Continuous non-invasive measurement of cardiac output in neonatal intensive care using regional impedance cardiography: a prospective observational study.

OBJECTIVES: To compare agreement between echocardiography and regional impedance cardiography (RIC)-derived cardiac output (CO), and to construct indicative normative ranges of CO for gestational age groups. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort observational study performed in a tertiary centre in London, UK, including neonates born between 25 and 42 weeks' gestational age. EXPOSURES: Neonates on the postnatal ward had 2 hours of RIC monitoring; neonates in intensive care had RIC monitoring for the first 72 hours, then weekly for 2 hours, with concomitant echocardiography measures. MAIN OUTCOMES AND MEASURES: RIC was used to measure CO continuously. Statistical analyses were performed using R (V.4.2.2; R Core Team 2022). RIC-derived CO and echocardiography-derived CO were compared using Pearson's correlations and Bland-Altman analyses. Differences in RIC-derived CO between infants born extremely, very and late preterm were assessed using analyses of variance and mixed-effects modelling. RESULTS: 127 neonates (22 extremely, 46 very, 29 late preterm and 30 term) were included. RIC and echocardiography-measured weight-adjusted CO were correlated (r=0.62, p<0.001) with a Bland-Altman bias of -31 mL/min/kg (limits of agreement -322 to 261 mL/min/kg). The RIC-derived CO fell over 12 hours, then increased until 72 hours after birth. The 72-hour weight-adjusted mean CO was higher in extremely preterm (424±158 mL/min/kg) compared with very (325±131 mL/min/kg, p<0.001) and late preterm (237±81 mL/min/kg, p<0.001) neonates; this difference disappeared by 2-3 weeks of age. CONCLUSIONS: RIC is valid for continuous, non-invasive CO measurement in neonates. Indicative normative CO ranges could help clinicians to make more informed haemodynamic management decisions, which should be explored in future studies. TRIAL REGISTRATION NUMBER: NCT04064177.

Comparison of clinical outcomes between active and permissive blood pressure management in extremely preterm infants.

Background: There remains uncertainty about the definition of normal blood pressure (BP), and when to initiate treatment for hypotension for extremely preterm infants. To determine the short-term outcomes of extremely preterm infants managed by active compared with permissive BP support regimens during the first 72 hours of life. Method: This is a retrospective medical records review of 23 +0-28 +6 weeks' gestational age (GA) infants admitted to neonatal units (NNU) with active BP support (aimed to maintain mean arterial BP (MABP) >30 mmHg irrespective of the GA) and permissive BP support (used medication only when babies developed signs of hypotension) regimens. Babies admitted after 12 hours of age, or whose BP data were not available were excluded. Results: There were 764 infants admitted to the participating hospitals; 671 (88%) were included in the analysis (263 active BP support and 408 permissive BP support). The mean gestational age, birth weight, admission temperature, clinical risk index for babies (CRIB) score and first haemoglobin of infants were comparable between the groups. Active BP support group infants had consistently higher MABP and systolic BP throughout the first 72 hours of life (p<0.01). In the active group compared to the permissive group 56 (21.3%) vs 104 (25.5%) babies died, and 21 (8%) vs 51 (12.5%) developed >grade 2 intra ventricular haemorrhage (IVH). Death before discharge (adjusted OR 1.38 (0.88 - 2.16)) or IVH (1.38 (0.96 - 1.98)) was similar between the two groups. Necrotising enterocolitis (NEC) ≥stage 2 was significantly higher in permissive BP support group infants (1.65 (1.07 - 2.50)). Conclusions: There was no difference in mortality or IVH between the two BP management approaches. Active BP support may reduce NEC. This should be investigated prospectively in large multicentre randomised studies.

