Fecal microbiota and volatile metabolome pattern alterations precede late-onset meningitis in preterm neonates.

OBJECTIVE: The fecal microbiota and metabolome are hypothesized to be altered before late-onset neonatal meningitis (LOM), in analogy to late-onset sepsis (LOS). The present study aimed to identify fecal microbiota composition and volatile metabolomics preceding LOM. METHODS: Cases and gestational age-matched controls were selected from a prospective, longitudinal preterm cohort study (born <30 weeks' gestation) at nine neonatal intensive care units. The microbial composition (16S rRNA sequencing) and volatile metabolome (gas chromatography-ion mobility spectrometry (GC-IMS) and GC-time-of-flight-mass spectrometry (GC-TOF-MS)), were analyzed in fecal samples 1-10 days pre-LOM. RESULTS: Of 1397 included infants, 21 were diagnosed with LOM (1.5%), and 19 with concomitant LOS (90%). Random Forest classification and MaAsLin2 analysis found similar microbiota features contribute to the discrimination of fecal pre-LOM samples versus controls. A Random Forest model based on six microbiota features accurately predicts LOM 1-3 days before diagnosis with an area under the curve (AUC) of 0.88 (n=147). Pattern recognition analysis by GC-IMS revealed an AUC of 0.70-0.76 (P<0.05) in the three days pre-LOM (n=92). No single discriminative metabolites were identified by GC-TOF-MS (n=66). CONCLUSION: Infants with LOM could be accurately discriminated from controls based on preclinical microbiota composition, while alterations in the volatile metabolome were moderately associated with preclinical LOM.

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.

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.

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.

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.

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.

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.

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.

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.

A comparative study using dual-energy X-ray absorptiometry, air displacement plethysmography, and skinfolds to assess fat mass in preterms at term equivalent age.

The aim of this study was to compare whole body composition, generated by air displacement plethysmography (ADP) and dual-energy X-ray absorptiometry (DXA), and to evaluate the potential predictive value of the sum of skinfolds (∑SFT) for whole body composition, in preterm infants at term equivalent age. A convenience sample of sixty-five preterm infants with a mean (SD) gestational age of 29 (1.6) weeks was studied at term equivalent age. Fat mass measured by DXA and ADP were compared and the ability of the ∑SFT to predict whole body fat mass was investigated. There was poor agreement between fat mass percentage measured with ADP compared with DXA (limits of agreement: - 4.8% and 13.7%). A previously modeled predictive equation with the ∑SFT as a predictor for absolute fat mass could not be validated. Corrected for confounders, the ∑SFT explained 42% (ADP, p = 0.001) and 75% (DXA, p = 0.001) of the variance in fat mass percentage.Conclusions: The ∑SFT was not able to accurately predict fat mass and ADP and DXA did not show comparable results. It remains to be elucidated whether or not DXA provides more accurate assessment of whole body fat mass than ADP in preterm infants.Trial registration: NTR5311 What is Known: • Diverse methods are used to assess fat mass in preterm infants. What is New: • This study showed that there is poor agreement between dual-energy X-ray absorptiometry, air displacement plethysmography, and skinfold thickness measurements. • Our results affirm the need for consensus guidelines on how to measure fat mass in preterm infants, to improve the assimilation of data from different studies and the implementation of the findings from those studies.

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.

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.

Propofol in neonates causes a dose-dependent profound and protracted decrease in blood pressure.

AIM: To analyse the effects of different propofol starting doses as premedication for endotracheal intubation on blood pressure in neonates. METHODS: Neonates who received propofol starting doses of 1.0 mg/kg (n = 30), 1.5 mg/kg (n = 23) or 2.0 mg/kg (n = 26) as part of a previously published dose-finding study were included in this analysis. Blood pressure in the 3 dosing groups was analysed in the first 60 minutes after start of propofol. RESULTS: Blood pressure declined after the start of propofol in all 3 dosing groups and was not restored 60 minutes after the start of propofol. The decline in blood pressure was highest in the 2.0 mg/kg dosing group. Blood pressure decline was mainly dependent on the initial propofol starting dose rather than the cumulative propofol dose. CONCLUSION: Propofol causes a dose-dependent profound and prolonged decrease in blood pressure. The use of propofol should be carefully considered. When using propofol, starting with a low dose and titrating according to sedative effect seems the safest strategy.

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.

rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial.

OBJECTIVE: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 230/7 weeks to 276/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01096784.

Fetal akinesia deformation sequence, arthrogryposis multiplex congenita, and bilateral clubfeet: Is motor assessment of additional value for in utero diagnosis? A 10-year cohort study.

OBJECTIVE: The diagnosis of fetal akinesia deformation sequence (FADS) is a challenge. Motor assessment is of additional value to advanced ultrasound examinations (AUE) for in utero FADS diagnosis before 24 weeks of gestation. METHODS: All consecutive fetuses with greater than or equal to two contractures on the 20 week structural anomaly scan (2007-2016) were included. Findings at AUE, including motor assessment were analysed and related to outcome. RESULTS: Sixty-six fetuses fulfilled the inclusion criteria. On the basis of the first AUE, FADS was suspected in 13 of 66, arthrogryposis multiplex congenita (AMC) in 12 of 66, bilateral pes equinovares (BPEV) in 40 of 66, and Holt-Oram syndrome in one of 66. On the basis of the first motor assessment, the suspected diagnosis changed in 19 of 66, in 13 of 66 worsening to FADS, six of 66 amelioration from FADS, and confirmed FADS in seven of 13. The result was 20 FADS, seven AMC, and 38 BPEV. Second AUE in 44 fetuses showed additional contractures in two of eight FADS, and one intrauterine fetal death (IUFD). The second motor assessment changed the diagnosis in three of 43, one worsening from BPEV into FADS, two ameliorations from FADS, and confirmed FADS in seven by deterioration of motility. The result was nine FADS, six AMC, and 29 BPEV. CONCLUSION: The results suggest that motor assessment has additional value to distinguish between FADS, AMC, and BPEV.

