Repeat placental growth factor-based testing in women with suspected preterm pre-eclampsia (PARROT-2): a multicentre, parallel-group, superiority, randomised controlled trial.

BACKGROUND: Placental growth factor (PlGF)-based testing has high diagnostic accuracy for predicting pre-eclampsia needing delivery, significantly reducing time to diagnosis and severe maternal adverse outcomes. The clinical benefit of repeat PlGF-based testing is unclear. We aimed to determine whether repeat PlGF-based testing (using a clinical management algorithm and nationally recommended thresholds) reduces adverse perinatal outcomes in pregnant individuals with suspected preterm pre-eclampsia. METHODS: In this multicentre, parallel-group, superiority, randomised controlled trial, done in 22 maternity units across England, Scotland, and Wales, we recruited women aged 18 years or older with suspected pre-eclampsia between 22 weeks and 0 days of gestation and 35 weeks and 6 days of gestation. Women were randomly assigned (1:1) to revealed repeat PlGF-based testing or concealed repeat testing with usual care. The intervention was not masked to women or partners, or clinicians or data collectors, due to the nature of the trial. The trial statistician was masked to intervention allocation. The primary outcome was a perinatal composite of stillbirth, early neonatal death, or neonatal unit admission. The primary analysis was by the intention-to-treat principle, with a per-protocol analysis restricted to women managed according to their allocation group. The trial was prospectively registered with the ISRCTN registry, ISRCTN 85912420. FINDINGS: Between Dec 17, 2019, and Sept 30, 2022, 1253 pregnant women were recruited and randomly assigned treatment; one patient was excluded due to randomisation error. 625 women were allocated to revealed repeat PlGF-based testing and 627 women were allocated to usual care with concealed repeat PlGF-based testing (mean age 32·3 [SD 5·7] years; 879 [70%] white). One woman in the concealed repeat PlGF-based testing group was lost to follow-up. There was no significant difference in the primary perinatal composite outcome between the revealed repeat PlGF-based testing group (195 [31·2%]) of 625 women) compared with the concealed repeat PlGF-based testing group (174 [27·8%] of 626 women; relative risk 1·21 [95% CI 0·95-1·33]; p=0·18). The results from the per-protocol analysis were similar. There were four serious adverse events in the revealed repeat PlGF-based testing group and six in the concealed repeat PlGF-based testing group; all serious adverse events were deemed unrelated to the intervention by the site principal investigators and chief investigator. INTERPRETATION: Repeat PlGF-based testing in pregnant women with suspected pre-eclampsia was not associated with improved perinatal outcomes. In a high-income setting with a low prevalence of adverse outcomes, universal, routine repeat PlGF-based testing of all individuals with suspected pre-eclampsia is not recommended. FUNDING: Tommy's Charity, Jon Moulton Charitable Trust, and National Institute for Health and Care Research Guy's and St Thomas' Biomedical Research Centre.

Methods of identifying surgical Necrotizing Enterocolitis-a systematic review and meta-analysis.

BACKGROUND: Current data suggests potential benefit of earlier surgery for necrotizing enterocolitis (NEC) however this requires accurate prognostication early in the disease course. This study aims to identify and determine the effectiveness of previously reported methods or tests for the identification of surgical NEC. METHODS: Systematic review and meta-analysis with registration on PROSPERO including articles describing a method of identifying surgical NEC. Outcomes of interest were effectiveness and repeatability of index test. RESULTS: Of the 190 full-text articles screened, 90 studies were included which contained 114 methods of identifying surgical NEC in 9546 infants. Of these methods, 44 were a scoring system, 37 a single biomarker, 24 an imaging method, and 9 an invasive method. Sensitivity and specificity ranged from 12.8-100% to 13-100%, respectively. Some methods (9.6%) provided insufficient methods for repeatability within clinical practice or research. Meta-analyses were possible for only 2 methods, the metabolic derangement 7 score and abdominal ultrasound. CONCLUSIONS: A range of methods for identifying surgical NEC have been identified with varying overall performance and uncertainties about reproducibility and superiority of any method. External validation in large multicentre datasets should allow direct comparison of accuracy and prospective study should evaluate impact on clinical outcomes. IMPACT: Earlier identification of need for surgery in necrotizing enterocolitis (NEC) has the potential to improve the unfavourable outcomes in this condition. As such, many methods have been developed and reported to allow earlier identification of surgical NEC. This study is the first synthesis of the literature which identifies previously reported methods and the effectiveness of these. Many methods, including scoring systems and biomarkers, appear effective for prognostication in NEC and external validation is now required in multicentre datasets prior to clinical utility.