THE PROBLEM: Doctors are still not clear what the normal blood pressure (BP) is for premature babies during the first three days of life. Furthermore, it is unclear when to start treatment for low BP in preterm babies born at or before 28 weeks of gestation. What we did: We compared clinical outcomes of a group of preterm babies who were treated with medication to maintain BP above 30mmHg ('active BP treatment' group) to a group of babies who were treated when they developed signs of low BP ('permissive BP treatment' group) from two large Neonatal Intensive Care Units (NICU) in London, UK. How we tested it: Preterm babies born between 23 and 28 weeks gestation were studied. Babies admitted after 12 hours of age, or whose BP information was not available were excluded. BP measurements for the first 72 hours of life, and clinical outcome details of babies from NICU admission to discharge home were collected from medical records. What we found: There was no difference in the level of prematurity, birth weight, and severity of illness score at admission between the active BP treatment and permissive BP treatment group babies. Active BP treatment group babies had a higher BP throughout the first 72 hours of life. There was no important difference in the number of babies who died or developed moderate grade brain haemorrhage between the active BP treatment group compared to the permissive BP treatment group. A significantly lower number of the active BP treatment group babies developed necrotising enterocolitis (NEC, inflammation of gut). CONCLUSIONS: There was no difference in death or brain haemorrhage in babies between the two BP treatment methods. Active BP treatment during the first 72 hours of life may reduce NEC in preterm babies. This should be studied in large multicentre clinical studies.

Impact of perinatal factors on biomarkers of cardiovascular disease risk in preadolescent children.

BACKGROUND: This review aims to summarize associations of the perinatal environment with arterial biophysical properties in childhood, to elucidate possible perinatal origins of adult cardiovascular disease (CVD). METHODS: A systematic search of PubMed database was performed (December 2020). Studies exploring associations of perinatal factors with arterial biophysical properties in children 12 years old or less were included. Properties studied included: pulse wave velocity; arterial stiffness or distensibility; augmentation index; intima-media thickness of aorta (aIMT) or carotids; endothelial function (laser flow Doppler, flow-mediated dilatation). Two reviewers independently performed study selection and data extraction. RESULTS: Fifty-two of 1084 identified records were included. Eleven studies explored associations with prematurity, 14 explored maternal factors during pregnancy, and 27 explored effects of low birth weight, small-for-gestational age and foetal growth restriction (LBW/SGA/FGR). aIMT was consistently higher in offspring affected by LBW/SGA/FGR in all six studies examining this variable. The cause of inconclusive or conflicting associations found with other arterial biophysical properties and perinatal factors may be multifactorial: in particular, measurements and analyses of related properties differed in technique, equipment, anatomical location, and covariates used. CONCLUSION: aIMT was consistently higher in LBW/SGA/FGR offspring, which may relate to increased long-term CVD risk. Larger and longer term cohort studies may help to elucidate clinical significance, particularly in relation to established CVD risk factors. Experimental studies may help to understand whether lifestyle or medical interventions can reverse perinatal changes aIMT. The field could be advanced by validation and standardization of techniques assessing arterial structure and function in children.

Biomarkers of gut injury in neonates - where are we in predicting necrotising enterocolitis?

Despite advances in neonatal care Necrotising Enterocolitis (NEC) continues to have a significant mortality and morbidity rate, and with increasing survival of those more immature infants the population at risk of NEC is increasing. Ischaemia, reperfusion, and inflammation underpin diseases affecting intestinal blood flow causing gut injury including Necrotising Enterocolitis. There is increasing interest in tissue biomarkers of gut injury in neonates, particularly those representing changes in intestinal wall barrier and permeability, to determine whether these could be useful biomarkers of gut injury. This article reviews current and newly proposed markers of gut injury, the available literature evidence, recent advances and considers how effective they are in clinical practice. We discuss each biomarker in terms of its effectiveness in predicting NEC onset and diagnosis or predicting NEC severity and then those that will aid in surveillance and identifying those infants are greatest risk of developing NEC.

Could Near Infrared Spectroscopy (NIRS) be the new weapon in our fight against Necrotising Enterocolitis?

There is no ideal single gut tissue or inflammatory biomarker available to help to try and identify Necrotising Enterocolitis (NEC) before its clinical onset. Neonatologists are all too familiar with the devastating consequences of NEC, and despite many advances in neonatal care the mortality and morbidity associated with NEC remains significant. In this article we review Near Infrared Spectroscopy (NIRS) as a method of measuring regional gut tissue oxygenation. We discuss its current and potential future applications, including considering its effectiveness as a possible new weapon in the early identification of NEC.

Regional cerebral and splanchnic tissue oxygen saturation in preterm infants - Longitudinal normative measurements.

