Brain MRI findings and their association with visual impairment in young adolescents born very preterm.

PURPOSE: Very preterm birth increases risk for neonatal white matter injury, but there is limited data on to what extent this persists into adolescence and how this relates to ophthalmological outcomes. The aim of this study was to assess brain MRI findings in 12-year-old children born very preterm compared to controls and their association with concurrent ophthalmological outcomes. METHODS: We included 47 children born very preterm and 22 full-term controls (gestational age <32 and >37 weeks, respectively). Brain MRI findings were studied in association with concurrent ophthalmological outcomes at 12-year follow-up. RESULTS: Evans index (0.27 vs 0.25, p<0.001) and a proposed "posterior ventricle index" (0.47 vs 0.45, p=0.018) were increased in children born very preterm. Higher gestational age associated with larger corpus callosum area (ß=10.7, 95%CI 0.59-20.8). Focal white matter lesions were observed in 15 (32%) of very preterm children and in 1 (5%) of full-term controls. Increased posterior ventricle index increased risk for visual acuity ≤1.0 (OR=1.07×1011, 95%CI=7.78-1.48×1021) and contrast sensitivity <0.5 (OR=2.6×1027, 95%CI=1.9×108-3.5×1046). Decreased peritrigonal white matter thickness associated with impaired visual acuity (ß=0.04, 95%CI 0.002-0.07). CONCLUSION: More white matter lesions and evidence of lower white matter volume were found in children born very preterm compared with full-term controls at 12-year follow-up. The association between larger posterior ventricle index and reduced visual acuity and contrast sensitivity suggests disturbances of the posterior visual pathway due to diffuse white matter lesions.

Neuromonitoring in neonatal critical care part I: neonatal encephalopathy and neonates with possible seizures.

The blooming of neonatal neurocritical care over the last decade reflects substantial advances in neuromonitoring and neuroprotection. The most commonly used brain monitoring tools in the neonatal intensive care unit (NICU) are amplitude integrated EEG (aEEG), full multichannel continuous EEG (cEEG), and near-infrared spectroscopy (NIRS). While some published guidelines address individual tools, there is no consensus on consistent, efficient, and beneficial use of these modalities in common NICU scenarios. This work reviews current evidence to assist decision making for best utilization of neuromonitoring modalities in neonates with encephalopathy or with possible seizures. Neuromonitoring approaches in extremely premature and critically ill neonates are discussed separately in the companion paper. IMPACT: Neuromonitoring techniques hold promise for improving neonatal care. For neonatal encephalopathy, aEEG can assist in screening for eligibility for therapeutic hypothermia, though should not be used to exclude otherwise eligible neonates. Continuous cEEG, aEEG and NIRS through rewarming can assist in prognostication. For neonates with possible seizures, cEEG is the gold standard for detection and diagnosis. If not available, aEEG as a screening tool is superior to clinical assessment alone. The use of seizure detection algorithms can help with timely seizures detection at the bedside.

Neuromonitoring in neonatal critical care part II: extremely premature infants and critically ill neonates.

Neonatal intensive care has expanded from cardiorespiratory care to a holistic approach emphasizing brain health. To best understand and monitor brain function and physiology in the neonatal intensive care unit (NICU), the most commonly used tools are amplitude-integrated EEG, full multichannel continuous EEG, and near-infrared spectroscopy. Each of these modalities has unique characteristics and functions. While some of these tools have been the subject of expert consensus statements or guidelines, there is no overarching agreement on the optimal approach to neuromonitoring in the NICU. This work reviews current evidence to assist decision making for the best utilization of these neuromonitoring tools to promote neuroprotective care in extremely premature infants and in critically ill neonates. Neuromonitoring approaches in neonatal encephalopathy and neonates with possible seizures are discussed separately in the companion paper. IMPACT: For extremely premature infants, NIRS monitoring has a potential role in individualized brain-oriented care, and selective use of aEEG and cEEG can assist in seizure detection and prognostication. For critically ill neonates, NIRS can monitor cerebral perfusion, oxygen delivery, and extraction associated with disease processes as well as respiratory and hypodynamic management. Selective use of aEEG and cEEG is important in those with a high risk of seizures and brain injury. Continuous multimodal monitoring as well as monitoring of sleep, sleep-wake cycling, and autonomic nervous system have a promising role in neonatal neurocritical care.

