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1.  Risk factors for maternal death and trends in maternal mortality in low- and middle-income countries: a prospective longitudinal cohort analysis 
Reproductive Health  2015;12(Suppl 2):S5.
Background
Because large, prospective, population-based data sets describing maternal outcomes are typically not available in low- and middle-income countries, it is difficult to monitor maternal mortality rates over time and to identify factors associated with maternal mortality. Early identification of risk factors is essential to develop comprehensive intervention strategies preventing pregnancy-related complications. Our objective was to describe maternal mortality rates in a large, multi-country dataset and to determine maternal, pregnancy-related, delivery and postpartum characteristics that are associated with maternal mortality.
Methods
We collected data describing all pregnancies from 2010 to 2013 among women enrolled in the multi-national Global Network for Women’s and Children’s Health Research Maternal and Neonatal Health Registry (MNHR). We reported the proportion of mothers who died per pregnancy and the maternal mortality ratio (MMR). Generalized linear models were used to evaluate the relationship of potential medical and social factors and maternal mortality and to develop point and interval estimates of relative risk associated with these factors. Generalized estimating equations were used to account for the correlation of outcomes within cluster to develop appropriate confidence intervals.
Results
We recorded 277,736 pregnancies and 402 maternal deaths for an MMR of 153/100,000 live births. We observed an improvement in the total MMR from 166 in 2010 to 126 in 2013. The MMR in Latin American sites (91) was lower than the MMR in Asian (178) and African sites (125). When adjusted for study site and the other variables, no formal education (RR 3.2 [1.5, 6.9]), primary education only (RR 3.4 [1.6, 7.5]), secondary education only (RR 2.5 [1.1, 5.7]), lack of antenatal care (RR 1.8 [1.2, 2.5]), caesarean section delivery (RR 1.9 [1.3, 2.8]), hemorrhage (RR 3.3 [2.2, 5.1]), and hypertensive disorders (RR 7.4 [5.2, 10.4]) were associated with higher risks of death.
Conclusions
The MNHR identified preventable causes of maternal mortality in diverse settings in low- and middle-income countries. The MNHR can be used to monitor public health strategies and determine their association with reducing maternal mortality.
Trial Registration
clinicaltrials.gov NCT01073475
doi:10.1186/1742-4755-12-S2-S5
PMCID: PMC4464034  PMID: 26062992
2.  A Cross-Sectional Survey of Plasmodium falciparum pfcrt Mutant Haplotypes in the Democratic Republic of Congo 
In the Democratic Republic of the Congo (DRC), artesunate-amodiaquine is first-line therapy for falciparum malaria; little is known about the prevalence of molecular markers of parasite drug resistance. Across the DRC, we genotyped 166 parasites in Plasmodium falciparum chloroquine resistance transporter (pfcrt) using polymerase chain reaction (PCR) and sequencing. Of these parasites, 73 (44%) parasites were pure wild-type CVMNK, 55 (31%) parasites were chloroquine-resistant CVIET, 35 (21.1%) parasites were mixed CVMNK and CVIET, and 3 parasites were other genotypes. Ninety-two infections (55.4%) harbored the pfcrt K76T substitution that is highly correlated with chloroquine failure. The amodiaquine-resistant SVMNT haplotype was absent. Geographically, pfcrt haplotypes were not clearly clustered. Chloroquine accounted for 19.4% of antimalarial use, and amodiaquine accounted for 15.3% of antimalarial use; there were no associations between drug use and mutant haplotype prevalence. In the DRC, our molecular survey indicates that resistance to chloroquine is substantial but that resistance to amodiaquine is absent. These contrasting findings highlight the need for molecular surveillance of drug resistance to inform malaria control policies.
doi:10.4269/ajtmh.13-0378
PMCID: PMC4047734  PMID: 24732459
3.  An operational comparative study of quinine and artesunate for the treatment of severe malaria in hospitals and health centres in the Democratic Republic of Congo: the MATIAS study 
Malaria Journal  2015;14:226.
Background
The Democratic Republic of the Congo (DRC) has the highest number of severe malaria cases in the world. In early 2012, the National Malaria Control Programme (NMCP) changed the policy for treating severe malaria in children and adults from injectable quinine to injectable artesunate. To inform the scaling up of injectable artesunate nationwide, operational research is needed to identify constraints and challenges in the DRC’s specific setting.
Methods
The implementation of injectable quinine treatment in 350 patients aged 2 months or older in eight health facilities from October 2012 to January 2013 and injectable artesunate in 399 patients in the same facilities from April to June 2013 was compared. Since this was an implementation study, concurrent randomized controls were not possible. Four key components were evaluated during each phase: 1) clinical assessment, 2) time and motion, 3) feasibility and acceptability, and 4) financial cost.
