Cardiovascular and cerebrovascular effects of caffeine maintenance in preterm infants during the transitional period.

BACKGROUND AND AIM: Caffeine is routinely used for the prophylaxis of prematurity-related apnoeas. We aimed to evaluate the effect of caffeine maintenance on cardiovascular and cerebrovascular haemodynamics using a non-invasive multimodal monitoring in preterm infants during the transitional period. METHODS: Infants <32 weeks' gestational age (GA) were enrolled in this observational prospective study. The following parameters were recorded before and after the administration of caffeine citrate 5 mg/kg using near-infrared spectroscopy, pulse oximetry and electrical velocimetry: heart rate, cardiac output, stroke volume, cardiac contractility, systemic vascular resistance (SVR), perfusion index, peripheral and cerebral oxygenation, cerebral fractional oxygen extraction, correlation index between cerebral oxygenation and heart rate (TOHRx, marker of cerebrovascular reactivity). Multilevel mixed-effects linear models were used to assess the impact of caffeine and of relevant clinical covariates on each parameter. RESULTS: Seventy-seven infants (mean GA 29.3 ± 2.5 weeks, mean birthweight 1148 ± 353 g) were included. Caffeine administration was associated with increased SVR (B = 0.623, p = 0.004) and more negative TOHRx values (B = -0.036, p = 0.022), which suggest improved cerebrovascular reactivity. CONCLUSIONS: Caffeine administration at maintenance dosage during postnatal transition is associated with increased systemic vascular tone and improved cerebrovascular reactivity. A possible role for caffeine-mediated inhibition of adenosine receptors may be hypothesized. IMPACT: This study provides a thorough and comprehensive overview of multiple cerebrovascular and cardiovascular parameters, monitored non-invasively by combining near-infrared spectroscopy, electrical velocimetry and pulse oximetry, before and after the administration of caffeine at maintenance dosage in preterm infants during postnatal transition. Caffeine was associated with an improvement in cerebrovascular reactivity and with a slight but significant increase in systemic vascular resistance, with no additional effects on other cardiovascular and cerebrovascular parameters. Our results support the safety of caffeine treatment even during a phase at risk for haemodynamic instability such as postnatal transition and suggest potential beneficial effects on cerebral haemodynamics.

Socioemotional and Psychological Outcomes of Hypoxic-Ischemic Encephalopathy: A Systematic Review.

BACKGROUND AND OBJECTIVES: Therapeutic hypothermia has reduced the risk of death or major disability following perinatal hypoxic-ischemic encephalopathy (HIE); however, many children who experience perinatal HIE still go on to develop personal and behavioral challenges, which can be difficult for caregivers and a public health burden for society. Our objective with this review is to systematically identify and synthesize studies that evaluate associations between perinatal HIE and socioemotional or psychological outcomes. METHODS: We screened all search-returned journal articles from Cochrane Library, Embase, Medline, PsycINFO, Scopus, and Web of Science from data inception through February 1, 2023. Keywords related to HIE (eg, neonatal encephalopathy, neonatal brain injury) and outcomes (eg, social*, emotion*, behav* problem, psycholog*, psychiatr*) were searched with a predefined search string. We included all observational human studies reporting socioemotional or psychological sequelae of term HIE. Study data were recorded on standardized sheets, and the Newcastle-Ottawa Scale was adapted to assess study quality. RESULTS: We included 43 studies documenting 3244 HIE participants and 2132 comparison participants. We found statistically significant associations between HIE and social and emotional, behavioral, and psychological and psychiatric deficits throughout infancy, childhood, and adolescence (19 studies). The authors of the included studies also report nonsignificant findings (11 studies) and outcomes without statistical comparison (25 studies). CONCLUSIONS: Perinatal HIE may be a risk factor for a range of socioemotional and psychological challenges in the short- and long-term. Routine screening, early intervention, and follow-up support may be particularly beneficial to this population.

Fetal brain growth and infant autistic traits.

BACKGROUND: Structural differences exist in the brains of autistic individuals. To date only a few studies have explored the relationship between fetal brain growth and later infant autistic traits, and some have used fetal head circumference (HC) as a proxy for brain development. These findings have been inconsistent. Here we investigate whether fetal subregional brain measurements correlate with autistic traits in toddlers. METHODS: A total of 219 singleton pregnancies (104 males and 115 females) were recruited at the Rosie Hospital, Cambridge, UK. 2D ultrasound was performed at 12-, 20- and between 26 and 30 weeks of pregnancy, measuring head circumference (HC), ventricular atrium (VA) and transcerebellar diameter (TCD). A total of 179 infants were followed up at 18-20 months of age and completed the quantitative checklist for autism in toddlers (Q-CHAT) to measure autistic traits. RESULTS: Q-CHAT scores at 18-20 months of age were positively associated with TCD size at 20 weeks and with HC at 28 weeks, in univariate analyses, and in multiple regression models which controlled for sex, maternal age and birth weight. LIMITATIONS: Due to the nature and location of the study, ascertainment bias could also have contributed to the recruitment of volunteer mothers with a higher than typical range of autistic traits and/or with a significant interest in the neurodevelopment of their children. CONCLUSION: Prenatal brain growth is associated with toddler autistic traits and this can be ascertained via ultrasound starting at 20 weeks gestation.