The contribution of hypertensive disorders of pregnancy to late preterm and term admissions to neonatal units in the UK 2012-2020 and opportunities to avoid admission: A population-based study using the National Neonatal Research Database.

OBJECTIVE: To quantify maternal hypertensive disorder of pregnancy (HDP) prevalence in late preterm and term infants admitted to neonatal units (NNU) and assess opportunities to avoid admissions. DESIGN: A retrospective population-based study using the National Neonatal Research Database. SETTING: England and Wales. POPULATION: Infants born ≥34 weeks' gestation admitted to NNU between 2012 and 2020. METHODS: Outcomes in HDP infants are compared with non-HDP infants using regression models. MAIN OUTCOME MEASURES: Hypertensive disorder of pregnancy, primary reason for admission, clinical diagnoses and resource use. RESULTS: 16 059/136 220 (11.8%) of late preterm (34+0 to 36+6 weeks' gestation) and 14 885/284 646 (5.2%) of term (≥37 weeks' gestation) admitted infants were exposed to maternal HDP. The most common primary reasons for HDP infant admission were respiratory disease (28.3%), prematurity (22.7%) and hypoglycaemia (16.4%). HDP infants were more likely to be admitted with primary hypoglycaemia than were non-HDP infants (odds ratio [OR] 2.1, 95% confidence interval [CI] 2.0-2.2, P < 0.0001). 64.5% of HDP infants received i.v. dextrose. 35.7% received mechanical or non-invasive ventilation. 8260/30 944 (26.7%) of HDP infants received intervention for hypoglycaemia alone (i.v. dextrose) with no other major intervention (respiratory support, parenteral nutrition, central line, arterial line or blood transfusion). CONCLUSIONS: The burden of maternal HDP on late preterm and term admissions to NNU is high, with hypoglycaemia and respiratory disease being the main drivers for admission. Over one in four were admitted solely for management of hypoglycaemia. Further research should determine whether maternal antihypertensive agent choice or postnatal pathways may reduce NNU admission.

The Contribution of Hypertensive Disorders of Pregnancy to Neonatal Unit Admissions and Iatrogenic Preterm Delivery at < 34+0 Weeks' Gestation in the UK: A Population-Based Study Using the National Neonatal Research Database.

OBJECTIVES: The objectives of this study were to (i) quantify the contribution of maternal hypertensive disorders of pregnancy (HDP) to iatrogenic preterm birth (PTB) and neonatal unit (NNU) admissions < 34+0 weeks and (ii) describe short-term population-level outcomes for HDP infants, exploring ethnic disparities and comparing outcomes by HDP exposure. DESIGN: Retrospective population-based study using the National Neonatal Research Database. SETTING: England and Wales. POPULATION: Infants born < 34+0 weeks and admitted to NNU 2012-2020. METHODS: Descriptive statistics, linear and logistic regression models to compare outcomes between groups. MAIN OUTCOME MEASURES: Survival to discharge with/without comorbidity. RESULTS: 122 228 infants met inclusion criteria. Where collected, 49 839/114 164 (43.7%, 95% CI 43.4%-43.9%) of infants had an iatrogenic PTB. HDP was recorded in 16 510/122 228 (13.5%) of all infants and 13 560/49 839 (27.2%) of iatrogenic PTBs. HDP and/or foetal growth restriction (FGR) were recorded in 24 124/49 839 (48.4%) of iatrogenic PTBs. Singleton HDP infants < 10th BWC had ≥ 90% survival to discharge from 28 weeks' gestation, versus from 26 weeks' gestation for those born ≥ 10th BWC. In extreme preterm HDP infants (< 27 weeks), 27.3% of infants < 10th BWC died compared to 15.2% of those ≥ 10th BWC. Survival without comorbidity was ≥ 90% from 32 weeks' gestation in HDP infants across BWC. CONCLUSIONS: These contemporaneous population-level data show that almost one in two PTB < 34+0 weeks' gestation are iatrogenic, with HDP and/or FGR being the major contributors to iatrogenic prematurity. This has substantial implications for strategies to reduce preterm birth in the UK and internationally. The data further inform antenatal and at-birth counselling of HDP-exposed infants.

Childhood outcomes after low-grade intraventricular haemorrhage: A systematic review and meta-analysis.

