Vasoactive peptides as biomarkers for the prediction of retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a major complication in preterm infants. We assessed if plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) serve as early markers for subsequent ROP development in preterm infants <32 weeks gestation. METHODS: Prospective, two-centre, observational cohort study. MR-proANP and CT-proET1 were measured on day seven of life. Associations with ROP ≥ stage II were investigated by univariable and multivariable logistic regression models. RESULTS: We included 224 infants born at median (IQR) 29.6 (27.1-30.8) weeks gestation and birth weight of 1160 (860-1435) g. Nineteen patients developed ROP ≥ stage II. MR-proANP and CT-proET1 levels were higher in these infants (median (IQR) 864 (659-1564) pmol/L and 348 (300-382) pmol/L, respectively) compared to infants without ROP (median (IQR) 299 (210-502) pmol/L and 196 (156-268) pmol/L, respectively; both P < 0.001). MR-proANP and CT-proET1 levels were significantly associated with ROP ≥ stage II in univariable logistic regression models and after adjusting for co-factors, including gestational age and birth weight z-score. CONCLUSIONS: MR-proANP and CT-proET1 measured on day seven of life are strongly associated with ROP ≥ stage II in very preterm infants and might improve early prediction of ROP in the future. IMPACT: Plasma levels of midregional pro-atrial natriuretic peptide and C-terminal pro-endothelin-1 measured on day seven of life in very preterm infants show a strong association with development of retinopathy of prematurity ≥ stage II. Both biomarkers have the potential to improve early prediction of retinopathy of prematurity. Vasoactive peptides might allow to reduce the proportion of screened infants substantially.

Volumetric Capnography at 36 Weeks Postmenstrual Age and Bronchopulmonary Dysplasia in Very Preterm Infants.

OBJECTIVES: To assess the feasibility of volumetric capnography in spontaneously breathing very preterm infants at 36 weeks postmenstrual age (PMA) and its association with clinical markers of lung disease including the duration of respiratory support and bronchopulmonary dysplasia (BPD). STUDY DESIGN: We obtained mainstream volumetric capnography measurements in 143 very preterm infants at 36 weeks PMA. BPD was categorized into no, mild, moderate, and severe according to the 2001 National Heart, Lung and Blood Institute workshop report. Normalized capnographic slopes of phase II (SnII) and phase III (SnIII) were calculated. We assessed the effect of BPD, duration of respiratory support, and duration of supplemental oxygen on capnographic slopes. RESULTS: SnIII was steeper in infants with moderate to severe BPD (76 ± 25/L) compared with mild (31 ± 20/L) or no BPD (26 ± 18/L) (P < .001). The association of SnIII with moderate to severe BPD persisted after adjusting for birth weight z-score, respiratory rate, and airway dead space to tidal volume ratio. The diagnostic usefulness of SnIII to discriminate between infants with and without moderate to severe BPD was high (area under the curve, 0.94; 95% CI, 0.89-0.99). CONCLUSIONS: Volumetric capnography is feasible in spontaneously breathing preterm infants at 36 weeks PMA and reflects the degree of lung disease. This promising bedside lung function technique may offer an objective, continuous physiological outcome measure for assessment of BPD severity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02083562.

Respiratory morbidity in preterm infants predicted by natriuretic peptide (MR-proANP) and endothelin-1 (CT-proET-1).

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major complication in preterm infants <32 weeks. We aimed to assess whether plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) predict respiratory morbidity. METHODS: This was a prospective, two-center, observational cohort study. MR-proANP and CT-proET-1 were measured at day 7 (±2) of life. Associations with duration of supplemental oxygen and the composite outcome of moderate or severe BPD or death (BPD/death) were investigated. RESULTS: Two hundred and twenty-nine infants <32 weeks were included (median gestational age [GA] 29.6 weeks [interquartile range 29.0-30.7], median birth weight 1150 g [IQR 840-1410]). MR-proANP and CT-proET-1 were associated with the duration of supplemental oxygen in univariable analysis (both p < 0.001) but not after adjusting for co-factors. Infants with BPD/death showed higher plasma levels of MR-proANP (623.50 pmol/L [IQR 458.50-881.38] vs. 308.35 pmol/L [IQR 216.72-538.10]; p < 0.001) and CT-proET-1 (255.40 pmol/L [IQR 202.60-311.15] vs. 198.30 pmol/L [IQR 154.70-297.95]; p = 0.015) compared to infants without BPD/death. Levels of both biomarkers were significantly associated with BPD/death in univariable models but not after adjusting for co-factors. CONCLUSIONS: MR-proANP and CT-proET-1 are associated with the duration of supplemental oxygen and the composite outcome BPD/death, but their prognostic value does not complement that of clinical risk factors. IMPACT: Plasma levels of MR-proANP and CT-proET-1, measured on day 7 of life (±2 days) are associated in univariable analyses with duration of supplemental oxygen and the combined outcome of BPD or death in VLGA infants. Associations between both biomarkers and respiratory morbidity do not persist in multivariable models, in particular when gestational age is included. MR-proANP and CT-proET-1 have limited additional value to predict respiratory morbidity in VLGA infants compared to clinical parameters.

