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.

Trends in Outcomes of Major Intracerebral Haemorrhage in a National Cohort of Very Preterm Born Infants in Switzerland.

BACKGROUND: Major brain lesions, such as grade 3 intraventricular haemorrhage (G3-IVH) and periventricular haemorrhagic infarction (PVHI) are among the main predictors for poor neurodevelopment in preterm infants. In the last decades advancements in neonatal care have led to a general decrease in adverse outcomes. AIM: To assess trends of mortality and neurodevelopmental impairment (NDI) in a recent Swiss cohort of very preterm infants with grade 3 intraventricular haemorrhage (G3-IVH) and periventricular haemorrhagic infarction (PVHI). METHODS: In this retrospective population-based cohort study, rates of mortality, and NDI at 2 years corrected age were reported in infants born at 24-29 weeks gestational age (GA) in Switzerland in 2002-2014, with G3-IVH and/or PVHI. RESULTS: Out of 4956 eligible infants, 462 (9%) developed G3-IVH (n = 172) or PVHI (n = 290). The average mortality rates for the two pathologies were 33% (56/172) and 60% (175/290), respectively. In 2002-2014, no change in rates of mortality (G3-IVH, p = 0.845; PVHI, p = 0.386) or NDI in survivors (G3-IVH, p = 0.756; PVHI, p = 0.588) were observed, while mean GA decreased (G3-IVH, p = 0.020; PVHI, p = 0.004). Multivariable regression analysis showed a strong association of G3-IVH and PVHI for both mortality and NDI. Death occurred after withdrawal of care in 81% of cases. CONCLUSION: In 2002-2014, rates of mortality and NDI in very preterm born infants with major brain lesions did not change. The significant decrease in mean GA and changing hospital policies over this time span may factor into the interpretation of these results.

Impact of SARS-CoV-2 on incidence, treatment and outcome of very preterm born infants in Switzerland: a retrospective, population-based cohort study.

AIMS OF THE STUDY: To assess whether the COVID-19 pandemic caused by SARS-CoV-2 had an impact on incidence, treatment or major adverse short-term outcome of preterm-born infants in Switzerland. METHODS: Retrospective cohort study of preterm infants born in 2020 based on two independent data sources from the Swiss Federal Statistics Office (FSO) and SwissNeoNet. Based on FSO data, we calculated the odds ratios for extremely preterm (22-27 weeks gestation), very preterm (28-31 weeks gestation), and late preterm (32-36 weeks gestation) births during the pandemic. Based on SwissNeoNet data of infants born between 22 and 31 weeks gestation, we compared infants born during the Swiss lockdown period in 2020 with infants born during the same period between 2015 and 2019, all infants of 2020 with all infants between 2015 and 2019 and infants born to mothers tested SARS-CoV-2 positive and negative. Possible associations with the pandemic were tested using logistic regression adjusted for case-mix. As a control, we compared births of 2019 with those of 2015-2018. RESULTS: The FSO data revealed equivalent odds for extremely preterm births in 2020 (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.89-1.14), as well as somewhat lower odds ratios for very preterm (OR 0.9, 95% CI 0.82-1.00) and late preterm (OR 0.91, 95% CI 0.88-0.93) births in 2020. A comparison between 2019 and 2015-2018, however, revealed matching odds ratios rendering an association to the pandemic unlikely. In the SwissNeoNet data, 137 infants were born during lockdown in 2020 compared with 134 births per year during 2015-2019. When including all infants, 744 infants were compared to 845 births, respectively. The only difference observed in treatments and short term outcomes between 2020 and the reference years were a higher odds for respiratory distress syndrome (OR 1.6, 95% CI 1.08-2.37) and provision of continuous positive airway pressure (CPAP) (OR 1.39, 95% CI 1.05-1.84). CONCLUSIONS: Our Swiss population-based analysis did not identify the elsewhere reported association between the COVID-19 pandemic and a reduced preterm birth rate. However, we can confirm a possible link between the COVID-19 pandemic and higher odds of respiratory distress syndrome, possibly coupled with CPAP requirements. Further observation of potential effects of the pandemic on health and health care provision to newborns may however be indicated based on the literature available so far and that our data only covers the first 9 months of the current pandemic.

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.

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.

Right ventricular function and vasoactive peptides for early prediction of bronchopulmonary dysplasia.

BACKGROUND: To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants. METHODS: Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life. RESULTS: RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death. CONCLUSIONS: Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

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.

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.

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.

Late Diagnosis of Infants with PCD and Neonatal Respiratory Distress.