AIM: To undertake a systematic review and meta-analysis exploring school-age neurodevelopmental outcomes of children after low-grade intraventricular haemorrhage (IVH). METHOD: The published and grey literature was extensively searched to identify observational comparative studies exploring neurodevelopmental outcomes after IVH grades 1 and 2. Our primary outcome was neurodevelopmental impairment after 5 years of age, which included cognitive, motor, speech and language, behavioural, hearing, or visual impairments. RESULTS: This review included 12 studies and over 2036 infants born preterm with low grade IVH. Studies used 30 different neurodevelopmental tools to determine outcomes. There was conflicting evidence of the composite risk of neurodevelopmental impairment after low-grade IVH. There was evidence of an association between low-grade IVH and lower IQ at school age (-4.23, 95% confidence interval [CI] -7.53, -0.92, I2 = 0%) but impact on school performance was unclear. Studies reported an increased crude risk of cerebral palsy after low-grade IVH (odds ratio [OR] 2.92, 95% CI 1.95, 4.37, I2 = 41%). No increased risk of speech and language impairment or behavioural impairment was found. Few studies addressed hearing and visual impairment. INTERPRETATION: This systematic review presents evidence that low-grade IVH is associated with specific neurodevelopmental impairments at school age, lending support to the theory that low-grade IVH is not a benign condition. WHAT THIS PAPER ADDS: The functional impact of low-grade intraventricular haemorrhage (IVH) at school age is unknown. Low-grade IVH is associated with a lower IQ at school age. The risk of cerebral palsy is increased after low-grade IVH. Low-grade IVH is not associated with speech and language impairment.

Planned delivery or expectant management in preeclampsia: an individual participant data meta-analysis.

OBJECTIVE: Pregnancy hypertension is a leading cause of maternal and perinatal mortality and morbidity. Between 34+0 and 36+6 weeks gestation, it is uncertain whether planned delivery could reduce maternal complications without serious neonatal consequences. In this individual participant data meta-analysis, we aimed to compare planned delivery to expectant management, focusing specifically on women with preeclampsia. DATA SOURCES: We performed an electronic database search using a prespecified search strategy, including trials published between January 1, 2000 and December 18, 2021. We sought individual participant-level data from all eligible trials. STUDY ELIGIBILITY CRITERIA: We included women with singleton or multifetal pregnancies with preeclampsia from 34 weeks gestation onward. METHODS: The primary maternal outcome was a composite of maternal mortality or morbidity. The primary perinatal outcome was a composite of perinatal mortality or morbidity. We analyzed all the available data for each prespecified outcome on an intention-to-treat basis. For primary individual patient data analyses, we used a 1-stage fixed effects model. RESULTS: We included 1790 participants from 6 trials in our analysis. Planned delivery from 34 weeks gestation onward significantly reduced the risk of maternal morbidity (2.6% vs 4.4%; adjusted risk ratio, 0.59; 95% confidence interval, 0.36-0.98) compared with expectant management. The primary composite perinatal outcome was increased by planned delivery (20.9% vs 17.1%; adjusted risk ratio, 1.22; 95% confidence interval, 1.01-1.47), driven by short-term neonatal respiratory morbidity. However, infants in the expectant management group were more likely to be born small for gestational age (7.8% vs 10.6%; risk ratio, 0.74; 95% confidence interval, 0.55-0.99). CONCLUSION: Planned early delivery in women with late preterm preeclampsia provides clear maternal benefits and may reduce the risk of the infant being born small for gestational age, with a possible increase in short-term neonatal respiratory morbidity. The potential benefits and risks of prolonging a pregnancy complicated by preeclampsia should be discussed with women as part of a shared decision-making process.

Review of a frugal cooling mattress to induce therapeutic hypothermia for treatment of hypoxic-ischaemic encephalopathy in the UK NHS.

Hypoxic ischaemic encephalopathy (HIE) is a major cause of neonatal mortality and disability in the United Kingdom (UK) and has significant human and financial costs. Therapeutic hypothermia (TH), which consists of cooling down the newborn's body temperature, is the current standard of treatment for moderate or severe cases of HIE. Timely initiation of treatment is critical to reduce risk of mortality and disability associated with HIE. Very expensive servo-controlled devices are currently used in high-income settings to induce TH, whereas low-income settings rely on the use of low-tech devices such as water bottles, ice packs or fans. Cooling mattresses made with phase change materials (PCMs) were recently developed as a safe, efficient, and affordable alternative to induce TH in low-income settings. This frugal innovation has the potential to become a reverse innovation for the National Health Service (NHS) by providing a simple, efficient, and cost-saving solution to initiate TH in geographically remote areas of the UK where cooling equipment might not be readily available, ensuring timely initiation of treatment while waiting for neonatal transport to the nearest cooling centre. The adoption of PCM cooling mattresses by the NHS may reduce geographical disparity in the availability of treatment for HIE in the UK, and it could benefit from improvements in coordination across all levels of neonatal care given challenges currently experienced by the NHS in terms of constraints on funding and shortage of staff. Trials evaluating the effectiveness and safety of PCM cooling mattresses in the NHS context are needed in support of the adoption of this frugal innovation. These findings may be relevant to other high-income settings that experience challenges with the provision of TH in geographically remote areas. The use of promising frugal innovations such as PCM cooling mattresses in high-income settings may also contribute to challenge the dominant narrative that often favours innovation from North America and Western Europe, and consequently fight bias against research and development from low-income settings, promoting a more equitable global innovation landscape.