Economic Evaluation of Elective Cesarean Section on Maternal Request Compared With Planned Vaginal Birth-Application to Swedish Setting Using National Registry Data.

OBJECTIVES: There is a lack of consensus around the definition of delivery by cesarean section (CS) on maternal request, and clinical practice varies across and within countries. Previous economic evaluations have focused on specific populations and selected complications. Our aim was to evaluate the cost-effectiveness of CS on maternal request compared with planned vaginal birth in a Swedish context, based on a systematic review of benefits and drawbacks and national registry data on costs. METHODS: We used the results from a systematic literature review of somatic risks for long- and short-term complications for mother and child, in which certainty was rated low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation. Swedish national registry data were used for healthcare costs of delivery and complications. Utilities for long-term complications were based on a focused literature review. We constructed a decision tree and conducted separate analyses for primi- and multiparous women. Costs and effects were discounted by 3% and the time horizon was varied between 1 and 20 years. RESULTS: Planned vaginal birth leads to lower healthcare costs and somatic health gains compared with elective CS without medical indication over up to 20 years. Although there is uncertainty around, for example, quality-of-life effects, results remain stable across sensitivity analyses. CONCLUSIONS: CS on maternal request leads to increased hospitalization costs in a Swedish setting, taking into account short- and long-term consequences for both mother and child. Future research needs to study the psychological consequences related to different delivery methods, costs in outpatient care, and productivity losses.

Different aspects of visual perception are important for 12-year social functioning depending on gestational age.

AIM: Perceptual mechanisms in social functioning might promote interventions. We investigated relations between visual perception and social functioning, in preterm children. METHODS: A prospective preterm cohort born in Uppsala County, Sweden, in 2004-2007 and 49 full-term controls were examined at 12 years. Aspects of visual perception, including static shapes, emotions and time to detect biological motion, were related to social functioning and visual acuity. RESULTS: The preterm group comprised 25 extremely preterm children, EPT, born below 28 gestational weeks and 53 children born between 28 and 31 weeks. Preterm children had difficulties in perception of static shapes (p = 0.004) and biological motion (p < 0.001), but not in emotion perception, compared to controls. In the EPT children, poorer shape perception and lower scores on emotion perception were associated with more social problems (p = 0.008) and lower visual acuity (p = 0.004). Shape perception explained more variance in social functioning than emotion perception. In controls, fewer social problems were linked to faster biological motion perception (p = 0.04). CONCLUSION: Static shape and biological motion perception was affected in the preterm groups. Biological motion perception was relevant for social functioning in full-term children. In EPT children, only shape perception was linked to social functioning, suggesting differential visual perception mechanisms for social deficits.

Visual tracking at 4 months in preterm infants predicts 6.5-year cognition and attention.

BACKGROUND: Visual tracking of moving objects requires sustained attention and prediction of the object's trajectory. We tested the hypothesis that measures of eye-head tracking of moving objects are associated to long-term neurodevelopment in very preterm infants. METHODS: Visual tracking performance was assessed at 4 month's corrected age in 57 infants with gestational age <32 weeks. An object moved in front of the infant with sinusoidal or triangular (i.e. abrupt) turns of the direction. Gaze gain, smooth pursuit gain, and timing of gaze to object motion were analyzed. At 6.5 years the Wechsler Intelligence Scale for Children (WISC-IV), the Brown Attention Deficit Disorder (Brown ADD), and visual examination were performed. RESULTS: Gaze gain and smooth pursuit gain at 4 months were strongly related to all WISC-IV parameters at 6.5 years. Gaze gain for the triangular and sinusoidal motion patterns related similarly to the cognitive scores. For the sinusoidal motion pattern, timing related to most Brown ADD parameters. There were no statistically significant differences in associations dependent on motion pattern. Visual function did not influence the results. CONCLUSION: The ability to attend to and smoothly track a moving object in infancy is an early marker of cognition and attention at 6.5 years. IMPACT: Potential long-term implications of infant visual tracking of moving objects for school-age neurodevelopment has not been previously studied in very preterm infants. Early coordination of eye and head movements in gaze gain, smooth pursuit, and timing of gaze to object motion are closely associated with cognition and attention at 6.5 years. As related functions at 6.5 years include perceptual and verbal skills, working memory, processing speed and attention, predictive elements in gaze tracking of moving objects might be a suitable target for future intervention studies.