Review of measurements and imaging of cytochrome-c-oxidase in humans using near-infrared spectroscopy: an update.

This review examines advancements in the measurement and imaging of oxidized cytochrome-c-oxidase (oxCCO) using near-infrared spectroscopy (NIRS) in humans since 2016. A total of 34 published papers were identified, with a focus on both adult and neonate populations. The NIRS-derived oxCCO signal has been demonstrated to correlate with physiological parameters and hemodynamics. New instrumentation, such as systems that allow the imaging of changes of oxCCO with diffuse optical tomography or combine the oxCCO measurement with diffuse correlation spectroscopy measures of blood flow, have advanced the field in the past decade. However, variability in its response across different populations and paradigms and lack of standardization limit its potential as a reliable and valuable indicator of brain health. Future studies should address these issues to fulfill the vision of oxCCO as a clinical biomarker.

Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series).

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Near-infrared spectroscopy monitoring of neonatal cerebrovascular reactivity: where are we now?

Cerebrovascular reactivity defines the ability of the cerebral vasculature to regulate its resistance in response to both local and systemic factors to ensure an adequate cerebral blood flow to meet the metabolic demands of the brain. The increasing adoption of near-infrared spectroscopy (NIRS) for non-invasive monitoring of cerebral oxygenation and perfusion allowed investigation of the mechanisms underlying cerebrovascular reactivity in the neonatal population, confirming important associations with pathological conditions including the development of brain injury and adverse neurodevelopmental outcomes. However, the current literature on neonatal cerebrovascular reactivity is mainly still based on small, observational studies and is characterised by methodological heterogeneity; this has hindered the routine application of NIRS-based monitoring of cerebrovascular reactivity to identify infants most at risk of brain injury. This review aims (1) to provide an updated review on neonatal cerebrovascular reactivity, assessed using NIRS; (2) to identify critical points that need to be addressed with targeted research; and (3) to propose feasibility trials in order to fill the current knowledge gaps and to possibly develop a preventive or curative approach for preterm brain injury. IMPACT: NIRS monitoring has been largely applied in neonatal research to assess cerebrovascular reactivity in response to blood pressure, PaCO2 and other biochemical or metabolic factors, providing novel insights into the pathophysiological mechanisms underlying cerebral blood flow regulation. Despite these insights, the current literature shows important pitfalls that would benefit to be addressed in a series of targeted trials, proposed in the present review, in order to translate the assessment of cerebrovascular reactivity into routine monitoring in neonatal clinical practice.

Cot-side imaging of functional connectivity in the developing brain during sleep using wearable high-density diffuse optical tomography.

Studies of cortical function in newborn infants in clinical settings are extremely challenging to undertake with traditional neuroimaging approaches. Partly in response to this challenge, functional near-infrared spectroscopy (fNIRS) has become an increasingly common clinical research tool but has significant limitations including a low spatial resolution and poor depth specificity. Moreover, the bulky optical fibres required in traditional fNIRS approaches present significant mechanical challenges, particularly for the study of vulnerable newborn infants. A new generation of wearable, modular, high-density diffuse optical tomography (HD-DOT) technologies has recently emerged that overcomes many of the limitations of traditional, fibre-based and low-density fNIRS measurements. Driven by the development of this new technology, we have undertaken the first cot-side study of newborn infants using wearable HD-DOT in a clinical setting. We use this technology to study functional brain connectivity (FC) in newborn infants during sleep and assess the effect of neonatal sleep states, active sleep (AS) and quiet sleep (QS), on resting state FC. Our results demonstrate that it is now possible to obtain high-quality functional images of the neonatal brain in the clinical setting with few constraints. Our results also suggest that sleep states differentially affect FC in the neonatal brain, consistent with prior reports.

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.

Neuroprotective therapies in the NICU in term infants: present and future.

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

Digit ratio (2D:4D) and maternal testosterone-to-estradiol ratio measured in early pregnancy.