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.

A protocol for neoWONDER: Neonatal whole population data linkage to improve long-term health and wellbeing of preterm and sick babies.

INTRODUCTION: Early-life medical and surgical interventions in babies born preterm and/or with surgical conditions influence later life health and educational outcomes. Obtaining long-term outcomes post-discharge to evaluate the impact of interventions is complex, expensive, and burdensome to families. Linkage of routinely collected data offers a feasible and cost-effective solution. The NeoWONDER research programme aims to describe the short and long-term health and educational outcomes for babies born preterm and/or with surgical conditions and evaluate the impact of neonatal care and interventions on later health and educational outcomes. METHODS AND ANALYSIS: We will include babies who received care in neonatal units in England and Wales, born between 2007-2020 with a gestational age below 32 weeks (approximately 100,000), and/or born between 2012-2020 (all gestations) with any of six surgical conditions: necrotising enterocolitis, Hirschsprung's disease, gastroschisis, oesophageal atresia, congenital diaphragmatic hernia, and posterior urethral valves (approximately 8,000). A detailed list of surgical condition codes is shown in S3 File. We will obtain long-term health and education outcomes through linkage of the National Neonatal Research Database, which contains routine data for all babies admitted to NHS neonatal units, to other existing health and educational datasets. For England, these are: Hospital Episode Statistics, the Office for National Statistics, Mental Health Services Dataset, Paediatric Intensive Care Audit Network, National Pupil Database; and for Wales, the Secure Anonymised Information Linkage databank. Analysis will be undertaken on de-identified linked datasets. Outcomes of interest for health include mortality, hospital admissions, diagnoses indicative of neurodisability and/or chronic illness, health care utilisation; and for education are attainment (using national curriculum assessments), school absence and special educational needs status.

Two-year neurodevelopmental data for preterm infants born over an 11-year period in England and Wales, 2008-2018: a retrospective study using the National Neonatal Research Database.

OBJECTIVE: United Kingdom guidelines recommend all infants born <30 weeks' gestation receive neurodevelopmental follow-up at 2 years corrected age. In this study, we describe completeness and results of 2-year neurodevelopmental records in the National Neonatal Research Database (NNRD). DESIGN: This retrospective cohort study uses data from the NNRD, which holds data on all neonatal admissions in England and Wales, including 2year follow-up status. PATIENTS: We included all preterm infants born <30 weeks' gestation between 1 January 2008 and 31 December 2018 in England and Wales, who survived to discharge from neonatal care. MAIN OUTCOME MEASURES: Presence of a 2-year neurodevelopmental assessment record in the NNRD, use of standardised assessment tools, results of functional 2-year neurodevelopmental assessments (visual, auditory, neuromotor, communication, overall development). RESULTS: Of the 41 505 infants included, 24 125 (58%) had a 2-year neurodevelopmental assessment recorded. This improved over time, from 32% to 71% for births in 2008 and 2018, respectively.Of those with available data: 0.4% were blind; 1% had a hearing impairment not correctable with aids; 13% had <5 meaningful words, vocalisations or signs; 8% could not walk without assistance and 9% had severe (≥12 months) developmental delay. CONCLUSIONS: The proportion of infants admitted to neonatal units in England and Wales with a 2-year neurodevelopmental record has improved over time. Rates of follow-up data from recent years are comparable to those of bespoke observational studies. With continual improvement in data completeness, the potential for use of NNRD as a source of longer-term outcome data can be realised.

Paediatric intensive care admissions of preterm children born <32 weeks gestation: a national retrospective cohort study using data linkage.