Results
The time to discharge was lower in the artesunate (median = 2, 90 % central range 1–9) compared to the quinine group (3 (1–9) days; p <0.001). Similarly, the interval between admission and the start of intravenous (IV) treatment (2 (0–15) compared to 3 (0–20) hours; p <0.001) and parasite clearance time (23 (11–49) compared to 24 (10–82) hours; p <0.001) were lower in the artesunate group. The overall staff pre-administration time (13 (6–38) compared to 20 (7–50) minutes; p <0.001) and the personnel time spent on patient management (9 (1–24) compared to 12 (3–52) minutes; p <0.001) were lower in the artesunate group. In hospitals and health centres, the mean (standard deviation, SD) total cost per patient treated for severe malaria with injectable artesunate was USD 51.94 (16.20) and 19.51 (9.58); and USD 60.35 (17.73) and 20.36 (6.80) with injectable quinine.
Conclusions
This study demonstrates that injectable artesunate in the DRC is easier to use and it costs less than injectable quinine. These findings provide the basis for practical recommendations for rapid national deployment of injectable artesunate in the DRC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-015-0732-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12936-015-0732-1
PMCID: PMC4455055  PMID: 26024661
Malaria; Severe malaria; Democratic Republic of the Congo; DRC; Kinshasa; Injectable quinine; Injectable artesunate
4.  Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®) 
Malaria Journal  2015;14:157.
Background
Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.
Methods
This multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).
Results
A total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.
Conclusions
A three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.
Trial Registration
Clinicaltrials.gov NCT01619878.
doi:10.1186/s12936-015-0682-7
PMCID: PMC4407414  PMID: 25886021
Artemether-lumefantrine; Dispersible; Efficacy; Infants; Pharmacokinetics; Safety; <5 kg body weight
5.  Theory-driven process evaluation of a complementary feeding trial in four countries 
Health Education Research  2014;29(2):297-305.
We conducted a theory-driven process evaluation of a cluster randomized controlled trial comparing two types of complementary feeding (meat versus fortified cereal) on infant growth in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo. We examined process evaluation indicators for the entire study cohort (N = 1236) using chi-square tests to examine differences between treatment groups. We administered exit interviews to 219 caregivers and 45 intervention staff to explore why caregivers may or may not have performed suggested infant feeding behaviors. Multivariate regression analysis was used to determine the relationship between caregiver scores and infant linear growth velocity. As message recall increased, irrespective of treatment group, linear growth velocity increased when controlling for other factors (P < 0.05), emphasizing the importance of study messages. Our detailed process evaluation revealed few differences between treatment groups, giving us confidence that the main trial’s lack of effect to reverse the progression of stunting cannot be explained by differences between groups or inconsistencies in protocol implementation. These findings add to an emerging body of literature suggesting limited impact on stunting of interventions initiated during the period of complementary feeding in impoverished environments. The early onset and steady progression support the provision of earlier and comprehensive interventions.
doi:10.1093/her/cyt115
PMCID: PMC3959202  PMID: 24399265
6.  A Color-Coded Tape for Uterine Height Measurement: A Tool to Identify Preterm Pregnancies in Low Resource Settings 
PLoS ONE  2015;10(3):e0117134.
Introduction
Neonatal mortality associated with preterm birth can be reduced with antenatal corticosteroids (ACS), yet <10% of eligible pregnant women in low-middle income countries. The inability to accurately determine gestational age (GA) leads to under-identification of high-risk women who could receive ACS or other interventions. To facilitate better identification in low-resource settings, we developed a color-coded tape for uterine height (UH) measurement and estimated its accuracy identifying preterm pregnancies.
Methods
We designed a series of colored-coded tapes with segments corresponding to UH measurements for 20–23.6 weeks, 24.0–35.6 weeks, and >36.0 weeks GA. In phase 1, UH measurements were collected prospectively in the Democratic Republic of Congo, India and Pakistan, using distinct tapes to address variation across regions and ethnicities. In phase 2, we tested accuracy in 250 pregnant women with known GA from early ultrasound enrolled at prenatal clinics in Argentina, India, Pakistan and Zambia. Providers masked to the ultrasound GA measured UH. Receiver operating characteristics (ROC) analysis was conducted.
Results
1,029 pregnant women were enrolled. In all countries the tapes were most effective identifying pregnancies between 20.0–35.6 weeks, compared to the other GAs. The ROC areas under the curves and 95% confidence intervals were: Argentina 0.69 (0.63, 0.74); Zambia 0.72 (0.66, 0.78), India 0.84 (0.80, 0.89), and Pakistan 0.83 (0.78, 0.87). The sensitivity and specificity (and 95% confidence intervals) for identifying pregnancies between 20.0–35.6 weeks, respectively, were: Argentina 87% (82%–92%) and 51% (42%–61%); Zambia 91% (86%–95%) and 50% (40%–60%); India 78% (71%–85%) and 89% (83%–94%); Pakistan 63% (55%–70%) and 94% (89%–99%).
