Blood pressure and lipid profiles in children born after ART with frozen embryo transfer.

STUDY QUESTION: Are blood pressure (BP) and lipid profiles different between children conceived after ART with frozen embryo transfer (FET), fresh embryo transfer (fresh-ET), and natural conception (NC)? SUMMARY ANSWER: Girls conceived after FET had significantly higher systolic BP and heart rate compared with girls born after fresh-ET; boys conceived after FET had a slightly more favourable lipid profile compared with boys born after fresh-ET and NC. WHAT IS KNOWN ALREADY: Children conceived after ART with FET are more often born large for gestational age (LGA). LGA in general increases the risk of obesity, diabetes, and cardiovascular disease later in life. Studies on mice and humans on the whole ART population have raised concerns about premature vascular ageing and higher BP. The cardiovascular health of children born after FET is scarcely explored and the results are diverging. STUDY DESIGN SIZE DURATION: This study was part of the cohort study 'Health in Childhood following Assisted Reproductive Technology' (HiCART), which included 606 singletons (292 boys) born between December 2009 and December 2013: 200 children were conceived after FET; 203 children were conceived after fresh-ET; and 203 children were conceived naturally and matched for birth year and sex. The study period lasted from January 2019 to September 2021. PARTICIPANTS/MATERIALS SETTING METHODS: The included children were 7-10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging, and BP measurement. Additionally, a fasting blood sample was collected and analysed for cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides. Systolic and diastolic BP were converted to standard deviation scores (SDS) using an appropriate reference and accounting for height (SDS) of the child. The three study groups were compared pairwise using a univariate linear regression model. Mean differences were adjusted for confounders using multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Girls and boys conceived after FET had significantly higher birthweight (SDS) compared with naturally conceived peers (mean difference: girls: 0.35, 95% CI (0.06-0.64), boys: 0.35, 95% CI (0.03-0.68)). Girls conceived after FET had significantly higher systolic BP (SDS) and heart rate compared with girls conceived after fresh-ET (adjusted mean difference: systolic BP (SDS): 0.25 SDS, 95% CI (0.03-0.47), heart rate: 4.53, 95% CI (0.94-8.13)). Regarding lipid profile, no significant differences were found between the three groups of girls. For the boys, no significant differences were found for BP and heart rate. Lipid profiles were more favourable in boys born after FET compared with both boys conceived after fresh-ET and NC. All outcomes were adjusted for parity, maternal BMI at early pregnancy, smoking during pregnancy, educational level, birthweight, breastfeeding, child age at examination, and onset of puberty. LIMITATIONS REASONS FOR CAUTION: The participation rate varied from 18 to 42% in the three groups, and therefore selection bias cannot be excluded. However, extensive non-participant analyses were performed that showed almost no differences in background characteristics between participants and non-participants in the three groups, making selection bias less likely. WIDER IMPLICATIONS OF THE FINDINGS: The higher birthweight in children conceived after FET was associated with increased systolic BP (SDS) and heart rate in girls conceived after FET compared with fresh-ET. This may be an early indicator of compromised long-term cardiovascular health in this group. The study was not powered to investigate these outcomes and further studies are therefore warranted to confirm the findings. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Forskningsfond. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Alternative consent methods used in the multinational, pragmatic, randomised clinical trial SafeBoosC-III.

BACKGROUND: The process of obtaining prior informed consent for experimental treatment does not fit well into the clinical reality of acute and intensive care. The therapeutic window of interventions is often short, which may reduce the validity of the consent and the rate of enrolled participants, to delay trial completion and reduce the external validity of the results. Deferred consent and 'opt-out' are alternative consent methods. The SafeBoosC-III trial was a randomised clinical trial investigating the benefits and harms of cerebral oximetry monitoring in extremely preterm infants during the first 3 days after birth, starting within the first 6 h after birth. Prior, deferred and opt-out consent were all allowed by protocol. This study aimed to evaluate the use of different consent methods in the SafeBoosC-III trial, Furthermore, we aimed to describe and analyse concerns or complaints that arose during the first 6 months of trial conduct. METHODS: All 70 principal investigators were invited to join this descriptive ancillary study. Each principal investigator received a questionnaire on the use of consent methods in their centre during the SafeBoosC-III trial, including the possibility to describe any concerns related to the consent methods used during the first 6 months of the trial, as raised by the parents or the clinical staff. RESULTS: Data from 61 centres were available. In 43 centres, only prior informed consent was used: in seven, only deferred consent. No centres used the opt-out method only, but five centres used prior and deferred, five used prior, deferred and opt-out (all possibilities) and one used both deferred and opt-out. Six centres applied to use the opt-out method by their local research ethics committee but were denied using it. One centre applied to use deferred consent but was denied. There were only 23 registered concerns during the execution of the trial. CONCLUSIONS: Consent by opt-out was allowed by the protocol in this multinational trial but only a few investigators opted for it and some research ethics boards did not accept its use. It is likely to need promotion by the clinical research community to unfold its potential.

