Paid leave to support parenting-A neglected tool to improve societal well-being and prosperity.

Cohesive families and stimulating and caring environments promoting attachment to caregivers is fundamental for a child's physical and psychosocial growth and development. Parental care, supporting early years development, presupposes the presence and involvement of parents in children's daily life with activities that include breastfeeding, playing, reading and storytelling. However, parents have to balance their child's well-being against employment, career progression and gender equality. Universally accessible and equitably available parental leave addresses this challenge. CONCLUSION: Distinct from compulsory maternity leave, leave at full or nearly full pay for both parents benefits not only families but also societal well-being and prosperity.

Valuing maternal, newborn, child and adolescent health for societal progress - Going beyond the economic orthodoxy of gross domestic product.

AIM: In view of the long-standing recognition that gross domestic product (GDP) does not capture the unremunerated work largely conducted by women upon which societal well-being depends, to discuss the implications for GDP of maternal, newborn, child and adolescent health (MNCAH), and its influences on health, well-being and prosperity across the life course and across generations. METHODS: A wide-ranging discussion of the informal think-tank The Venice Forum was held over two days, with inputs from invited experts in person and online. RESULTS: There was consensus that a strong case could be made for inclusion of unremunerated work largely conducted by women as a positive contribution to GDP in view of its impact on future health and prosperity, and conversely exclusion from GDP of outputs from industries which harm health. CONCLUSION: Taken with the current challenges from COVID, climate change and conflict, there is a compelling need to redefine economic progress through equitable models and metrics that incorporate short-/medium-/long-term societal value of activities that improve MNCAH.

Improving clinical paediatric research and learning from COVID-19: recommendations by the Conect4Children expert advice group.

BACKGROUND: The COVID-19 pandemic has had a devastating impact on multiple aspects of healthcare, but has also triggered new ways of working, stimulated novel approaches in clinical research and reinforced the value of previous innovations. Conect4children (c4c, www.conect4children.org ) is a large collaborative European network to facilitate the development of new medicines for paediatric populations, and is made up of 35 academic and 10 industry partners from 20 European countries, more than 50 third parties, and around 500 affiliated partners. METHODS: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equity. FINDINGS: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equityWe provide examples of research innovation, and follow this with recommendations to improve the efficiency of future trials, drawing on industry perspectives, regulatory considerations, infrastructure requirements and parent-patient-public involvement. We end with a comment on progress made towards greater international harmonisation of paediatric research and how lessons learned from COVID-19 studies might assist in further improvements in this important area.

Variations in Neonatal Length of Stay of Babies Born Extremely Preterm: An International Comparison Between iNeo Networks.

OBJECTIVE: To compare length of stay (LOS) in neonatal care for babies born extremely preterm admitted to networks participating in the International Network for Evaluating Outcomes of Neonates (iNeo). STUDY DESIGN: Data were extracted for babies admitted from 2014 to 2016 and born at 24 to 28 weeks of gestational age (n = 28 204). Median LOS was calculated for each network for babies who survived and those who died while in neonatal care. A linear regression model was used to investigate differences in LOS between networks after adjusting for gestational age, birth weight z score, sex, and multiplicity. A sensitivity analysis was conducted for babies who were discharged home directly. RESULTS: Observed median LOS for babies who survived was longest in Japan (107 days); this result persisted after adjustment (20.7 days more than reference, 95% CI 19.3-22.1). Finland had the shortest adjusted LOS (-4.8 days less than reference, 95% CI -7.3 to -2.3). For each week's increase in gestational age at birth, LOS decreased by 12.1 days (95% CI -12.3 to -11.9). Multiplicity and male sex predicted mean increases in LOS of 2.6 (95% CI 2.0-3.2) and 2.1 (95% CI 1.6-2.6) days, respectively. CONCLUSIONS: We identified between-network differences in LOS of up to 3 weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries.

Equity in coronavirus disease 2019 vaccine development and deployment.