Conclusions
We observed moderate-good accuracy identifying pregnancies ≤35.6 weeks gestation, with potential usefulness at the community level in low-middle income countries to facilitate the preterm identification and interventions to reduce preterm neonatal mortality. Further research is needed to validate these findings on a population basis.
doi:10.1371/journal.pone.0117134
PMCID: PMC4379082  PMID: 25822529
7.  Antiretroviral Treatment Program Retention among HIV-Infected Children in the Democratic Republic of Congo 
PLoS ONE  2014;9(12):e113877.
Background
Retaining patients with HIV infection in care is still a major challenge in sub- Saharan Africa, particularly in the Democratic Republic of Congo (DRC) where the antiretroviral treatment (ART) coverage is low. Monitoring retention is an important tool for evaluating the quality of care.
Methods and Findings
A review of medical records of HIV -infected children was performed in three health facilities in the DRC: the Amo-Congo Health center, the Monkole Clinic in Kinshasa, and the HEAL Africa Clinic in Goma. Medical records of 720 children were included. Kaplan Meier curves were constructed with the probability of retention at 6 months, 1 year, 2 years and 3 years. Retention rates were: 88.2% (95% CI: 85.1%–90.8%) at 6 months; 85% (95% CI: 81.5%–87.6%) at one year; 79.4% (95%CI: 75.5%–82.8%) at two years and 74.7% (95% CI: 70.5%–78.5%) at 3 years. The retention varied across study sites: 88.2%, 66.6% and 92.5% at 6 months; 84%, 59% and 90% at 12 months and 75.7%, 56.3% and 85.8% at 24 months respectively for Amo-Congo/Kasavubu, Monkole facility and HEAL Africa. After multivariable Cox regression four variables remained independently associated with attrition: study site, CD4 cell count <350 cells/µL, children younger than 2 years and children whose caregivers were member of an independent church.
Conclusions
Attrition remains a challenge for pediatric HIV positive patients in ART programs in DRC. In addition, the low coverage of pediatric treatment exacerbates the situation of pediatric HIV/AIDS.
doi:10.1371/journal.pone.0113877
PMCID: PMC4277274  PMID: 25541707
8.  A multi-country study of the “intrapartum stillbirth and early neonatal death indicator” in hospitals in low-resource settings 
Objective
To determine the feasibility of introducing a simple indicator of quality of obstetric and neonatal care and to determine the proportion of potentially avoidable perinatal deaths in hospitals in low-income countries.
Methods
Between September 1, 2011, and February 29, 2012, data were collected from women who had a term pregnancy and were admitted to the labor ward of 1 of 6 hospitals in 4 low-income countries. Fetal heart tones on admission were monitored, and demographic and birth data were recorded.
Results
Data were obtained for 3555 women and 3593 neonates (including twins). The doptone was used on 97% of women admitted. The overall perinatal mortality rate was 34 deaths per 1000 deliveries. Of the perinatal deaths, 40%–45% occurred in the hospital and were potentially preventable by better hospital care.
Conclusion
The results demonstrated that it is possible to accurately determine fetal viability on admission via a doptone. Implementation of doptone use, coupled with a concise data record, might form the basis of a low-cost and sustainable program to monitor and evaluate efforts to improve quality of care and ultimately might to help to reduce the in-hospital component of perinatal mortality in low-income countries.
doi:10.1016/j.ijgo.2013.04.008
PMCID: PMC3893914  PMID: 23796259
Doptone; Fetal heart tones; Hospital-based perinatal mortality; Neonatal mortality; Perinatal mortality; Stillbirth
9.  Independent Lineages of Highly Sulfadoxine-Resistant Plasmodium falciparum Haplotypes, Eastern Africa 
Emerging Infectious Diseases  2014;20(7):1140-1148.
Parasites with increased resistance to sulfadoxine might undermine malaria control measures.
Sulfadoxine-resistant Plasmodium falciparum undermines malaria prevention with sulfadoxine/pyrimethamine. Parasites with a highly resistant mutant dihydropteroate synthase (dhps) haplotype have recently emerged in eastern Africa; they negated preventive benefits of sulfadoxine/pyrimethamine, and might exacerbate placental malaria. We explored emerging lineages of dhps mutant haplotypes in Malawi, the Democratic Republic of the Congo, and Tanzania by using analyses of genetic microsatellites flanking the dhps locus. In Malawi, a triple-mutant dhps SGEG (mutant amino acids are underlined) haplotype emerged in 2010 that was closely related to pre-existing double-mutant SGEA haplotypes, suggesting local origination in Malawi. When we compared mutant strains with parasites from the Democratic Republic of the Congo and Tanzania by multiple independent analyses, we found that SGEG parasites were partitioned into separate lineages by country. These findings support a model of local origination of SGEG dhps haplotypes, rather than geographic diffusion, and have implications for investigations of emergence and effects of parasite drug resistance.
doi:10.3201/eid2007.131720
PMCID: PMC4073871  PMID: 24960247
malaria; Plasmodium falciparum; parasites; sulfadoxine; drug resistance; lineages; genetics; haplotypes; population; eastern Africa
10.  Genetic Evidence of Importation of Drug-Resistant Plasmodium falciparum to Guatemala from the Democratic Republic of the Congo 
Emerging Infectious Diseases  2014;20(6):932-940.