Multichannel esophageal signals to monitor respiratory rate in preterm infants.

BACKGROUND: Apnea of prematurity cannot be reliably measured with current monitoring techniques. Instead, indirect parameters such as oxygen desaturation or bradycardia are captured. We propose a Kalman filter-based detection of respiration activity and hence apnea using multichannel esophageal signals in neonatal intensive care unit patients. METHODS: We performed a single-center observational study with moderately preterm infants. Commercially available nasogastric feeding tubes containing multiple electrodes were used to capture signals with customized software. Multichannel esophageal raw signals were manually annotated, processed using extended Kalman filter, and compared with standard monitoring data including chest impedance to measure respiration activity. RESULTS: Out of a total of 405.4 h captured signals in 13 infants, 100 episodes of drop in oxygen saturation or heart rate were examined. Median (interquartile range) difference in respiratory rate was 0.04 (-2.45 to 1.48)/min between esophageal measurements annotated manually and with Kalman filter and -3.51 (-7.05 to -1.33)/min when compared to standard monitoring, suggesting an underestimation of respiratory rate when using the latter. CONCLUSIONS: Kalman filter-based estimation of respiratory activity using multichannel esophageal signals is safe and feasible and results in respiratory rate closer to visual annotation than that derived from chest impedance of standard monitoring.

Update on ventilatory management of extremely preterm infants-A Neonatal Intensive Care Unit perspective.

Extremely preterm infants commonly suffer from respiratory distress syndrome. Ventilatory management of these infants starts from birth and includes decisions such as timing of respiratory support in relation to umbilical cord management, oxygenation targets, and options of positive pressure support. The approach of early intubation and surfactant administration through an endotracheal tube has been challenged in recent years by primary noninvasive respiratory support and newer methods of surfactant administration via thin catheters. Available data comparing the thin catheter method to endotracheal tube and delayed extubation in extremely preterm infants born before 28 weeks of gestation did not show differences in survival free of bronchopulmonary dysplasia. Data from numerous randomized trials comparing conventional ventilation with high-frequency oscillatory ventilation did not show differences in meaningful outcomes. Among conventional modes of ventilation, there is good evidence to favor volume-targeted ventilation over pressure-limited ventilation. The former reduces the combined risk of bronchopulmonary dysplasia or death and several important secondary outcomes without an increase in adverse events. There are no evidence-based guidelines to set positive end-expiratory pressure in ventilated preterm infants. Recent research suggests that the forced oscillation technique may help to find the lowest positive end-expiratory pressure at which lung recruitment is optimal. Benefits and risks of the various modes of noninvasive ventilation depend on the clinical setting, degree of prematurity, severity of lung disease, and competency of staff in treating associated complications. Respiratory care after discharge includes home oxygen therapy, lung function monitoring, weaning from medication started in the neonatal unit, and treatment of asthma-like symptoms.

Outcomes for Infants Born in Perinatal Centers Performing Fewer Surgical Ligations for Patent Ductus Arteriosus: A Swiss Population-Based Study.

OBJECTIVE: To assess patent ductus arteriosus treatment variation between Swiss perinatal centers and to determine its effect on outcome in a population-based setting. STUDY DESIGN: This was a retrospective cohort study of infants born less than 28 weeks of gestation between 2012 and 2017. Outcomes between surgically ligated and pharmacologically treated infants as well as infants born in centers performing ≤10% ligation ("low" group) and >10% ("high" group) were compared using logistic regression and 1:1 propensity score matching. Matching was based on case-mix and preligation confounders: intraventricular hemorrhages grades 3-4, necrotizing enterocolitis, sepsis, and ≥28 days' oxygen supply. RESULTS: Of 1389 infants, 722 (52%) had pharmacologic treatment and 156 (11.2%) received surgical ligation. Compared with infants who received pharmacologic treatment, ligated infants had greater odds for major morbidities (OR 2.09, 95% CI 1.44-3.04) and 2-year neurodevelopmental impairment (OR 1.81, 95% CI 1.15-2.84). Mortality was comparable after restricting the cohort to infants surviving at least until day 10 to avoid survival bias. In the "low" group, 34 (4.9%) of 696 infants were ligated compared with 122 (17.6%) of 693 infants in the "high" group. Infants in the "high" group had greater odds for major morbidities (OR 1.49, 95% CI 1.11-2.0). CONCLUSIONS: Our analysis identified a burden on infants receiving surgical ligation vs pharmacologic treatment in a population-based setting where there was no agreed-on common procedure. These results may guide a revision of patent ductus arteriosus treatment practice in Switzerland.

