Associations between Bronchopulmonary Dysplasia, Insulin-like Growth Factor I and Nutrition.

Insulin-like growth factor I (IGF-I) has been suggested as an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD). In turn, nutrition has been associated with IGF-I levels and could be of importance in the pathogenesis of BPD. This study aimed to explore the association between nutrition, the IGF-I axis and the occurrence of BPD. Eighty-six preterm infants (44 male, mean gestational age: 29.0 weeks (standard deviation: 1.7 weeks)) were enrolled in an observational study. Serum IGF-I (µg/L) and insulin-like growth factor binding protein 3 (IGFBP-3; mg/L) were measured at birth and at 2, 4 and 6 weeks postnatal age. BPD was diagnosed at 36 weeks postmenstrual age. Twenty-nine infants were diagnosed with BPD. For every µg/L per week increase in IGF-I, the odds of BPD decreased (0.68, 95% CI 0.48-0.96, corrected for gestational age). The change in IGF-I in µg/L/week, gestational age in weeks and a week of predominant donor human milk feeding were associated with the occurrence of BPD in the multivariable analysis (respectively, OR 0.63 (0.43-0.92), OR 0.44 (0.26-0.76) and 7.6 (1.2-50.4)). IGFBP-3 was not associated with the occurrence of BPD in the multivariable analysis. In conclusion, a slow increase in IGF-I levels and a lower gestational age increase the odds of BPD. Donor human milk might increase the odds of BPD and should be further explored.

Identifying effect modifiers of systemic hydrocortisone treatment initiated 7-14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial.

OBJECTIVE: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA). DESIGN: Secondary analysis of a randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life. INTERVENTION: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots. RESULTS: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups. CONCLUSION: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

Neonatal pain score after use of paracetamol: Is there a relationship with serum trough concentration at steady state in preterm and term neonates?

OBJECTIVE: An easy to establish and patient-friendly biomarker to guide dosing of paracetamol in neonates is currently not available. The aim of this study was to determine the potential association between the serum trough concentration and area under the curve (AUC) of paracetamol at steady state and differences in pain scores in preterm and term neonates. MATERIALS AND METHODS: A retrospective observational study was performed, using an academic hospital database to identify neonates treated with intravenous or rectal paracetamol for at least 48 hours. At steady state, serum trough concentrations and the 24-hour AUC were determined. Pain was measured by COMFORTneo scores, before the 1st and 6th dose. Linear regression was performed to assess the association between serum trough concentration and 24-hour AUC and differences in pain scores. Subgroup analyses were performed for patients who received paracetamol due to a COMFORTneo score ≥ 14 (group 1) or who received prophylactic paracetamol because of upcoming surgery (group 2). RESULTS: 21 neonates were included. The median (interquartile range (IQR)) serum trough concentration of paracetamol before the 6th dose was 4.5 mg/L (2.7 - 8.5 mg/L). In subgroup 1, the median (IQR) COMFORTneo scores before the 1st and 6th dose were 17 (16.5 - 20) and 12 (11 - 16.5), respectively. In subgroup 2, the median (IQR) scores were 9 (8 - 10) and 11 (9 - 12), respectively. The serum trough concentration and 24-hour AUC were not associated with reduced pain scores (p = 0.12 and p = 0.67, respectively). CONCLUSION: No association was found between the serum trough concentration and 24-hour AUC of paracetamol at steady state and differences in pain scores in preterm and term neonates. Future research is needed to prospectively determine a patient-friendly biomarker to optimize the treatment with paracetamol.

Duration of Neonatal Antibiotic Exposure in Preterm Infants in Association with Health and Developmental Outcomes in Early Childhood.