Molecular markers and population genetics were effective tracking tools.
Imported malaria threatens control and elimination efforts in countries that have low rates of transmission. In 2010, an outbreak of Plasmodium falciparum malaria was reported among United Nations peacekeeping soldiers from Guatemala who had recently returned from the Democratic Republic of the Congo (DRC). Epidemiologic evidence suggested that the soldiers were infected in the DRC, but local transmission could not be ruled out in all cases. We used population genetic analyses of neutral microsatellites to determine the outbreak source. Genetic relatedness was compared among parasites found in samples from the soldiers and parasite populations collected in the DRC and Guatemala; parasites identified in the soldiers were more closely related to those from the DRC. A phylogenetic clustering analysis confirms this identification with >99.9% confidence. Thus, results support the hypothesis that the soldiers likely imported malaria from the DRC. This study demonstrates the utility of molecular genotyping in outbreak investigations.
doi:10.3201/eid2006.131204
PMCID: PMC4036788  PMID: 24856348
Malaria; Plasmodium falciparum; protozoan; parasite; Anopheles mosquito; microsatellites; molecular genotyping; drug-resistant; chloroquine phosphate; antimalarial; Guatemala; Democratic Republic of the Congo
11.  Histopathologies, Immunolocalization, and a Glycan Binding Screen Provide Insights into Plasmodium falciparum Interactions with the Human Placenta1 
Biology of Reproduction  2013;88(6):154.
ABSTRACT
During pregnancy, Plasmodium falciparum-infected erythrocytes cytoadhere to the placenta. Infection is likely initiated at two sites where placental trophoblasts contact maternal blood: 1) via syncytiotrophoblast (STB), a multicellular transporting and biosynthetic layer that forms the surface of chorionic villi and lines the intervillous space, and 2) through invasive cytotrophoblasts, which line uterine vessels that divert blood to the placenta. Here, we investigated mechanisms of infected erythrocyte sequestration in relationship to the microanatomy of the maternal-fetal interface. Histological analyses revealed STB denudation in placental malaria, which brought the stromal cores of villi in direct contact with maternal blood. STB denudation was associated with hemozoin deposition (P = 0.01) and leukocyte infiltration (P = 0.001) and appeared to be a feature of chronic placental malaria. Immunolocalization of infected red blood cell receptors (CD36, ICAM1/CD54, and chondroitin sulfate A) in placentas from uncomplicated pregnancies showed that STB did not stain, while the underlying villous stroma was immunopositive. Invasive cytotrophoblasts expressed ICAM1. In malaria, STB denudation exposed CD36 and chondroitin sulfate A in the villous cores to maternal blood, and STB expressed ICAM1. Finally, we investigated infected erythrocyte adherence to novel receptors by screening an array of 377 glycans. Infected erythrocytes bound Lewis antigens that immunolocalized to STB. Our results suggest that P. falciparum interactions with STB-associated Lewis antigens could initiate placental malaria. Subsequent pathologies, which expose CD36, ICAM1, and chondroitin sulfate A, might propagate the infection.
Malaria-associated pathological changes expose previously masked placental antigens that may facilitate Plasmodium falciparum cytoadhesion to the placenta; novel placental glycans are also positioned to support cytoadhesion.
doi:10.1095/biolreprod.112.106195
PMCID: PMC4070867  PMID: 23575149
placenta; pregnancy; stroma; syncytiotrophoblast; trophoblast
12.  WHO multicentre study for the development of growth standards from fetal life to childhood: the fetal component 
Background
In 2006 WHO presented the infant and child growth charts suggested for universal application. However, major determinants for perinatal outcomes and postnatal growth are laid down during antenatal development. Accordingly, monitoring fetal growth in utero by ultrasonography is important both for clinical and scientific reasons. The currently used fetal growth references are derived mainly from North American and European population and may be inappropriate for international use, given possible variances in the growth rates of fetuses from different ethnic population groups. WHO has, therefore, made it a high priority to establish charts of optimal fetal growth that can be recommended worldwide.
Methods
This is a multi-national study for the development of fetal growth standards for international application by assessing fetal growth in populations of different ethnic and geographic backgrounds. The study will select pregnant women of high-middle socioeconomic status with no obvious environmental constraints on growth (adequate nutritional status, non-smoking), and normal pregnancy history with no complications likely to affect fetal growth. The study will be conducted in centres from ten developing and industrialized countries: Argentina, Brazil, Democratic Republic of Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand. At each centre, 140 pregnant women will be recruited between 8 + 0 and 12 + 6 weeks of gestation. Subsequently, visits for fetal biometry will be scheduled at 14, 18, 24, 28, 32, 36, and 40 weeks (+/− 1 week) to be performed by trained ultrasonographers.