BACKGROUND: To investigate regional splanchnic and cerebral tissue oxygen saturation in preterm infants <30 weeks gestation. METHODS: Cerebral (cTOI) and splanchnic (sTOI) Tissue Oxygenation Index were measured weekly in 5 min epochs for a total period of 60 min using NIRS (NIRO-300) for the first 8 weeks of life, in 48 appropriately grown preterm infants born at <30 weeks gestation. Infants who developed HPI and/or NEC (n = 12) and those that died (n = 1) were excluded from our main outcome measure of regional gut and cerebral tissue oxygenation in healthy preterm infants <30 weeks gestation. RESULTS: Median birthweight 789 g (460-1486), gestational age 25+6 weeks (23+0-29+1) and 51.4% female. 217 NIRS measurements were completed across the first 8 weeks of life. Mean weekly cTOI ranged from 56.8-65.4% and sTOI ranged from 36.7-46.0%. Mean cTOI was significantly higher than mean sTOI (p < 0.001) throughout the first 8 weeks of life. Mean cTOI decreased significantly with increasing postnatal age [-0.59% each week (-1.26% to -0.07%) p = 0.04]. None of the examined confounding factors had a significant effect. CONCLUSIONS: This is the first report of regional cerebral and splanchnic tissue oxygen saturation ranges during the first 8 weeks of life for preterm infants born at <30 weeks gestation.

Cardiac Output Measurement in Neonates and Children Using Noninvasive Electrical Bioimpedance Compared With Standard Methods: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review and meta-analyze the validity of electrical bioimpedance-based noninvasive cardiac output monitoring in pediatrics compared with standard methods such as thermodilution and echocardiography. DATA SOURCES: Systematic searches were conducted in MEDLINE and EMBASE (2000-2019). STUDY SELECTION: Method-comparison studies of transthoracic electrical velocimetry or whole body electrical bioimpedance versus standard cardiac output monitoring methods in children (0-18 yr old) were included. DATA EXTRACTION: Two reviewers independently performed study selection, data extraction, and risk of bias assessment. Mean differences of cardiac output, stroke volume, or cardiac index measurements were pooled using a random-effects model (R Core Team, R Foundation for Statistical Computing, Vienna, Austria, 2019). Bland-Altman statistics assessing agreement between devices and author conclusions about inferiority/noninferiority were extracted. DATA SYNTHESIS: Twenty-nine of 649 identified studies were included in the qualitative analysis, and 25 studies in the meta-analyses. No significant difference was found between means of cardiac output, stroke volume, and cardiac index measurements, except in exclusively neonatal/infant studies reporting stroke volume (mean difference, 1.00 mL; 95% CI, 0.23-1.77). Median percentage error in child/adolescent studies approached acceptability (percentage error less than or equal to 30%) for cardiac output in L/min (31%; range, 13-158%) and stroke volume in mL (26%; range, 14-27%), but not in neonatal/infant studies (45%; range, 29-53% and 45%; range, 28-70%, respectively). Twenty of 29 studies concluded that transthoracic electrical velocimetry/whole body electrical bioimpedance was noninferior. Transthoracic electrical velocimetry was considered inferior in six of nine studies with heterogeneous congenital heart disease populations. CONCLUSIONS: The meta-analyses demonstrated no significant difference between means of compared devices (except in neonatal stroke volume studies). The wide range of percentage error reported may be due to heterogeneity of study designs, devices, and populations included. Transthoracic electrical velocimetry/whole body electrical bioimpedance may be acceptable for use in child/adolescent populations, but validity in neonates and congenital heart disease patients remains uncertain. Larger studies in specific clinical contexts with standardized methodologies are required.

Cuddling very and extremely preterm babies in the delivery room is a positive and normal experience for mothers after the birth.

AIM: Extremely preterm infants are separated from their mothers immediately after birth and not placed skin-to-skin in routine neonatal intensive care unit settings. Visual and physical contact in the delivery room as a first cuddle potentially can facilitate early parent-infant interaction and reduce the trauma of separation. Our aim in this study was to explore mothers' experience of delivery room cuddle by collecting qualitative feedback via emotional mapping. METHODS: Six mothers experiencing delivery room cuddle had been recruited (GA of their babies 24 + 5-29 + 0 weeks, birth weight 540-1019 g). Using a descriptive qualitative approach, semi-structured interviews were performed with six mothers following consent via Zoom or phone between September 2020 and March 2021. Interviews were transcribed using AI Otter and then analysed using thematic analysis. RESULTS: Analysis of the participants' experiences revealed five themes: fears and hopes around delivery; the moment of delivery-recognising uncertainty; reclaiming normalcy; forming connections; and the journey ahead as an empowered parent. CONCLUSION: All mothers reported positive emotions about the cuddle with their baby. They highlighted that this physical contact was often the only positive and 'normal' birth experience they had from the time of delivery.

