Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder: results of a prospective multicenter clinical utility study in the Netherlands.

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10-20) vs. 59 days (95% CI 23-98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). CONCLUSION:  Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin. WHAT IS KNOWN: • Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used. • Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing. WHAT IS NEW: • This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests. • Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.

Profound Pathogen-Specific Alterations in Intestinal Microbiota Composition Precede Late-Onset Sepsis in Preterm Infants: A Longitudinal, Multicenter, Case-Control Study.

BACKGROUND: The role of intestinal microbiota in the pathogenesis of late-onset sepsis (LOS) in preterm infants is largely unexplored but could provide opportunities for microbiota-targeted preventive and therapeutic strategies. We hypothesized that microbiota composition changes before the onset of sepsis, with causative bacteria that are isolated later in blood culture. METHODS: This multicenter case-control study included preterm infants born under 30 weeks of gestation. Fecal samples collected from the 5 days preceding LOS diagnosis were analyzed using a molecular microbiota detection technique. LOS cases were subdivided into 3 groups: gram-negative, gram-positive, and coagulase-negative Staphylococci (CoNS). RESULTS: Forty LOS cases and 40 matched controls were included. In gram-negative LOS, the causative pathogen could be identified in at least 1 of the fecal samples collected 3 days prior to LOS onset in all cases, whereas in all matched controls, this pathogen was absent (P = .015). The abundance of these pathogens increased from 3 days before clinical onset. In gram-negative and gram-positive LOS (except CoNS) combined, the causative pathogen could be identified in at least 1 fecal sample collected 3 days prior to LOS onset in 92% of the fecal samples, whereas these pathogens were present in 33% of the control samples (P = .004). Overall, LOS (expect CoNS) could be predicted 1 day prior to clinical onset with an area under the curve of 0.78. CONCLUSIONS: Profound preclinical microbial alterations underline that gut microbiota is involved in the pathogenesis of LOS and has the potential as an early noninvasive biomarker.

Predictive factors for surgical treatment in preterm neonates with necrotizing enterocolitis: a multicenter case-control study.

Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (< 30 weeks of gestation) diagnosed with NEC (stage ≥ IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86-0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04-0.82]), early onset of NEC (0.003, 0.85 [0.77-0.95]), low serum bicarbonate (0.009, 0.85 [0.76-0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03-28.47]) were identified as independent risk factors for sNEC.Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known: • In 27-52% of the infants with NEC, a surgical intervention is indicated during its disease course. • Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New: • Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC. • Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC.

Dynamics of the bacterial gut microbiota in preterm and term infants after intravenous amoxicillin/ceftazidime treatment.

BACKGROUND: It is important to understand the consequences of pre-emptive antibiotic treatment in neonates, as disturbances in microbiota development during this key developmental time window might affect early and later life health outcomes. Despite increasing knowledge regarding the detrimental effect of antibiotics on the gut microbiota, limited research focussed on antibiotic treatment duration. We determined the effect of short and long amoxicillin/ceftazidime administration on gut microbiota development during the immediate postnatal life of preterm and term infants. METHODS: Faeces was collected from 63 (pre) term infants at postnatal weeks one, two, three, four and six. Infants received either no (control), short-term (ST) or long-term (LT) postpartum amoxicillin/ceftazidime treatment. RESULTS: Compared to control infants, ST and LT infants' microbiota contained significantly higher abundance of Enterococcus during the first two postnatal weeks at the expense of Bifidobacterium and Streptococcus. Short and long antibiotic treatment both allowed for microbiota restoration within the first six postnatal weeks. However, Enterococcus and Bifidobacterium abundances were affected in fewer ST than LT infants. CONCLUSIONS: Intravenous amoxicillin/ceftazidime administration affects intestinal microbiota composition by decreasing the relative abundance of Escherichia-Shigella and Streptococcus, while increasing the relative abundance of Enterococcus and Lactobacillus species during the first two postnatal weeks. Thriving of enterococci at the expense of bifidobacteria and streptococci should be considered as aspect of the cost-benefit determination for antibiotic prescription.

Late-onset Sepsis in Preterm Infants Can Be Detected Preclinically by Fecal Volatile Organic Compound Analysis: A Prospective, Multicenter Cohort Study.

