Christoph Rüegger

Population based trends in mortality, morbidity and treatment for very preterm- and very low birth weight infants over 12 years

BackgroundOver the last two decades, improvements in medical care have been associated with a significant increase and better outcome of very preterm (VP, < 32 completed gestational weeks) and very low birth weight (VLBW, < 1500 g) infants. Only a few publications analyse changes of their short-term outcome in a geographically defined area over more than 10 years. We therefore aimed to investigate the net change of VP- and VLBW infants leaving the hospital without major complications.MethodsOur population-based observational cohort study used the Minimal Neonatal Data Set, a database maintained by the Swiss Society of Neonatology including information of all VP- and VLBW infants. Perinatal characteristics, mortality and morbidity rates and the survival free of major complications were analysed and their temporal trends evaluated.ResultsIn 1996, 2000, 2004, and 2008, a total number of 3090 infants were enrolled in the Network Database. At the same time the rate of VP- and VLBW neonates increased significantly from 0.87% in 1996 to 1.10% in 2008 (p < 0.001). The overall mortality remained stable by 13%, but the survival free of major complications increased from 66.9% to 71.7% (p < 0.01). The percentage of infants getting a full course of antenatal corticosteroids increased from 67.7% in 1996 to 91.4% in 2008 (p < 0.001). Surfactant was given more frequently (24.8% in 1996 compared to 40.1% in 2008, p < 0.001) and the frequency of mechanical ventilation remained stable by about 43%. However, the use of CPAP therapy increased considerably from 43% to 73.2% (p < 0.001). Some of the typical neonatal pathologies like bronchopulmonary dysplasia, necrotising enterocolitis and intraventricular haemorrhage decreased significantly (p ≤ 0.02) whereas others like patent ductus arteriosus and respiratory distress syndrome increased (p < 0.001).ConclusionsOver the 12-year observation period, the number of VP- and VLBW infants increased significantly. An unchanged overall mortality rate and an increase of survivors free of major complication resulted in a considerable net gain in infants with potentially good outcome.

Safety of Early High-Dose Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants.

OBJECTIVE To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants. STUDY DESIGN Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth. RESULTS There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. CONCLUSIONS Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. TRIAL REGISTRATION ClinicalTrials.gov: NCT00413946.

Benign neonatal sleep myoclonus in newborn infants of opioid dependent mothers

Objective: The aim of our study was to evaluate the incidence, duration and risk factors for benign neonatal sleep myoclonus (BNSM) in infants with neonatal abstinence syndrome (NAS) treated with opioids or sedatives, compared with control infants.

Pulse oximetry in the newborn: Is the left hand pre- or post-ductal?

BackgroundOver the past few years, great efforts have been made to screen duct-dependent congenital heart diseases in the newborn. Arterial pulse oximetry screening (foot and/or right hand) has been put forth as the most useful strategy to prevent circulatory collapse. The left hand, however, has always been ignored, as it was unclear if the ductus arteriosus influences left-hand arterial perfusion. The objective of our study was to evaluate the impact of the arterial duct on neonatal pulse oximetry saturation (POS) on the left hand.MethodsIn this observational study, arterial oxygen saturation on both hands and on one foot was measured within the first 4 hours of life.ResultsTwo hundred fifty-one newborns were studied: 53% males and 47% were delivered by caesarean section. The median gestational age was 38 4/7 weeks (90% CI, 32 6/7 - 41 2/7 weeks), the median birth weight was 3140 g (90% CI, 1655 - 4110 g) and the median age at recording was 60 minutes (90% CI, 15 - 210 minutes). The mean POS for the overall study population was 95.7% (90% CI, 90 - 100%) on the right hand, 95.7% (90% CI, 90 - 100%) on the left hand, and 94.9% (90% CI, 86 - 100%) on the foot. Four subgroups (preterm infants, babies with respiratory disorders, neonates delivered by caesarean section, and newborns ≤15 minutes of age) were formed and analysed separately. None of the subgroups showed a statistically significant difference between the right and left hands. Additionally, multivariate logistic regression did not identify any associated factors influencing the POS on the left hand.ConclusionsWith the exception of some children with complex or duct dependent congenital heart defects and some children with persistent pulmonary hypertension, POS on both hands can be considered equally pre-ductal.

Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair)

Background: Preterm infants suffering from intraventricular hemorrhage (IVH) are at increased risk for neurodevelopmental impairment. Observational data suggest that recombinant human erythropoietin (rEPO) improves long-term cognitive outcome in infants with IVH. Recent studies revealed a beneficial effect of early high-dose rEPO on white matter development in preterm infants determined by magnetic resonance imaging (MRI). Objectives: To summarize the current evidence and to delineate the study protocol of the EpoRepair trial (Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants). Methods: The study involves a review of the literature and the design of a double-blind, placebo-controlled, multicenter trial of repetitive high-dose rEPO administration, enrolling 120 very preterm infants with moderate-to-severe IVH diagnosed by cranial ultrasound in the first days of life, qualitative and quantitative MRI at term-equivalent age and long-term neurodevelopmental follow-up until 5 years of age. Results and Conclusions: The hypothesis generated by observational data that rEPO may improve long-term cognitive outcomes of preterm infants suffering from IVH are to be confirmed or refuted by the randomized controlled trial, EpoRepair.

Association of early versus late caffeine administration on neonatal outcomes in very preterm neonates.

Caffeine is commonly used for preterm infants with apnoea of prematurity. The caffeine for apnoea of prematurity trial (CAP) was launched to determine whether survival without neurodevelopmental disability at a corrected age of 18 months is improved if apnoea of prematurity is managed without methylxanthines in infants at a high risk of apnoeic attacks (1). Infants had to be within 10 days of birth. Forty per cent of the patients assigned to caffeine died or survived with a neurodevelopmental disability compared with 46% assigned to placebo (OR 0.77, 95% CI 0.64–0.93; p = 0.008). Physicians were not asked to alter their own prescribing indications for caffeine. However, only 22.5% of the neonatologists in the trial started caffeine to prevent apnoea (2). Thus, the risk–benefit ratio of caffeine administered exclusively for prophylaxis and therefore likely earlier remains unclear. This was emphasised by Schmidt in a recent editorial (3) commenting upon a large observational cohort study that showed that early administration decreased the incidence of BPD in their US group of NICUs (4). This is in line with another retrospective data analysis by Taha et al. (5). In addition, a subgroup analysis of the CAP trial demonstrated that early caffeine treatment correlated with a larger reduction in days of respiratory support compared to late caffeine (6). In this third large-scale observational study of the Canadian Neonatal Network, Lodha et al. retrospectively investigated the effect of early versus late initiation of caffeine therapy on neonatal short-term outcomes of very preterm infants. The nationwide participation resulted in an impressive number of included infants. Nevertheless, there are a few comments to make. First, the diagnosis of a PDA was based on clinical signs, with or without echocardiography. However, several studies have demonstrated that echocardiograms are required for the diagnosis of a PDA in preterm infants, as clinical signs are not reliable in the first few days of life (7,8). Second, there are imbalances between the infants of the early and those of the late treatment groups. We also suggest that some baseline characteristics should rather be declared as outcomes and/or co-interventions (table 3) due to their timely relation to the intervention. The late treatment group, for example, showed a more frequent use of postnatal steroids and an increased occurrence of air leak syndromes. The differences in baseline characteristics may have resulted in an early administration of caffeine in those babies without and a late administration in those with major risk factors for adverse outcomes, such as BPD for example. Despite adjustments for known imbalances between groups, observational studies do not have the ability to completely eliminate selection bias and observational studies investigating the effect of drug treatments are prone to confounding by indication. Thirdly, information concerning the indication to start caffeine is lacking, and no information on dosages is provided. In conclusion, this is an important study, but more data from randomised controlled trials on the optimal timing of caffeine administration are needed before introducing early prophylactic caffeine into routine clinical practice (9).

Randomized controlled trials in very preterm infants: does inclusion in the study result in any long-term benefit?