The coronavirus disease 2019 pandemic exposed weaknesses in multiple domains and widened gender-based inequalities across the world. It also stimulated extraordinary scientific achievement by bringing vaccines to the public in less than a year. In this article, we discuss the implications of current vaccination guidance for pregnant and lactating women, if their exclusion from the first wave of vaccine trials was justified, and if a change in the current vaccine development pathway is necessary. Pregnant and lactating women were not included in the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. Therefore, perhaps unsurprisingly, the first vaccine regulatory approvals have been accompanied by inconsistent advice from public health, governmental, and professional authorities around the world. Denying vaccination to women who, although pregnant or breastfeeding, are fully capable of autonomous decision making is a throwback to a paternalistic era. Conversely, lack of evidence generated in a timely manner, upon which to make an informed decision, shifts responsibility from research sponsors and regulators and places the burden of decision making upon the woman and her healthcare advisor. The World Health Organization, the Task Force on Research Specific to Pregnant Women and Lactating Women, and others have highlighted the long-standing disadvantage experienced by women in relation to the development of vaccines and medicines. It is uncertain whether there was sufficient justification for excluding pregnant and lactating women from the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. In future, we recommend that regulators mandate plans that describe the development pathway for new vaccines and medicines that address the needs of women who are pregnant or lactating. These should incorporate, at the outset, a careful consideration of the balance of the risks of exclusion from or inclusion in initial studies, patient and public perspectives, details of "developmental and reproductive toxicity" studies, and approaches to collect data systematically from participants who are unknowingly pregnant at the time of exposure. This requires careful consideration of any previous knowledge about the mode of action of the vaccine and the likelihood of toxicity or teratogenicity. We also support the view that the default position should be a "presumption of inclusion," with exclusion of women who are pregnant or lactating only if justified on specific, not generic, grounds. Finally, we recommend closer coordination across countries with the aim of issuing consistent public health advice.

Contribution of de novo and inherited rare CNVs to very preterm birth.

BACKGROUND: The genomic contribution to adverse health sequelae in babies born very preterm (<32 weeks' gestation) is unknown. We conducted an investigation of rare CNVs in infants born very preterm as part of a study to determine the feasibility and acceptability of a larger, well-powered genome-wide investigation in the UK, with follow-up using linked National Health Service records and DNA storage for additional research. METHODS: We studied 488 parent-offspring trios. We performed genotyping using Illumina Infinium OmniExpress Arrays. CNV calling and quality control (QC) were undertaken using published protocols. We examined de novo CNVs in infants and the rate of known pathogenic variants in infants, mothers and fathers and compared these with published comparator data. We defined rare pathogenic CNVs as those consistently reported to be associated with clinical phenotypes. RESULTS: We identified 14 de novo CNVs, representing a mutation rate of 2.9%, compared with 2.1% reported in control populations. The median size of these CNV was much higher than in comparator data (717 kb vs 255 kb). The rate of pathogenic CNVs was 4.3% in infants, 2.7% in mothers and 2% in fathers, compared with 2.3% in UK Biobank participants. CONCLUSION: Our findings suggest that the rate of de novo CNVs, especially rare pathogenic CNVs, could be elevated in those born very preterm. However, we will need to conduct a much larger study to corroborate this conclusion.

Recent advances in the genetics of preterm birth.

Preterm birth is associated with short- and long-term impairments affecting physical, cognitive, and neuropsychiatric health. These sequelae, together with a rising preterm birth rate and increased survival, make prematurity a growing public health issue because of the increased number of individuals with impaired health throughout the life span. Although a major contribution to preterm birth comes from environmental factors, it is also modestly heritable. Little is known about the architecture of this genetic contribution. Studies of common and of rare genetic variation have had limited power, but recent findings implicate variation in both the maternal and fetal genome. There is some evidence risk alleles in mothers may be enriched for processes related to immunity and inflammation, and in the preterm infant, processes related to brain development. Overall genomic discoveries for preterm birth lag behind progress for many other multifactorial diseases and traits. Investigations focusing on gene-environment interactions may also provide insights, but these studies still have a number of limitations. Adequately sized genetic studies of preterm birth are a priority for the future especially given the breadth of its negative health impacts across the life span and the current interest in newborn genome sequencing.

Evaluating preterm care across Europe using the eNewborn European Network database.

BACKGROUND: The inefficiency of recording data repeatedly limits the number of studies conducted. Here we illustrate the wider use of data captured as part of the European eNewborn benchmarking programme. METHODS: We extracted data on 39,529 live-births from 22 weeks 0 days to 31 weeks 6 days gestational age (GA) or ≤1500 g birth weight. We explored relationships between delivery room care and Apgar scores on mortality and bronchopulmonary dysplasia (BPD) and calculated the time needed for each country to detect a clinically relevant change in these outcomes following a hypothetical intervention. RESULTS: Early neonatal, neonatal, and in-hospital mortality were 3.90% (95% CI 3.71, 4.09), 6.00% (5.77, 6.24) and 7.57% (7.31, 7.83), respectively. The odds of death were greater with decreasing GA, lower Apgar scores, growth restriction, male sex, multiple birth and no antenatal steroids. Relationships for BPD were similar. The time required for participating countries to achieve 80% power to detect a relevant change in outcomes following a hypothetical intervention in 23-25 weeks' GA infants ranged from 12 years for neonatal mortality and 22 years for BPD compared to 1 year for the whole network. CONCLUSIONS: The eNewborn platform offers opportunity to drive efficiencies in benchmarking, quality control and research.