The ratio of index to ring finger (2D:4D) has been hypothesised to indicate prenatal androgen exposure, yet evidence for its validity is lacking. We report the first pre-registered study to investigate mothers' early pregnancy sex hormone concentrations in relation to their children's digit ratios measured at 18-22-month follow-up. Although the testosterone (T) to estradiol (E) ratio correlated negatively with right hand digit ratio (R2D:4D) and directional asymmetry (right-minus-left) in digit ratio (D[R-L]), neither effect remained statistically significant once demographic and obstetric covariates were controlled for. Nevertheless, the multivariate level of analysis did reveal that T correlated positively with left hand digit ratio (L2D:4D) and negatively with D[R-L]. However, the first of these effects is in the opposite direction to that predicted by theory. Taken together, the results of our study suggest research with larger samples is required to determine whether digit ratios are valid proxies for maternal sex hormone exposure.

COVID-19 in the context of pregnancy, infancy and parenting (CoCoPIP) study: protocol for a longitudinal study of parental mental health, social interactions, physical growth and cognitive development of infants during the pandemic.

INTRODUCTION: While the secondary impact of the COVID-19 pandemic on the psychological well-being of pregnant women and parents has become apparent over the past year, the impact of these changes on early social interactions, physical growth and cognitive development of their infants is unknown, as is the way in which a range of COVID-19-related changes have mediated this impact. This study (CoCoPIP) will investigate: (1) how parent's experiences of the social, medical and financial changes during the pandemic have impacted prenatal and postnatal parental mental health and parent-infant social interaction; and (2) the extent to which these COVID-19-related changes in parental prenatal and postnatal mental health and social interaction are associated with fetal and infant development. METHODS AND ANALYSIS: The CoCoPIP study is a national online survey initiated in July 2020. This ongoing study (n=1700 families currently enrolled as of 6 May 2021) involves both quantitative and qualitative data being collected across pregnancy and infancy. It is designed to identify the longitudinal impact of the pandemic from pregnancy to 2 years of age as assessed using a range of parent- and self-report measures, with the aim of identifying if stress-associated moderators (ie, loss of income, COVID-19 illness, access to ante/postnatal support) appear to impact parental mental health, and in turn, infant development. In addition, we aim to document individual differences in social and cognitive development in toddlers who were born during restrictions intended to mitigate COVID-19 spread (eg, social distancing, national lockdowns). ETHICS AND DISSEMINATION: Ethical approval was given by the University of Cambridge, Psychology Research Ethics Committee (PRE.2020.077). Findings will be made available via community engagement, public forums (eg, social media,) and to national (eg, NHS England) and local (Cambridge Universities Hospitals NHS Foundation Trust) healthcare partners. Results will be submitted for publication in peer-reviews journals.

The Impact of Preterm Birth on Sleep through Infancy, Childhood and Adolescence and Its Implications.

There is emergent literature on the relationship between the development of sleep-wake cycles, sleep architecture, and sleep duration during the neonatal period on neurodevelopmental outcomes among children born preterm. There is also a growing literature on techniques to assess sleep staging in preterm neonates using either EEG methods or heart and respiration rate. Upon discharge from hospital, sleep in children born preterm has been assessed using parent report, actigraphy, and polysomnography. This review describes the ontogeny and measurement of sleep in the neonatal period, the current evidence on the impact of preterm birth on sleep both in the NICU and in childhood and adolescence, and the interaction between sleep, cognition, and social-emotional outcomes in this population.

Expectant parents' perceptions of healthcare and support during COVID-19 in the UK: a thematic analysis.

BACKGROUND: In response to the COVID-19 pandemic, expectant parents experienced changes in the availability and uptake of both National Health Service (NHS) community and hospital-based healthcare. OBJECTIVE: To examine how COVID-19 and its societal related restrictions have impacted the provision of healthcare support for pregnant women during the COVID-19 pandemic. METHOD: A thematic analysis using an inductive approach was undertaken using data from open-ended responses to the national COVID in Context of Pregnancy, Infancy and Parenting (CoCoPIP) Study online survey (n = 507 families). FINDINGS: The overarching theme identified was the way in which the changes to healthcare provision increased parents' anxiety levels, and feelings of not being supported. Five sub-themes, associated with the first wave of the pandemic, were identified: (1) rushed and/or fewer antenatal appointments, (2) lack of sympathy from healthcare workers, (3) lack of face-to-face appointments, (4) requirement to attend appointments without a partner, and (5) requirement to use PPE. A sentiment analysis, that used quantitative techniques, revealed participant responses to be predominantly negative (50.1%), with a smaller proportion of positive (21.8%) and neutral (28.1%) responses found. CONCLUSION: This study provides evidence indicating that the changes to healthcare services for pregnant women during the pandemic increased feelings of anxiety and have left women feeling inadequately supported. Our findings highlight the need for compensatory social and emotional support for new and expectant parents while COVID-19 related restrictions continue to impact on family life and society.