Placental Pathology Findings during and after SARS-CoV-2 Infection: Features of Villitis and Malperfusion.

Since the outbreak of coronavirus disease 2019 (COVID-19), there has been a debate whether pregnant women are at a specific risk for COVID-19 and whether it might be vertically transmittable through the placenta. We present a series of five placentas of SARS coronavirus 2 (SARS-CoV-2)-positive women who had been diagnosed with mild symptoms of COVID-19 or had been asymptomatic before birth. We provide a detailed histopathologic description of morphological changes accompanied by an analysis of presence of SARS-CoV-2 in the placental tissue. All placentas were term deliveries (40th and 41st gestational weeks). One SARS-CoV-2-positive patient presented with cough and dyspnoea. This placenta showed prominent lymphohistiocytic villitis and intervillositis and signs of maternal and foetal malperfusion. Viral RNA was present in both placenta tissue and the umbilical cord and could be visualized by in situ hybridization in the decidua. SARS-CoV-2 tests were negative at the time of delivery of 3/5 women, and their placentas did not show increased inflammatory infiltrates. Signs of maternal and/or foetal malperfusion were present in 100% and 40% of cases, respectively. There was no transplacental transmission to the infants. In our cohort, we can document different time points regarding SARS-CoV-2 infection. In acute COVID-19, prominent lymphohistiocytic villitis may occur and might potentially be attributable to SARS-CoV-2 infection of the placenta. Furthermore, there are histopathological signs of maternal and foetal malperfusion, which might have a relationship to an altered coagulative or microangiopathic state induced by SARS-CoV-2, yet this cannot be proven considering a plethora of confounding factors.

The rhythm of a preterm neonate's life: ultradian oscillations of heart rate, body temperature and sleep cycles.

The objectives are to characterize oscillations of physiological functions such as heart rate and body temperature, as well as the sleep cycle from behavioral states in generally stable preterm neonates during the first 5 days of life. Heart rate, body temperature as well as behavioral states were collected during a daily 3-h observation interval in 65 preterm neonates within the first 5 days of life. Participants were born before 32 weeks of gestational age or had a birth weight below 1500 g; neonates with asphyxia, proven sepsis or malformation were excluded. In total 263 observation intervals were available. Heart rate and body temperature were analyzed with mathematical models in the context of non-linear mixed effects modeling, and the sleep cycles were characterized with signal processing methods. The average period length of an oscillation in this preterm neonate population was 159 min for heart rate, 290 min for body temperature, and the average sleep cycle duration was 19 min. Oscillation of physiological functions as well as sleep cycles can be characterized in very preterm neonates within the first few days of life. The observed parameters heart rate, body temperature and sleep are running in a seemingly uncorrelated pace at that stage of development. Knowledge about such oscillations may help to guide nursing and medical care in these neonates as they do not yet follow a circadian rhythm.

Forced oscillation measurements in the first week of life and pulmonary outcome in very preterm infants on noninvasive respiratory support.

BACKGROUND: We aimed at investigating whether early lung mechanics in non-intubated infants below 32 weeks of gestational age (GA) are associated with respiratory outcome. METHODS: Lung mechanics were assessed by the forced oscillation technique using a mechanical ventilator (Fabian HFOi, ACUTRONIC Medical Systems AG, Hirzel, Switzerland) that superimposed small-amplitude oscillations (10 Hz) on a continuous positive airway pressure. Measurements were performed during regular tidal breathing using a face mask on days 2, 4, and 7 of life. Respiratory system resistance (Rrs) and reactance (Xrs) were computed from flow and pressure. RESULTS: One hundred and seventy-seven measurements were successfully performed in 68 infants. Infants had a mean (range) GA of 29.3 (24.1-31.7) weeks and a birth weight of 1257 (670-2350)g. Xrs was associated with the duration of respiratory support (R2 = 0.39, p < 0.001). A multilevel regression model, including Xrs and GA, explained the duration of respiratory support better than GA alone (R2 = 0.51 vs. 0.45, p = 0.005, likelihood ratio test). CONCLUSION: Assessment of Xrs in the first week of life is feasible and improves prognostication of respiratory outcome in very preterm infants on noninvasive respiratory support.

Heart rate fluctuation after birth predicts subsequent cardiorespiratory stability in preterm infants.