OBJECTIVE: Survival of babies born very preterm (<32 weeks gestational age) has increased, although preterm-born children may have ongoing morbidity. We aimed to investigate the risk of admission to paediatric intensive care units (PICUs) of children born very preterm following discharge home from neonatal care. DESIGN: Retrospective cohort study, using data linkage of National Neonatal Research Database and the Paediatric Intensive Care Audit Network datasets. SETTING: All neonatal units and PICUs in England and Wales. PATIENTS: Children born very preterm between 1 January 2013 and 31 December 2018 and admitted to neonatal units. MAIN OUTCOME MEASURES: Admission to PICU after discharge home from neonatal care, before 2 years of age. RESULTS: Of the 40 690 children discharged home from neonatal care, there were 2308 children (5.7%) with at least one admission to PICU after discharge. Of these children, there were 1901 whose first PICU admission after discharge was unplanned.The percentage of children with unplanned PICU admission varied by gestation, from 10.2% of children born <24 weeks to 3.3% born at 31 weeks.Following adjustment, unplanned PICU admission was associated with lower gestation, male sex (adjusted OR (aOR) 0.79), bronchopulmonary dysplasia (aOR 1.37), necrotising enterocolitis requiring surgery (aOR 1.39) and brain injury (aOR 1.42). For each week of increased gestation, the aOR was 0.90. CONCLUSIONS: Most babies born <32 weeks and discharged home from neonatal care do not require PICU admission in the first 2 years. The odds of unplanned admissions to PICU were greater in the most preterm and those with significant neonatal morbidity.

UK neonatal stoma practice: a population study.

OBJECTIVE: The optimal time for neonatal stoma closure is unclear and there have been calls for a trial to compare early and late surgery. The feasibility of such a trial will depend on the population of eligible infants and acceptability to families and health professionals. In this study, we aimed to determine current UK practice and characteristics of those undergoing stoma surgery. DESIGN: A retrospective cohort study of neonates who had undergone stoma surgery (excluding anorectal malformations and Hirschsprung's disease) using three national databases: the National Neonatal Research Database (NNRD, 2012-2019), British Association of Paediatric Surgeons Congenital Anomalies Surveillance System (BAPS-CASS, 2013-2014) and Hospital Episode Statistics-Admitted Patient Care (HES-APC, 2011-2018). RESULTS: 1830 eligible neonates were identified from NNRD, 163 from BAPS-CASS, 2477 from HES-APC. Median (IQR) duration of stoma in days was 57 (36-80) in NNRD, 63 (41-130) in BAPS-CASS and 78 (55-122) for neonates identified from HES-APC. At the time of closure, there were low rates of invasive ventilation (13%), inotrope use (5%) and recent steroids use (4%). Infants who underwent earlier closure (<9 weeks) were less preterm (median 28 weeks vs 25 weeks), have higher birth weight (median 986 g vs 764 g) and more likely to have stoma complications (29% vs 5%). CONCLUSION: There are sufficient UK neonates undergoing stoma formation for a trial. Stoma closure is performed at around 2 months, with clinical stability, gestation, weight and stoma complications appearing to influence timing. The variation in practice we document indicates there is opportunity to optimise practice through a trial.

Place of birth and postnatal transfers in infants with congenital diaphragmatic hernia in England and Wales: a descriptive observational cohort study.

OBJECTIVE: To describe clinical pathways for infants with congenital diaphragmatic hernia (CDH) and short-term outcomes. DESIGN: Retrospective observational cohort study using the UK National Neonatal Research Database (NNRD). PATIENTS: Babies with a diagnosis of CDH admitted to a neonatal unit in England and Wales between 2012 and 2020. MAIN OUTCOME MEASURES: Clinical pathways defined by place of birth (with or without colocated neonatal and surgical facilities), transfers, clinical interventions, length of hospital stay and discharge outcome. RESULTS: There were 1319 babies with a diagnosis of CDH cared for in four clinical pathways: born in maternity units with (1) colocated tertiary neonatal and surgical units ('neonatal surgical units'), 50% (660/1319); (2) designated tertiary neonatal unit and transfer to stand-alone surgical centre ('tertiary designated'), 25% (337/1319); (3) non-designated tertiary neonatal unit ('tertiary non-designated'), 7% (89/1319); or (4) non-tertiary unit ('non-tertiary'), 18% (233/1319)-the latter three needing postnatal transfers. Infant characteristics were similar for infants born in neonatal surgical and tertiary designated units. Excluding 149 infants with minimal data due to early transfer (median (IQR) 2.2 (0.4-4.5) days) to other settings, survival to neonatal discharge was 73% (851/1170), with a median (IQR) stay of 26 (16-44) days. CONCLUSIONS: We found that half of the babies with CDH were born in hospitals that did not have on-site surgical services and required postnatal transfer. Similar characteristics between infants born in neonatal surgical units and tertiary designated units suggest that organisation rather than infant factors influence place of birth. Future work linking the NNRD to other datasets will enable comparisons between care pathways.

