Perinatal Outcomes of Subjects Enrolled in a Multicenter Trial with a Waiver of Antenatal Consent.

OBJECTIVE: This study aimed to determine whether outcomes differed between infants enrolled in the PREMOD2 trial and those otherwise eligible but not enrolled, and whether the use of waiver effected these differences. STUDY DESIGN: The multicenter PREMOD2 (PREmature infants receiving Milking Or Delayed cord clamping) trial was approved for waiver of antenatal consent by six of the nine sites institutional review boards, while three sites exclusively used antenatal consent. Every randomized subject delivered at a site with a waiver of consent was approached for postnatal consent to allow for data collection. Four of those six sites IRBs required the study team to attempt antenatal consent when possible. Three sites exclusively used antenatal consent. RESULTS: Enrolled subjects had higher Apgar scores, less use of positive pressure ventilation, a lower rate of bronchopulmonary dysplasia, and a less frequent occurrence of the combined outcome of severe intraventricular hemorrhage or death. A significantly greater number of infants were enrolled at sites with an option of waiver of consent (66 vs. 26%, risk ratio = 2.54, p < 0.001). At sites with an option of either approaching families before delivery or after delivery with a waiver of antenatal consent, those approached prior to delivery refused consent 40% (range 15-74% across six sites) of the time. CONCLUSION: PREMOD2 trial demonstrated analytical validity limitations because of the variable mix of antenatal consent and waiver of consent. A waiver of antenatal consent for minimal risk interventional trials conducted during the intrapartum period will be more successful in enrolling a representative sample of low and high-risk infants if investigators are able to enroll all eligible subjects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03019367. KEY POINTS: · Waiver of consent is when informed consent cannot be obtained prior to delivery.. · Cord milking is a procedure in which blood is pushed (stripped) two to four times towards the newborn.. · Delayed clamping means the umbilical cord is not clamped immediately after birth..

Early Cardiac and Cerebral Hemodynamics with Umbilical Cord Milking Compared with Delayed Cord Clamping in Infants Born Preterm.

OBJECTIVE: To evaluate changes in cerebral oxygenation, peripheral arterial oxygenation, respiratory status, and administered fraction of inspired oxygen during the first 10 minutes of life in premature infants receiving umbilical cord milking compared with delayed cord clamping (DCC). STUDY DESIGN: Premature infants born at 230/7 to 276/7 weeks of gestation were randomized to umbilical cord milking or DCC. A near infrared spectroscopy sensor, pulse oximeter, and electrocardiogram electrodes were placed. Pulse rate, cerebral tissue oxygenation, peripheral oxygen saturation, airway pressure, and fraction of inspired oxygen were collected for 10 minutes in the delivery room. Longitudinal models were used to compare effects of umbilical cord milking and DCC. RESULTS: Fifty-six infants had cerebral oximetry and advanced monitoring at birth. There was an increased incidence of severe intraventricular hemorrhage in infants who received umbilical cord milking compared with DCC (P = .0211). Longitudinal models suggested that peripheral oxygen saturation was higher in the umbilical cord milking group in the first 4 minutes (P = .0221) and that mean airway pressures were lower in the umbilical cord milking group after the first 7 minutes (P = .0072). No statistical differences were observed for fraction of inspired oxygen, cerebral tissue oxygenation, or heart rates. CONCLUSIONS: The data suggest that the rapid transfer of blood during umbilical cord milking may facilitate lung expansion with improved pulmonary blood flow, but may also increase cerebral blood flow, resulting in severe intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03145142.

Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial.

Importance: Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds. Objective: To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability. Design, Setting, and Participants: Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018. Interventions: Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state. Main Outcome and Measures: The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth. Results: Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups. Conclusions and Relevance: Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age. Trial Registration: ClinicalTrials.gov Identifier: NCT01393496.

Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants.

Importance: Umbilical cord milking as an alternative to delayed umbilical cord clamping may provide equivalent benefits to preterm infants, but without delaying resuscitation. Objective: To determine whether the rates of death or severe intraventricular hemorrhage differ among preterm infants receiving placental transfusion with umbilical cord milking vs delayed umbilical cord clamping. Design, Setting, and Participants: Noninferiority randomized clinical trial of preterm infants (born at 23-31 weeks' gestation) from 9 university and private medical centers in 4 countries were recruited and enrolled between June 2017 and September 2018. Planned enrollment was 750 per group. However, a safety signal comprising an imbalance in the number of severe intraventricular hemorrhage events by study group was observed at the first interim analysis; enrollment was stopped based on recommendations from the data and safety monitoring board. The planned noninferiority analysis could not be conducted and a post hoc comparison was performed instead. Final date of follow-up was December 2018. Interventions: Participants were randomized to umbilical cord milking (n = 236) or delayed umbilical cord clamping (n = 238). Main Outcomes and Measures: The primary outcome was a composite of death or severe intraventricular hemorrhage to determine noninferiority of umbilical cord milking with a 1% noninferiority margin. Results: Among 540 infants randomized, 474 (88%) were enrolled and completed the trial (mean gestational age of 28 weeks; 46% female). Twelve percent (29/236) of the umbilical cord milking group died or developed severe intraventricular hemorrhage compared with 8% (20/238) of the delayed umbilical cord clamping group (risk difference, 4% [95% CI, -2% to 9%]; P = .16). Although there was no statistically significant difference in death, severe intraventricular hemorrhage was statistically significantly higher in the umbilical cord milking group than in the delayed umbilical cord clamping group (8% [20/236] vs 3% [8/238], respectively; risk difference, 5% [95% CI, 1% to 9%]; P = .02). The test for interaction between gestational age strata and treatment group was significant for severe intraventricular hemorrhage only (P = .003); among infants born at 23 to 27 weeks' gestation, severe intraventricular hemorrhage was statistically significantly higher with umbilical cord milking than with delayed umbilical cord clamping (22% [20/93] vs 6% [5/89], respectively; risk difference, 16% [95% CI, 6% to 26%]; P = .002). Conclusions and Relevance: In this post hoc analysis of a prematurely terminated randomized clinical trial of umbilical cord milking vs delayed umbilical cord clamping among preterm infants born at less than 32 weeks' gestation, there was no statistically significant difference in the rate of a composite outcome of death or severe intraventricular hemorrhage, but there was a statistically significantly higher rate of severe intraventricular hemorrhage in the umbilical cord milking group. The early study termination and resulting post hoc nature of the analyses preclude definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT03019367.