Background: The intestinal microbiota has increasingly been considered to play a role in the etiology of late-onset sepsis (LOS). We hypothesize that early alterations in fecal volatile organic compounds (VOCs), reflecting intestinal microbiota composition and function, allow for discrimination between infants developing LOS and controls in a preclinical stage. Methods: In 9 neonatal intensive care units in the Netherlands and Belgium, fecal samples of preterm infants born at a gestational age ≤30 weeks were collected daily, up to the postnatal age of 28 days. Fecal VOC were measured by high-field asymmetric waveform ion mobility spectrometry (FAIMS). VOC profiles of LOS infants, up to 3 days prior to clinical LOS onset, were compared with profiles from matched controls. Results: In total, 843 preterm born infants (gestational age ≤30 weeks) were included. From 127 LOS cases and 127 matched controls, fecal samples were analyzed by means of FAIMS. Fecal VOCs allowed for preclinical discrimination between LOS and control infants. Focusing on individual pathogens, fecal VOCs differed significantly between LOS cases and controls at all predefined time points. Highest accuracy rates were obtained for sepsis caused by Escherichia coli, followed by sepsis caused by Staphylococcus aureus and Staphylococcus epidermidis. Conclusions: Fecal VOC analysis allowed for preclinical discrimination between infants developing LOS and matched controls. Early detection of LOS may provide clinicians a window of opportunity for timely initiation of individualized therapeutic strategies aimed at prevention of sepsis, possibly improving LOS-related morbidity and mortality.

From population reference to national standard: new and improved birthweight charts.

BACKGROUND: Antenatal detection of intrauterine growth restriction remains a major obstetrical challenge, with the majority of cases not detected before birth. In these infants with undetected intrauterine growth restriction, the diagnosis must be made after birth. Clinicians use birthweight charts to identify infants as small-for-gestational-age if their birthweights are below a predefined threshold for gestational age. The choice of birthweight chart strongly affects the classification of small-for-gestational-age infants and has an impact on both research findings and clinical practice. Despite extensive literature on pathological risk factors associated with small-for-gestational-age, controversy exists regarding the exclusion of affected infants from a reference population. OBJECTIVE: This study aims to identify pathological risk factors for abnormal fetal growth, to quantify their effects, and to use these findings to calculate prescriptive birthweight charts for the Dutch population. MATERIALS AND METHODS: We performed a retrospective cross-sectional study, using routinely collected data of 2,712,301 infants born in The Netherlands between 2000 and 2014. Risk factors for abnormal fetal growth were identified and categorized in 7 groups: multiple gestation, hypertensive disorders, diabetes, other pre-existing maternal medical conditions, maternal substance (ab)use, medical conditions related to the pregnancy, and congenital malformations. The effects of these risk factors on mean birthweight were assessed using linear regression. Prescriptive birthweight charts were derived from live-born singleton infants, born to ostensibly healthy mothers after uncomplicated pregnancies and spontaneous onset of labor. The Box-Cox-t distribution was used to model birthweight and to calculate sex-specific percentiles. The new charts were compared to various existing birthweight and fetal-weight charts. RESULTS: We excluded 111,621 infants because of missing data on birthweight, gestational age or sex, stillbirth, or a gestational age not between 23 and 42 weeks. Of the 2,599,640 potentially eligible infants, 969,552 (37.3%) had 1 or more risk factors for abnormal fetal growth and were subsequently excluded. Large absolute differences were observed between the mean birthweights of infants with and without these risk factors, with different patterns for term and preterm infants. The final low-risk population consisted of 1,629,776 live-born singleton infants (50.9% male), from which sex-specific percentiles were calculated. Median and 10th percentiles closely approximated fetal-weight charts but consistently exceeded existing birthweight charts. CONCLUSION: Excluding risk factors that cause lower birthweights results in prescriptive birthweight charts that are more akin to fetal-weight charts, enabling proper discrimination between normal and abnormal birthweight. This proof of concept can be applied to other populations.

Metaproteomics reveals functional differences in intestinal microbiota development of preterm infants.

