Outcome reporting in neonates experiencing withdrawal following opioid exposure in pregnancy: a systematic review

BackgroundNeonatal withdrawal secondary to in utero opioid exposure is a growing global concern stressing the psychosocial well-being of affected families and scarce hospital resources. In the ongoing search for the most effective treatment, randomized controlled trials are indispensable. Consistent outcome selection and measurement across randomized controlled trials enables synthesis of results, fostering the translation of research into practice. Currently, there is no core outcome set to standardize outcome selection, definition and reporting. This study identifies the outcomes currently reported in the literature for neonates experiencing withdrawal following opioid exposure during pregnancy.MethodsA comprehensive literature search of MEDLINE, EMBASE and Cochrane Central was conducted to identify all primary research studies (randomized controlled trials, clinical trials, case-controlled studies, uncontrolled trials, observational cohort studies, clinical practice guidelines and case reports) reporting outcomes for interventions used to manage neonatal abstinence syndrome between July 2007 and July 2017. All “primary” and “secondary” neonatal outcomes were extracted by two independent reviewers and were assigned to one of OMERACT’s core areas of “pathophysiological manifestation”, “life impact”, “resource use”, “adverse events”, or “death”.ResultsForty-seven primary research articles reporting 107 “primary” and 127 “secondary” outcomes were included. The most frequently reported outcomes were “duration of pharmacotherapy” (68% of studies, N = 32), “duration of hospital stay” (66% of studies, N = 31) and “withdrawal symptoms” (51% of studies, N = 24). The discrepancy between the number of times an outcome was reported and the number of articles was secondary to the use of composite outcomes. Frequently reported outcomes had heterogeneous definitions or were not defined by the study and were measured at different times. Outcomes reported in the literature to date were mainly assigned to the core areas “pathophysiologic manifestations” or “resource use”. No articles reported included parent or former patient involvement in outcome selections.ConclusionsInconsistent selection and definition of primary and secondary outcomes exists in the present literature of pharmacologic and nonpharmacologic interventions for managing opioid withdrawal in neonates. No studies involved parents in the process of outcome selection. These findings hinder evidence synthesis to generate clinically meaningful practice guidelines. The development of a specific core outcome set is imperative

Gut microbes shape microglia and cognitive function during malnutrition

Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target

Whether weather matters: Evidence of association between in utero meteorological exposures and foetal growth among Indigenous and non-Indigenous mothers in rural Uganda

Pregnancy and birth outcomes have been found to be sensitive to meteorological variation, yet few studies explore this relationship in sub-Saharan Africa where infant mortality rates are the highest in the world. We address this research gap by examining the association between meteorological factors and birth weight in a rural population in southwestern Uganda. Our study included hospital birth records (n = 3197) from 2012 to 2015, for which we extracted meteorological exposure data for the three trimesters preceding each birth. We used linear regression, controlling for key covariates, to estimate the timing, strength, and direction of meteorological effects on birth weight. Our results indicated that precipitation during the third trimester had a positive association with birth weight, with more frequent days of precipitation associated with higher birth weight: we observed a 3.1g (95% CI: 1.0–5.3g) increase in birth weight per additional day of exposure to rainfall over 5mm. Increases in average daily temperature during the third trimester were also associated with birth weight, with an increase of 41.8g (95% CI: 0.6–82.9g) per additional degree Celsius. When the sample was stratified by season of birth, only infants born between June and November experienced a significant associated between meteorological exposures and birth weight. The association of meteorological variation with foetal growth seemed to differ by ethnicity; effect sizes of meteorological were greater among an Indigenous subset of the population, in particular for variation in temperature. Effects in all populations in this study are higher than estimates of the African continental average, highlighting the heterogeneity in the vulnerability of infant health to meteorological variation in different contexts. Our results indicate that while there is an association between meteorological variation and birth weight, the magnitude of these associations may vary across ethnic groups with differential socioeconomic resources, with implications for interventions to reduce these gradients and offset the health impacts predicted under climate change

The impacts of meteorological exposures on perinatal health: a mixed methods study of Kanungu District, Uganda