Systematic review confirmed the benefits of early skin-to-skin contact but highlighted lack of studies on very and extremely preterm infants.

AIM: We systematically reviewed the literature to identify the benefits of early skin-to-skin contact (SSC) for all gestational ages. METHODS: The MEDLINE, Embase and CINAHL databases were searched for papers published in English from 1 January 1975 to 31 March 2020. Early SSC was defined as when the infant was placed directly onto the mother's chest within 180 min of birth. Two authors independently searched the databases, appraised study quality and extracted the study design and outcome data. The primary outcomes were the infants' physiological stability after birth: thermoregulation and stabilisation. The secondary outcomes were exclusive breastfeeding and mother-infant interaction. RESULTS: We reviewed 30 studies that assessed the benefits of early SSC: 22 comprised term-born healthy infants and eight focused on preterm or ill infants. These included various gestational ages, birth methods and cultural backgrounds. The studies demonstrated that early SSC stabilised neonatal physiological parameters, promoted exclusive breastfeeding and supported bonding. Most of the data were from term and late preterm births. CONCLUSION: This systematic review showed that early SSC could be beneficial. Further studies that focus on providing very and extremely preterm infants with SSC, and parental experiences, are needed to enable SSC to be adopted as routine practice.

Pregnancy and neonatal outcomes in COVID-19: study protocol for a global registry of women with suspected or confirmed SARS-CoV-2 infection in pregnancy and their neonates, understanding natural history to guide treatment and prevention.

INTRODUCTION: Previous novel COVID-19 pandemics, SARS and middle east respiratory syndrome observed an association of infection in pregnancy with preterm delivery, stillbirth and increased maternal mortality. COVID-19, caused by SARS-CoV-2 infection, is the largest pandemic in living memory.Rapid accrual of robust case data on women in pregnancy and their babies affected by suspected COVID-19 or confirmed SARS-CoV-2 infection will inform clinical management and preventative strategies in the current pandemic and future outbreaks. METHODS AND ANALYSIS: The pregnancy and neonatal outcomes in COVID-19 (PAN-COVID) registry are an observational study collecting focused data on outcomes of pregnant mothers who have had suspected COVID-19 in pregnancy or confirmed SARS-CoV-2 infection and their neonates via a web-portal. Among the women recruited to the PAN-COVID registry, the study will evaluate the incidence of: (1) miscarriage and pregnancy loss, (2) fetal growth restriction and stillbirth, (3) preterm delivery, (4) vertical transmission (suspected or confirmed) and early onset neonatal SARS-CoV-2 infection.Data will be centre based and collected on individual women and their babies. Verbal consent will be obtained, to reduce face-to-face contact in the pandemic while allowing identifiable data collection for linkage. Statistical analysis of the data will be carried out on a pseudonymised data set by the study statistician. Regular reports will be distributed to collaborators on the study research questions. ETHICS AND DISSEMINATION: This study has received research ethics approval in the UK. For international centres, evidence of appropriate local approval will be required to participate, prior to entry of data to the database. The reports will be published regularly. The outputs of the study will be regularly disseminated to participants and collaborators on the study website (https://pan-covid.org) and social media channels as well as dissemination to scientific meetings and journals. STUDY REGISTRATION NUMBER: ISRCTN68026880.

Cerebral Oxygenation in Preterm Infants With Necrotizing Enterocolitis.