The main outcome of the proposed study will be the development of fetal growth standards (either global or population specific) for international applications.
Discussion
The data from this study will be incorporated into obstetric practice and national health policies at country level in coordination with the activities presently conducted by WHO to implement the use of the Child Growth Standards.
doi:10.1186/1471-2393-14-157
PMCID: PMC4014086  PMID: 24886101
Fetal growth; Child development; Ultrasound; Growth standards
13.  Stillbirth and early neonatal mortality in rural Central Africa 
Objective
To develop a prospective perinatal registry that characterizes all deliveries, differentiates between stillbirths and early neonatal deaths (ENDs), and determines the ratio of fresh to macerated stillbirths in the northwest Democratic Republic of Congo.
Method
Birth outcomes were obtained from 4 rural health districts.
Results
A total of 8230 women consented, END rate was 32 deaths per 1000 live births, and stillbirth rate was 33 deaths per 1000 deliveries. The majority (75%) of ENDs and stillbirths occurred in neonates weighing 1500 g or more. Odds of stillbirth and END increased in mothers who were single or who did not receive prenatal care, and among premature, low birth weight, or male infants. The ratio of fresh to macerated stillbirths was 4:1.
Conclusion
Neonates weighing 1500 g or more at birth represent a group with a high likelihood of survival in remote areas, making them potentially amenable to targeted intervention packages. The ratio of fresh to macerated stillbirths was approximately 10-fold higher than expected, suggesting a more prominent role for improved intrapartum obstetric interventions.
doi:10.1016/j.ijgo.2008.12.012
PMCID: PMC3972762  PMID: 19201402
Africa; Early neonatal death; Fresh and macerated stillbirth; Low-income country
14.  Preconception maternal nutrition: a multi-site randomized controlled trial 
Background
Research directed to optimizing maternal nutrition commencing prior to conception remains very limited, despite suggestive evidence of its importance in addition to ensuring an optimal nutrition environment in the periconceptional period and throughout the first trimester of pregnancy.
Methods/Study design
This is an individually randomized controlled trial of the impact on birth length (primary outcome) of the time at which a maternal nutrition intervention is commenced: Arm 1: ≥ 3 mo preconception vs. Arm 2: 12-14 wk gestation vs. Arm 3: none.
192 (derived from 480) randomized mothers and living offspring in each arm in each of four research sites (Guatemala, India, Pakistan, Democratic Republic of the Congo). The intervention is a daily 20 g lipid-based (118 kcal) multi-micronutient (MMN) supplement. Women randomized to receive this intervention with body mass index (BMI) <20 or whose gestational weight gain is low will receive an additional 300 kcal/d as a balanced energy-protein supplement. Researchers will visit homes biweekly to deliver intervention and monitor compliance, pregnancy status and morbidity; ensure prenatal and delivery care; and promote breast feeding. The primary outcome is birth length. Secondary outcomes include: fetal length at 12 and 34 wk; incidence of low birth weight (LBW); neonatal/infant anthropometry 0-6 mo of age; infectious disease morbidity; maternal, fetal, newborn, and infant epigenetics; maternal and infant nutritional status; maternal and infant microbiome; gut inflammatory biomarkers and bioactive and nutritive compounds in breast milk. The primary analysis will compare birth Length-for-Age Z-score (LAZ) among trial arms (independently for each site, estimated effect size: 0.35). Additional statistical analyses will examine the secondary outcomes and a pooled analysis of data from all sites.
Discussion
Positive results of this trial will support a paradigm shift in attention to nutrition of all females of child-bearing age.
Trial registration
ClinicalTrials.gov NCT01883193.
doi:10.1186/1471-2393-14-111
PMCID: PMC4000057  PMID: 24650219
Preconception; Maternal; Nutrition; Birth length; Epigenetics; Microbiome
15.  First look: a cluster-randomized trial of ultrasound to improve pregnancy outcomes in low income country settings 
Background
In high-resource settings, obstetric ultrasound is a standard component of prenatal care used to identify pregnancy complications and to establish an accurate gestational age in order to improve obstetric care. Whether or not ultrasound use will improve care and ultimately pregnancy outcomes in low-resource settings is unknown.