Neonatal respiratory distress (NRD) is common among infants with primary ciliary dyskinesia (PCD), but we do not know whether affected neonates receive a timely diagnosis. We used data from the international PCD cohort and assessed the proportion of patients with PCD who had a history of NRD and their age at diagnosis, stratifying by presence of laterality defects. First we analyzed data from all participants diagnosed after 2000, followed by individuals from a subgroup diagnosed using stricter criteria. Among the 1375 patients in the study, 45% had a history of NRD and 42% had laterality defects. Out of the 476 children with definite PCD diagnosis, 55% had a history of NRD and 50% had laterality defects. Overall, 30% of children with PCD were diagnosed during the first 12 months of life. This varied from 13% in those with situs solitus and no NRD, to 21% in those with situs solitus and NRD, 33% in those with situs anomalies but no NRD, and 52% in those with both situs anomalies and NRD. Our results suggest that we need to improve our knowledge of the neonatal presentation of infants with PCD and apply it so that these patients will receive appropriate care sooner.

Caffeine preserves quiet sleep in preterm neonates.

Caffeine is widely used in preterm neonates suffering from apnea of prematurity (AOP), and it has become one of the most frequently prescribed medications in neonatal intensive care units. Goal of this study is to investigate how caffeine citrate treatment affects sleep-wake behavior in preterm neonates. The observational study consists of 64 preterm neonates during their first 5 days of life with gestational age (GA) <32 weeks or very low birthweight of < 1500 g. A total of 52 patients treated with caffeine citrate and 12 patients without caffeine citrate were included. Sleep-wake behavior was scored in three stages: active sleep, quiet sleep, and wakefulness. Individual caffeine concentration of every neonate was simulated with a pharmacokinetic model. In neonates with GA ≥ 28 weeks, wakefulness increased and active sleep decreased with increasing caffeine concentrations, whereas quiet sleep remained unchanged. In neonates with GA < 28 weeks, no clear caffeine effects on sleep-wake behavior could be demonstrated. Caffeine increases fraction of wakefulness, alertness, and most probably also arousability at cost of active but not quiet sleep in preterm neonates. As such, caffeine should therefore not affect time for physical and cerebral regeneration during sleep in preterm neonates.

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.

Surface electromyography for analysis of heart rate variability in preterm infants.

OBJECTIVE: Characterizing heart rate variability (HRV) in neonates has gained increased attention and is helpful in quantifying maturation and risk of sepsis in preterm infants. Raw data used to derive HRV in a clinical setting commonly contain noise from motion artifacts. Thoracic surface electromyography (sEMG) potentially allows for pre-emptive removal of motion artifacts and subsequent detection of interbeat interval (IBI) of heart rate to calculate HRV. We tested the feasibility of sEMG in preterm infants to exclude noisy raw data and to derive IBI for HRV analysis. We hypothesized that a stepwise quality control algorithm can identify motion artifacts which influence IBI values, their distribution in the time domain, and outcomes of nonlinear time series analysis. APPROACH: This is a prospective observational study in preterm infants <6 days of age. We used 100 sEMG measurements from 24 infants to develop a semi-automatic quality control algorithm including synchronized video recording, threshold-based sEMG envelope curve, optimized QRS-complex detection, and final targeted visual inspection of raw data. MAIN RESULTS: Analysis of HRV from sEMG data in preterm infants is feasible. A stepwise algorithm to exclude motion artifacts and improve QRS detection significantly influenced data quality (34% of raw data excluded), distribution of IBI values in the time domain, and nonlinear time series analysis. The majority of unsuitable data (94%) were excluded by automated steps of the algorithm. SIGNIFICANCE: Thoracic sEMG is a promising method to assess motion artifacts and calculate HRV in preterm neonates.

Dynamics and complexity of body temperature in preterm infants nursed in incubators.

BACKGROUND: Poor control of body temperature is associated with mortality and major morbidity in preterm infants. We aimed to quantify its dynamics and complexity to evaluate whether indices from fluctuation analyses of temperature time series obtained within the first five days of life are associated with gestational age (GA) and body size at birth, and presence and severity of typical comorbidities of preterm birth. METHODS: We recorded 3h-time series of body temperature using a skin electrode in incubator-nursed preterm infants. We calculated mean and coefficient of variation of body temperature, scaling exponent alpha (Talpha) derived from detrended fluctuation analysis, and sample entropy (TSampEn) of temperature fluctuations. Data were analysed by multilevel multivariable linear regression. RESULTS: Data of satisfactory technical quality were obtained from 285/357 measurements (80%) in 73/90 infants (81%) with a mean (range) GA of 30.1 (24.0-34.0) weeks. We found a positive association of Talpha with increasing levels of respiratory support after adjusting for GA and birth weight z-score (p<0.001; R2 = 0.38). CONCLUSION: Dynamics and complexity of body temperature in incubator-nursed preterm infants show considerable associations with GA and respiratory morbidity. Talpha may be a useful marker of autonomic maturity and severity of disease in preterm infants.

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.