BACKGROUND AND OBJECTIVES: Preterm infants with necrotizing enterocolitis (NEC) are known to have worse neurodevelopmental outcomes, but there is no substantial evidence to support an underlying pathophysiology. We aimed to examine whether cerebral oxygenation differs in those infants who develop NEC compared to cerebral oxygenation in those who do not. METHODS: We examined 48 infants <30 weeks' gestation admitted to a tertiary level NICU from October 2016 to May 2018. Infants with birth weight less than or equal to the second percentile, abnormal antenatal dopplers or twin-to-twin-transfusion-syndrome were excluded. Cerebral oximetry measurements were performed by using a near-infrared spectroscopy (NIRS) monitor weekly for 60 minutes, allowing measurement of cerebral tissue oxygenation index from the first week of life to 36 weeks postconceptional age. Weekly clinical status was also recorded. NEC was defined as greater than or equal to Bell stage 2. RESULTS: The median birth weight was 884 g (range of 460-1600 g), the median weeks' gestational age was 26 + 3/7 (23 + 0/7 to 29 + 6/7), and 52% were girls. In total, 276 NIRS measurements were completed, and 7 infants developed NEC. NIRS measurements from 1 infant with NEC and 4 infants without NEC who developed hemorrhagic parenchymal infarcts were excluded from analysis. Infants who developed NEC had significantly lower cerebral tissue oxygenation index than those who did not (P = .011), even when adjusted for confounders, including gestational age, birth weight, patent ductus arteriosus, enteral feeds, sex, ethnicity, and hemoglobin. CONCLUSIONS: Infants with NEC have significantly lower cerebral tissue oxygenation throughout their neonatal intensive care stay in comparison with those who did not develop NEC. This is a novel finding and could explain their worse neurodevelopmental outcome.

Improving infant outcomes through implementation of a family integrated care bundle including a parent supporting mobile application.

OBJECTIVE: The aim of the Integrated Family Delivered Care (IFDC) programme was to improve infant health outcomes and parent experience through education and competency-based training. DESIGN: In collaboration with veteran parents' focus groups, we created an experienced co-designed care bundle including IFDC mobile application, which together with staff training programme comprised the IFDC programme. Infant outcomes were compared with retrospective controls in a prepost intervention analysis. MAIN OUTCOME MEASURES: The primary outcome measure was the length of stay (LOS). RESULTS: Between April 2017 and May 2018, 89 families were recruited; 37 infants completed their entire care episode in our units with a minimum LOS >14 days. From a gestational age (GA) and birth weight-matched retrospective cohort, 57 control infants were selected. Data were also analysed for subgroup under 30 weeks GA (n=20).Infants in the IFDC group were discharged earlier: median corrected GA (36+0 (IQR 35+0-38+0) vs 37+1 (IQR 36+3-38+4) weeks; p=0.003), with shorter median LOS (41 (32-63) vs 55 (41-73) days; p=0.022). This was also evident in the subgroup <30 weeks GA (61 (39-82) vs 76 (68-84) days; p=0.035). Special care days were significantly lower in the IFDC group (30 (21-41) vs 40 (31-46); p=0.006). The subgroup of infants (<30 weeks) reached full suck feeding earlier (median: 47 (37-76) vs 72 (66-82) days; p=0.006). CONCLUSION: This is the first reported study from a UK tertiary neonatal unit demonstrating significant benefits of family integrated care programme. The IFDC programme has significantly reduced LOS, resulted in the earlier achievement of full enteral and suck feeds.

Measurement of gut oxygenation in the neonatal population using near-infrared spectroscopy: a clinical tool?

CONTEXT: Near-infrared spectroscopy (NIRS) is a non-invasive bedside monitor of tissue oxygenation that may be a useful clinical tool in monitoring of gut oxygenation in newborn infants. OBJECTIVE: To systematically review literature to determine whether NIRS is a reliable tool to monitor gut oxygenation on neonatal units. DATA SOURCES: PubMed and Embase databases were searched using the terms 'neonate', 'preterm infants', 'NIRS' and 'gut oxygenation' (2001-2018). STUDY SELECTION: Studies were included if they met inclusion criteria (clinical trial, observational studies, neonatal population, articles in English and reviewing regional gut oxygen saturations) and exclusion criteria (not evaluating abdominal NIRS or regional oxygen saturations). DATA EXTRACTION: Two authors independently searched PubMed and Embase using the predefined terms, appraised study quality and extracted from 30 studies the study design and outcome data. LIMITATIONS: Potential for publication bias, majority of studies were prospective cohort studies and small sample sizes. RESULTS: Thirty studies were reviewed assessing the validity of abdominal NIRS and potential application in neonates. Studies reviewed assessed abdominal NIRS in different settings including normal neonates, bolus and continuous feeding, during feed intolerance, necrotising enterocolitis and transfusion with packed red cells. Several observational studies demonstrated how NIRS could be used in clinical practice. CONCLUSIONS: NIRS may prove to be a useful bedside tool on the neonatal unit, working alongside current clinical tools in the monitoring of newborn infants (preterm and term) and inform clinical management. We recommend further studies including randomised controlled trials looking at specific measurements and cut-offs for abdominal NIRS for use in further clinical practice.