BACKGROUND: Cardiorespiratory stability of preterm infants is a prerequisite for discharge from the neonatal intensive care unit (NICU) but very difficult to predict. We aimed to assess whether characterizing heart rate fluctuation (HRF) within the first days of life has prognostic utility. METHODS: We conducted a prospective cohort study in 90 preterm infants using a previously validated surface diaphragmatic electromyography (sEMG) method to derive interbeat intervals. We characterized HRF by time series parameters including sample entropy (SampEn) and scaling exponent alpha (ScalExp) obtained from daily 3-h measurements. Data were analyzed by multivariable, multilevel linear regression. RESULTS: We obtained acceptable raw data from 309/330 sEMG measurements in 76/90 infants born at a mean (range) of 30.2 (24.7-34.0) weeks gestation. We found a significant negative association of SampEn with duration of respiratory support (R2 = 0.53, p < 0.001) and corrected age at discontinuation of caffeine therapy (R2 = 0.35, p < 0.001) after adjusting for sex, gestational age, birth weight z-score, and sepsis. CONCLUSIONS: Baseline SampEn calculated over the first 5 days of life carries prognostic utility for an estimation of subsequent respiratory support and pre-discharge cardiorespiratory stability in preterm infants, both important for planning of treatment and utilization of health care resources.

Beta-blockers for prevention and treatment of retinopathy of prematurity in preterm infants.

BACKGROUND: Retinopathy of prematurity (ROP) is a vision-threatening disease of preterm neonates. The use of beta-adrenergic blocking agents (beta-blockers), which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP. OBJECTIVES: To determine the effect of beta-blockers on short-term structural outcomes, long-term functional outcomes, and the need for additional treatment, when used either as prophylaxis in preterm infants without ROP, stage 1 ROP (zone I), or stage 2 ROP (zone II) without plus disease or as treatment in preterm infants with at least prethreshold ROP. SEARCH METHODS: We searched the Cochrane Neonatal Review Group Specialized Register; CENTRAL (in the Cochrane Library Issue 7, 2017); Embase (January 1974 to 7 August 2017); PubMed (January 1966 to 7 August 2017); and CINAHL (January 1982 to 7 August 2017). We checked references and cross-references and handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings. SELECTION CRITERIA: We considered for inclusion randomised or quasi-randomised clinical trials that used beta-blockers for prevention or treatment of ROP in preterm neonates of less than 37 weeks' gestational age. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane and the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease.In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or laser therapy; and arterial hypotension or bradycardia requiring inotropic support. Evidence was of moderate quality for the following outcomes: progression to stage 2 with plus disease; progression to stage 3 ROP; and progression to stage 4 or 5 ROP.Meta-analysis of three trials (N = 366) suggested beneficial effects of oral beta-blockers on the risk of requiring anti-VEGF agents (typical risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.86; I² = 0%; typical risk difference (RD) -0.06, 95% CI -0.10 to -0.01; I² = 75%; number needed to treat for an additional beneficial outcome (NNTB) 18, 95% CI 14 to 84) and laser therapy (typical RR 0.54, 95% CI 0.32 to 0.89; typical RD -0.09, 95% CI -0.16 to -0.02; I² = 31%; NNTB 12, 95% CI 8 to 47). Meta-analysis of two trials (N = 161) demonstrated a beneficial effect of oral beta-blockers on progression to stage 3 ROP (typical RR 0.60, 95% CI 0.37 to 0.96; I² = 0%; typical RD -0.15, 95% CI -0.28 to -0.02; I² = 73%; NNTB 7, 95% CI 5 to 67). There was no significant effect of oral beta-blockers on progression to stage 2 ROP with plus disease or to stage 4 or 5 ROP. Although meta-analysis did not indicate a significant effect of beta-blockers on arterial hypotension or bradycardia, propranolol dosage in one study was reduced by 50% in infants of less than 26 weeks' gestational age due to severe hypotension, bradycardia, and apnoea in several participants. Analyses did not indicate significant effects of beta-blockers on complications of prematurity or mortality. None of the trials reported on long-term visual impairment. AUTHORS' CONCLUSIONS: Limited evidence of low-to-moderate quality suggests that prophylactic administration of oral beta-blockers might reduce progression towards stage 3 ROP and decrease the need for anti-VEGF agents or laser therapy. The clinical relevance of those findings is unclear as no data on long-term visual impairment were reported. Adverse events attributed to oral propranolol at a dose of 2 mg/kg/d raise concerns regarding systemic administration of this drug for prevention of ROP at the given dose. There is insufficient evidence to determine the efficacy and safety of beta-blockers for prevention of ROP due to high risk of bias in two included trials and the lack of long-term functional outcomes. We would encourage researchers to conduct large, well-designed trials to confirm or refute the role of beta-blockers for prevention and treatment of ROP in preterm infants. Trials should report on long-term visual impairment. Researchers should consider dose-finding studies of systemic beta-blockers and topical administration of beta-blockers, in order to optimise drug delivery and minimise adverse events.

Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.

OBJECTIVE: To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. METHODS: A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. RESULTS: A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. CONCLUSIONS: To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment.

Fourfold increase in prevalence of gestational diabetes mellitus after adoption of the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria.

BACKGROUND: The aim was to evaluate the influence of the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) guidelines for screening of gestational diabetes mellitus (GDM) on GDM prevalence in a cohort from a Swiss tertiary hospital. METHODS: This was a retrospective cohort study involving all pregnant women who were screened for GDM between 24 and 28 weeks of gestation. From 2008 until 2010 (period 1), a two-step approach with 1-h 50 g glucose challenge test (GCT) was used, followed by fasting, 1- and 2-h glucose measurements after a 75 g oral glucose tolerance test (OGTT) in case of a positive GCT. From 2010 until 2013 (period 2), all pregnant women were tested with a one-step 75 g OGTT according to new IADPSG guidelines. In both periods, women with risk factors could be screened directly with a 75 g OGTT in early pregnancy. RESULTS: Overall, 647 women were eligible for the study in period 1 and 720 in period 2. The introduction of the IADPSG criteria resulted in an absolute increase of GDM prevalence of 8.5% (3.3% in period 1 to 11.8% in period 2). CONCLUSIONS: The adoption of the IADPSG criteria resulted in a considerable increase in GDM diagnosis in our Swiss cohort. Further studies are needed to investigate if the screening is cost effective and if treatment of our additionally diagnosed GDM mothers might improve short-term as well as long-term outcome.

The predictive value of quantitative fibronectin testing in combination with cervical length measurement in symptomatic women.

BACKGROUND: The combination of the qualitative fetal fibronectin test and cervical length measurement has a high negative predictive value for preterm birth within 7 days; however, positive prediction is poor. A new bedside quantitative fetal fibronectin test showed potential additional value over the conventional qualitative test, but there is limited evidence on the combination with cervical length measurement. OBJECTIVE: The purpose of this study was to compare quantitative fetal fibronectin and qualitative fetal fibronectin testing in the prediction of spontaneous preterm birth within 7 days in symptomatic women who undergo cervical length measurement. STUDY DESIGN: We performed a European multicenter cohort study in 10 perinatal centers in 5 countries. Women between 24 and 34 weeks of gestation with signs of active labor and intact membranes underwent quantitative fibronectin testing and cervical length measurement. We assessed the risk of preterm birth within 7 days in predefined strata based on fibronectin concentration and cervical length. RESULTS: Of 455 women who were included in the study, 48 women (11%) delivered within 7 days. A combination of cervical length and qualitative fibronectin resulted in the identification of 246 women who were at low risk: 164 women with a cervix between 15 and 30 mm and a negative fibronectin test (<50 ng/mL; preterm birth rate, 2%) and 82 women with a cervix at >30 mm (preterm birth rate, 2%). Use of quantitative fibronectin alone resulted in a predicted risk of preterm birth within 7 days that ranged from 2% in the group with the lowest fibronectin level (<10 ng/mL) to 38% in the group with the highest fibronectin level (>500 ng/mL), with similar accuracy as that of the combination of cervical length and qualitative fibronectin. Combining cervical length and quantitative fibronectin resulted in the identification of an additional 19 women at low risk (preterm birth rate, 5%), using a threshold of 10 ng/mL in women with a cervix at <15 mm, and 6 women at high risk (preterm birth rate, 33%) using a threshold of >500 ng/mL in women with a cervix at >30 mm. CONCLUSION: In women with threatened preterm birth, quantitative fibronectin testing alone performs equal to the combination of cervical length and qualitative fibronectin. Possibly, the combination of quantitative fibronectin testing and cervical length increases this predictive capacity. Cost-effectiveness analysis and the availability of these tests in a local setting should determine the final choice.

Immediate effects of phototherapy on sleep in very preterm neonates: an observational study.