Time intervals between pumping did not affect breastmilk protein produced by mothers of preterm infants.

AIM: Few studies investigate factors that might influence the content of expressed breastmilk. This study aims to investigate the influence of the intervals between breastmilk pumping and the time of the day on protein and fat concentration in breastmilk. METHODS: Mothers of very preterm infants in a neonatal ward who expressed more than 400 mL per day were included. Expressed breastmilk was obtained from each mother over 30 h who were pumping at strictly planned and varying intervals: 2, 3, 4 and 6 h. All samples were analysed using infrared transmission spectroscopy. RESULTS: Ten mothers participated at a median of 22 days postpartum. A total of 176 milk samples were analysed, and the average protein and fat concentrations in g/100 mL were 1.1 ± 0.23 and 4.2 ± 1.3, respectively. The time intervals between breast pumping sessions did not impact protein content, but fat content decreased by longer intervals (p < 0.01). The time of the day for milk pumping did not influence the protein or fat content. CONCLUSION: A single milk sample collected after any 2-6 h interval, at any time during the day, represents the protein content in the breastmilk, but not the fat content which decreased with longer intervals.

The parent perspective on paediatric delirium and an associated care bundle: A qualitative study.

AIMS: To explore how parents experienced their child with delirium and how parents viewed our delirium management bundle. DESIGN: We conducted a qualitative exploratory descriptive study using semi-structured individual or dyad interviews. METHODS: Twelve semi-structured interviews with 16 parents of 12 critically ill children diagnosed with delirium in a paediatric intensive care unit were conducted from October 2022 to January 2023 and analysed through a reflexive thematic analysis. FINDINGS: We generated five themes: (1) knowing that something is very wrong, (2) observing manifest changes in the child, (3) experiencing fear of long-term consequences, (4) adding insight to the bundle, and (5) family engagement. CONCLUSION: The parents in our study were able to observe subtle and manifest changes in their child with delirium. This caused fear of lasting impact. The parents regarded most of the interventions in the delirium management bundle as relevant but needed individualization in the application. The parents requested more information regarding delirium and a higher level of parent engagement in the care of their child during delirium. IMPACT: This paper contributes to understanding how parents might experience delirium in their critically ill child, how our delirium management bundle was received by the parents, and their suggestions for improvement. Our study deals with critically ill children with delirium, their parents, and staff working to prevent and manage paediatric delirium (PD) in the paediatric intensive care unit. REPORTING METHOD: The consolidated criteria for reporting qualitative research guidelines were used to ensure the transparency of our reporting. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution to the research design. WHAT DOES THIS PAPER CONTRIBUTE TO THE WIDER GLOBAL COMMUNITY?: - It increases awareness of the parent's perspective on PD in critically ill children. - It shows how PD might affect parents, causing negative emotions such as distress, frustration, and fear of permanent damage. - It shows that the parents in our study, in addition to the care bundle, requested more information on delirium and more involvement in the care of their delirious child.

Prospective validation of Sophia observation withdrawal symptoms: A paediatric delirium scale in critically ill children in Denmark.