The association of the cerebral oxygenation during neonatal sepsis with the Bayley-III Scale of Infant and Toddler Development index scores at 18-24 months of age.

BACKGROUND: Neonatal sepsis has been associated with poor neurodevelopmental outcome, however the evidence regarding the exact mechanism of the inflammation to the developing neonatal brain are inconclusive. AIMS: To investigate association between cerebral oxygenation during neonatal sepsis and neurodevelopmental outcome. STUDY DESIGN: Follow-up assessment of a previously described prospective case-control study. SUBJECTS: A cohort of late preterm (34-37 weeks' gestation) and preterm (<34 weeks' gestation) infants with sepsis and healthy controls, evaluated at 18-24 months of corrected gestational age with Bayley-III Scales for Infant and Toddler Development (BSID-III). OUTCOME MEASURES: To evaluate the association between cerebral tissue oxygenation index (cTOI) and fractional tissue oxygen extraction (FTOE), measured with near-infrared spectroscopy, during sepsis and the composite cognitive and motor index scores. RESULTS: Thirty-one infants with blood culture confirmed neonatal sepsis and thirty-five controls were recruited. The cerebral oxygenation was significantly lower in septic neonates, compared to controls (61 ±â€¯7 compared to 72 ±â€¯5; p < 0.001). Infants with sepsis had significantly lower cognitive and motor index scores and higher proportion of suboptimal cognitive (16% compared to 3%, p = 0.045) and motor (16% compared to none, p = 0.008) index score. The low mean cTOI and FTOE noted in septic infants were significantly associated with worse cognitive and motor composite index scores. CONCLUSIONS: Infants with lower cerebral oxygenation during neonatal sepsis are at increased risk of worse cognitive and motor scores in the neurodevelopmental assessment.

The impact of cross-border IVF on maternal and neonatal outcomes in multiple pregnancies: Experience from a UK fetal medicine service.

OBJECTIVES: To determine whether women seeking NHS care for IVF multiple pregnancies were more likely to have sought IVF treatment overseas and whether this was associated with different maternal and neonatal outcomes. STUDY DESIGN: A single large tertiary centre, for perinatal care in northwest London. Sixty-five women were referred to our fetal medicine centre, between 2012-2016, with IVF conceived multiple pregnancies. INCLUSION CRITERIA: In Vitro fertilisation and conception of twins/ triplets/quadruplets. EXCLUSION CRITERIA: Intra-uterine insemination, ovulation induction, Clomid-conception and singleton pregnancies. The primary outcome measure was the Country where IVF treatment was performed. The secondary outcomes measures included the specifics of IVF treatment (e.g. number of embryos transferred), subsequent pregnancy outcomes (e.g. live-births and prematurity) and neonatal outcomes (e.g. length and cost of care). RESULTS AND CONCLUSION: Thirty-eight women had IVF overseas; they were older and had more pre-existing medical conditions. Eleven pregnancies used donor embryos, of which ten were from overseas treatment. 75% of women treated overseas conceived a triplet or higher order pregnancy compared to fewer than 10% of women who conceived in the UK. Almost half of all women treated overseas had more than two embryos transferred. Overseas IVF pregnancies had poorer obstetric and neonatal outcomes: 24% of live born babies died in the neonatal period compared to 0% in the UK group. The average neonatal costs per baby born from overseas IVF were £20, 600: two-and-a-half times higher than for those whose mothers conceived in the UK. Higher order multiple pregnancies are greatly over-represented by those undergoing IVF in overseas clinics. These are associated with poorer obstetric and neonatal outcomes. Perhaps paradoxically, improving NHS provision of fertility services might improve outcomes for the mother and babies while reducing the long-term burden to both fertility patients and the NHS.