Maternal psychological distress after severe pregnancy hypertension was associated with increased child behavioural problems at the age of 12.

AIM: We examined the association between early maternal psychological distress after severe hypertensive disorders of pregnancy (HDP) and behavioural issues in their 12-year-old offspring. METHODS: This secondary analyses of a prospective mother-child birth cohort focused on 95 women with severe HDP and their singleton offspring. The mothers were recruited during pregnancy from 2000 to 2003 in Amsterdam, the Netherlands. Maternal distress at child term age and three months post-term was measured using the Symptom Checklist-90. The Child Behaviour Checklist for six years to 18 years was used to quantify social and attention problems in their offspring at 12 years of age. Perinatal and neonatal risk factors were also analysed. RESULTS: The children were born at a mean age of just under 32 weeks and 90% weighed below the 10th percentile. High psychological distress (score ≥133) affected 45% of the mothers at term age and 44% three months post-term. Child social problems were significantly associated with maternal distress at three months and were highest in cases of high maternal distress in combination with major neonatal morbidity. Child attention problems were associated with maternal anxiety at three months post-term. CONCLUSION: Early maternal psychological distress after severe maternal HDP was associated with childhood behavioural issues at the age of 12.

Development of severe bronchopulmonary dysplasia is associated with alterations in fecal volatile organic compounds.

BackgroundThe aim of this study was to evaluate the potential of fecal volatile organic compounds (VOCs), obtained by means of an electronic nose device (Cyranose 320), as early non-invasive biomarker for BPD.MethodsIn this nested case-control study performed at three Neonatal Intensive Care Units, fecal samples obtained at postnatal age of 7, 14, 21, and 28 days from preterm infants with severe bronchopulmonary dysplasia (BPD) were compared with fecal VOC profiles from matched controls. Microbiota analysis was performed by means of IS-pro technique on fecal samples collected at 28 days postnatally.ResultsVOC profiles of infants developing severe BPD (n=15) could be discriminated from matched controls (n=15) at postnatal age of 14 days (area under the curve (±95% confidence interval), P-value, sensitivity, specificity; 0.72 (0.54-0.90), 0.040, 60.0%, 73.3%), 21 days (0.71 (0.52-0.90), 0.049, 66.7%, 73.3%) and 28 days (0.77 (0.59-0.96), 0.017, 69.2%, 69.2%) but not at 7 days. Intestinal microbiota did not differ between BPD subjects and controls.ConclusionFecal VOC profiles of infants developing BPD could be differentiated from controls at postnatal day 14, 21, and 28. VOC differences could not be directed to intestinal microbiota alterations but presumably reflect local and systemic metabolic and inflammatory pathways associated with BPD.

Evaluation of a real-time PCR assay for detection and quantification of bacterial DNA directly in blood of preterm neonates with suspected late-onset sepsis.

BACKGROUND: Rapid and accurate diagnosis of neonatal sepsis is highly warranted because of high associated morbidity and mortality. The aim of this study was to evaluate the performance of a novel multiplex PCR assay for diagnosis of late-onset sepsis and to investigate the value of bacterial DNA load (BDL) determination as a measure of infection severity. METHODS: This cross-sectional study was conducted in a neonatal intensive care unit. Preterm and/or very low birth weight infants suspected for late-onset sepsis were included. Upon suspicion of sepsis, a whole blood sample was drawn for multiplex PCR to detect the eight most common bacteria causing neonatal sepsis, as well as for blood culture. BDL was determined in episodes with a positive multiplex PCR. RESULTS: In total, 91 episodes of suspected sepsis were investigated, and PCR was positive in 53 (58%) and blood culture in 60 (66%) episodes, yielding no significant difference in detection rate (p = 0.17). Multiplex PCR showed a sensitivity of 77%, specificity of 81%, positive predictive value of 87%, and negative predictive value of 68% compared with blood culture. Episodes with discordant results of PCR and blood culture included mainly detection of coagulase-negative staphylococci (CoNS). C-reactive protein (CRP) level and immature to total neutrophil (I/T) ratio were lower in these episodes, indicating less severe disease or even contamination. Median BDL was high (4.1 log10 cfu Eq/ml) with a wide range, and was it higher in episodes with a positive blood culture than in those with a negative blood culture (4.5 versus 2.5 log10 cfu Eq/ml; p < 0.0001). For CoNS infection episodes BDL and CRP were positively associated (p = 0.004), and for Staphylococcus aureus infection episodes there was a positive association between BDL and I/T ratio (p = 0.049). CONCLUSIONS: Multiplex PCR provides a powerful assay to enhance rapid identification of the causative pathogen in late-onset sepsis. BDL measurement may be a useful indicator of severity of infection.

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.