Childhood Health and Educational outcomes afteR perinatal Brain injury (CHERuB): protocol for a population-matched cohort study.

INTRODUCTION: Over 3000 infants suffer a brain injury around the time of birth every year in England. Although these injuries can have important implications for children and their families, our understanding of how these injuries affect children's lives is limited. METHODS AND ANALYSIS: The aim of the CHERuB study (Childhood Health and Educational outcomes afteR perinatal Brain injury) is to investigate longitudinal childhood health and educational outcomes after perinatal brain injury through the creation of a population-matched cohort study. This study will use the Department of Health and Social Care definition of perinatal brain injury which includes infants with intracranial haemorrhage, preterm white matter injury, hypoxic ischaemic encephalopathy, perinatal stroke, central nervous system infections, seizures and kernicterus. All children born with a perinatal brain injury in England between 2008 and 2019 will be included (n=54 176) and two matched comparator groups of infants without brain injury will be created: a preterm control group identified from the National Neonatal Research Data Set and a term/late preterm control group identified using birth records. The national health, education and social care records of these infants will be linked to ascertain their longitudinal childhood outcomes between 2008 and 2023. This cohort will include approximately 170 000 children. The associations between perinatal brain injuries and survival without neurosensory impairment, neurodevelopmental impairments, chronic health conditions and mental health conditions throughout childhood will be examined using regression methods and time-to-event analyses. ETHICS AND DISSEMINATION: This study has West London Research Ethics Committee and Confidential Advisory Group approval (20/LO/1023 and 22/CAG/0068 issued 20/10/2022). Findings will be published in open-access journals and publicised via the CHERuB study website, social media accounts and our charity partners.

Characteristics of children requiring admission to neonatal care and paediatric intensive care before the age of 2 years in England and Wales: a data linkage study.

OBJECTIVE: To quantify the characteristics of children admitted to neonatal units (NNUs) and paediatric intensive care units (PICUs) before the age of 2 years. DESIGN: A data linkage study of routinely collected data. SETTING: National Health Service NNUs and PICUs in England and Wales PATIENTS: Children born from 2013 to 2018. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Admission to PICU before the age of 2 years. RESULTS: A total of 384 747 babies were admitted to an NNU and 4.8% (n=18 343) were also admitted to PICU before the age of 2 years. Approximately half of all children admitted to PICU under the age of 2 years born in the same time window (n=18 343/37 549) had previously been cared for in an NNU.The main reasons for first admission to PICU were cardiac (n=7138) and respiratory conditions (n=5386). Cardiac admissions were primarily from children born at term (n=5146), while respiratory admissions were primarily from children born preterm (<37 weeks' gestational age, n=3550). A third of children admitted to PICU had more than one admission. CONCLUSIONS: Healthcare professionals caring for babies and children in NNU and PICU see some of the same children in the first 2 years of life. While some children are following established care pathways (eg, staged cardiac surgery), the small proportion of children needing NNU care subsequently requiring PICU care account for a large proportion of the total PICU population. These differences may affect perceptions of risk for this group of children between NNU and PICU teams.

Repeat Placental Growth Factor-Based Testing in Women With Suspected Preterm Preeclampsia: A Stratified Analysis of the PARROT-2 Trial.

BACKGROUND: PlGF (placental growth factor)-based testing reduces severe maternal adverse outcomes. Repeat PlGF-based testing is not associated with improved perinatal or maternal outcomes. This planned secondary analysis aimed to determine whether there is a subgroup of women who benefit from repeat testing. METHODS: Pregnant individuals with suspected preterm preeclampsia were randomized to repeat revealed PlGF-based testing, compared with usual care where testing was concealed. Perinatal and maternal outcomes were stratified by trial group, by initial PlGF-based test result, and by PlGF-based test type (PlGF or sFlt-1 [soluble fms-like tyrosine kinase-1]/PlGF ratio). RESULTS: A total of 1252 pregnant individuals were included. Abnormal initial PlGF-based test identified a more severe phenotype of preeclampsia, at increased risk of adverse maternal and perinatal outcomes. Repeat testing was not significantly associated with clinical benefit in women with abnormal initial results. Of women with a normal initial result, 20% developed preeclampsia, with the majority at least 3 to 4 weeks after initial presentation. Repeat test results were more likely to change from normal to abnormal in symptomatic women (112/415; 27%) compared with asymptomatic women (163/890; 18%). A higher proportion of symptomatic women who changed from normal to abnormal were diagnosed with preeclampsia, compared with asymptomatic women. CONCLUSIONS: Our results do not demonstrate evidence of the clinical benefit of repeating PlGF-based testing if the initial result is abnormal. Judicious use of repeat PlGF-based testing to stratify risk may be considered at least 2 weeks after a normal initial test result, particularly in women who have symptoms or signs of preeclampsia. REGISTRATION: URL: https://www.isrctn.com/ISRCTN85912420; Unique identifier: ISRCTN85912420.