Process C (internal clock) and Process S (sleep-wake homeostasis) are the basis of sleep-wake regulation. In the last trimester of pregnancy, foetal heart rate is synchronized with the maternal circadian rhythm. At birth, this interaction fails and an ultradian rhythm appears. Light exposure is a strong factor influencing the synchronization of sleep-wake processes. However, little is known about the effects of phototherapy on the sleep rhythm of premature babies. It was hypothesized that sleep in preterm infants would not differ during phototherapy, but that a maturation effect would be seen. Sleep states were studied in 38 infants born < 32 weeks gestational age and/or < 1 500 g birth weight. Videos of 3 h were taken over the first 5 days of life. Based on breathing and movement patterns, behavioural states were defined as: awake; active sleep; or quiet sleep. Videos with and without phototherapy were compared for amounts of quiet sleep and active states (awake + active sleep). No significant association between phototherapy and amount of quiet sleep was found (P = 0.083). Analysis of videos in infants not under phototherapy revealed an increase in time spent awake with increasing gestational age. The current data suggest that the ultradian rhythm of preterm infants seems to be independent of phototherapy, supporting the notion that sleep rhythm in this population is mainly driven by their internal clock.

Longchain polyunsaturated fatty acid supplementation in preterm infants.

BACKGROUND: Controversy exists over whether longchain polyunsaturated fatty acids (LCPUFA) are essential nutrients for preterm infants because they may not be able to synthesise sufficient amounts of LCPUFA to meet the needs of the developing brain and retina. OBJECTIVES: To assess whether supplementation of formula milk with LCPUFA is safe and of benefit to preterm infants. The main areas of interest were the effects of supplementation on the visual function, development and growth of preterm infants. SEARCH METHODS: Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 28 February 2016), MEDLINE Ovid (1966 to 28 February 2016), Embase Ovid (1980 to 28 February 2016), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1980 to 28 February 2016), MEDLINE In Process & Other Non-indexed Citations (1966 to 28 February 2016) and by checking reference lists of articles and conference proceedings. We also searched ClinicalTrials.gov (13 April 2016). No language restrictions were applied. SELECTION CRITERIA: All randomised trials evaluating the effect of LCPUFA-supplemented formula in enterally-fed preterm infants (compared with standard formula) on visual development, neurodevelopment and physical growth. Trials reporting only biochemical outcomes were not included. DATA COLLECTION AND ANALYSIS: All authors assessed eligibility and trial quality, two authors extracted data separately. Study authors were contacted for additional information. MAIN RESULTS: Seventeen trials involving 2260 preterm infants were included in the review. The risk of bias varied across the included trials with 10 studies having low risk of bias in a majority of the domains. The median gestational age (GA) in the included trials was 30 weeks and median birth weight (BW) was 1300 g. The median concentration of docosahexaenoic acid (DHA) was 0.33% (range: 0.15% to 1%) and arachidonic acid (AA) 0.37% (range: 0.02% to 0.84%). Visual acuity Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by visual evoked potential (VEP) in six studies and by electroretinogram (ERG) in two studies. Most studies found no significant differences in visual acuity between supplemented and control infants. The form of data presentation and the varying assessment methods precluded the use of meta-analysis. A GRADE analysis for this outcome indicated that the overall quality of evidence was low. Neurodevelopment Three out of seven studies reported some benefit of LCPUFA on neurodevelopment at different postnatal ages. Meta-analysis of four studies evaluating Bayley Scales of Infant Development at 12 months (N = 364) showed no significant effect of supplementation (Mental Development Index (MDI): MD 0.96, 95% CI -1.42 to 3.34; P = 0.43; I² = 71% - Psychomotor DeveIopment Index (PDI): MD 0.23, 95% CI -2.77 to 3.22; P = 0.88; I² = 81%). Furthermore, three studies at 18 months (N = 494) also revealed no significant effect of LCPUFA on neurodevelopment (MDI: MD 2.40, 95% CI -0.33 to 5.12; P = 0.08; I² = 0% - PDI: MD 0.74, 95% CI -1.90 to 3.37; P = 0.58; I² = 54%). A GRADE analysis for these outcomes indicated that the overall quality of evidence was low. Physical growth Four out of 15 studies reported benefits of LCPUFA on growth of supplemented infants at different postmenstrual ages (PMAs), whereas two trials suggested that LCPUFA-supplemented infants grow less well. One trial reported mild reductions in length and weight z scores at 18 months. Meta-analysis of five studies (N = 297) showed increased weight and length at two months post-term in supplemented infants (Weight: MD 0.21, 95% CI 0.08 to 0.33; P = 0.0010; I² = 69% - Length: MD 0.47, 95% CI 0.00 to 0.94; P = 0.05; I² = 0%). Meta-analysis of four studies at a corrected age of 12 months (N = 271) showed no significant effect of supplementation on growth outcomes (Weight: MD -0.10, 95% CI -0.31 to 0.12; P = 0.34; I² = 65% - Length: MD 0.25; 95% CI -0.33 to 0.84; P = 0.40; I² = 71% - Head circumference: MD -0.15, 95% CI -0.53 to 0.23; P = 0.45; I² = 0%). No significant effect of LCPUFA on weight, length or head circumference was observed on meta-analysis of two studies (n = 396 infants) at 18 months (Weight: MD -0.14, 95% CI -0.39 to 0.10; P = 0.26; I² = 66% - Length: MD -0.28, 95% CI -0.91 to 0.35; P = 0.38; I² = 90% - Head circumference: MD -0.18, 95% CI -0.53 to 0.18; P = 0.32; I² = 0%). A GRADE analysis for this outcome indicated that the overall quality of evidence was low. AUTHORS' CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA-supplemented formula.

Nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates.

OBJECTIVE: To evaluate the efficacy and safety of nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates at high risk of bronchopulmonary dysplasia (BPD). STUDY DESIGN: Single-center, randomized, double-blind, placebo-controlled trial was conducted. Infants of 23(0) to 27(6) weeks' gestational age requiring mechanical ventilation or ≥30% supplemental oxygen on continuous positive airway pressure at 72-168 hours were randomized to receive 20 mg/kg (1 mL/kg) nebulized pentoxifylline or an equal volume of normal saline placebo every 6 hours for 10 consecutive days via a vibrating mesh nebulizer. The primary outcome was the duration of oxygen supplementation at 40 weeks' postmenstrual age. We used Cox proportional hazards regression modeling to analyze outcomes. RESULTS: All infants had adequate data for analysis of the primary outcome. Intention-to-treat analysis revealed no differences in duration of oxygen supplementation at 40 weeks' postmenstrual age between pentoxifylline (n=41) and placebo (n=40) groups (median 2262 vs 2160 hours, adjusted hazard ratio: 1.14, 95% CI 0.72-1.80, P=.63). There was no difference in mortality and further secondary outcomes. No adverse effects were noted. CONCLUSIONS: Nebulized pentoxifylline is safe but did not reduce the duration of oxygen supplementation in extremely preterm infants at high risk of BPD. Dose-ranging studies and large, well-designed clinical trials are required to determine whether the use of nebulized or systemic pentoxifylline as a prophylactic therapy offers small but relevant benefits for prevention of BPD. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12611000145909.

Swiss medical centres vary significantly when it comes to outcomes of neonates with a very low gestational age.

AIM: This study quantified the impact of perinatal predictors and medical centre on the outcome of very low-gestational-age neonates (VLGANs) born at <32 completed weeks in Switzerland. METHODS: Using prospectively collected data from a 10-year cohort of VLGANs, we developed logistic regression models for three different time points: delivery, NICU admission and seven days of age. The data predicted survival to discharge without severe neonatal morbidity, such as major brain injury, moderate or severe bronchopulmonary dysplasia, retinopathy of prematurity (≥stage three) or necrotising enterocolitis (≥stage three). RESULTS: From 2002 to 2011, 6892 VLGANs were identified: 5854 (85%) of the live-born infants survived and 84% of the survivors did not have severe neonatal complications. Predictors for adverse outcome at delivery and on NICU admission were low gestational age, low birthweight, male sex, multiple birth, birth defects and lack of antenatal corticosteroids. Proven sepsis was an additional risk factor on day seven of life. The medical centre remained a statistically significant factor at all three time points after adjusting for perinatal predictors. CONCLUSION: After adjusting for perinatal factors, the survival of Swiss VLGANs without severe neonatal morbidity was strongly influenced by the medical centre that treated them.