Methods/Design
This multi-country cluster randomized trial will assess the impact of antenatal ultrasound screening performed by health care staff on a composite outcome consisting of maternal mortality and maternal near-miss, stillbirth and neonatal mortality in low-resource community settings. The trial will utilize an existing research infrastructure, the Global Network for Women’s and Children’s Health Research with sites in Pakistan, Kenya, Zambia, Democratic Republic of Congo and Guatemala. A maternal and newborn health registry in defined geographic areas which documents all pregnancies and their outcomes to 6 weeks post-delivery will provide population-based rates of maternal mortality and morbidity, stillbirth, neonatal mortality and morbidity, and health care utilization for study clusters. A total of 58 study clusters each with a health center and about 500 births per year will be randomized (29 intervention and 29 control). The intervention includes training of health workers (e.g., nurses, midwives, clinical officers) to perform ultrasound examinations during antenatal care, generally at 18–22 and at 32–36 weeks for each subject. Women who are identified as having a complication of pregnancy will be referred to a hospital for appropriate care. Finally, the intervention includes community sensitization activities to inform women and their families of the availability of ultrasound at the antenatal care clinic and training in emergency obstetric and neonatal care at referral facilities.
Discussion
In summary, our trial will evaluate whether introduction of ultrasound during antenatal care improves pregnancy outcomes in rural, low-resource settings. The intervention includes training for ultrasound-naïve providers in basic obstetric ultrasonography and then enabling these trainees to use ultrasound to screen for pregnancy complications in primary antenatal care clinics and to refer appropriately.
Trial registration
Clinicaltrials.gov (NCT # 01990625)
doi:10.1186/1471-2393-14-73
PMCID: PMC3996090  PMID: 24533878
Maternal mortality; Maternal near miss; Perinatal mortality; Obstetric ultrasound; Low-income countries
16.  High Mortality Rates for Very Low Birth Weight Infants in Developing Countries Despite Training 
Pediatrics  2010;126(5):e1072-e1080.
OBJECTIVE
The goal was to determine the effect of training in newborn care and resuscitation on 7-day (early) neonatal mortality rates for very low birth weight (VLBW) infants. The study was designed to test the hypothesis that these training programs would reduce neonatal mortality rates for VLBW infants.
METHODS
Local instructors trained birth attendants from 96 rural communities in 6 developing countries in protocol and data collection, the World Health Organization Essential Newborn Care (ENC) course, and a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP), by using a train-the-trainer model. To test the impact of ENC training, data on infants of 500 to 1499 g were collected by using a before/after, active baseline, controlled study design. A cluster-randomized, controlled trial design was used to test the impact of the NRP.
RESULTS
A total of 1096 VLBW (500–1499 g) infants were enrolled, and 98.5% of live-born infants were monitored to 7 days. All-cause, 7-day neonatal mortality, stillbirth, and perinatal mortality rates were not affected by ENC or NRP training.
CONCLUSIONS
Neither ENC nor NRP training of birth attendants decreased 7-day neonatal, stillbirth, or perinatal mortality rates for VLBW infants born at home or at first-level facilities. Encouragement of delivery in a facility where a higher level of care is available may be preferable when delivery of a VLBW infant is expected.
doi:10.1542/peds.2010-1183
PMCID: PMC3918943  PMID: 20937655
neonatal mortality; perinatal mortality; stillbirth; developing countries; health care systems; very low birth weight; prematurity
17.  Meat consumption is associated with less stunting among toddlers in four diverse low-income settings 
Food and nutrition bulletin  2011;32(3):185-191.
Background
Early growth faltering is common but is difficult to reverse after the first 2 years of life.
Objective
To describe feeding practices and growth in infants and young children in diverse low-income settings prior to undertaking a complementary feeding trial.
Methods
This cross-sectional study was conducted through the Global Network for Women’s and Children’s Health Research in Guatemala, Democratic Republic of Congo, Zambia, and Pakistan. Feeding questionnaires were administered to convenience samples of mothers of 5- to 9-month old infants and 12- to 24-month-old toddlers. After standardized training, anthropometric measurements were obtained from the toddlers. Following the 2006 World Health Organization Growth Standards, stunting was defined as length-for-age < −2SD, and wasting as weight-for-length < −2SD. Logistic regression was applied to evaluate relationships between stunting and wasting and consumption of meat (including chicken and liver and not including fish).
Results
Data were obtained from 1,500 infants with a mean (± SD) age of 6.9 ± 1.4 months and 1,658 toddlers with a mean age of 17.2 ± 3.5 months. The majority of the subjects in both age groups were breastfed. Less than 25% of the infants received meat regularly, whereas 62% of toddlers consumed these foods regularly, although the rates varied widely among sites. Stunting rate ranged from 44% to 66% among sites; wasting prevalence was less than 10% at all sites. After controlling for covariates, consumption of meat was associated with a reduced likelihood of stunting (OR = 0.64; 95% CI, 0.46 to 0.90).
Conclusions
The strikingly high stunting rates in these toddlers and the protective effect of meat consumption against stunting emphasize the need for interventions to improve complementary feeding practices, beginning in infancy.
