Neonatal mortality risk of large-for-gestational-age and macrosomic live births in 15 countries, including 115.6 million nationwide linked records, 2000-2020.

OBJECTIVE: We aimed to compare the prevalence and neonatal mortality associated with large for gestational age (LGA) and macrosomia among 115.6 million live births in 15 countries, between 2000 and 2020. DESIGN: Population-based, multi-country study. SETTING: National healthcare systems. POPULATION: Liveborn infants. METHODS: We used individual-level data identified for the Vulnerable Newborn Measurement Collaboration. We calculated the prevalence and relative risk (RR) of neonatal mortality among live births born at term + LGA (>90th centile, and also >95th and >97th centiles when the data were available) versus term + appropriate for gestational age (AGA, 10th-90th centiles) and macrosomic (≥4000, ≥4500 and ≥5000 g, regardless of gestational age) versus 2500-3999 g. INTERGROWTH 21st served as the reference population. MAIN OUTCOME MEASURES: Prevalence and neonatal mortality risks. RESULTS: Large for gestational age was common (median prevalence 18.2%; interquartile range, IQR, 13.5%-22.0%), and overall was associated with a lower neonatal mortality risk compared with AGA (RR 0.83, 95% CI 0.77-0.89). Around one in ten babies were ≥4000 g (median prevalence 9.6% (IQR 6.4%-13.3%), with 1.2% (IQR 0.7%-2.0%) ≥4500 g and with 0.2% (IQR 0.1%-0.2%) ≥5000 g). Overall, macrosomia of ≥4000 g was not associated with increased neonatal mortality risk (RR 0.80, 95% CI 0.69-0.94); however, a higher risk was observed for birthweights of ≥4500 g (RR 1.52, 95% CI 1.10-2.11) and ≥5000 g (RR 4.54, 95% CI 2.58-7.99), compared with birthweights of 2500-3999 g, with the highest risk observed in the first 7 days of life. CONCLUSIONS: In this population, birthweight of ≥4500 g was the most useful marker for early mortality risk in big babies and could be used to guide clinical management decisions.

Acoustic Cry Characteristics of Infants as a Marker of Neurological Dysfunction: A Systematic Review and Meta-Analysis.

BACKGROUND: Atypical cries have been identified in infants with neurological dysfunction. The aim of this study was to conduct a systematic review and meta-analysis to appraise existing evidence for associations between acoustic cry characteristics and neurological dysfunction in infants aged 18 months or less. METHODS: PubMed/MEDLINE, PsycINFO, CINAHL, and Embase were searched for original, peer-reviewed studies published in English reporting cry variables in infants aged 18 months or less with or at risk of neurological dysfunction. Studies without a nonneurologically impaired control sample were excluded. Pooled effect sizes were estimated using standardized mean difference (SMD) and odds ratio (OR). I2 indicated study heterogeneity, and the risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: From March 2018 to February 2019, 28,294 studies were retrieved. Eight were meta-analyzed. Infants with or at risk of neurological dysfunction exhibited higher mean (SMD = 0.11 [95% confidence interval, 0.00 to 0.23]) and minimum (SMD = 0.93 [0.64 to 1.23]) fundamental frequency; higher odds of hyperphonation (OR = 13.17 [1.05 to 165.87]), biphonation (OR = 10.62 [1.53 to 73.59]), rise-fall-rise melodies (OR = 4.66 [1.16 to 18.66]), and flat melodies (OR = 4.47 [1.27 to 15.68]); and lower odds of fall-rise-fall melodies (OR = 0.21 [0.05 to 0.83]). CONCLUSIONS: Infants with underlying neuropathology have unique cries characterized by higher fundamental frequency, dysphonation, and atypical melodies, although study heterogeneity and imprecision of effect size estimates limited our interpretation. Assessment of acoustic cry characteristics offers the potential for noninvasive, rapid, point-of-care screening for neurologically high-risk infants.

Associations between malaria in pregnancy and neonatal neurological outcomes.