Serum osteocalcin levels at 4 months of age were associated with neurodevelopment at 4 years of age in term-born children.

AIM: The hormone osteocalcin influenced neurodevelopment and cognition in mice models; this human study explored potential associations between total serum levels in human infants and neurodevelopment at 4 years of age. METHODS: The data were based on two Swedish birth cohorts from 2008 to 2009. We followed 158 healthy full-term vaginal births (51% girls) by measuring serum osteocalcin in cord blood and at 4, 12 and 36 months. The values were compared with neurodevelopment tests at 4 years of age. RESULTS: There was an association between osteocalcin at 4 months and later full-scale intelligence quotient (IQ; r2 0.031, p < 0.05). Children with osteocalcin levels in the highest quartile scored 5.6 (95% confidence interval [1.3, 9.9]) points higher than those in the lowest quartile, with mean scores of 118.8 ± 8.8 and 113.2 ± 9.2 (p < 0.05). They also scored higher on gross motor skills (p < 0.05) and showed greater ability during the drawing trail test (p < 0.005). Cord levels of osteocalcin were negatively associated with processing speed and fine motor development at 4 years, but levels at 12 and 36 months were not associated with later neurodevelopment. CONCLUSION: Osteocalcin levels in infancy appeared to be associated with later IQ and motor development, but more research is needed.

Antenatal steroids and neurodevelopment in 12-year-old children born extremely preterm.

AIM: To investigate neurodevelopmental outcome in 12-year-old children born very preterm in relation to perinatal, neonatal and socioeconomic variables. To examine whether previously described positive effects of antenatal steroids on cognition persist at 12 years. METHODS: Prospective cohort, 78 children with gestational ages 22.7-31.9 weeks, born in 2004-2007 and examined at 12 years of age with cognitive, motor and visual motor integration tasks and compared to an age-matched control group (n = 50). Two preterm subgroups were studied: very preterm children (28-31 gestational weeks, n = 53) and extremely preterm children (22-27 gestational weeks, n = 25). RESULTS: The preterm children had significantly lower scores on all cognitive, motor and visual motor integration tasks than the controls. Gestational age and maternal education influenced associations differently in the two preterm subgroups. Also, severe retinopathy of prematurity demonstrated strong associations to outcome. In the extremely preterm group, administration of antenatal steroids was associated with better cognition, basic attention, word generation and motor skills. CONCLUSION: At 12 years of age, very preterm children born in the 2000s still have deficits across several neurodevelopmental domains compared to term-born peers. Administration of antenatal steroids has long-lasting associations to cognition and motor skills in extremely preterm-born children.

Neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation.

AIM: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. METHODS: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. RESULTS: We studied 383 children born at a median of 23.3 (range 21.9-23.9) weeks, with a median birthweight of 565 (range 340-874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). CONCLUSION: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.

National cohort of infants born before 24 gestational weeks showed increased survival rates but no improvement in neonatal morbidity.

AIM: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12-year period. METHODS: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007-2018 in Sweden. Temporal changes were evaluated. RESULTS: In 2007-2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. CONCLUSION: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long-term outcome.

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.

Structured Observation of Motor Performance in Infants: Level and quality associated with later motor development.

AIM: The aim of this study was to investigate the level of motor development and the quality of motor performance during the first 10 months in relation to the Bayley Scales of Infant Development-third edition (Bayley-III) motor index at 2.5 years. METHODS: Children born very preterm from a population-based study (n = 113) were assessed with the Structured Observation of Motor Performance in Infants (SOMP-I) at 2, 4, 6 and 10 months corrected age and the Bayley-III motor index at 2.5 years corrected age (n = 98). Logistic regressions were performed to investigate the independent association of each SOMP-I domain to Bayley-III motor index. RESULTS: There were significant associations between the SOMP-I-scores and Bayley-III motor index per every assessment age. At 4 months, both level and quality were independently associated with a later motor outcome, OR for level was 1.26 (95% CI = 1.08-1.50, P = .002) and for quality, 0.75 (95% CI = 0.63-0.90, P = .002). Quality was independently associated with the Bayley-III motor index at 6 and 10 months: OR 0.080 (95% CI = 0.67-0.95 P = .010) and 0.79 (95% CI = 0.64-0.97, P = .026). CONCLUSION: Both SOMP-I domains, level and quality, are markers to identify motor problems early. Quality became more important with age.