Over 90% of preterm neonates are, often empirically, exposed to antibiotics as a potentially life-saving measure against sepsis. Long-term outcome in association with antibiotic exposure (NABE) has insufficiently been studied after preterm birth. We investigated the association of NABE-duration with early-childhood developmental and health outcomes in preterm-born children and additionally assessed the impact of GA on outcomes. Preterm children (GA < 30 weeks) participating in a multicenter cohort study were approached for follow-up. General expert-reviewed health questionnaires on respiratory, atopic and gastrointestinal symptoms were sent to parents of children > 24 months' corrected age (CA). Growth and developmental assessments (Bayley Scales of Infant and Toddler Development (BSID) III) were part of standard care assessment at 24 months' CA. Uni- and multivariate regressions were performed with NABE (per 5 days) and GA (per week) as independent variables. Odds ratios (OR) for health outcomes were adjusted (aOR) for confounders, where appropriate. Of 1079 infants whose parents were approached, 347 (32%) responded at a mean age of 4.6 years (SD 0.9). In children with NABE (97%), NABE duration decreased by 1.6 days (p < 0.001) per week of gestation. Below-average gross-motor development (BSID-III gross-motor score < 8) was associated with duration of NABE (aOR = 1.28; p = 0.04). The aOR for constipation was 0.81 (p = 0.04) per gestational week. Growth was inversely correlated with GA. Respiratory and atopic symptoms were not associated with NABE, nor GA. We observed that prolonged NABE after preterm birth was associated with below-average gross-motor development at 24 months' CA, while a low GA was associated with lower weight and stature Z-scores and higher odds for constipation.

Time to first passage of meconium and defecation frequency preceding necrotizing enterocolitis in preterm infants: a case-control study.

Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in preterm infants. Early recognition and treatment of NEC are critical to improving outcomes. Enteric nervous system (ENS) immaturity has been proposed as a key factor in NEC pathophysiology. Gastrointestinal dysmotility is associated with ENS immaturity and may serve as a predictive factor for the development of NEC. In this case-control study, preterm infants (gestational age (GA) < 30 weeks) were included in two level-IV neonatal intensive care units. Infants with NEC in the first month of life were 1:3 matched to controls based on GA (± 3 days). Odds ratios for NEC development were analyzed by logistic regression for time to first passage of meconium (TFPM), duration of meconial stool, and mean daily defecation frequency over the 72 h preceding clinical NEC onset (DF < T0). A total of 39 NEC cases and 117 matched controls (median GA 27 + 4 weeks) were included. Median TFPM was comparable in cases and controls (36 h [IQR 13-65] vs. 30 h [IQR 9-66], p = 0.83). In 21% of both cases and controls, TFPM was ≥ 72 h (p = 0.87). Duration of meconial stool and DF < T0 were comparable in the NEC and control group (median 4 and 3, resp. in both groups). Odds of NEC were not significantly associated with TFPM, duration of meconial stools, and DF < T0 (adjusted odds ratio [95% confidence interval]: 1.00 [0.99-1.03], 1.16 [0.86-1.55] and 0.97 [0.72-1.31], resp.). CONCLUSION: In this cohort, no association was found between TFPM, duration of meconium stool, and DF < T0 and the development of NEC. WHAT IS KNOWN: • Necrotizing enterocolitis (NEC) is a life-threatening acute intestinal inflammatory disease of the young preterm infant. Early clinical risk factors for NEC have been investigated in order to facilitate early diagnosis and treatment. • Signs of disrupted gastrointestinal mobility, such as gastric retention and paralytic ileus, have been established to support the diagnosis of NEC. Nevertheless, defecation patterns have insufficiently been studied in relation to the disease. WHAT IS NEW: • Defecation patterns in the three days preceding NEC did not differ from gestational age-matched controls of corresponding postnatal age. Additionally, the first passage of meconium and the duration of meconium passage were comparable between cases and controls. Currently, defecation patterns are not useful as early warning signs for NEC. It remains to be elucidated whether these parameters are different based on the location of intestinal necrosis.

Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study.

Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography-ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker.

NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related venous thrombosis.

