Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

OBJECTIVE: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes. DESIGN: Superiority, double-blind randomised controlled trial. SETTING: A total of 20 UK fetal medicine units. POPULATION: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22+0 and 29+6 weeks of gestation. METHODS: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation. MAIN OUTCOME MEASURES: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85. RESULTS: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm). CONCLUSIONS: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2.

BACKGROUND: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. METHODS: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. RESULTS: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition. CONCLUSIONS: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.

Rule-based deep learning method for prognosis of neonatal hypoxic-ischemic encephalopathy by using susceptibility weighted image analysis.

OBJECTIVE: Susceptibility weighted imaging (SWI) of neonatal hypoxic-ischemic brain injury can provide assistance in the prognosis of neonatal hypoxic-ischemic encephalopathy (HIE). We propose a convolutional neural network model to classify SWI images with HIE. MATERIALS AND METHODS: Due to the lack of a large dataset, transfer learning method with fine-tuning a pre-trained ResNet 50 is introduced. We randomly select 11 datasets from patients with normal neurology outcomes (n = 31) and patients with abnormal neurology outcomes (n = 11) at 24 months of age to avoid bias in classification due to any imbalance in the data. RESULTS: We develop a rule-based system to improve the classification performance, with an accuracy of 0.93 ± 0.09. We also compute heatmaps produced by the Grad-CAM technique to analyze which areas of SWI images contributed more to the classification patients with abnormal neurology outcome. CONCLUSION: Such regions that are important in the classification accuracy can interpret the relationship between the brain regions affected by hypoxic-ischemic and neurodevelopmental outcomes of infants with HIE at the age of 2 years.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 1, experiences and recommendations for service design.

Prospective parents whose fetus is diagnosed with a neurological anomaly go through a complex range of emotions. They describe their discussions of antenatal counselling from health care professionals as focusing too much on the nature of the anomaly involving unintelligible medical terminology, when what they really want is a picture of the best- and worst-case scenarios. Whilst information on the level of risk for their fetus is important, it is not the parents' primary concern. When statistics for risk are given, they may not be as well understood as the health care professionals think. This review discusses the published evidence on antenatal counselling and recommendations for explaining risk to parents of fetuses with neurological anomalies. From this data we make recommendations for the organization of antenatal counselling services.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 2, risks of adverse outcome in common anomalies.

After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst-case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide-memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling.

Training in neonatal neurocritical care: a proposal for a hybrid model of competence by design and time-based methods.

BACKGROUND: Neonatal neurocritical care (NNCC) is a rapidly advancing field with limited fellowship training available in locally developed, non-accredited programs. A standardized survey aimed to understand the training backgrounds of individuals practicing NNCC, the structure of existing clinical NNCC services/training programs, and suggested clinical competencies for new graduates. METHODS: We developed an anonymous survey electronically sent to members of societies related to NNCC. Using the survey results as a guide, we discuss a competence by design (CBD) curriculum as a complementary approach to traditional time-based training. RESULTS: There were 82 responses to the survey from 30 countries; 95% of respondents were physicians. Thirty-one (42%) institutions reported having an NNCC service, 24 (29%) individuals reported formal NNCC training, 81% reported "significant variability" across NNCC training programs, and 88% were both in favor of standardizing training programs and pursuing formal accreditation for NNCC in the next 5 years. CONCLUSIONS: The survey results demonstrate international interest in standardizing NNCC training and development of an accreditation or certification process. We propose consideration of a CBD-type curriculum as a training approach to focus on the development of specific NNCC competencies, rather than assuming the acquisition of these competencies based on time as a surrogate. IMPACT: Continued growth and development in the field of NNCC has led to increasing need for training programs suited to meet the diverse needs of trainees from varied backgrounds. We present the results of an international survey that assessed the structure of existing training programs and the priority areas in which graduates must demonstrate competence, highlighting the combination of CBD and time-based training as one approach to address these recommendations. The survey results support interest in translating published training competencies, existing expertise, and infrastructure across centers into a standardized curriculum for NNCC including certification opportunities.