Maternal and child health disparities and climate change are grand challenges to achieving global health equity. These challenges do not exist in isolation from one another; both manifest through existing social gradients. There is minimal research, however, on the interactions of climate and perinatal health, particularly among vulnerable populations. Though there is prior evidence that season and weather may affect birth outcomes, the nature of these effects and the causal mechanisms that drive them vary in different regional contexts. In this study, I aim to address this research gap by investigating how birth weight is affected by perinatal meteorological exposures in rural southwestern Uganda. This study was conducted in Kanungu District, Uganda, a remote and rural region that is home to both Indigenous Batwa and non-Indigenous Bakiga populations. Significant health disparities exist along these ethnic lines, with the historical traumas and deprivation faced by the Batwa manifesting in present-day poorer health outcomes. The objectives of this thesis are fourfold: 1) to assess associations between meteorological exposures incurred in utero and birth weight in Kanungu, 2) to test for effect modification by ethnicity (Indigenous vs. non-Indigenous) of these associations, 3) to elucidate potential causal pathways through which such exposures could lead to physiological impacts on mother and infant, and 4) to characterize the experiences and perceptions of Indigenous and non-Indigenous mothers of weather impacts on birth outcomes in Kanungu District. In Manuscript 1, I aim to establish the association between meteorological exposures and birth weight (Obj. 1), and to assess any effect modification of these associations by ethnicity (Obj. 2). Results indicate that exposure to more days of precipitation in the third trimester was associated with increased birth weight, while subset analyses of the Indigenous Batwa sample revealed associations between increased birth weight and increased average temperature throughout pregnancy. In Manuscript 2, I address my third objective: to understand the ways weather may impact perinatal health in sub-Saharan Africa in general, and Kanungu District in particular. The pathways though which mothers were affected by weather and season were consistent with those observed in the literature: variation in maternal nutritional status and physical labour output due to harvest cycles and patterns of seasonal illnesses. While the mechanisms linking weather to birth experiences did not differ between Indigenous and non-Indigenous mothers in Kanungu, the magnitudes of weather impacts on birth were reported to be substantially higher among Indigenous Batwa. The findings of this study provide evidence not only that in utero weather exposures are associated with birth weight in Kanungu, but that this relationship is influenced by the social gradient that exists between non-Indigenous and Indigenous mothers in the region. These results can be used to inform interventions to ensure that the nutritional needs of mothers facing a third trimester in the dry season are met, and that Batwa mothers receive additional support throughout their pregnancies. As the region faces a less predictable climate with more extreme weather conditions, this knowledge can be applied in adaptation planning to ensure future generations of mothers and babies are adequately protected from the elements. More broadly, these findings provide impetus for region-specific research to understand how relationships between meteorological exposures and birth outcomes may differ in different contexts and for further investigation into how interventions on social gradients can offer protection from adverse climate impacts.Les changements climatiques et les disparités dans le domaine de la santé maternelle et juvénile sont des enjeux importants dans la lutte pour l'équité en santé mondiale. Ces défis ne sont pas indépendants, mais se manifestent bien à travers des gradients sociaux existants. Il n'existe toutefois que très peu de recherches portant sur l'interaction entre les changements climatiques et la santé périnatale, particulièrement chez les populations vulnérables. La recherche provenant de régions de l'Afrique sub-saharienne est particulièrement limitée à ce sujet. Dans le cadre de cette étude, j'adresse cette lacune dans la recherche en investiguant les effets sur le poids à la naissance des expositions météorologiques périnatales en Ouganda rurale du sud-ouest. Cette étude s'est déroulée dans la région rurale et isolée du district de Kanungu, Ouganda, où résident deux populations ethniques, le groupe indigène des Batwas et le groupe non-indigène des Bakigas. Il existe d'importantes disparités en santé entre les deux groupes; les traumatismes historiques et la privation auxquels les Batwas ont été confronté se manifestant à travers un niveau de santé actuel précaire. Les objectifs de cette thèse sont quadruple: 1) évaluer les liens entre les expositions météorologiques encourues in utero et les poids à la naissance dans le district de Kanungu, 2) tester la modification d'effet de ces associations selon l'ethnicité (indigène vs non-indigène), 3) élucider les potentiels voies de causales à travers desquels ces expositions pourraient entraîner des répercussions sur les mères et les nourrissons, 4) décrire les expériences et perceptions de mères indigènes et non-indigènes quant aux impacts de la température sur l'issue des grossesses à Kanungu. Dans le manuscrit 1, je vise d'une part à déterminer l'association qui existe entre les expositions météorologiques et les poids à la naissance (obj. 1), et d'autre part à établir la modification de ces associations selon l'ethnicité (obj. 2). Les résultats indiquent que l'exposition à davantage de journées de précipitations au cours du troisième trimestre était associée à une augmentation du poids à la naissance, alors que l'analyse de sous-groupe de l'échantillon des Batwas indigènes démontre une association entre le poids à la naissance et l'augmentation moyenne de la température au cours de la grossesse. Dans le deuxième manuscrit, j'adresse mon objectif 3 : comprendre les mécanismes causaux sous-tendant les associations entre les expositions météorologiques et les poids à la naissance. Les voies par lesquelles les mères furent affectées par la température et les saisons concordent avec celles observées dans la littérature : variation dans le statut nutritionnel maternel et réalisation de travail physique résultant des cycles de récolte et tendances dans les maladies saisonnières. Alors que les mécanismes liant température et issues de grossesses ne différaient pas entre les mères indigènes et non-indigènes de Kanungu, les ampleurs des impacts de la température sur les naissances furent rapportées comme étant substantiellement plus significatives sur les Batwas indigènes. Les résultats de cette étude suggèrent non seulement que les expositions météorologiques in utero sont associées au poids à la naissance à Kanungu, mais aussi que cette relation est influencée par le gradient social qui existe entre les mères indigènes et non-indigènes de la région. Ces résultats peuvent être utiles pour l'élaboration d'interventions ciblées afin, d'une part, de s'assurer de répondre aux besoins nutritionnels des mères faisant face à leur troisième trimestre lors de la saison sèche, et d'autre part, d'offrir du soutien additionnel aux mères Batwas tout au long de leur grossesse. À la lumière de cette étude, il serait également important pour la recherche future d'investiguer de quelles manières les interventions auprès des gradients sociaux pourraient prémunir contre les impacts climatiques néfastes