Pentoxifylline for the prevention of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants. BPD is associated with poor long-term respiratory and neurodevelopmental outcome and increased mortality. The prophylactic use of agents that modulate inflammation such as pentoxifylline, a synthetic methylxanthine and phosphodiesterase inhibitor, may reduce the incidence of BPD. OBJECTIVES: The primary objective of this review was to determine the effect of pentoxifylline on the incidence of BPD, death prior to 36 weeks postmenstrual age (PMA), and BPD or death prior to 36 weeks PMA in preterm neonates. SEARCH METHODS: We searched the Cochrane Neonatal Review Group Specialized Register, CENTRAL (The Cochrane Library Issue 9, 2012), EMBASE (January 1974 to September 2012), PubMed (January 1966 to September 2012), and CINAHL (January 1982 to September 2012) in September 2012. We checked references and cross-references from identified studies. We handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings (from January 1990 to September 2012). We placed no restrictions on language. SELECTION CRITERIA: Randomised or quasi-randomised clinical trials of systemic or nebulised pentoxifylline in preterm neonates less than 32 weeks gestational age or less than 1500 g birth weight, reporting on at least one outcome of interest, were eligible for inclusion in the review. DATA COLLECTION AND ANALYSIS: We used the standard methods of the Cochrane Neonatal Review Group and The Cochrane Collaboration. Two review authors (SMS and SK) independently searched the literature as described above and selected studies. Any disagreements were resolved by discussion involving all review authors. MAIN RESULTS: We identified one randomised clinical trial eligible for inclusion in this review. This study compared the use of nebulised pentoxifylline versus placebo for prevention of BPD in 100 preterm infants and was at high risk of bias due to lack of blinding of intervention and outcome assessors, and incomplete outcome data. There was no statistically significant effect of nebulised pentoxifylline versus placebo on individual outcomes of BPD at 36 weeks PMA or on death prior to 36 weeks PMA. There was no significant effect of nebulised pentoxifylline on intraventricular haemorrhage, periventricular leukomalacia, sepsis, or patent ductus arteriosus (PDA) requiring ligation. The study did not report any of the other secondary outcomes considered for this review. Reporting of adverse events was very limited and did not allow for reliable judgement on the incidence of such events. No long-term outcomes were reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the safety and efficacy of pentoxifylline for prevention of BPD in preterm neonates. We encourage researchers to conduct clinical trials to confirm or refute the role of pentoxifylline for prevention of BPD in preterm neonates. These trials should report on clinically important outcomes and, ideally, on long-term neurodevelopmental outcome.

Physical activity programs for promoting bone mineralization and growth in preterm infants.

BACKGROUND: Lack of physical stimulation may contribute to metabolic bone disease of preterm infants, resulting in poor bone mineralization and growth. Physical activity programs combined with adequate nutrition might help to promote bone mineralization and growth. OBJECTIVES: The primary objective was to assess whether physical activity programs in preterm infants improve bone mineralization and growth and reduce the risk of fracture.The secondary objectives included other potential benefits in terms of length of hospital stay, skeletal deformities and neurodevelopmental outcomes, and adverse events.Subgroup analysis:• Given that the smallest infants are most vulnerable for developing osteopenia (Bishop 1999), a subgroup analysis was planned for infants with birth weight < 1000 g.• Calcium and phosphorus intake may affect an infant's ability to increase bone mineral content (Kuschel 2004). Therefore, an additional subgroup analysis was planned for infants receiving different amounts of calcium and phosphorus, along with full enteral feeds as follows. ∘ Below 100 mg/60 mg calcium/phosphorus or equal to/above 100 mg/60 mg calcium/phosphorus per 100 mL milk. ∘ Supplementation of calcium without phosphorus. ∘ Supplementation of phosphorus without calcium. SEARCH METHODS: The standard search strategy of the Cochrane Neonatal Review Group (CNRG) was used. The search included the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 9), MEDLINE, EMBASE, CINAHL (1966 to March 2013), and cross-references, as well as handsearching of abstracts of the Society for Pediatric Research and the International Journal of Sports Medicine. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing physical activity programs (extension and flexion, range-of-motion exercises) versus no organized physical activity programs in preterm infants. DATA COLLECTION AND ANALYSIS: Data collection, study selection, and data analysis were performed according to the methods of the CNRG. MAIN RESULTS: Eleven trials enrolling 324 preterm infants (gestational age 26 to 34 weeks) were included in this review. All were small (N = 16 to 50) single-center studies that evaluated daily physical activity for three and one-half to eight weeks during initial hospitalization. Methodological quality and reporting of included trials were variable.Four trials demonstrated moderate short-term benefits of physical activity for bone mineralization at completion of the physical activity program. The only trial assessing long-term effects on bone mineralization showed no effect of physical activity administered during initial hospitalization on bone mineralization at 12 months corrected age. Meta-analysis from four trials demonstrated a positive effect of physical activity on daily weight gain (weighted mean difference (WMD) 2.21 g/kg/d, 95% confidence interval (CI) 1.23 to 3.19). Data from four trials showed a positive effect on linear growth (WMD 0.12 cm/wk, 95% CI 0.01 to 0.24) but not on head growth (WMD -0.03 cm/wk, 95% CI -0.14 to 0.08) during the study period. Only one trial reported on fractures (this outcome did not occur in intervention and control groups) and complications of preterm birth (no significant differences between intervention and control groups). None of the trials assessed other outcomes relevant to this review. AUTHORS' CONCLUSIONS: Some evidence suggests that physical activity programs might promote short-term weight gain and bone mineralization in preterm infants. Data are inadequate to allow assessment of harm or long-term effects. Current evidence does not support the routine use of physical activity programs in preterm infants. Further trials incorporating infants with a high baseline risk of osteopenia are required. These trials should address adverse events, long-term outcomes, and the effects of nutritional intake (calories, protein, calcium, phosphorus).