BACKGROUND: In critically ill (preterm) neonates, catheter-related venous thromboembolism (CVTE) can be a life-threatening complication. Evidence on optimal management in the literature is lacking. In the Netherlands, a consensus-based national management guideline was developed to create uniform CVTE management. OBJECTIVES: To evaluate the efficacy and safety of the national guideline. METHODS: This prospective, multicenter, observational study included all infants aged ≤6 months with CVTE in the Netherlands between 2014 and 2019. CVTE was divided into thrombosis in veins and that in the right atrium, with their own treatment algorithms. The primary outcomes were recurrent venous thrombotic events (VTEs) and/or death due to CVTE as well as major bleeding. RESULTS: Overall, 115 neonates were included (62% male; 79% preterm). The estimated incidence of CVTE was 4.0 per 1000 neonatal intensive care unit admissions. Recurrent thrombosis occurred in 2 (1.7%) infants and death due to CVTE in 1 (0.9%) infant. Major bleeding developed in 9 (7.8%) infants: 2 of 7 (29%) on recombinant tissue plasminogen activator, which was given for high-risk right-atrium thrombosis, and 7 of 63 (11%) on low-molecular-weight heparin (LMWH). Five of the 7 bleedings because of LMWH were complications of subcutaneous catheter use for LMWH administration. CONCLUSION: The management of neonatal CVTE according to the Dutch CVTE management guideline led to a low incidence of recurrent VTEs and death due to VTEs. Major bleeding occurred in 7.8% of the infants. Specific guideline adjustments may improve efficacy and, especially, safety of CVTE management in neonates.

Effect of systemic hydrocortisone in ventilated preterm infants on parent-reported behavioural outcomes at 2 years' corrected age: follow-up of a randomised clinical trial.

OBJECTIVE: To report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years' corrected age (CA). DESIGN: Randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. INTERVENTION: Infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: Parent-reported behavioural outcomes at 2 years' CA assessed with the Child Behavior Checklist (CBCL 1½-5). RESULTS: Parents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference -1.52 (95% CI -4.00 to 0.96), -2.40 (95% CI -4.99 to 0.20) and -0.81 (95% CI -3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference -1.26, 95% CI -2.41 to -0.12). CONCLUSION: This study found high rates of behaviour problems at 2 years' CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants. TRIAL REGISTRATION NUMBER: NTR2768; EudraCT 2010-023777-19.

Body composition in preterm infants: a systematic review on measurement methods.

BACKGROUND: There are several methods to measure body composition in preterm infants. Yet, there is no agreement on which method should be preferred. METHODS: PubMed, Embase.com, Wiley/Cochrane Library, and Google Scholar were searched for studies that reported on the predictive value or validity of body composition measurements in preterms, up to 6 months corrected age. RESULTS: Nineteen out of 1884 identified studies were included. Predictive equations based on weight and length indices, body area circumferences, skinfold thickness, bioelectrical impedance, and ultrasound did not show agreement with body composition measured with air displacement plethysmography (ADP), dual-energy x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), or isotope dilution. ADP agreed well with fat mass density measured by isotope dilution (bias -0.002 g/ml, limits of agreement ±0.012 g/ml, n = 14). Fat mass percentage measured with ADP did not agree well with fat mass percentage measured by isotope dilution (limits of agreement up to ±5.8%) and the bias between measurements was up to 2.2%. DXA, MRI, and isotope dilution were not compared to another reference method in preterms. CONCLUSIONS: DXA, ADP, and isotope dilution methods are considered trustworthy validated techniques. Nevertheless, this review showed that these methods may not yield comparable results. IMPACT: Based on validation studies that were conducted in a limited number of study subjects, weight and length indices, body area circumferences, skinfold thickness, bioelectrical impedance, and ultrasound seem to be a poor representation of body composition in preterm infants. DXA, ADP, and isotope dilution methods are considered trustworthy and validated techniques. Nevertheless, these methods may not yield comparable results.

Clinical predictors of bacteraemia in neonates with suspected early-onset sepsis in Malawi: a prospective cohort study.