BACKGROUND: Paediatric delirium (PD) is increasingly recognised as a common disorder in critically ill children with a reported prevalence ranging from 9% to 66%. We validated the PD component of the Sophia Observation withdrawal Symptoms-Paediatric Delirium (SOS-PD) scale in a Danish setting to provide increased awareness and reliable identification of this critical condition, thereby paving the way for improved pathways to targeted delirium care. OBJECTIVE: The objectives of this study were to criterion validate the PD component of the SOS-PD screening tool by comparing blinded psychiatric and nurse assessments and to estimate the prevalence of delirium in critically ill children in a Danish context. METHODS: A prospective observational study was performed on critically ill children aged between 3 m and 18 y, admitted to an intensive care unit, with a hospital stay of 48 h or more. Assessments took place on a fixed weekday over an 18-month period. To test accuracy and criterion validity, bedside nurses' SOS-PD assessments were compared to the reference standard, a diagnostic assessment performed by a child psychiatrist according to the Diagnostic and Statistical Manual-V criteria by use of the Vanderbilt Assessment of Delirium in Infants and Children. RESULTS: We included 141 children in the study, 30 (21%) of whom were diagnosed with delirium by the child psychiatrist. The accuracy of the delirium diagnosis was 93.6% (95% confidence interval [CI]: 88.3-97.1) among the nurses' SOS-PD assessments compared to the reference standard. The SOS-PD demonstrated a high sensitivity of 83.3% (95% CI: 65.3-94.4) and a high specificity of 96.4% (95% CI: 91.0-99.0) with five false-negative and four false-positive cases. CONCLUSION: The PD component of the SOS-PD tool has good accuracy and validity for assessments performed by nurses compared to a child psychiatrist's diagnosis in critically ill children in a Danish setting. We recommend the use of the SOS-PD instrument in clinical practice.

Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had ∼17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; ∼22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and ∼37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.NEW & NOTEWORTHY We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.

Early EEG-burst sharpness and 2-year disability in extremely preterm infants.

BACKGROUND: Automated computational measures of EEG have the potential for large-scale application. We hypothesised that a predefined measure of early EEG-burst shape (increased burst sharpness) could predict neurodevelopmental impairment (NDI) and mental developmental index (MDI) at 2 years of age over-and-above that of brain ultrasound. METHODS: We carried out a secondary analysis of data from extremely preterm infants collected for an RCT (SafeBoosC-II). Two hours of single-channel cross-brain EEG was used to analyse burst sharpness with an automated algorithm. The co-primary outcomes were moderate-or-severe NDI and MDI. Complete data were available from 58 infants. A predefined statistical analysis was adjusted for GA, sex and no, mild-moderate, and severe brain injury as detected by cranial ultrasound. RESULTS: Nine infants had moderate-or-severe NDI and the mean MDI was 87 ± 17.3 SD. The typical burst sharpness was low (negative values) and varied relatively little (mean -0.81 ± 0.11 SD), but the odds ratio for NDI was increased by 3.8 (p = 0.008) and the MDI was reduced by -3.2 points (p = 0.14) per 0.1 burst sharpness units increase (+1 SD) in the adjusted analysis. CONCLUSION: This study confirms the association between EEG-burst measures in preterm infants and neurodevelopment in childhood. Importantly, this was by a priori defined analysis. IMPACT: A fully automated, computational measure of EEG in the first week of life was predictive of neurodevelopmental impairment at 2 years of age. This confirms many previous studies using expert reading of EEG. Only single-channel EEG data were used, adding to the applicability. EEG was recorded by several different devices thus this measure appears to be robust to differences in electrodes, amplifiers and filters. The likelihood ratio of a positive EEG test, however, was only about 2, suggesting little immediate clinical value.

Preterm children born below 33-35 weeks of gestation have an increased risk of mathematical difficulties.

AIM: To investigate the association between gestational age (GA) and grade point averages by domains of language and mathematics at the end of lower secondary education. METHODS: A nationwide register-based study including all Danish children born in 1992-1997 who completed lower secondary education. Grades were evaluated by GA. Domain-specific differences in grades were investigated, and academic profiles were made. RESULTS: The study population comprised 319 796 children. For language, only minor differences in grades were observed. The grades in mathematics ranged from 7.02 (95% confidence interval [CI]: 7.00-7.04) at GA = 40 weeks to 5.86 (95% CI: 5.61-6.11) at GA <28 weeks. Grade differences showed lower grades in mathematics, compared to language, below GA 33-35 weeks. The academic profile of mathematical difficulties was more prevalent among GA <32 weeks. Average/high grades within both domains represented the predominant academic profile, constituting 68.8% at GA 39-41 weeks and 56.6% at GA <28 weeks. CONCLUSION: Only in mathematics decreasing GA was associated with lower grades. Increased mathematical difficulties were found below GA 33-35 weeks. The academic profile of mathematical difficulties was more prevalent among GA <32 weeks. However, the absolute differences in grades were small, and the predominant academic profile was average/high grades within both domains across all GA.