PMCID: PMC3918945  PMID: 22073791
Complementary feeding; infant growth; infant nutrition; stunting
18.  Tobacco Use and Secondhand Smoke Exposure During Pregnancy in Two African Countries: Zambia and the Democratic Republic of the Congo 
Acta obstetricia et gynecologica Scandinavica  2010;89(4):10.3109/00016341003605693.
Objective
To study pregnant women’s knowledge, attitudes and behaviors towards tobacco use and secondhand smoke (SHS) exposure, and exposure to advertising for and against tobacco products in Zambia and the Democratic Republic of the Congo (DRC).
Design
Prospective cross-sectional survey between November 2004 and September 2005.
Setting
Antenatal care clinics in Lusaka, Zambia and Kinshasa, DRC.
Population
Pregnant women in Zambia (909) and the DRC (847).
Methods
Research staff administered a structured questionnaire to pregnant women attending antenatal care clinics.
Main Outcome Measures
Pregnant women’s use of tobacco, exposure to SHS, knowledge of the harms of tobacco, and exposure to advertising for and against tobacco products.
Results
Only about 10% of pregnant women reported having ever tried cigarettes (6.6% Zambia; 14.1% DRC). However, in the DRC, 41.8% of pregnant women had ever tried other forms of tobacco, primarily snuff. About 10% of pregnant women and young children were frequently or always exposed to SHS. Pregnant women’s knowledge of the hazards of smoking and SHS exposure was extremely limited. About 13% of pregnant women had seen or heard advertising for tobacco products in the last 30 days.
Conclusions
Tobacco use and SHS exposure pose serious threats to the health of women, infants, and children. In many African countries, maternal and infant health outcomes are often poor and will likely worsen if maternal tobacco use increases. Our findings suggest that a “window of opportunity” exists to prevent increased tobacco use and SHS exposure of pregnant women in Zambia and the DRC.
doi:10.3109/00016341003605693
PMCID: PMC3875167  PMID: 20230310
19.  EVALUATION OF MEAT AS A FIRST COMPLEMENTARY FOOD FOR BREASTFED INFANTS: IMPACT ON IRON INTAKE & GROWTH 
Nutrition reviews  2011;69(0 1):10.1111/j.1753-4887.2011.00434.x.
The rationale is considered for promoting the availability of local, affordable, non-fortified food sources of bioavailable iron in developing countries. Intakes of iron from the regular consumption of meat from the age of six months are evaluated with respect to physiological requirements. The paper includes a description of two major randomized controlled trials of meat as a first and regular complementary food that are currently in progress. These trials involve poor communities in Guatemala, Pakistan, Zambia, Democratic Republic of the Congo and China.
doi:10.1111/j.1753-4887.2011.00434.x
PMCID: PMC3875190  PMID: 22043884
iron; meat; complementary feeding
20.  Newborn Care Training and Perinatal Mortality in Communities in Developing Countries 
The New England journal of medicine  2010;362(7):614-623.
Background
Ninety-eight percent of the 3.7 million neonatal deaths and 3.3 million stillbirths per year occur in developing countries, and evaluation of community-based interventions is needed.
Methods
Using a train-the-trainer model, local instructors trained birth attendants from rural communities in six countries (Argentina, Democratic Republic of Congo, Guatemala, India, Pakistan, and Zambia) in the World Health Organization Essential Newborn Care course (routine neonatal care, resuscitation, thermoregulation, breastfeeding, kangaroo care, care of the small baby, and common illnesses), and in a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (in depth basic resuscitation), except in Argentina.
The Essential Newborn Care intervention was assessed with a before and after design (N=57, 643). The Neonatal Resuscitation Program intervention was assessed as a cluster randomized controlled trial (N=62,366). The primary outcome was 7-day neonatal mortality.
Results
The 7-day follow-up rate was 99.2%. Following Essential Newborn Care training, there was no significant reduction from baseline in all-cause 7-day neonatal (RR 0.99; CI 0.81, 1.22) or perinatal mortality; there was a significant reduction in the stillbirth rate (RR 0.69; CI 0.54, 0.88; p<0.01). Seven-day neonatal mortality, stillbirth, and perinatal mortality were not reduced in clusters randomized to Neonatal Resuscitation Program training as compared with control clusters.
Conclusions
Seven-day neonatal mortality did not decrease following the introduction of Essential Newborn Care training of community-based birth attendants, although the rate of stillbirths was reduced following this intervention. Subsequent training in the Neonatal Resuscitation Program did not significantly reduce the mortality rates. (clinicaltrials.gov number, NCT00136708).
doi:10.1056/NEJMsa0806033
PMCID: PMC3565382  PMID: 20164485
neonatal mortality; perinatal mortality; developing countries; health systems; effectiveness
21.  Plasmodium falciparum sulfadoxine resistance is geographically and genetically clustered within the DR Congo 
Scientific Reports  2013;3:1165.