Clinical and molecular evidence of accelerated ageing following very preterm birth.

BACKGROUND: The mechanisms responsible for the associations between very preterm birth and a higher risk of poor cardiovascular and metabolic health in adult life are unknown. METHODS: Here, we compare the clinical and molecular phenotypes of healthy, normal-weight young adults (18-27 years), born very preterm (<33 weeks gestational age (GA)) and at full-term (37-42 weeks GA). Outcomes included whole-body MRI, hepatic and muscle 1H MRS, blood pressure measurements and telomere length. RESULTS: We recruited 156 volunteers, 69 preterm (45 women; 24 men) and 87 born at full-term (45 women; 42 men). Preterm individuals had a significantly altered blood pressure profile, including higher systolic blood pressure (SBP mmHg: preterm men 133.4 ± 10.1, term men 23.0 ± 6.9; preterm women 124.3 ± 7.1, term women 118.4 ± 8.0, p < 0.01 for all). Furthermore, preterm men had fewer long telomeres (145-48.5 kb: preterm men 14.1 ± 0.9%, term men 17.8 ± 1.1%, p < 0.05; 48.5-8.6 kb: preterm men 28.2 ± 2.6, term men 37.0 ± 2.4%, p < 0.001) and a higher proportion of shorter telomeres (4.2-1.3 kb: preterm men 40.4 ± 3.5%, term men 29.9 ± 3.2%, p < 0.01). CONCLUSION: Our data indicate that healthy young adults born very preterm manifest clinical and molecular evidence of accelerated ageing.

Review of guidelines and recommendations from 17 countries highlights the challenges that clinicians face caring for neonates born to mothers with COVID-19.

AIM: This review examined how applicable national and regional clinical practice guidelines and recommendations for managing neonates born to mothers with COVID-19 mothers were to the evolving pandemic. METHODS: A systematic search and review identified 20 guidelines and recommendations that had been published by May 25, 2020. We analysed documents from 17 countries: Australia, Brazil, Canada, China, France, India, Italy, Japan, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, the UK and the United States. RESULTS: The documents were based on expert consensus with limited evidence and were of variable, low methodological rigour. Most did not provide recommendations for delivery methods or managing symptomatic infants. None provided recommendations for post-discharge assimilation of potentially infected infants into the community. The majority encouraged keeping mothers and infants together, subject to infection control measures, but one-third recommended separation. Although breastfeeding or using breastmilk was widely encouraged, two countries specifically prohibited this. CONCLUSION: The guidelines and recommendations for managing infants affected by COVID-19 were of low, variable quality and may be unsustainable. It is important that transmission risks are not increased when new information is incorporated into clinical recommendations. Practice guidelines should emphasise the extent of uncertainty and clearly define gaps in the evidence.

Adult outcomes after preterm birth.

Extremely preterm birth reflects global disruption of the third trimester environment. Young adults born preterm have an adverse cardiovascular and metabolic health profile, together with molecular evidence of accelerated ageing and a reduced life expectancy. The underlying mechanism for these observations is unknown. This review summarises recent evidence of the lifetime effects of preterm birth and highlights the risks survivors face.

Trends in Outcomes for Neonates Born Very Preterm and Very Low Birth Weight in 11 High-Income Countries.