A Core Outcome Set for Neonatal Opioid Withdrawal Syndrome

BACKGROUND: As rates of neonatal opioid withdrawal are increasing, the need for research to evaluate new treatments is growing. Large heterogeneity exists in health outcomes reported in current literature. Our objective is to develop an evidence-informed and consensus-based core outcome set in neonatal opioid withdrawal syndrome (NOWS-COS) for use in studies and clinical practice.METHODS: An international multidisciplinary steering committee was established. A systematic review and a 3-round Delphi was performed with open-ended and score-based assessments of the importance of each outcome to inform clinical management of neonatal opioid withdrawal. Interviews were conducted with parents and/or caregivers on outcome importance. Finally, a consensus meeting with diverse stakeholders was held to review all data from all sources and establish a core set of outcomes with definitions.RESULTS: The NOWS-COS was informed by 47 published studies, 41 Delphi participants, and 6 parent interviews. There were 63 outcomes evaluated. Final core outcomes include (1) pharmacologic treatment, (2) total dose of opioid treatment, (3) duration of treatment, (4) adjuvant therapy, (5) feeding difficulties, (6) consolability, (7) time to adequate symptom control, (8) parent-infant bonding, (9) duration of time the neonate spent in the hospital, (10) breastfeeding, (11) weight gain at hospital discharge, (12) readmission to hospital for withdrawal, and (13) neurodevelopment.CONCLUSIONS: We developed an evidence-informed and consensus-based core outcome set. Implementation of this core outcome set will reduce heterogeneity between studies and facilitate evidence-based decision-making. Future research will disseminate all the findings and pilot test the validity of the NOWS-COS in additional countries and populations to increase generalizability and impact

Map of the study region, Kanungu District, Uganda.

<p>The study area is located northwest of Bwindi Impenetrable National Park, hemmed in by the border of the Democratic Republic of the Congo (DRC).</p

Descriptive summary of birth outcome, meteorological and control variables in the dataset.

<p>Descriptive summary of birth outcome, meteorological and control variables in the dataset.</p

Table of variables used in regression analyses.

<p>Table of variables used in regression analyses.</p

Sensitivity analyses of multivariable models for subsets of term births and ultrasound-dated births.

<p>Sensitivity analyses of multivariable models for subsets of term births and ultrasound-dated births.</p