Neonatal mortality and video assessment of resuscitation in four district hospitals in Pemba, Tanzania.

BACKGROUND: We aimed to assess risk factors for neonatal mortality, quality of neonatal resuscitation (NR) on videos and identify potential areas for improvement. METHODS: This prospective cohort study included women in childbirth and their newborns at four district hospitals in Pemba, Tanzania. Videos were analysed for quality-of-care. Questionnaires on quality-of-care indicators were answered by health workers (HW) and women. Risk factors for neonatal mortality were analysed in a binomial logistic regression model. RESULTS: 1440 newborns were enrolled. 34 newborns died within the neonatal period (23.6 per 1000 live births). Ninety neonatal resuscitations were performed, 20 cases on video. Positive pressure ventilation (PPV) was inadequate in 15 cases (75%). Half (10/20) did not have PPV initiated within the first minute, and in one case (5.0%), no PPV was performed. PPV was not sustained in 16/20 (80%) newborns. Of the 20 videos analysed, death occurred in 10 newborns: 8 after resuscitation attempts and two within the first 24 h. Most of HW 49/56 (87.5%) had received training in NR. CONCLUSIONS: Video analysis of NR revealed significant deviations from guidelines despite 87.5% of HW being trained in NR. Videos provided direct evidence of gaps in the quality of care and areas for future education, particularly effective PPV. IMPACT: Neonatal mortality in Pemba is 23.6 per 1000 livebirths, with more than 90% occurring in the first 24 h of life. Video assessment of neonatal resuscitation revealed deviations from guidelines and can add to understanding challenges and aid intervention design. The present study using video assessment of neonatal resuscitation is the first one performed at secondary-level hospitals where many of the world's births are conducted. Almost 90% of the health workers had received training in neonatal resuscitation, and the paper can aid intervention design by understanding the actual challenges in neonatal resuscitation.

Detailed statistical analysis plan for a secondary Bayesian analysis of the SafeBoosC-III trial: a multinational, randomised clinical trial assessing treatment guided by cerebral oximetry monitoring versus usual care in extremely preterm infants.

BACKGROUND: Extremely preterm infants have a high mortality and morbidity. Here, we present a statistical analysis plan for secondary Bayesian analyses of the pragmatic, sufficiently powered multinational, trial-SafeBoosC III-evaluating the benefits and harms of cerebral oximetry monitoring plus a treatment guideline versus usual care for such infants. METHODS: The SafeBoosC-III trial is an investigator-initiated, open-label, randomised, multinational, pragmatic, phase III clinical trial with a parallel-group design. The trial randomised 1601 infants, and the frequentist analyses were published in April 2023. The primary outcome is a dichotomous composite outcome of death or severe brain injury. The exploratory outcomes are major neonatal morbidities associated with neurodevelopmental impairment later in life: (1) bronchopulmonary dysplasia; (2) retinopathy of prematurity; (3) late-onset sepsis; (4) necrotising enterocolitis; and (5) number of major neonatal morbidities (count of bronchopulmonary dysplasia, retinopathy of prematurity, and severe brain injury). The primary Bayesian analyses will use non-informed priors including all plausible effects. The models will use a Hamiltonian Monte Carlo sampler with 1 chain, a sampling of 10,000, and at least 25,000 iterations for the burn-in period. In Bayesian statistics, such analyses are referred to as 'posteriors' and will be presented as point estimates with 95% credibility intervals (CrIs), encompassing the most probable results based on the data, model, and priors selected. The results will be presented as probability of any benefit or any harm, Bayes factor, and the probability of clinical important benefit or harm. Two statisticians will analyse the blinded data independently following this protocol. DISCUSSION: This statistical analysis plan presents a secondary Bayesian analysis of the SafeBoosC-III trial. The analysis and the final manuscript will be carried out and written after we publicise the primary frequentist trial report. Thus, we can interpret the findings from both the frequentists and Bayesian perspective. This approach should provide a better foundation for interpreting of our findings. TRIAL REGISTRATION: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

The effects of cerebral oximetry in mechanically ventilated newborns: a protocol for the SafeBoosC-IIIv randomised clinical trial.