OBJECTIVE: To compare neurological functioning of neonates born to mothers with and without malaria in pregnancy. METHODS: Pregnant women presenting at Korle Bu Teaching Hospital, Ghana were recruited into this prospective observational study. Malaria exposure was determined by clinically documented antenatal malaria infection; parasitemia in maternal, placental, or umbilical cord blood; or placental histology. Neurological functioning was assessed using the Hammersmith Neonatal Neurological Examination within 48 hours of birth. Performance was classified as "optimal" or "suboptimal" by subdomain and overall. RESULTS: Between November 21, 2018 and February 10, 2019, a total of 211 term-born neonates, of whom 27 (13%) were exposed to malaria in pregnancy, were included. In the reflexes subdomain, exposed neonates tended to score lower (adjusted mean difference -0.34, 95% confidence interval -0.70 to 0.03), with an increased risk (adjusted risk ratio 1.63, 95% confidence interval 1.09 to 2.44) of suboptimal performance compared with unexposed neonates. There were no significant between-group differences in scores or optimality classification for the remaining subdomains and overall. CONCLUSIONS: Malaria-exposed neonates had similar neurological functioning relative to unexposed neonates, with differences confined to the reflexes subdomain, suggesting potential underlying neurological immaturity or injury. Further studies are needed to confirm these findings and determine the significance of malaria in pregnancy on long-term neurological outcomes.

Gestational Age-Specific Distribution of the Hammersmith Neonatal Neurological Examination Scores Among Low-Risk Neonates in Ghana.

OBJECTIVE: To describe gestational age-specific distribution of scores for the Hammersmith Neonatal Neurological Examination (HNNE) up to 48 h after birth in a low-risk, term-born, single-center sample in Ghana. STUDY DESIGN: This is a nested substudy of a larger prospective study (IMPRINT: Impact of Malaria in Pregnancy on Infant Neurodevelopment) comprising 140 low-risk, term-born neonates at Korle Bu Teaching Hospital in Accra, Ghana, between November 2018 and February 2019. The sample was stratified into three gestational age groups: early-term (37 + 0-38 + 6, weeks + days; n = 61), full-term (39 + 0-40 + 6, weeks + days; n = 52), and late/post-term (41 + 0-42 + 6, weeks + days; n = 27). Neonates were administered the 34-item HNNE by trained physicians. As per the original British scoring system, raw scores for the Ghanaian sample were plotted and scores > 10th centile were assigned a score of 1, 5th-10th centile 0.5, and < 5th centile 0. RESULTS: The range of raw scores for 16/34 HNNE items varied with gestational age. Specifically, 100% (7/7), 50% (5/10), 33% (1/3), 33% (1/3), 20% (1/5), and 14% (1/7) of items within the orientation and behavior, tone, abnormal signs/patterns, movements, tone patterns, and reflexes subdomain, respectively showed a different distribution of scores above the 10th centile across the three gestational age groups. CONCLUSION: Differences in gestational age-specific results within our sample in comparison to the original British sample could be, albeit unlikely, due to misclassification of gestational age, unmeasured maternal or fetal morbidity, or perhaps more likely, variation in testing or test conditions, or some combination of these. Genetic variation in neurological development is also a possibility. Further research is warranted to determine the reasons for differences. Our findings highlight the need to determine the accuracy and reliability of standardized neurologic assessments in predicting neurodevelopmental risk for infants in low- and middle-income countries.

Neonatal neurological examination in a resource-limited setting: What defines normal?