OBJECTIVE: Development of the gastrointestinal tract and immune system can be modulated by the gut microbiota. Establishment of the intestinal microbiota, in its turn, is affected by host and environmental factors. As such, development of the gut microbiota is greatly impacted in preterm infants, who have an immature gut and are exposed to factors like hospitalization, caesarean section, antibiotics, and respiratory support. DESIGN: We analyzed fecal microbiota composition and activity of ten preterm infants (gestational age 25-30 weeks; birthweight 630-1750 g) during the first six postnatal weeks through metaproteomics (LC-MS/MS) and 16S-rRNA gene sequencing. RESULTS: A gestational-age-dependent microbial signature is observed, enabling microbiota-based differentiation between extremely preterm (25-27 weeks gestation) and very preterm (30 weeks gestation) infants. In very preterm infants, the intestinal microbiota developed toward a Bifidobacterium-dominated community and was associated with high abundance of proteins involved in carbohydrate and energy metabolism. Extremely preterm infants remained predominantly colonized by facultative anaerobes and were associated with proteins involved in membrane transport and translation. Delayed colonization by obligate anaerobes could be associated with antibiotic treatment and respiratory support. CONCLUSION: We speculate that gestational age and its associated intensity of care (e.g. antibiotics and respiratory support) affects intestinal microbiota composition and activity in preterm infants. As the gut microbiota plays a major role in development of the neonate, gestational age and its associated factors could set the stage for early and later life health complications via interference with microbiota development.

Association between duration of intravenous antibiotic administration and early-life microbiota development in late-preterm infants.

Antibiotic treatment is common practice in the neonatal ward for the prevention and treatment of sepsis, which is one of the leading causes of mortality and morbidity in preterm infants. Although the effect of antibiotic treatment on microbiota development is well recognised, little attention has been paid to treatment duration. We studied the effect of short and long intravenous antibiotic administration on intestinal microbiota development in preterm infants. Faecal samples from 15 preterm infants (35 ± 1 weeks gestation and 2871 ± 260 g birth weight) exposed to no, short (≤ 3 days) or long (≥ 5 days) treatment with amoxicillin/ceftazidime were collected during the first six postnatal weeks. Microbiota composition was determined through 16S rRNA gene sequencing and by quantitative polymerase chain reaction (qPCR). Short and long antibiotic treat ment significantly lowered the abundance of Bifidobacterium right after treatment (p = 0.027) till postnatal week three (p = 0.028). Long treatment caused Bifidobacterium abundance to remain decreased till postnatal week six (p = 0.009). Antibiotic treatment was effective against members of the Enterobacteriaceae family, but allowed Enterococcus to thrive and remain dominant for up to two weeks after antibiotic treatment discontinuation. Community richness and diversity were not affected by antibiotic treatment, but were positively associated with postnatal age (p < 0.023) and with abundance of Bifidobacterium (p = 0.003). Intravenous antibiotic administration during the first postnatal week greatly affects the infant's gastrointestinal microbiota. However, quick antibiotic treatment cessation allows for its recovery. Disturbances in microbiota development caused by short and, more extensively, by long antibiotic treatment could affect healthy development of the infant via interference with maturation of the immune system and gastrointestinal tract.

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

BACKGROUND: In critically ill (preterm) neonates, central venous catheters (CVCs) are increasingly used for administration of medication or parenteral nutrition. A serious complication, however, is the development of catheter-related thrombosis (CVC-thrombosis), which may resolve by itself or cause severe complications. Due to lack of evidence, management of neonatal CVC-thrombosis varies among neonatal intensive care units (NICUs). In the Netherlands an expert-based national management guideline has been developed which is implemented in all 10 NICUs in 2014. METHODS: The NEOCLOT study is a multicentre prospective observational cohort study, including 150 preterm and term infants (0-6 months) admitted to one of the 10 NICUs, developing CVC-thrombosis. Patient characteristics, thrombosis characteristics, risk factors, treatment strategies and outcome measures will be collected in a web-based database. Management of CVC-thrombosis will be performed as recommended in the protocol. Violations of the protocol will be noted. Primary outcome measures are a composite efficacy outcome consisting of death due to CVC-thrombosis and recurrent thrombosis, and a safety outcome consisting of the incidence of major bleedings during therapy. Secondary outcomes include individual components of primary efficacy outcome, clinically relevant non-major and minor bleedings and the frequency of risk factors, protocol variations, residual thrombosis and post thrombotic syndrome. DISCUSSION: The NEOCLOT study will evaluate the efficacy and safety of the new, national, neonatal CVC-thrombosis guideline. Furthermore, risk factors as well as long-term consequences of CVC-thrombosis will be analysed. TRIAL REGISTRATION: Trial registration: Nederlands Trial Register NTR4336 . Registered 24 December 2013.