Understanding the spatial clustering of Plasmodium falciparum populations can assist efforts to contain drug-resistant parasites and maintain the efficacy of future drugs. We sequenced single nucleotide polymorphisms (SNPs) in the dihydropteroate synthase gene (dhps) associated with sulfadoxine resistance and 5 microsatellite loci flanking dhps in order to investigate the genetic backgrounds, genetic relatedness, and geographic clustering of falciparum parasites in the Democratic Republic of the Congo (DRC). Resistant haplotypes were clustered into subpopulations: one in the northeast DRC, and the other in the balance of the DRC. Network and clonal lineage analyses of the flanking microsatellites indicate that geographically-distinct mutant dhps haplotypes derive from separate lineages. The DRC is therefore a watershed for haplotypes associated with sulfadoxine resistance. Given the importance of central Africa as a corridor for the spread of antimalarial resistance, the identification of the mechanisms of this transit can inform future policies to contain drug-resistant parasite strains.
doi:10.1038/srep01165
PMCID: PMC3558697  PMID: 23372922
22.  Quantification of the Burden and Consequences of Pregnancy-Associated Malaria in the Democratic Republic of the Congo 
The Journal of Infectious Diseases  2011;204(11):1762-1771.
Background. Pregnancy-associated malaria (PAM) produces poor birth outcomes, but its prevalence is commonly estimated in convenience samples.
Methods. We assessed the prevalence of malaria using real-time polymerase chain reaction (PCR) and estimated the consequences of infection on birth outcomes, using specimens from a nationally representative sample of 4570 women of childbearing age (WOCBA) responding to the 2007 Demographic and Health Survey in Democratic Republic of the Congo (DRC).
Results. Overall, 31.2% (95% confidence interval [CI], 29.2–33.1) of WOCBA were parasitemic, which was significantly more common in pregnant (37.2% [31.0–43.5]) than nonpregnant women (30.4% [CI, 28.4–32.5], prevalence ratio [PR] 1.22 [1.02–1.47]). Plasmodium falciparum was highest among pregnant women (36.6% vs 28.8%, PR 1.27 [1.05–1.53]). By contrast, P malariae was less common in pregnant (0.6%) compared with nonpregnant women (2.7%, PR 0.23 [0.09–0.56]). Extrapolation of the prevalence estimate to the population at risk of malaria in DRC suggests 1.015 million births are affected by P falciparum infection annually, and that adherence to preventive measures could prevent up to 549 000 episodes of pregnancy-associated malaria and 47 000 low-birth-weight births.
Conclusions. Pregnancy-associated malaria and its consequences are highly prevalent in the DRC. Increasing the uptake of malaria preventive measures represents a significant opportunity to improve birth outcomes and neonatal health.
doi:10.1093/infdis/jir625
PMCID: PMC3635529  PMID: 21990422
23.  Determinants of male involvement in maternal and child health services in sub-Saharan Africa: a review 
Reproductive Health  2012;9:32.
Introduction
Male participation is a crucial component in the optimization of Maternal and Child Health (MCH) services. This is especially so where prevention strategies to decrease Mother-to-Child Transmission (MTCT) of Human Immunodeficiency Virus (HIV) are sought. This study aims to identify determinants of male partners’ involvement in MCH activities, focusing specifically on HIV prevention of maternal to child transmission (PMTCT) in sub-Saharan Africa.
Methods
Literature review was conducted using the following data bases: Pubmed/MEDLINE; CINAHL; EMBASE; COCHRANE; Psych INFORMATION and the websites of the International AIDS Society (IAS), the International AIDS Conference and the International Conference on AIDS in Africa (ICASA) 2011.
Results
We included 34 studies in this review, which reported on male participation in MCH and PMTCT services. The majority of studies defined male participation as male involvement solely during antenatal HIV testing. Other studies defined male involvement as any male participation in HIV couple counseling. We identified three main determinants for male participation in PMTCT services: 1) Socio-demographic factors such as level of education, income status; 2) health services related factors such as opening hours of services, behavior of health providers and the lack of space to accommodate male partners; and 3) Sociologic factors such as beliefs, attitudes and communication between men and women.
Conclusion
There are many challenges to increase male involvement/participation in PMTCT services. So far, few interventions addressing these challenges have been evaluated and reported. It is clear however that improvement of antenatal care services by making them more male friendly, and health education campaigns to change beliefs and attitudes of men are absolutely needed.
doi:10.1186/1742-4755-9-32
PMCID: PMC3573948  PMID: 23171709
Male involvement; HIV/AIDS; MCH services
24.  Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial 
Malaria Journal  2012;11:364.
Background
Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.
Methods
This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days.
Results
Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy’s law definition).
Conclusions
The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes.
Trial registration
ClinicalTrials.gov: identifier NCT00541385
doi:10.1186/1475-2875-11-364
PMCID: PMC3566922  PMID: 23113947
Pyronaridine-artesunate; Artemether-lumefantrine; Malaria; Plasmodium falciparum; Pediatric

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