OBJECTIVES: We studied neonates with suspected early-onset sepsis (EOS, sepsis developing in the first 72 hours after delivery) in Malawi to (1) describe clinical characteristics and microbiological findings, (2) identify which patient characteristics may be associated with pathogen positivity on blood culture, and (3) describe mortality and its potential determinants. DESIGN: Prospective observational study (May 2018-June 2019). SETTING: Neonatal ward in Queen Elizabeth Central Hospital, the largest government hospital in Malawi. PATIENTS: All neonates with suspected EOS in whom a blood culture was obtained. RESULTS: Out of 4308 neonatal admissions, 1244 (28.9%) had suspected EOS. We included 1149 neonates, of which 109 blood cultures had significant growth (9.5%). The most commonly isolated pathogens were Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli and Acinetobacter baumanii. Many of the Gram negatives were extended-spectrum beta lactamase-producing Enterobacteriaceae, and these were 40-100% resistant to first-line and second-line antimicrobials. Gestational age (GA) of <32 weeks was associated with pathogen-positive blood cultures (<28 weeks: adjusted OR (AOR) 2.72, 95% CI 1.04 to 7.13; 28-32 weeks: AOR 2.26, 95% CI 1.21 to 4.21; p=0.005). Mortality was 17.6% (202/1149) and associated with low birth weight (<1000 g: AOR 47.57, 95% CI 12.59 to 179.81; 1000-1500 g: AOR 11.31, 95% CI 6.97 to 18.36; 1500-2500 g: AOR 2.20, 95% CI 1.42 to 3.39; p<0.001), low Apgar scores at 5 min (0-3: AOR 18.60, 95% CI 8.81 to 39.27; 4-6: AOR 4.41, 95% CI 2.81 to 6.93; p<0.001), positive maternal venereal disease research laboratory status (AOR 2.53, 95% CI 1.25 to 5.12; p=0.001) and congenital anomalies (AOR 7.37, 95% CI 3.61 to 15.05; p<0.001). Prolonged rupture of membranes was inversely associated with mortality (AOR 0.43, 95% CI 0.19 to 0.98; p 0.007). CONCLUSION: In Malawi, EOS was suspected in nearly a third of neonatal admissions and had a high mortality. Ten per cent were culture-confirmed and predicted by low GA. To reduce the impact of suspected neonatal sepsis in least developed countries, improved maternal and antenatal care and development of rapid point of care methods to more accurately guide antimicrobial use could simultaneously improve outcome and reduce antimicrobial resistance.

Healthcare-associated Infections in Very Low Birth-weight Infants in a South African Neonatal Unit: Disease Burden, Associated Factors and Short-term Outcomes.

BACKGROUND: Infection is a leading cause of death among very low birth-weight (VLBW) infants in resource-limited settings. METHODS: We performed a retrospective review of healthcare-associated infection (HAI) episodes among VLBW infants from January 1, 2016, to December 31, 2017. The epidemiology, causative organisms and short-term outcomes were analyzed. Logistic regression was used to investigate for factors associated with development of HAI. RESULTS: During the study period, 715 VLBW infants with suspected HAI were investigated, including 162/715 (22.7%) proven and 158/715 (22.1%) presumed HAI. Of the proven infections, 99/162 (61.1%) contained at least one Gram-negative organism per blood culture; 84/162 (51.9%) single Gram-negative organisms and 15/162 (9.3%) polymicrobial growth. Independent factors associated with development of any HAI included low gestational age, small for gestational age, indwelling central venous catheter and invasive ventilation. Compared with infants in whom HAI had been excluded, infants with HAI were more likely to be diagnosed with necrotizing enterocolitis (5.6% vs. 23.1%; P < 0.001) and bronchopulmonary dysplasia (1.0% vs. 4.4%; P = 0.007). Infants with any HAI also had a longer hospital stay [44 (25-65) vs. 38 (26-53) days; P < 0.001] and increased mortality [90/320 (28.1%) vs. 21/395 (5.3%); P < 0.001] compared with infants who did not develop HAI episodes. CONCLUSIONS: Proven and presumed HAI are a major contributor to neonatal morbidity and mortality; further research is urgently needed to better understand potential targets for prevention and treatment of HAI in resource-limited neonatal units.

Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: a multicenter cohort study.

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003). CONCLUSION: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. WHAT IS KNOWN: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. WHAT IS NEW: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.

Getting a grip in the middle of chaos: Preparing for preterm parenthood during a high-risk pregnancy - Parental experiences and needs.

AIM: Admitting an infant to a neonatal intensive care unit (NICU) is stressful for parents. A great source of stress is the loss of their desired parental role. This study explores parents' experiences and needs during a high-risk pregnancy in preparation for their role as parents of a preterm infant. METHODS: An exploratory qualitative study was conducted among parents with a preterm infant admitted to two level-III NICUs in the Netherlands. A thematic analysis was performed. RESULTS: Nineteen interviews were conducted with parents of preterm infants (26-34 weeks gestational age). Getting a grip in the middle of chaos was identified as the central theme. In the pre-admission phase, coping with potential preterm parenthood was a theme, with coping strategies as subthemes that changed over time from avoidance to being ready to parent a preterm infant. The theme envisioning the NICU emerged in the NICU admission phase, with subthemes preterm care journey and opportunities for involvement fostering parental empowerment. CONCLUSION: Timing and content of information about a parental role in the NICU should be tailored to the individual expectant parent. A customisable intervention bundle may provide a vision of the NICU and the parents' active role in care.

Growth of exclusively breastfed small for gestational age term infants in the first six months of life: a prospective cohort study.

BACKGROUND: Compared to their appropriate-for-gestational-age (AGA) peers, small-for-gestational-age (SGA) infants are prone to growth deficits. As the first 6 months of exclusive breastfeeding is generally recommended, it is essential to understand how this intervention might impact SGA infants' growth. This study aims to assess growth of exclusively breastfed SGA term infants in the first 6 months of life. METHODS: A prospective cohort study was conducted on term infants born in Dr. Sardjito General Hospital and two private hospitals in Yogyakarta, Indonesia. SGA was defined as birth weight less than the 10th percentile according to Fenton criteria. Weight, length, and head circumference (HC) were measured at birth and monthly until 6 months old. RESULTS: A total of 39 AGA and 17 SGA term infants who were exclusively breastfed in their first 6 months were included and followed. In SGA compared to AGA, birth weight, length, and HC (mean ± SD) were significantly lower (p < 0.001). During the first 6 months, the SGAs grew in weight and length in parallel with the AGAs. At sixth months of age, the weight and length (mean ± SD) of the SGAs were significantly lower compared to the AGAs (p < 0.001). However, HC (mean ± SD) of SGAs grew significantly faster than the AGAs (p < 0.005). At sixth months of age, there were no significant differences in HC between the two groups (p = 0.824). CONCLUSIONS: In the first 6 months, exclusively breastfed SGA term infants, in contrast to weight and length, only show catch up growth in HC, leading to HC comparable to their AGA peers at the age of 6 months.

Exposure to intrauterine inflammation and late-onset sepsis in very preterm infants.

BACKGROUND: Late-onset sepsis is an important cause of mortality and morbidity in preterm infants. As these infants rely mostly on their innate immune system to fight off infection, enhancing this immune system by appropriate stimuli may prevent late-onset sepsis. However, it remains unclear which stimuli can enhance the neonatal immune system. This study aims to investigate the influence of intrauterine inflammation on late-onset sepsis. METHODS: This is a retrospective cohort study in a Neonatal Intensive Care Unit in the Netherlands. Between 2005 and 2016, 1014 infants with ≤32 weeks gestational age and/or with a birth weight ≤1500 g were included. Intrauterine inflammation was subdivided into histological chorioamnionitis, fetal inflammatory response, and funisitis. Logistic and Cox regression analyses were performed to investigate the influence of intrauterine inflammation on late-onset sepsis. RESULTS: Thirty-six percent of the included infants developed late-onset sepsis; 24% of placentas showed intrauterine inflammation. Late-onset sepsis incidence did not differ between infants with or without exposure to intrauterine inflammation after adjustment for gestational age (histological chorioamnionitis aHR 0.928 [CI: 0.727-1.185], p = 0.551; fetal inflammatory response aHR 1.011 [CI: 0.793-1.288], p = 0.930); funisitis aHR 0.965 [CI: 0.738-1.263], p = 0.797). CONCLUSIONS: Late-onset sepsis in very preterm infants seems not to be associated with intrauterine inflammation. IMPACT: Intrauterine inflammation is not protective of developing late-onset sepsis in premature infants. A large cohort study on the effect of intrauterine inflammation on neonatal outcome. This study adds to existing knowledge on finding appropriate stimuli to enhance the immune system of premature infants to improve neonatal outcome.