Weaning oxygen in infants with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease commonly seen in preterm infants as the sequelae following respiratory distress syndrome. The management of evolving BPD aims to minimise lung injury and prevent the impact of hypoxia and hyperoxia. Proposed morbidities include respiratory instability, pulmonary hypertension, suboptimal growth, altered cerebral oxygenation and long-term neurodevelopmental impairment. The ongoing management and associated morbidity present a significant burden for carers and healthcare systems. Long-term oxygen therapy may be required for variable duration, though there is a lack of consensus and wide variation in practise when weaning supplemental oxygen. Furthermore, a shift in care towards earlier discharge and community care underlines the importance of a structured discharge and weaning process that eliminates the potential risks associated with hypoxia and hyperoxia. This review article describes recent evidence outlining oxygen saturation reference ranges in young infants, on which structured guidance can be based.

Severity of retinopathy of prematurity was associated with a higher risk of cerebral dysfunction in young adults born extremely preterm.

AIM: This Swedish study evaluated whether the severity of retinopathy of prematurity (ROP) in extremely preterm infants was related to their overall outcome in young adulthood. METHODS: We followed 39 individuals born between 1988 and 1993 at less than 28 gestational weeks, included in the Stockholm Neonatal Project. A total of 19 were treated for severe ROP, and 20 had no or mild ROP. They were assessed for general cognitive abilities and mental health at 18 years of age and compared with 23 term-born controls. Visual acuity was examined at 21-25 years. They were asked about their education and everyday life. RESULTS: The 19 individuals with severe treated ROP had lower visual acuity and higher risk for intellectual deficits, cerebral palsy and neuropsychiatric diagnoses than those with no or mild ROP and the term controls. Three were visually impaired, none were blind. They were less physically active than the other groups and had more problems finding their way around. However, nine were at university. CONCLUSION: Young adults treated for severe ROP had more problems resulting from cerebral dysfunction than those with no or mild ROP and term-born controls. Retinal and brain pathologies in the extremely preterm infant constitute different expressions of neurovascular disease.

Children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia are not as school ready as their peers.

AIM: We aimed to determine whether children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia (TH) differ from their peers on measures of fine motor skills, executive function, language and general cognitive abilities, factors that are important for school readiness. METHODS: We compared school readiness in 31children with HIE treated with TH (without Cerebral Palsy; mean age 5 years 4 months) with 20 typically developing children without HIE (mean age 5 years 6 months). RESULTS: Children with HIE scored significantly lower than typically developing children on fine motor skills, executive functions, memory and language. CONCLUSION: While general cognitive abilities and attainment were in the normal range, our findings suggest those scores mask specific underlying difficulties identified by more focussed assessments. Children with HIE treated with TH may not be as 'school ready' as their typically developing classmates and may benefit from long-term follow-up until starting school.

Systematic review: long-term cognitive and behavioural outcomes of neonatal hypoxic-ischaemic encephalopathy in children without cerebral palsy.

AIM: To evaluate long-term cognitive and behavioural outcomes of children with neonatal hypoxic-ischaemic encephalopathy (HIE) in the absence of cerebral palsy (CP). METHODS: A systematic search was performed on five databases (EMBASE, Medline, PubMed, Web of Science, PsycInfo). Randomised controlled trials, non-randomised controlled trials, or observational studies, published between 1990 and 2017, that reported long-term (age greater than or equal to four years) cognitive and/or behavioural outcomes of neonatal HIE without CP were included. RESULTS: Seven articles met the inclusion criteria (n = 352 total participants, n = 53 treated with therapeutic hypothermia). Studies reporting cognitive outcome demonstrate impairment of general cognitive abilities in 25-63% of participants with HIE without CP. Specific cognitive difficulties were reported in two studies for attention, executive functioning, memory function and language. Results regarding behavioural outcome possibly indicate a higher risk of difficulties. CONCLUSION: A substantial proportion of children with neonatal HIE who survive without CP are at increased risk of general and/or specific cognitive impairments. Behavioural problems may be more common, but evidence is limited. Results highlight the importance of comprehensive long-term follow-up to identity difficulties and enable intervention to optimise educational achievement and behavioural adjustment.