OBJECTIVE: To evaluate outcome trends of neonates born very preterm in 11 high-income countries participating in the International Network for Evaluating Outcomes of neonates. STUDY DESIGN: In a retrospective cohort study, we included 154 233 neonates admitted to 529 neonatal units between January 1, 2007, and December 31, 2015, at 240/7 to 316/7 weeks of gestational age and birth weight <1500 g. Composite outcomes were in-hospital mortality or any of severe neurologic injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia (BPD); and same composite outcome excluding BPD. Secondary outcomes were mortality and individual morbidities. For each country, annual outcome trends and adjusted relative risks comparing epoch 2 (2012-2015) to epoch 1 (2007-2011) were analyzed. RESULTS: For composite outcome including BPD, the trend decreased in Canada and Israel but increased in Australia and New Zealand, Japan, Spain, Sweden, and the United Kingdom. For composite outcome excluding BPD, the trend decreased in all countries except Spain, Sweden, Tuscany, and the United Kingdom. The risk of composite outcome was lower in epoch 2 than epoch 1 in Canada (adjusted relative risks 0.78; 95% CI 0.74-0.82) only. The risk of composite outcome excluding BPD was significantly lower in epoch 2 compared with epoch 1 in Australia and New Zealand, Canada, Finland, Japan, and Switzerland. Mortality rates reduced in most countries in epoch 2. BPD rates increased significantly in all countries except Canada, Israel, Finland, and Tuscany. CONCLUSIONS: In most countries, mortality decreased whereas BPD increased for neonates born very preterm.

Macronutrient content of donor milk from a regional human milk bank: variation with donor mother-infant characteristics.

Better understanding of the variation in macronutrient content of human donor milk (HDM) potentiates targeted nutrition for preterm babies. The present study describes the relationship of maternal age, parity, monthly lactation stage estimate (LSEm), daily volume of milk expressed (Vd), sex, gestation and birth weight z scores with macronutrient content of HDM. Multilevel mother-infant pair ID random intercept models were performed using the predictor variables above on the outcome HDM macronutrient content determined using mid-IR spectroscopy. Mean macronutrient content was also compared by gestational age and small for gestational age (SGA) (z score < -1·28) or appropriate for gestational age (AGA) (z score ≥ -1·28) categories. A total of 2966 samples of donations from 1175 mother-infant pairs to the UK Northwest Human Milk Bank between 2011 and 2017 were analysed. Mean protein, fat, carbohydrate and calculated energy were 0·89 (SD 0·24) g/dl, 2·99 (SD 0·96) g/dl, 7·09 (SD 0·44) g/dl, and 60·37 (SD 8·41) kcal/dl (252·59 (SD 35·19) kJ/dl), respectively. Preterm SGA HDM was significantly higher in protein, fat and energy content than term AGA HDM and significantly lower in carbohydrate content than term AGA HDM after controlling for LSEm, Vd and between-subject effects. Degree of prematurity did not influence macronutrient content. Between-subject effects accounted for more of the variance in macronutrient content than the fixed effects in the model. Despite this, SGA status, as well as prematurity, may be an important determinant of macronutrient content in human milk. As bioavailability of macronutrients from HDM is uncertain, studies evaluating growth and body composition in preterm and SGA babies fed HDM are warranted.

Scoping review shows wide variation in the definitions of bronchopulmonary dysplasia in preterm infants and calls for a consensus.

The use of different definitions for bronchopulmonary dysplasia (BPD) has been an ongoing challenge. We searched papers published in English from 2010 and 2015 reporting BPD as an outcome, together with studies that compared BPD definitions between 1978 and 2015. We found that the incidence of BPD ranged from 6% to 57%, depending on the definition chosen, and that studies that investigated correlations with long-term pulmonary and/or neurosensory outcomes reported moderate-to-low predictive values regardless of the BPD criteria. CONCLUSION: A comprehensive and evidence-based definition for BPD needs to be developed for benchmarking and prognostic use.

Development of a Pipeline for Exploratory Metabolic Profiling of Infant Urine.

Numerous metabolic profiling pipelines have been developed to characterize the composition of human biofluids and tissues, the vast majority of these being for studies in adults. To accommodate limited sample volume and to take into account the compositional differences between adult and infant biofluids, we developed and optimized sample handling and analytical procedures for studying urine from newborns. A robust pipeline for metabolic profiling using NMR spectroscopy was established, encompassing sample collection, preparation, spectroscopic measurement, and computational analysis. Longitudinal samples were collected from five infants from birth until 14 months of age. Methods of extraction and effects of freezing and sample dilution were assessed, and urinary contaminants from breakdown of polymers in a range of diapers and cotton wool balls were identified and compared, including propylene glycol, acrylic acid, and tert-butanol. Finally, assessment of urinary profiles obtained over the first few weeks of life revealed a dramatic change in composition, with concentrations of phenols, amino acids, and betaine altering systematically over the first few months of life. Therefore, neonatal samples require more stringent standardization of experimental design, sample handling, and analysis compared to that of adult samples to accommodate the variability and limited sample volume.