OBJECTIVE: To describe the results of the Hammersmith Neonatal Neurological Examination (HNNE) in a low-risk, term-born, contemporary sample in Ghana. Of particular interest was to compare these findings with the original British study that validated the HNNE, and published data from other low- and middle-income countries. STUDY DESIGN: In a nested substudy of a larger prospective study (IMPRINT: Impact of Malaria in Pregnancy on Infant Neurodevelopment), 140 low-risk, term-born neonates (39.3 ± 1.4 weeks gestation) at Korle Bu Teaching Hospital in Accra, Ghana were administered the 34-item HNNE from birth to 48 h of age by trained physicians. Neonates' performance was compared with previously published normative data from the United Kingdom (1998), and published data from Thailand, Myanmar, Vietnam, and Uganda. RESULTS: Ghanaian neonates demonstrated lower scores on 29/34 HNNE items relative to normative data from the United Kingdom (P < .05), with only 5% of Ghanaian neonates in our sample classified as neurologically optimal. There were significant differences in the proportion of neonates scoring optimally per HNNE item between our Ghanaian sample, compared with published data from other settings (Thai [13/16 items], Burmese [14/16 items], Vietnamese [7/9 items], and Ugandan [22/34 items] neonates). Raw scores were markedly different between Ghanaian and British neonates, with Ghanaian neonates demonstrating lower median and wider range of scores. These differences were less prominent between Ghanaian and Ugandan neonates. CONCLUSION: Our findings raise questions as to whether or not the thresholds for optimality for the HNNE based on data from the United Kingdom are applicable to Ghanaian newborns. Our study could not fully resolve whether the differences in scores were due to genetic differences in developmental pathways, the implementation of the assessment, or the characteristics of our sample. Low proportions of neonates scoring optimally from other low- and middle-income countries suggest the need for further research to determine the clinical utility of the HNNE in resource-limited settings, including the predictive value for neurodevelopment later in infancy.

Establishing a conceptual framework of the impact of placental malaria on infant neurodevelopment.

A novel conceptual framework to describe the relationship between placental malaria and adverse infant neurodevelopmental outcomes is proposed. This conceptual framework includes three distinct stages: (1) maternal and environmental risk factors for the development of placental malaria; (2) placental pathology and inflammation associated with placental malaria infection; and (3) postnatal impacts of placental malaria. The direct, indirect, and bidirectional effects of these risk factors on infant neurodevelopment across the three stages were critically examined. These factors ultimately culminate in an infant phenotype that not only leads to adverse birth outcomes, but also to increased risks of neurological, cognitive, and behavioural deficits that may impact the quality of life in this high-risk population. Multiple risk factors were identified in this conceptual framework; nonetheless, based on current evidence, a key knowledge gap is the uncertainty regarding which are the most important and how exactly they interact.

High mobility, low access thwarts interventions among seasonal workers in the Greater Mekong Sub-region: lessons from the malaria containment project.

BACKGROUND: During the process of malaria elimination in the Greater Mekong Sub-region, mobile and migrant populations (MMPs) have been identified as the most at-risk demographic. An important sub-group of MMPs are seasonal workers, and this paper presents an evaluation of the reach and effectiveness of interventions tailored towards this group and was carried out as part of the Containment Project from 2009-11. METHODS: A mixed-methods study was conducted in Pailin Province in Western Cambodia. Three-hundred-and-four seasonal workers were surveyed using a structured questionnaire. Qualitative data were gathered through a total of eight focus group discussions and 14 in-depth interviews. Data triangulation of the qualitative and quantitative data was used during analysis. RESULTS: High mobility and low access of the target population to the interventions, as well as lack of social and anthropological research that led to implementation oversights, resulted in under-exposure of seasonal workers to interventions. Consequently, their reach and impact were severely limited. Some services, particularly Mobile Malaria Workers, had the ability to significantly impact key factors, such as risky behaviours among those they did reach. Others, like Listening and Viewing Clubs and mass media campaigns, showed little impact. CONCLUSIONS: There is potential in two of the interventions assessed, but high mobility and inadequate exposure of seasonal workers to these interventions must be considered in the development and planning of future interventions to avoid investing in low-impact activities and ensure that all interventions perform according to their maximum potential. This will be critical in order for Cambodia to achieve its aim of malaria elimination. The lessons learned from this study can be extrapolated to other areas of health care in Cambodia and other countries in order to reduce the gap between healthcare provided to MMPs, especially seasonal workers, and to the general population.

Establishing research priorities for malaria elimination in the context of the emergency response to artemisinin resistance framework-the Cambodian approach.