Young Adult Motor, Sensory, and Cognitive Outcomes and Longitudinal Development after Very and Extremely Preterm Birth.

In this narrative review, we report on adult outcomes after very (before 32 weeks of gestation [wGA]) and extremely (before 28 wGA) preterm birth, with a focus on neuromotor function, neurosensory impairment, general cognitive abilities, executive function, and attentional abilities, all of which are important for academic progress, peer relationships, and participation. Longitudinal development from childhood to adulthood is described. Preterm born individuals have a higher risk for impairment of general cognitive abilities, executive function, attention, and neuromotor abilities well into adulthood, with, however, considerable variability in outcomes. Differences between individuals born preterm and their term born peers persist. Long-term outcomes of general cognitive ability can be predicted with some degree of certainty from childhood assessments: those who perform poor on early childhood age assessments very likely will not catch up, whereas those who perform within the normal range on early assessments sometimes accelerate their development relative to term born peers. This appears similar for executive function and attention, although data on trajectories for these functions are somewhat inconsistent. In adulthood, some studies describe poorer educational outcomes, employment, independent living, and/or economic situation compared with term born individuals; however, large proportion of those born preterm report similar self-perceived quality of life.

Minor neurological dysfunction and associations with motor function, general cognitive abilities, and behaviour in children born extremely preterm.

AIM: To study the prevalence of minor neurological dysfunction (MND) at 6 years of age in a cohort of children born extremely preterm without cerebral palsy (CP) and to investigate associations with motor function, cognitive abilities, and behaviour. METHOD: This study assessed 80 children born at less than 27 weeks of gestation and 90 children born at term age between 2004 and 2007 at a mean age of 6 years 6 months. The assessments included a simplified version of the Touwen Infant Neurological Examination, the Movement Assessment Battery for Children, Second Edition (MABC-2), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV), the Strengths and Difficulties Questionnaire (SDQ), and the parent version of the Five to Fifteen questionnaire. RESULTS: Fifty-one of the children born preterm had normal neurology, 23 had simple MND, and six had complex MND compared with 88 who had normal neurology and two simple MND in the term-born group (p<0.001). There were significant differences between the children with normal neurology and MND in the preterm group in MABC-2-assessed motor function (p<0.001), general cognitive abilities with WISC-IV (p=0.005), and SDQ overall behavioural problems and peer problems reported by the parents (p=0.021 and p=0.003 respectively). SDQ teacher-reported overall behavioural and hyperactivity problems were significantly different between children with normal and simple MND (p=0.036 and p=0.019). INTERPRETATION: Children born extremely preterm, in the absence of CP, are at risk of MND and this is associated with motor function, cognitive ability, and behaviour. WHAT THIS PAPER ADDS: Extremely preterm birth carries a risk of minor neurological dysfunction (MND). MND in children born extremely preterm is associated with impaired motor function and cognitive abilities, and behavioural problems. Male sex is associated with MND in children born extremely preterm.

Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review.

UNLABELLED: A systematic review with meta-analysis was carried out to investigate the effects of increased nutritional intake, via either macronutrient or multinutrient intervention, during the neonatal period on neurodevelopmental outcomes in infants born at <32 weeks of gestation or weighing <1501 g at birth. CONCLUSION: Although the relationship remains unclear, increased early nutrition may reduce neurodevelopmental impairment in this group of infants. Future research should focus on using standardised nutritional interventions and an agreed neurodevelopmental assessment battery.

Growth, head growth, and neurocognitive outcome in children born very preterm: methodological aspects and selected results.

In light of the growing number of surviving children born very preterm, there is an increasing focus on their long-term outcomes in terms of growth, metabolic status, and neurocognitive development. Therefore, it is of importance to follow such children from birth onwards with the aim of identifying the causes of atypical development, developing preventative measures, and improving outcomes. Since such long-term follow-up needs to be conducted with the least possible burden, clinical investigations such as anthropometry and neurocognitive tests, if conducted rigorously, will continue to have a predominant role. The aim of this review is to discuss the complexity of longitudinal anthropometry in children born very preterm and to provide an overview of the main studies that have examined associations between growth, in particular head growth, and neurocognitive outcomes at around school age.