-blocking agents has come to fruition after years of preparation. SUMMARY: These and other developments can help inform the GTS as the world looks ahead to the next two decades of its implementation. To remain ahead of the threat that drug resistance poses, wider application of genomic-based surveillance and optimization of existing and forthcoming antimalarial drugs are essential.

Safety and efficacy of intermittent presumptive treatment with sulfadoxine-pyrimethamine using rapid diagnostic test screening and treatment with dihydroartemisinin-piperaquine at the first antenatal care visit (IPTp-SP+): study protocol for a randomized controlled trial.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization for the prevention of malaria in pregnancy (MIP)-associated adverse outcomes in high burden areas. However, the efficacy of IPTp-SP has decreased in step with increasing parasite drug resistance. Suitable alternative strategies are needed. METHODS: This is a protocol for a phase IIIb open-label, two-armed randomized controlled superiority trial to assess the safety and efficacy of a hybrid approach to IPTp combining screening and treatment with dihydroartemisinin-piperaquine (DP) to the current IPTp-SP regimen at the first antenatal care clinic visit. Pregnant women without HIV infection and without signs or symptoms of malaria will be randomized to either standard IPTp-SP or hybrid IPTp-SP plus screening and treatment (IPTp-SP+). In the IPTp-SP+ arm, participants who screen positive by rapid diagnostic test for P. falciparum will be treated with DP at the first antenatal visit while those who screen negative will receive SP per current guidelines. All participants will be administered SP on days 35 and 63 and will be actively followed biweekly up to day 63 and then monthly until delivery. Infants will be followed until 1 year after delivery. The primary endpoint is incident PCR-confirmed MIP at day 42. Secondary endpoints include incident MIP at other time points, placental malaria, congenital malaria, hemoglobin trends, birth outcomes, and incidence of adverse events in infants up to the first birthday. DISCUSSION: A hybrid approach to IPTp that combines screening and treatment with an artemisinin-based combination therapy at the first visit with standard IPTp-SP is hypothesized to confer added benefit over IPTp-SP alone in a high malaria transmission area with prevalent SP resistant parasites. TRIAL REGISTRATION: Pan African Clinical Trials Registry 201905721140808 . Registered retrospectively on 11 May 2019.