BACKGROUND: The SafeBoosC project aims to test the clinical value of non-invasive cerebral oximetry by near-infrared spectroscopy in newborn infants. The purpose is to establish whether cerebral oximetry can be used to save newborn infants' lives and brains or not. Newborns contribute heavily to total childhood mortality and neonatal brain damage is the cause of a large part of handicaps such as cerebral palsy. The objective of the SafeBoosC-IIIv trial is to evaluate the benefits and harms of cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. METHODS/DESIGN: SafeBoosC-IIIv is an investigator-initiated, multinational, randomised, pragmatic phase-III clinical trial. The inclusion criteria will be newborns with a gestational age more than 28 + 0 weeks, postnatal age less than 28 days, predicted to require mechanical ventilation for at least 24 h, and prior informed consent from the parents or deferred consent or absence of opt-out. The exclusion criteria will be no available cerebral oximeter, suspicion of or confirmed brain injury or disorder, or congenital heart disease likely to require surgery. A total of 3000 participants will be randomised in 60 neonatal intensive care units from 16 countries, in a 1:1 allocation ratio to cerebral oximetry versus usual care. Participants in the cerebral oximetry group will undergo cerebral oximetry monitoring during mechanical ventilation in the neonatal intensive care unit for as long as deemed useful by the treating physician or until 28 days of life. The participants in the cerebral oximetry group will be treated according to the SafeBoosC treatment guideline. Participants in the usual care group will not receive cerebral oximetry and will receive usual care. We use two co-primary outcomes: (1) a composite of death from any cause or moderate to severe neurodevelopmental disability at 2 years of corrected age and (2) the non-verbal cognitive score of the Parent Report of Children's Abilities-Revised (PARCA-R) at 2 years of corrected age. DISCUSSION: There is need for a randomised clinical trial to evaluate cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. TRIAL REGISTRATION: The protocol is registered at www. CLINICALTRIALS: gov (NCT05907317; registered 18 June 2023).

Video Tutorials to Empower Caregivers of Ill Children and Reduce Health Care Utilization: A Randomized Clinical Trial.

Importance: Young children often fall ill, leading to concern among their caregivers and urgent contact with health care services. Objective: To assess the effectiveness and safety of video tutorials to empower caregivers in caring for acutely ill children. Design, Setting, and Participants: Caregivers calling the out-of-hours Medical Helpline 1813 (MH1813), Emergency Medical Services Capital Region, Denmark, and their children aged 0.5 to 11.9 years were randomized to video tutorials (intervention) or telephone triage by a nurse or physician (control) from October 2020 to December 2021 and followed up for 72 hours blinded to the intervention. Data were analyzed from March to July 2022. Intervention: The intervention group had the call disconnected before telephone triage and received video tutorials on managing common symptoms in acutely ill children and when to seek medical help. Caregivers could subsequently call MH1813 for telephone triage. Main outcomes and measures: The primary outcome was caregivers' self-efficacy, reported in an electronic survey the following day. Secondary outcomes were satisfaction, child status, assessment by a general practitioner or physician at the hospital, telephone triage, and adverse events during the 72-hour follow-up period. Results: In total, 4686 caregivers and children were randomized to intervention (2307 participants) or control (2379 participants), with a median (IQR) child age of 2.3 (1.3-5.1) years and 53% male distribution in both groups (2493 participants). Significantly more caregivers in the intervention group reported high self-efficacy (80% vs 76%; crude odds ratio [OR], 1.30; 95% CI, 1.01-1.67; P = .04). The intervention group received fewer telephone triages during follow-up (887 vs 2374 in the control group). Intention-to-treat analysis showed no difference in secondary outcomes, but per-protocol subanalysis showed fewer hospital assessments when caregivers watched video tutorials (27% vs 35%; adjusted OR, 0.67; 95% CI, 0.55-0.82). Randomization to video tutorials did not increase adverse outcomes. Conclusions and relevance: In this randomized clinical trial, offering caregivers video tutorials significantly and safely increased self-efficacy and reduced use of telephone triage. Children had fewer hospital assessments when caregivers watched videos. This suggests a future potential of health care information to empower caregivers and reduce health care utilization. Trial Registration: ClinicalTrials.gov Identifier: NCT04301206.