Prescriptive birthweight charts can improve the prediction of adverse outcomes in very preterm infants who are small for gestational age.

AIM: We compared three anthropometric charts to determine which provided the best predictions for adverse outcomes in very preterm small for gestational age (SGA) infants to address a lack of consensus on this subject. METHODS: This was a retrospective cohort study of infants born below 32 weeks, who were admitted to two-level three neonatal intensive care units in The Netherlands from 2008 to 2013. The birthweights of 1720 infants were classified as SGA using a conventional, gender-specific birthweight chart, based on births in The Netherlands between 2000 and 2007, a prescriptive, gender-specific birthweight chart, based on the same data but without risk factors for intrauterine growth restriction (IUGR), and a non-gender-specific foetal weight chart derived from American ultrasonographic measurements. RESULTS: The conventional, prescriptive and foetal weight charts classified 126 (7.3%), 494 (28.7%) and 630 (36.6%) infants as SGA. The prescriptive chart, which excluded IUGR, identified 368 SGA infants with significantly increased risks of neonatal mortality and morbidity. The 136 SGA infants just classified by the American foetal weight chart were not at increased risk. CONCLUSION: The prescriptive birthweight chart, which excluded infants with IUGR, was the most effective chart when it came to identifying clinically important risk increases in SGA infants.

Fecal Volatile Organic Compounds in Preterm Infants Are Influenced by Enteral Feeding Composition.

Fecal volatile organic compound (VOC) analysis has shown great potential as a noninvasive diagnostic biomarker for a variety of diseases. Before clinical implementation, the factors influencing the outcome of VOC analysis need to be assessed. Recent studies found that the sampling conditions can influence the outcome of VOC analysis. However, the dietary influences remains unknown, especially in (preterm) infants. Therefore, we assessed the effects of feeding composition on fecal VOC patterns of preterm infants (born at <30 weeks gestation). Two subgroups were defined: (1) daily intake >75% breastmilk (BM) feeding and (2) daily intake >75% formula milk (FM) feeding. Fecal samples, which were collected at 7, 14 and 21 days postnatally, were analyzed by an electronic nose device (Cyranose 320®). In total, 30 preterm infants were included (15 FM, 15 BM). No differences in the fecal VOC patterns were observed at the three predefined time-points. Combining the fecal VOC profiles of these time-points resulted in a statistically significant difference between the two subgroups although this discriminative accuracy was only modest (AUC [95% CI]; p-value; sensitivity; and specificity of 0.64 [0.51⁻0.77]; 0.04; 68%; and 51%, respectively). Our results suggest that the influence of enteral feeding on the outcome of fecal VOC analysis cannot be ignored in this population. Furthermore, in both subgroups, the fecal VOC patterns showed a stable longitudinal course within the first month of life.

Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants.

BackgroundExposure to acetaminophen and its metabolites in very-preterm infants is partly unknown. We investigated the exposure to acetaminophen and its metabolites upon 10, 15, or 20 mg/kg intravenous acetaminophen in preterm infants.MethodsIn a randomized trial, 59 preterm infants (24-32 weeks' gestational age, postnatal age <1 week) received 10, 15, or 20 mg/kg acetaminophen intravenously. Plasma concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined in 293 blood samples. Area under the plasma concentration-time curves (AUC0-500 min) was related to dose and gestational age.ResultsBetween 10 and 20 mg/kg dose, median AUCs of acetaminophen, glucuronide, sulfate, and cysteine increased significantly resulting in unchanged ratios of AUC of metabolite to acetaminophen. The AUC ratio of glucuronide to acetaminophen increased with gestational age, that of sulfate decreased, and the ratio of cysteine and mercapturate remained unchanged.ConclusionWe found a gestational-age-dependent increase in glucuronidation but no evidence for saturation of a specific pathway as there was a proportional increase in exposure of acetaminophen and all metabolites. Compared with adults, very low exposure to glucuronide but higher exposure to sulfate, cysteine, and mercapturate metabolites was found, of which the relevance is not yet known.

Using benchmarking to identify inter-centre differences in persistent ductus arteriosus treatment: can we improve outcome?