Preterm birth as a determinant of neurodevelopment and cognition in children (PRENCOG): protocol for an exposure-based cohort study in the UK.

INTRODUCTION: Preterm birth (PTB) is strongly associated with encephalopathy of prematurity (EoP) and neurocognitive impairment. The biological axes linking PTB with atypical brain development are uncertain. We aim to elucidate the roles of neuroendocrine stress activation and immune dysregulation in linking PTB with EoP. METHODS AND ANALYSIS: PRENCOG (PREterm birth as a determinant of Neurodevelopment and COGnition in children: mechanisms and causal evidence) is an exposure-based cohort study at the University of Edinburgh. Three hundred mother-infant dyads comprising 200 preterm births (gestational age, GA <32 weeks, exposed) and 100 term births (GA >37 weeks, non-exposed), will be recruited between January 2023 and December 2027. We will collect parental and infant medical, demographic, socioeconomic characteristics and biological data which include placental tissue, umbilical cord blood, maternal and infant hair, infant saliva, infant dried blood spots, faecal material, and structural and diffusion MRI. Infant biosamples will be collected between birth and 44 weeks GA.EoP will be characterised by MRI using morphometric similarity networks (MSNs), hierarchical complexity (HC) and magnetisation transfer saturation imaging (MTsat). We will conduct: first, multivariable regressions and statistical association assessments to test how PTB-associated risk factors (PTB-RFs) relate to MSNs, HC and or MTsat; second, structural equation modelling to investigate neuroendocrine stress activation and immune dysregulation as mediators of PTB-RFs on features of EoP. PTB-RF selection will be informed by the variables that predict real-world educational outcomes, ascertained by linking the UK National Neonatal Research Database with the National Pupil Database. ETHICS AND DISSEMINATION: A favourable ethical opinion has been given by the South East Scotland Research Ethics Committee 02 (23/SS/0067) and NHS Lothian Research and Development (2023/0150). Results will be reported to the Medical Research Council, in scientific media, via stakeholder partners and on a website in accessible language (https://www.ed.ac.uk/centre-reproductive-health/prencog).

Neonatal outcomes and indirect consequences following maternal SARS-CoV-2 infection in pregnancy: a systematic review.

OBJECTIVES: To identify the association between maternal SARS-CoV-2 infection in pregnancy and individual neonatal morbidities and outcomes, particularly longer-term outcomes such as neurodevelopment. DESIGN: Systematic review of outcomes of neonates born to pregnant women diagnosed with a SARS-CoV-2 infection at any stage during pregnancy, including asymptomatic women. DATA SOURCES: MEDLINE, Embase, Global Health, WHOLIS and LILACS databases, last searched on 28 July 2021. ELIGIBILITY CRITERIA: Case-control and cohort studies published after 1 January 2020, including preprint articles were included. Study outcomes included neonatal mortality and morbidity, preterm birth, caesarean delivery, small for gestational age, admission to neonatal intensive care unit, level of respiratory support required, diagnosis of culture-positive sepsis, evidence of brain injury, necrotising enterocolitis, visual or hearing impairment, neurodevelopmental outcomes and feeding method. These were selected according to a core outcome set. DATA EXTRACTION AND SYNTHESIS: Data were extracted into Microsoft Excel by two researchers, with statistical analysis completed using IBM SPSS (Version 27). Risk of bias was assessed using a modified Newcastle-Ottawa Scale. RESULTS: The search returned 3234 papers, from which 204 were included with a total of 45 646 infants born to mothers with SARS-CoV-2 infection during pregnancy across 36 countries. We found limited evidence of an increased risk of some neonatal morbidities, including respiratory disease. There was minimal evidence from low-income settings (1 study) and for neonatal outcomes following first trimester infection (17 studies). Neonatal mortality was very rare. Preterm birth, neonatal unit admission and small for gestational age status were more common in infants born following maternal SARS-CoV-2 infection in pregnancy in most larger studies. CONCLUSIONS: There are limited data on neonatal morbidity and mortality following maternal SARS-CoV-2 infection, particularly from low-income countries and following early pregnancy infections. Large, representative studies addressing these outcomes are needed to understand the consequences for babies born to women with SARS-CoV-2. PROSPERO REGISTRATION NUMBER: CRD42021249818.