Cerebral oximetry monitoring versus usual care for extremely preterm infants: a study protocol for the 2-year follow-up of the SafeBoosC-III randomised clinical trial.

BACKGROUND: In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks' postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment. METHODS: Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks' postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children's Abilities-Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all. DISCUSSION: Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary. TRIAL REGISTRATION: ClinicalTrials.gov NCT05134116 . Registered on 24 November 2021.

Cerebrovascular reactivity to carbon dioxide tension in newborns: data from combined time-resolved near-infrared spectroscopy and diffuse correlation spectroscopy.

Significance: Critically ill newborns are at risk of brain damage from cerebrovascular disturbances. A cerebral hemodynamic monitoring system would have the potential role to guide targeted intervention. Aim: To obtain, in a population of newborn infants, simultaneous near-infrared spectroscopy (NIRS)-based estimates of cerebral tissue oxygen saturation (StO2) and blood flow during variations of carbon dioxide tension (pCO2) levels within physiologic values up to moderate permissive hypercapnia, and to examine if the derived estimate of metabolic rate of oxygen would stay constant, during the same variations. Approach: We enrolled clinically stable mechanically ventilated newborns at postnatal age >24 h without brain abnormalities at ultrasound. StO2 and blood flow index were measured using a non-invasive device (BabyLux), which combine time-resolved NIRS and diffuse-correlation spectroscopy. The effect of changes in transcutaneous pCO2 on StO2, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen index (tCMRO2i) were estimated. Results: Ten babies were enrolled and three were excluded. Median GA at enrollment was 39 weeks and median weight 2720 g. StO2 increased 0.58% (95% CI 0.55; 0.61, p<0.001), CBF 2% (1.9; 2.3, p<0.001), and tCMRO2 0.3% (0.05; 0.46, p=0.017) per mmHg increase in pCO2. Conclusions: BabyLux device detected pCO2-induced changes in cerebral StO2 and CBF, as expected. The small statistically significant positive relationship between pCO2 and tCMRO2i variation is not considered clinically relevant and we are inclined to consider it as an artifact.

Blood-Biomarkers for Glucose Metabolism in Preterm Infants.

This was an exploratory, prospective, longitudinal, cohort study that aimed to establish "healthy" reference levels related to growth parameters and glucose metabolites in preterm infants. This was conducted to further investigate growth and metabolic disturbances potentially related to neonatal illness. The study sample consisted of 108 preterm infants born before 32 weeks in 2018-2019 in the Capital Region of Denmark. Repetitive blood samples were acquired at the neonatal wards, while clinical data were obtained from the regional hospital medical record system. Thirty-four "healthy" preterm infants (31%) were identified. The "ill" infants were divided into four subgroups dependent on gestational age and small for gestational age. Reference levels for the growth parameters and metabolic biomarkers glucose, albumin, and adiponectin, and two glucose control indicators, glycated albumin and fructosamine, were determined for the "healthy" and "ill" subgroups. The "ill" extremely preterm infants had increased glucose levels (mean difference 0.71 mmol/L, 95% CI 0.23; 1.18 mmol/L) and glycated albumin (corrected; %) (mean difference 0.92 mmol/L, 95% CI 0.38 mmol/L;1.47 mmol/L) compared to the "healthy" infants. In "ill" extremely preterm infants and "ill" very preterm infants born small for gestational age, levels of biomarkers containing proteins were decreased. In the "Ill" extremely preterm infants and infants born small for gestational age, postnatal growth was continuously decreased throughout the postconceptional period. The short-term glucose-control indicator, glycated albumin (corrected; %), reflected well the high glucose levels due to its correction for the depleted plasma-protein pool.

Validity of parent-reported weight and length of infants.