OBJECTIVE: The aim of this study was to identify inter-centre differences in persistent ductus arteriosus treatment and their related outcomes. Materials and methods We carried out a retrospective, multicentre study including infants between 24+0 and 27+6 weeks of gestation in the period between 2010 and 2011. In all centres, echocardiography was used as the standard procedure to diagnose a patent ductus arteriosus and to document ductal closure. RESULTS: In total, 367 preterm infants were included. All four participating neonatal ICU had a comparable number of preterm infants; however, differences were observed in the incidence of treatment (33-63%), choice and dosing of medication (ibuprofen or indomethacin), number of pharmacological courses (1-4), and the need for surgical ligation after failure of pharmacological treatment (8-52%). Despite the differences in treatment, we found no difference in short-term morbidity between the centres. Adjusted mortality showed independent risk contribution of gestational age, birth weight, ductal ligation, and perinatal centre. CONCLUSIONS: Using benchmarking as a tool identified inter-centre differences. In these four perinatal centres, the factors that explained the differences in patent ductus arteriosus treatment are quite complex. Timing, choice of medication, and dosing are probably important determinants for successful patent ductus arteriosus closure.

Defining small-for-gestational-age: prescriptive versus descriptive birthweight standards.

UNLABELLED: Descriptive population-based birthweight standards possess low sensitivity in detecting infants with growth impairment. A prescriptive birthweight standard based on a 'healthy' subpopulation without risk factors for intrauterine growth restriction might be superior. We created two birthweight standards based on live born, singleton infants with gestational age 24-42 weeks and born in The Netherlands between 2000 and 2007. Inclusion criteria for the prescriptive birthweight standard were restricted to infants without congenital malformations, born to healthy mothers after uncomplicated pregnancies. We defined small-for-gestational-age (SGA) as birthweight <10th percentile and assessed the ability of both standards to predict adverse neonatal outcomes. The prescriptive birthweight standard identified significantly more infants as SGA, up to 38.0 % at 29 weeks gestation. SGA infants classified according to both standards as well as those classified according to the prescriptive birthweight standard only, were at increased risk of both major and minor adverse neonatal outcomes. The prescriptive birthweight standard was both more sensitive and less specific, with a maximum increase in sensitivity predicting bronchopulmonary dysplasia (+42.6 %) and a maximum decrease in specificity predicting intraventricular haemorrhage (-26.9 %) in infants aged 28-31 weeks. CONCLUSION: Prescriptive birthweight standards could improve identification of infants born SGA and at risk of adverse neonatal outcomes. WHAT IS KNOWN: • Descriptive birthweight standards possess low sensitivity in detecting growth restricted infants at risk of adverse neonatal outcomes. • Prescriptive standards could improve identification of very preterm small-for-gestational-age (SGA) infants at risk of intraventricular haemorrhage. What is New: • Prescriptive standards identify more preterm and term SGA infants at risk of major adverse neonatal outcomes. • Late preterm and term SGA infants classified according to the prescriptive standard are at increased risk of minor adverse neonatal outcomes with potentially harmful implications.

Feasibility of monitoring stress using skin conduction measurements during intubation of newborns.

The objective of this study was to assess the feasibility of monitoring stress responses in newborns during naso-tracheal intubation after two different premedication regimens, using skin conductance measurements (SCM). Twenty-two newborns were randomised and premedicated with morphine + vecuronium or propofol. SCM (peaks/s) were collected prior to, during and after the procedure. Threshold for interpreting responses as stressful was 0.21 peaks/s. Intubation conditions and physiological parameters were registered. Intubation conditions were good in all newborns. Administration of morphine (range 1.4-10.3 min) before administration of vecuronium did not affect SCM when a stressful stimulus was applied. Within 1.6 min (range 0.8-3 min) after administration of vecuronium, SCM disappeared in 10 of 11 newborns. Propofol reduced SCM in 10 of 11 newborns at the first attempt. Further attempts were associated with increasing SCM, mostly above a threshold of 0.21 peaks/s. There were no significant changes in physiological parameters during the procedure for either premedication regimen. CONCLUSION: The variation in SCM between individual newborns limits the usefulness of SCM as stress monitor during intubation. The use of neuromuscular blockers for premedication precludes monitoring of SCM completely in newborns. WHAT IS KNOWN: Skin conductance measurements have been used successfully to monitor pain in awake newborn infants. WHAT IS NEW: Premedicated newborns display significant interindividual variation in skin conductance measurements during an intubation procedure. Neuromuscular blockade causes skin conductance measurements to disappear completely.