Clinical determinants of cerebrovascular reactivity in very preterm infants during the transitional period.

BACKGROUND: Preterm infants are at enhanced risk of brain injury due to altered cerebral haemodynamics during postnatal transition. This observational study aimed to assess the clinical determinants of transitional cerebrovascular reactivity and its association with intraventricular haemorrhage (IVH). METHODS: Preterm infants <32 weeks underwent continuous monitoring of cerebral oxygenation and heart rate over the first 72 h after birth. Serial cranial and cardiac ultrasound assessments were performed to evaluate the ductal status and to diagnose IVH onset. The moving correlation coefficient between cerebral oxygenation and heart rate (TOHRx) was calculated. Linear mixed-effect models were used to analyse the impact of relevant clinical variables on TOHRx. The association between TOHRx and IVH development was also assessed. RESULTS: Seventy-seven infants were included. A haemodynamically significant patent ductus arteriosus (hsPDA) (ß = 0.044, 95% CI: 0.007-0.081) and ongoing dopamine treatment (ß = 0.096, 95% CI: 0.032-0.159) were associated with increasing TOHRx, indicating impaired cerebrovascular reactivity. A significant association between TOHRx, mean arterial blood pressure (ß = -0.004, 95% CI: -0.007, -0.001) and CRIB-II score (ß = 0.007, 95% CI: 0.001-0.015) was also observed. TOHRx was significantly higher in infants developing high-grade IVH compared to those without IVH. CONCLUSIONS: Dopamine treatment, low blood pressure, hsPDA and high CRIB-II are associated with impaired cerebrovascular reactivity during postnatal transition, with potential implications on IVH development. IMPACT: The correlation coefficient between cerebral oxygenation and heart rate (TOHRx) provides a non-invasive estimation of cerebrovascular reactivity, whose failure has a potential pathogenic role in the development of IVH in preterm infants. This study shows that cerebrovascular reactivity during the transitional period improves over time and is affected by specific clinical and therapeutic factors, whose knowledge could support the development of individualized neuroprotective strategies in at-risk preterm infants. The evidence of increased TOHRx in infants developing high-grade compared to low-grade or no IVH during the transitional period further supports the role of impaired cerebrovascular reactivity in IVH pathophysiology.

Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood.

To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.

Giving birth in a pandemic: women's birth experiences in England during COVID-19.

BACKGROUND: Expectant parents worldwide have experienced changes in the way they give birth as a result of COVID-19, including restrictions relating to access to birthing units and the presence of birthing partners during the birth, and changes to birth plans. This paper reports the experiences of women in England. METHODS: Data were obtained from both closed- and open-ended responses collected as part of the national COVID in Context of Pregnancy, Infancy and Parenting (CoCoPIP) Study online survey (n = 477 families) between 15th July 2020 - 29th March 2021. Frequency data are presented alongside the results of a sentiment analysis; the open-ended data was analysed thematically. RESULTS: Two-thirds of expectant women reported giving birth via spontaneous vaginal delivery (SVD) (66.1%) and a third via caesarean section (CS) (32.6%) or 'other' (1.3%). Just under half (49.7%) of the CS were reported to have been elective/planned, with 47.7% being emergencies. A third (37.4%) of participants reported having no changes to their birth (as set out in their birthing plan), with a further 25% reporting COVID-related changes, and 37.4% reporting non-COVID related changes (e.g., changes as a result of birthing complications). One quarter of the sample reported COVID-related changes to their birth plan, including limited birthing options and reduced feelings of control; difficulties accessing pain-relief and assistance, and feelings of distress and anxiety. Under half of the respondents reported not knowing whether there could be someone present at the birth (44.8%), with 2.3% of respondents reporting no birthing partner being present due to COVID-related restrictions. Parental experiences of communication and advice provided by the hospital prior to delivery were mixed, with significant stress and anxiety being reported in relation to both the fluctuating guidance and lack of certainty regarding the presence of birthing partners at the birth. The sentiment analysis revealed that participant experiences of giving birth during the pandemic were predominately negative (46.9%) particularly in relation to the first national lockdown, with a smaller proportion of positive (33.2%) and neutral responses (19.9%). CONCLUSION: The proportion of parents reporting birthing interventions (i.e., emergency CS) was higher than previously reported, as were uncertainties related to the birth, and poor communication, leading to increased feelings of anxiety and high levels of negative emotions. The implications of these findings are discussed.