Background: Since the introduction of randomized controlled trials (RCT) in clinical research, there has been discussion of whether enrolled patients have worse or better outcomes than comparable non-participants. Objective: To investigate whether very preterm infants randomized to a placebo group in an RCT have equivalent neurodevelopmental outcomes to infants who were eligible but not randomized (eligible NR). Methods: In the course of an RCT investigating the neuroprotective effect of early high-dose erythropoietin on the neurodevelopment of very preterm infants, the outcome data of 72 infants randomized to placebo were retrospectively compared with those of 108 eligible NR infants. Our primary outcome measures were the mental (MDI) and psychomotor (PDI) developmental indices of the Bayley Scales of Infant Development II at 24 months of corrected age. The outcomes of the two groups were considered equivalent if the confidence intervals (CIs) of their mean differences fitted within our ±5-point margin of equivalence. Results: Except for a higher socioeconomic status of the trial participants, both groups were balanced for most perinatal variables. The mean difference (90% CI) between the eligible NR and the placebo group was -2.1 (-6.1 and 1.9) points for the MDI and -0.8 (-4.2 and 2.5) points for the PDI. After adjusting for the socioeconomic status, maternal age and child age at follow-up, the mean difference for the MDI was -0.5 (-4.3 and 3.4) points. Conclusions: Our results indicate that the participation of very preterm infants in an RCT is associated with equivalent long-term outcomes compared to non-participating infants.

Placebo by Proxy in Neonatal Randomized Controlled Trials: Does It Matter?

Placebo effects emerging from the expectations of relatives, also known as placebo by proxy, have seldom been explored. The aim of this study was to investigate whether in a randomized controlled trial (RCT) there is a clinically relevant difference in long-term outcome between very preterm infants whose parents assume that verum (PAV) had been administered and very preterm infants whose parents assume that placebo (PAP) had been administered. The difference between the PAV and PAP infants with respect to the primary outcome–IQ at 5 years of age–was considered clinically irrelevant if the confidence interval (CI) for the mean difference resided within our pre-specified ±5-point equivalence margins. When adjusted for the effects of verum/placebo, socioeconomic status (SES), head circumference and sepsis, the CI was [−3.04, 5.67] points in favor of the PAV group. Consequently, our study did not show equivalence between the PAV and PAP groups, with respect to the pre-specified margins of equivalence. Therefore, our findings suggest that there is a small, but clinically irrelevant degree to which a preterm infant’s response to therapy is affected by its parents’ expectations, however, additional large-scale studies are needed to confirm this conjecture.

Suction Mask vs Conventional Mask Ventilation in Term and Near-Term Infants in the Delivery Room: A Randomized Controlled Trial

Objective To compare the suction mask, a new facemask that uses suction to create a seal between the mask and the infants face, with a conventional soft, round silicone mask during positive pressure ventilation (PPV) in the delivery room in newborn infants >34 weeks of gestation. Study design Single‐center randomized controlled trial in the delivery room. The primary outcome was mask leak. Results Forty‐five infants were studied at a median gestational age of 38.1 weeks (IQR, 36.4‐39.0 weeks); 22 were randomized to the suction mask and 23 to the conventional mask. The suction mask did not reduce mask leak (49.9%; IQR, 11.0%‐92.7%) compared with the conventional mask (30.5%; IQR, 10.6%‐48.8%; P = .51). The suction mask delivered lower peak inspiratory pressure (27.2 cm H2O [IQR, 25.0‐28.7 cm H2O] vs 30.4 cm H2O [IQR, 29.4‐32.5 cm H2O]; P < .05) and lower positive end expiratory pressure (3.7 cm H2O [IQR, 3.1‐4.5 cm H2O] vs 5.1 cm H2O [IQR, 4.2‐5.7 cm H2O ]; P < .05). There was no difference in the duration of PPV or rates of intubation or admission to the neonatal intensive care unit. In 5 infants (23%), the clinician switched from the suction to the conventional mask, 2 owing to intermittently low peak inspiratory pressure, 2 owing to failure to respond to PPV, and 1 owing to marked facial bruising after 6 minutes of PPV. Conclusions The use of the suction mask to provide PPV in newborn infants did not reduce facemask leak. Adverse effects such as the inability to achieve the set pressures and transient skin discoloration are concerning. Trial registration Australian and New Zealand Clinical Trial Registry ACTRN12616000768493.

The Effect of Noninvasive High-Frequency Oscillatory Ventilation on Desaturations and Bradycardia in Very Preterm Infants: A Randomized Crossover Trial

&NA; Noninvasive high‐frequency oscillatory ventilation compared with nasal continuous positive airway pressure significantly reduced the number of desaturations and bradycardia in preterm infants. However, noninvasive high‐frequency oscillatory ventilation was associated with increased oxygen requirements and higher heart rates. Trial registration Australian and New Zealand Clinical Trial Registry: ACTRN12616001516471.