INTRODUCTION: Anthropometric data are key to evaluating infant health. This study assessed the validity of parent-reported infant weight and length, and their reliability to categorise children by BMI z-score, as compared to clinical measurements. METHODS: From a cohort of 4,262 infants, parent-reported and clinically measured anthropometric data were obtained and compared at three months and one year of age. RESULTS: Parent-reported and clinically measured data generally correlated well. Mean differences at three months and at one year, respectively, were 0.08 kg (95% confidence interval (CI): 0.07-0.09 kg) and 0.10 kg (95% CI: 0.08-0.12 kg) for weight, 0.8 cm (95% CI: 0.8-0.9 cm) and 1.0 cm (95% CI: 0.9-1.1 cm) for length and -0.16 kg/m2 (95% CI: -0.20--0.12 kg/m2) and -0.22 kg/m2 (95% CI: -0.27--0.18 kg/m2) for BMI. Effect sizes were negligible to small. Bland-Altman plots showed clinically insignificant bias, but 95% limits of agreement were wide enough to be significant. Comparing categorisation of BMI z-score showed only fair agreement. CONCLUSION: Parents' reports of measured infant weight and length are reliable at a population level in a setting with routine preventive care. Parent-reported data should not be used for assessment of individual infants, particularly not if a health condition is suspected. BMI calculated from parent-reported anthropometrics is not reliable. FUNDING: None. TRIAL REGISTRATION: This study was registered with www. CLINICALTRIALS: gov, registration number NCT01694108.

Switch from intravenous-to-oral antibiotics in neonatal probable and proven early-onset infection: a prospective population-based real-life multicentre cohort study.

OBJECTIVE: To evaluate the implementation of switch from intravenous-to-oral antibiotic therapy with amoxicillin in neonates with early-onset infection (EOI). DESIGN, SETTING AND PATIENTS: A population-based multicentre cohort study. All term-born neonates with EOI were prospectively included between 1 December 2018 to 30 November 2020. INTERVENTION: Intravenous-to-oral switch antibiotic therapy in clinically stable neonates. MAIN OUTCOME MEASURES: The primary outcome was readmission due to infection. Secondary outcomes were days of hospitalisation and antibiotic use in the pre-implementation versus post implementation period. RESULTS: During 2 years, 835 neonates commenced antibiotics for EOI (1.5% (95% CI 1.4% to 1.6%)) of all term live births). Of those, 554 (66%) underwent a full course of treatment. There were 23 episodes of culture-proven infection (0.42 per 1000 term live births (95% CI 0.27 to 0.63)). A total of 478 of 531 (90%) neonates with probable infection underwent switch therapy. None was readmitted due to infection. The median duration of hospitalisation was 3.0 days (IQR 2.5-3.5) and 7.4 days (IQR 7.0-7.5) in the switch and intravenous therapy groups, respectively. According to antibiotic surveillance data, 1.2% underwent a full course of treatment following implementation of oral switch therapy (2019-2020), compared with 1.2% before (2017-2018). CONCLUSION: In clinical practice, switch therapy was safe and used in 9 of 10 neonates with probable EOI. Knowledge of the safety of antibiotic de-escalation is important as home-based oral therapy ameliorates the treatment burden for neonates, caregivers and healthcare systems. Despite the ease of oral administration, implementation of switch therapy did not increase the overall use of antibiotics.

Childhood BMI after ART with frozen embryo transfer.