Data-driven approach to understanding neonatal palliative care needs in England and Wales: a population-based study 2015-2020.

OBJECTIVE: To quantify admissions to neonatal units in England and Wales with potential need for palliative care. DESIGN, SETTING AND PATIENTS: Diagnoses and clinical attributes indicating a high likelihood of requiring palliative care were mapped to categories within the British Association of Perinatal Medicine's (BAPM) framework on palliative care. We extracted data from the National Neonatal Research Database on all babies born and admitted to neonatal units in England and Wales 2015-2020. OUTCOMES: The number and proportion of babies meeting BAPM categories, their discharge outcomes and the characteristics of babies who died during neonatal care but did not fulfil any BAPM category. RESULTS: 12 123/574 954 (2.1%) babies met one or more BAPM category: 6239/12 123 (51%) conformed to BAPM category 4 (postnatal conditions with high risk of severe impairment), 3796 (31%) to category 2 (antenatal/postnatal diagnosis with high risk of significant morbidity or death), 1399 (12%) to category 3 (born at margin of viability) and 288 (2%) to category 1 (antenatal/postnatal diagnosis not compatible with long-term survival); 401 babies (3%) met criteria for multiple categories. 6814/12 123 (56%) were discharged home, 2385 (20%) were discharged to other settings and 2914 (24%) died before neonatal discharge. 3000/5914 (51%) babies who died during neonatal care did not conform to any BAPM category. Of these, 2630/3000 (88%) were born preterm. CONCLUSIONS: At least 2% of babies admitted to neonatal units had palliative care needs according to existing BAPM categories; most survived to discharge. Of deaths, 51% were not captured by the BAPM categories; most were extremely preterm.

National Trends in Preterm Infant Mortality in the United States by Race and Socioeconomic Status, 1995-2020.

Importance: Inequalities in preterm infant mortality exist between population subgroups within the United States. Objective: To characterize trends in preterm infant mortality by maternal race and socioeconomic status to assess how inequalities in preterm mortality rates have changed over time. Design, Setting, and Participants: This was a retrospective longitudinal descriptive study using the US National Center for Health Statistics birth infant/death data set for 12 256 303 preterm infant births over 26 years, between 1995 and 2020. Data were analyzed from December 2022 to March 2023. Exposures: Maternal characteristics including race, smoking status, educational attainment, antenatal care, and insurance status were used as reported on an infant's US birth certificate. Main Outcomes and Measures: Preterm infant mortality rate was calculated for each year from 1995 to 2020 for all subgroups, with a trend regression coefficient calculated to describe the rate of change in preterm mortality. Results: The average US preterm infant mortality rate (IMR) decreased from 33.71 (95% CI, 33.71 to 34.04) per 1000 preterm births per year between 1995-1997, to 23.32 (95% CI, 23.05 to 23.58) between 2018-2020. Black non-Hispanic infants were more likely to die following preterm births than White non-Hispanic infants (IMR, 31.09; 95% CI, 30.44 to 31.74, vs 21.81; 95% CI, 21.43 to 22.18, in 2018-2020); however, once born, extremely prematurely Black and Hispanic infants had a narrow survival advantage (IMR rate ratio, 0.87; 95% CI, 0.84 to 0.91, in 2018-2020). The rate of decrease in preterm IMR was higher in Black infants (-0.015) than in White (-0.013) and Hispanic infants (-0.010); however, the relative risk of preterm IMR among Black infants compared with White infants remained the same between 1995-1997 vs 2018-2020 (relative risk, 1.40; 95% CI, 1.38 to 1.44, vs 1.43; 95% CI, 1.39 to 1.46). The rate of decrease in preterm IMR was higher in nonsmokers compared with smokers (-0.015 vs -0.010, respectively), in those with high levels of education compared with those with intermediate or low (-0.016 vs - 0.010 or -0.011, respectively), and in those who had received adequate antenatal care compared with those who did not (-0.014 vs -0.012 for intermediate and -0.013 for inadequate antenatal care). Over time, the relative risk of preterm mortality widened within each of these subgroups. Conclusions and Relevance: This study found that between 1995 and 2020, US preterm infant mortality improved among all categories of prematurity. Inequalities in preterm infant mortality based on maternal race and ethnicity have remained constant while socioeconomic disparities have widened over time.