Infants born before 32 weeks of gestation or with respiratory disease are most likely to receive palivizumab in the Netherlands.

AIM: Palivizumab is reported to be effective in reducing respiratory syncytial virus hospitalisation. Its licensed uses include infants younger than six months of age, born before 35 weeks of gestation or under two years old with congenital heart disease or bronchopulmonary dysplasia. We redressed lack of research in the Netherlands by studying whether infants who met the licensed indications received the drug. METHODS: Data were obtained from the PHARMO Database Network and The Netherlands Perinatal Registry for all linked infants born between 1 April 1999 and 31 March 2007. Determinants for receiving palivizumab were examined using logistic regression analyses. RESULTS: Only 15% of the 3321 infants who met the licensed indications received palivizumab and the strongest predictor was being born before 32 weeks of gestation, with an odds ratio of 49.1 (95% confidence interval 31.5-76.4). However, 50% of infants born before 32 weeks did not receive palivizumab and the subanalyses showed that the probability increased for infants born in later years, those who had respiratory distress syndrome and those hospitalised during the respiratory syncytial virus season. CONCLUSION: Only 15% of eligible infants in the Netherlands received palivizumab and they were mostly born before 32 weeks, in line with Dutch guidelines.

Five-year follow-up of effects of neonatal intensive care and morphine infusion during mechanical ventilation on diurnal cortisol rhythm.

OBJECTIVE: To test the hypothesis that the diurnal cortisol secretion rhythm of children who as neonates had been hospitalized differs from that of children without a history of neonatal hospital admission and that this rhythm differs between these hospitalized children treated with either continuous morphine infusion or placebo. STUDY DESIGN: A follow-up cohort study was performed with 5-year-old children who as neonates participated in a randomized controlled trial of continuous morphine infusion (born 24-42 weeks' gestation), and a control group of healthy term born (≥ 37 weeks' gestation) children. Five saliva samples over a school day were assayed for cortisol concentrations. The diurnal cortisol rhythm was analyzed with random regression analysis for repeated measurements. RESULTS: Compared with the healthy controls, the trial participants had greater cortisol levels (P = .002) after adjustment for sex and socioeconomic status. The administration of morphine did not affect the cortisol concentrations (P = .66) after adjustment for sex, socioeconomic status, and gestational age at birth. CONCLUSIONS: The finding that former trial participants had greater cortisol levels at 5 years of age supports the concept of long-lasting programming of the hypothalamic-pituitary-adrenal axis. Morphine infusion in the neonatal period did not alter cortisol secretion at 5 years of age.

First year of life medication use and hospital admission rates: premature compared with term infants.

OBJECTIVE: To compare hospitalization and medication use during the first year of life in preterm-born and term-born infants. STUDY DESIGN: Data for this retrospective cohort study were obtained from the linked PHARMO-Netherlands Perinatal Registry cohort. From this linked birth cohort, preterm infants (<37 weeks) born between 2004 and 2007 were randomly matched to 4 full-term infants. During follow-up, hospitalization and medication use were assessed. Cox proportional hazard regression models were used to estimate and compare the relative risk (RR) of hospitalization and medication use in preterm and full-term infants. Population-attributable risk percentages were calculated to estimate the proportion of hospitalizations and medication use attributable to preterm birth. RESULTS: Among the 71,607 singletons born between 2004-2007, 4277 (6%) were born preterm. Of these, 90% were hospitalized at birth, compared with 55% of full-term infants. Preterm infants were twice as likely to be rehospitalized (RR, 2.0; 95% CI, 1.9-2.2), specifically for respiratory-related diseases. Prematurity accounted for 6% of the respiratory disease readmissions. The most frequently used outpatient drugs in the second half year of life were antibacterials for systemic use and drugs for obstructive airway diseases. Preterm infants were 50% more likely to receive a respiratory medication (RR, 1.5; 95% CI, 1.4-1.7). CONCLUSION: In the first year of life, preterm born infants are up to 2 times more likely than full-term infants to be hospitalized or use medication, especially related to respiratory disease.

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.