STUDY QUESTION: Does BMI at 7-10 years of age differ in children conceived after frozen embryo transfer (FET) compared to children conceived after fresh embryo transfer (fresh-ET) or natural conception (NC)? SUMMARY ANSWER: BMI in childhood does not differ between children conceived after FET compared to children conceived after fresh-ET or NC. WHAT IS KNOWN ALREADY: High childhood BMI is strongly associated with obesity and cardiometabolic disease and mortality in adulthood. Children conceived after FET have a higher risk of being born large for gestational age (LGA) than children conceived after NC. It is well-documented that being born LGA is associated with an increased risk of obesity in childhood, and it has been hypothesized that ART induces epigenetic variations around fertilization, implantation, and early embryonic stages, which influence fetal size at birth as well as BMI and health later in life. STUDY DESIGN, SIZE, DURATION: The study 'Health in Childhood following Assisted Reproductive Technology' (HiCART) is a large retrospective cohort study with 606 singletons aged 7-10 years divided into three groups according to mode of conception: FET (n = 200), fresh-ET (n = 203), and NC (n = 203). All children were born in Eastern Denmark from 2009 to 2013 and the study was conducted from January 2019 to September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We anticipated that the participation rate would differ between the three study groups owing to variation in the motivation to engage. To reach the goal of 200 children in each group, we invited 478 in the FET-group, 661 in the fresh-ET-group, and 1175 in the NC-group. The children underwent clinical examinations including anthropometric measurements, whole-body dual-energy x-ray absorptiometry-scan, and pubertal staging. Standard deviation scores (SDS) were calculated for all anthropometric measurements using Danish reference values. Parents completed a questionnaire regarding the pregnancy and the current health of the child and themselves. Maternal, obstetric, and neonatal data were obtained from the Danish IVF Registry and Danish Medical Birth Registry. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, children conceived after FET had a significantly higher birthweight (SDS) compared to both children born after fresh-ET (mean difference 0.42, 95% CI (0.21; 0.62)) and NC (mean difference 0.35, 95% CI (0.14; 0.57)). At follow-up (7-10 years), no differences were found in BMI (SDS) comparing FET to fresh-ET, FET to NC, and fresh-ET to NC. Similar results were also found regarding the secondary outcomes weight (SDS), height (SDS), sitting height, waist circumference, hip circumference, fat, and fat percentage. In the multivariate linear regression analyses, the effect of mode of conception remained non-significant after adjusting for multiple confounders. When stratified on sex, weight (SDS), and height (SDS) were significantly higher for girls born after FET compared to girls born after NC. Further, FET-girls also had significantly higher waist, hip, and fat measurements compared to girls born after fresh-ET. However, for the boys the differences remained insignificant after confounder adjustment. LIMITATIONS, REASONS FOR CAUTION: The sample size was decided in order to detect a difference of 0.3 SDS in childhood BMI (which corresponds to an adult cardiovascular mortality hazard ratio of 1.034). Thus, smaller differences in BMI SDS may be overlooked. As the overall participation rate was 26% (FET: 41%, fresh-ET: 31%, NC: 18%), selection bias cannot be excluded. Regarding the three study groups, many possible confounders have been included but there might be a small risk of selection bias as information regarding cause of infertility is not available in this study. WIDER IMPLICATIONS OF THE FINDINGS: The increased birthweight in children conceived after FET did not translate into differences in BMI, however, for the girls born after FET, we observed increased height (SDS) and weight (SDS) compared to the girls born after NC, while for the boys the results remained insignificant after confounder adjustment. Since body composition in childhood is a strong biomarker of cardiometabolic disease later in life, longitudinal studies of girls and boys born after FET are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Research Foundation. There were no competing interests. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Risk factors of stillbirths in four district hospitals on Pemba Island, Tanzania: a prospective cohort study.

BACKGROUND: More than 2 million third-trimester stillbirths occur yearly, most of them in low- and middle-income countries. Data on stillbirths in these countries are rarely collected systematically. This study investigated the stillbirth rate and risk factors associated with stillbirth in four district hospitals in Pemba Island, Tanzania. METHODS: A prospective cohort study was completed between the 13th of September and the 29th of November 2019. All singleton births were eligible for inclusion. Events and history during pregnancy and indicators for adherence to guidelines were analysed in a logistic regression model that identified odds ratios [OR] with a 95% confidence interval [95% CI]. RESULTS: A stillbirth rate of 22 per 1000 total births in the cohort was identified; 35.5% were intrapartum stillbirths (total number of stillbirths in the cohort, n = 31). Risk factors for stillbirth were breech or cephalic malpresentation (OR 17.67, CI 7.5-41.64), decreased or no foetal movements (OR 2.6, CI 1.13-5.98), caesarean section [CS] (OR 5.19, CI 2.32-11.62), previous CS (OR 2.63, CI 1.05-6.59), preeclampsia (OR 21.54, CI 5.28-87.8), premature rupture of membranes or rupture of membranes 18 h before birth (OR 2.5, CI 1.06-5.94) and meconium stained amniotic fluid (OR 12.03, CI 5.23-27.67). Blood pressure was not routinely measured, and 25% of women with stillbirths with no registered foetal heart rate [FHR] at admission underwent CS. CONCLUSIONS: The stillbirth rate in this cohort was 22 per 1000 total births and did not fulfil the Every Newborn Action Plan's goal of 12 stillbirths per 1000 total births in 2030. Awareness of risk factors associated with stillbirth, preventive interventions and improved adherence to clinical guidelines during labour, and hence improved quality of care, are needed to decrease the stillbirth rate in resource-limited settings.