Average 2.5-year neurodevelopmental test results in children born very preterm did not rule out cognitive deficits at 6.5 years of age.

AIM: The aim of the study was to investigate cognitive outcomes at 6.5 years in children born very preterm, in relation to neonatal characteristics and 2.5-year neurodevelopment. METHODS: A prospective cohort, with gestational age 22.3-31.9 weeks, born 2004-2007, were examined at 2.5 years with the Bayley Scales of Infant and Toddler Development (Bayley-III) (n = 100) and at 6.5 years with the Wechsler Intelligence Scales (n = 91). RESULTS: Neonatal factors independently related to 6.5-year outcome were gestational age, retinopathy of prematurity and treated persistent ductus arteriosus. The Bayley-III cognitive scores explained only 44% of the Full-Scale Intelligence Quotient result at 6.5 years, and 22% of the children had Wechsler index results below -1 SD, indicating cognitive impairment, after average test results at 2.5 years. The relative risk to score below -1 SD on the Full-Scale IQ was 2.83 (95% CI 1.45-5.53) in children with gestational age below 28 weeks and 2.22 (95% CI 1.18-4.17) at gestational age 28-31 weeks. CONCLUSION: Very preterm infants born in the 2000s had increased risks for impaired cognition at 6.5 years, but individual predictions based on neonatal risks and 2.5-year test results were not enough to identify all high-risk children.

Using different definitions affected the reported prevalence of neurodevelopmental impairment in children born very preterm.

AIM: We investigated the impact of varying definitions on the prevalence of neurodevelopmental impairment (NDI) in children born very preterm at 6.5 years of age. METHODS: Cognitive development and neurosensory impairments were assessed in 91 children (40/51 girls/boys) born <32 gestational weeks, in 2004-2007 in Uppsala county, Sweden. The results were compared with data from a reference group of 67 children born full term. The prevalence of NDI in the present cohort was reported according to definitions used by seven contemporary studies of children born very or extremely preterm. RESULTS: The prevalence of severe NDI varied from 2% to 23% depending on the definition used. The prevalence of cognitive impairment varied from 2% (-3 SD according to test norms) to 16% (-2 SD according to control group), the prevalence of cerebral palsy from 0% (severe) to 9% (any) and the prevalence of severe visual impairment from 0% (blindness) to 1% (visual acuity < 0.3). There were no children with severe hearing impairment. CONCLUSION: A high variability in definitions affects the reporting of the prevalence of NDI in long-term follow-up studies of very or extremely preterm born children. There is a need for a better consensus to enable comparisons across studies.

Hypothermic treatment for neonatal asphyxia in low-resource settings using phase-changing material-An easy to use and low-cost method.

AIM: To evaluate whether phase-changing material can be used for therapeutic hypothermia of asphyxiated newborns in low-resource settings. METHODS: Prospective interventional study of asphyxiated term infants fulfilling criteria for hypothermia treatment at Vietnam National Children's Hospital from September 2014 to September 2016. Hypothermia was induced within 6 hours after birth and maintained for 72 hours by a phase-changing material mattress with melting point of 32°C. Rectal temperature was continuously measured, and deviations from target temperature range 33.5-34.5°C were recorded. RESULTS: In total 52 infants (mean gestational age 39.3 ± 1.1 weeks) included and cooled, the median temperature at initiation of cooling was 35.3 (IQR 34.5-35.9)°C. The median time to reach target temperature was 2.5 (IQR 2-3) hours. The mean temperature during the cooling phase was 33.95 ± 0.2°C. Throughout the cooling phase, the target temperature range (33.5-34.5°C) was maintained more than 80% of the time. Rate of rewarming was 0.5 ± 0.14°C/hour. CONCLUSION: Phase-changing material can be used as an effective cooling method. Though not a servo-controlled system, it is easy to induce hypothermia, maintain target temperature and rewarm infants in a slow and controlled manner without need for frequent changes and minimum risk of skin injury.

When all I wanted was to hold my baby-The experiences of parents of infants who received therapeutic hypothermia.