BACKGROUND: Countries of the greater Mekong subregion have made a transition from malaria control to an aim for falciparum and vivax malaria elimination. The elimination of falciparum malaria will have to be achieved against a background of increasing artemisinin and multi-drug resistance. This ambitious goal requires an operational research (OR) agenda that addresses the dynamic challenges encountered on the path to elimination, which will need to be flexible and developed in close relation with the cambodian national programme for parasitology, entomology and malaria control (CNM). In Cambodia, a number of meetings with stakeholders were convened by the CNM and emergency response to artemisinin resistance (ERAR) hub, producing an initial list of priority OR topics. The process and outcome of these meetings are described, which could serve as a template for other countries in the region. METHODS: A landscaping exercise was conducted to gather all past, on-going and planned malaria focussed OR activities conducted by the cambodian research consortium in Cambodia and categorized according to research theme. The six themes included (1) malaria epidemiology, surveillance and response, (2) malaria case management, (3) malaria vector control, (4) malaria behavioural issues, (5) malaria clinical studies, and (6) other vector-borne diseases (dengue, neglected tropical diseases, soil-transmitted helminths). The different themes were discussed in small focus groups, which made an initial prioritization list which was then presented to a plenary group for further discussion. This produced a list of research questions ranked according to priority. RESULTS: OR priorities produced by the thematic groups were discussed in the plenary meeting and given a priority score by group voting. A list of 17 OR questions were developed, finalized and listed, which included questions on surveillance, active case detection and treatment efficacy. CONCLUSION: This paper describes ERAR's work on supporting Cambodia's transition to malaria elimination by identifying national operational research priorities. ERAR has initiated and currently plays a critical role in the development of country specific research agendas for malaria elimination. The first example of this has been the described exercise in Cambodia, which could serve a template for setting OR priorities in the wider region.

The Cambodia Research Consortium: expediting research for malaria elimination with the emergency response to artemisinin resistance framework.

This commentary offers insight into how to best address barriers that may hinder the translation of malaria research findings into policy. It also proposes viable methods of implementing these policies in Cambodia. Currently, a wide range of malaria research is being conducted by in-country stakeholders, including Cambodia's National Programme for Parasitology, Entomology and Malaria Control's (CNM), non-governmental organizations, and academic institutions. Coordinating research amongst these partners, as well as within the Ministry of Health, is a challenge. Results are rarely disseminated widely and seldom inform programme and policy decisions. CNM and its research partners have severely limited access to each other's databases. This lack of accessibility, timeliness, engagement and cooperation between CNM and its partners greatly impacts overall research efficiency in this field, and is stifling innovation both within and beyond CNM. Cambodia has set a goal to eradicate all forms of malaria by 2030. As countries approach the elimination phase, there is a greater need for sharing research-generated evidence amongst partners, in order to ensure that appropriate and impactful activities are conducted. The Cambodian Research Consortium was established to serve as a framework for partners, stakeholders and researchers to share research projects, information and results, and to promote the goals of CNM. The sharing of malaria research results will help to inform prevention, control and elimination activities in the country. It will also determine and address the country's operational research needs, and could potentially become a framework model to be used in other countries aiming to transition from malaria control to elimination.

Quality of antimalarials at the epicenter of antimalarial drug resistance: results from an overt and mystery client survey in Cambodia.

Widespread availability of monotherapies and falsified antimalarials is thought to have contributed to the historical development of multidrug-resistant malaria in Cambodia. This study aimed to document the quality of artemisinin-containing antimalarials (ACAs) and to compare two methods of collecting antimalarials from drug outlets: through open surveyors and mystery clients (MCs). Few oral artemisinin-based monotherapies and no suspected falsified medicines were found. All 291 samples contained the stated active pharmaceutical ingredient (API) of which 69% were considered good quality by chemical analysis. Overall, medicine quality did not differ by collection method, although open surveyors were less likely to obtain oral artemisinin-based monotherapies than MCs. The results are an encouraging indication of the positive impact of the country's efforts to tackle falsified antimalarials and artemisinin-based monotherapies. However, poor-quality medicines remain an ongoing challenge that demands sustained political will and investment of human and financial resources.