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates.

BACKGROUND: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. OBJECTIVE: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. METHODS: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. RESULTS: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42). CONCLUSION: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.

Care Pathway for Foetal Joint Contractures, Foetal Akinesia Deformation Sequence, and Arthrogryposis Multiplex Congenita.

INTRODUCTION: The majority of arthrogryposis multiplex congenita (AMC) and lethal forms of AMC such as foetal akinesia deformation sequence (FADS) cases are missed prenatally. We have demonstrated the additional value of foetal motor assessment and evaluation in a multidisciplinary team for the period 2007-2016. An applied care pathway was developed for foetuses presenting with joint contracture(s) in one anatomic region (e.g., talipes equinovarus [TEV]), more than one body part with non-progressive contractures and motility (AMC) and with deterioration over time (FADS). METHODS: The multidisciplinary team of Amsterdam University Medical Centre Expertise Centre FADS and AMC developed the care pathway. Additional tools are provided including a motor assessment by ultrasound examination and a post-mortem assessment form. RESULTS: An eight-step care pathway is presented with a proposed timing for prenatal sonographic examination, genetic examinations, multidisciplinary meetings, prenatal and postnatal counselling of the parents by a specialist also treating after birth, and the follow-up of prenatal and postnatal findings with counselling for future pregnancies. DISCUSSION/CONCLUSION: The scheduled serial structural and motor sonograpahic assessment together with follow-up examinations and genetic analysis should be tailored per prenatal centre per available resources. The multidisciplinary care pathway may pave the way to increase the detection rate and diagnosis of isolated contracture(s), TEV with underlying genetic causes, and the rare phenotypes AMC/FADS and prompt treatment after birth within expertise teams.

IGF-I, Growth, and Body Composition in Preterm Infants up to Term Equivalent Age.

CONTEXT: There are concerns that a higher fat mass in the early life of preterm infants is associated with adverse cardiometabolic outcomes in young adulthood. OBJECTIVE: To investigate the role of IGF-I and growth in determining body composition of preterm infants at term equivalent age. METHODS: An observational study was conducted from August 2015 to August 2018. From birth to term equivalent age, IGF-I levels were measured bi-weekly and growth was assessed weekly. At term equivalent age, body composition was assessed through air displacement plethysmography; 65 infants with a gestational age of 24 to 32 weeks were assessed at term equivalent age, of whom 58 completed body composition measurement. The main outcome measures were fat (free) mass (g) and fat (free) mass percentage at term equivalent age. RESULTS: In the first month of life, each 0.1 nmol/L per week increase in IGF-I was associated with a 465 g (SE 125 g) increase in fat free mass. A greater increase in weight SDS in the first month of life was associated with a higher fat free mass percentage (B 200.9; 95% CI, 12.1-389.6). A higher head circumference SDS was associated with more fat free mass (r = 0.46; 95% CI, 0.21-0.65). However, a greater increase in weight SDS up to term equivalent age was associated with a lower fat free mass percentage (B -55.7, SE 9.4). CONCLUSION: These findings suggest that impaired growth in the first month of life is associated with a less favorable body composition at term equivalent age.