AIM: The knowledge is limited about how parents experience the time when their infant is receiving therapeutic hypothermia (TH) after severe perinatal asphyxia. The aim of this study was to explore parents' experience of closeness and involvement in their infant's care while in the neonatal intensive care unit (NICU) with their newborn undergoing TH. METHODS: Face-to-face, semi-structured interviews were conducted with parents (n = 11) whose infants (n = 8, aged 3-5 years at the time of the study) underwent TH at a level III Swedish NICU during 2013-2016. The interviews were analysed using qualitative content analysis. RESULTS: All the parents shared the trauma of being both physically and psychologically separated from their infant. They all described a need for information and emotional support, and reported that the NICU staff had influenced the extent to which they as parents had been able to be near and actively participate in the care. Parents described the wish to be closer to their infant and to be more actively involved in their infant's care. CONCLUSION: Strategies to enable parent-infant closeness and active guidance from staff might help alleviate the emotional stress of parents and promote their participation during TH.

Prelabour caesarean section and neurodevelopmental outcome at 4 and 12 months of age: an observational study.

BACKGROUND: With prelabour caesarean section rates growing globally, there is direct and indirect evidence of negative cognitive outcomes in childhood. The objective of this study was to assess the short-term neurodevelopmental outcomes after prelabour caesarean section as compared to vaginally born infants. METHODS: We conducted a prospective, observational study of infants delivered by prelabour caesarean section at the Hospital of Halland, Halmstad, Sweden and compared their development with an historical group of infants born by non-instrumental vaginal delivery. RESULTS: Infants born by prelabour caesarean section were compared with a group of vaginally born infants. Follow-up assessments were performed at 4 and 12 months. Prelabour caesarean infants (n = 66) had significantly lower Ages and Stages Questionnaire, second edition (ASQ-II) scores in all domains (communication, gross motor, fine motor, problem solving and personal-social) at 4 months of age with an adjusted mean difference (95% CI) of - 20.7 (- 28.7 to - 12.6) in ASQ-II total score as compared to vaginally born infants (n = 352). These differences remained for gross-motor skills at the 12 month assessment, adjusted mean difference (95% CI) -4.7 (- 8.8 to - 0.7), n = 62 and 336. CONCLUSIONS: Adverse neurodevelopmental outcomes in infants born by prelabour caesarean section may be apparent already a few months after birth. Additional studies are warranted to explore this relationship further.

Longitudinal cohort study reveals different patterns of stress in parents of preterm infants during the first year after birth.

AIM: To compare experiences of stress in mothers and fathers of preterm infants during the first year of life, assess changes in parental stress and explore potential predictors of parental stress. METHODS: Between 2013 and 2015, data on parental stress were collected at 8 weeks after discharge and at 6 and 12 months postpartum from 493 mothers and 329 fathers of 547 preterm infants in Sweden. The Swedish Parenting Stress Questionnaire was used as a secondary outcome in a randomised clinical trial of breastfeeding support. RESULTS: At the three time points, mothers perceived more role restriction and fathers more social isolation (P < .001). Stress decreased in mothers during the first year (P = .018), whereas stress increased in fathers between 6 and 12 months (P = .048). Mothers of very preterm infants (P = .024), parents of twins (P = .038) and parents with lower perceived general health (P = .003) reported higher levels of stress during the first year after birth. CONCLUSION: This study identified several factors that influenced parental stress. Mothers and fathers showed different patterns of stress levels during the first year after birth. This finding indicates different needs for mothers and fathers regarding the time at which parental support after discharge might be most beneficial.

When age really matters; ferritin reference intervals during infancy revisited.

Infants are at risk for iron deficiency. Despite research advances, assessing iron stores during infancy remains a challenge to the clinician. Ferritin is the first-choice laboratory marker for measuring iron stores but it is today still unclear how to evaluate reference intervals among infants. We have studied Swedish infants (n = 456), born at term after normal pregnancies. Ferritin was measured at birth (umbilical cord sample), 48-72 h, 4 months and 12 months. Lower and upper reference interval limits were constructed as the 2.5th and 97.5th percentiles. By a large study population, we were able to use more stringent measures to avoid interference from the acute phase response than previous reports on ferritin reference intervals. When we used mathematical transformation we furthermore avoided potential information loss in precision and confirmed earlier reports of sex differences. At the lower reference interval limits there were small differences between sexes. For the higher limits, the differences were more pronounced in the older infant. At 0-3 d of age we observed a difference between the sexes of only 5% at the upper limits. The differences peaked at 12 months, where the boys' upper 97.5th percentile was 56% compared to girls.