[EXIT - A Possible Intervention for New- and Earlyborn Babies with Severe Hydrops Fetalis and Hydrothoraces on Both Sides]. / Die EXIT-Prozedur ­ eine Option bei der Erstversorgung von Kindern mit schwerem Hydrops fetalis und beidseitigem Hydrothorax.

The EXIT (ex utero intrapartum treatment) procedure is an established method of respiratory protection, originally used in the delivery of fetuses with congenital obstructive airway diseases (tumors in the throat area, hygromas, so-called congenital high airway obstruction syndrome (CHAOS)). Meanwhile, the procedure is also carried out in large perinatal centers for pronounced diaphragmatic hernia or other special indications (EXIT to ECMO, congenital lung airway malformations (CCAM), pulmonary atresia). We present our experience with adapted EXIT procedures in 5 preterm infants with secondary generalized hydrops fetalis and pronounced bilateral hydrothoraces.

Dilated Cardiomyopathy Due to Alimentary Iron Deficiency.

Dilated cardiomyopathy (DCM) is a severe condition, characterised by left ventricular dilation and systolic dysfunction, necessitating heart transplantation when all other treatment options fail. This case report describes a 2-year-old girl initially presenting with oedema, listlessness, and severe iron deficiency anaemia. She was diagnosed with DCM. Extensive diagnostic workup ruled out other causes, leading to the suspicion of DCM due to alimentary iron deficiency. This was confirmed by the parents' report that the girl was fed almost exclusively with low-fat cow's milk. Prompt treatment, including packed red cell transfusion, iron supplementation, and heart failure medications (diuretics, ACE inhibitors, beta blockers, and aldosterone antagonists), resulted in significant improvement in cardiac function within days. This report demonstrates the potential risks of alimentary iron deficiency, the most common cause of microcytic hypochromic anaemia in young children, which might even result in the development of life-threatening cardiac dysfunction in extreme cases.

Umbilical Cord Milking Versus Delayed Cord Clamping in Infants 28 to 32 Weeks: A Randomized Trial.

OBJECTIVES: To determine whether rate of severe intraventricular hemorrhage (IVH) or death among preterm infants receiving placental transfusion with UCM is noninferior to delayed cord clamping (DCC). METHODS: Noninferiority randomized controlled trial comparing UCM versus DCC in preterm infants born 28 to 32 weeks recruited between June 2017 through September 2022 from 19 university and private medical centers in 4 countries. The primary outcome was Grade III/IV IVH or death evaluated at a 1% noninferiority margin. RESULTS: Among 1019 infants (UCM n = 511 and DCC n = 508), all completed the trial from birth through initial hospitalization (mean gestational age 31 weeks, 44% female). For the primary outcome, 7 of 511 (1.4%) infants randomized to UCM developed severe IVH or died compared to 7 of 508 (1.4%) infants randomized to DCC (rate difference 0.01%, 95% confidence interval: (-1.4% to 1.4%), P = .99). CONCLUSIONS: In this randomized controlled trial of UCM versus DCC among preterm infants born between 28 and 32 weeks' gestation, there was no difference in the rates of severe IVH or death. UCM may be a safe alternative to DCC in premature infants born at 28 to 32 weeks who require resuscitation.

Pre-viable preterm premature rupture of membranes under 20 weeks of pregnancy: A retrospective cohort analysis for potential outcome predictors.

OBJECTIVE: While preterm premature rupture of membranes complicates an estimated 3 % of pregnancies, rupture near the limit of fetal viability is rarer (estimated 0.04 %). This study aimed to analyze maternal and neonatal outcomes in patients with premature preterm rupture of membranes (PPROM) before 20 0/7 weeks of pregnancy with the goal of identifying potential outcome predictors. STUDY DESIGN: This retrospective cohort study examined 60 patients with preterm premature rupture of membranes before 20 0/7 weeks of pregnancy from 01/01/2008 through 12/31/2018 in a university hospital setting. Two patients were excluded from analysis due to fetal kidney dysplasia. Multiples (5 twins, 2 triplets) were excluded. The remaining 51 cases were analyzed. RESULTS: Thirty-three patients (Range 12 5/7 weeks to 19 2/7 weeks) medically terminated pregnancy (64.7 %). Ten patients spontaneously aborted (19.6 %). Fifteen patients were diagnosed with intraamniotic infection (29.4 %). Neonatal mortality was 28.6 %% (one case of pulmonary hypoplasia). The baby take home rate was 9.8 % (27.8 % after excluding medical terminations) after a mean prolongation of 92.9 days. Neonatal morbidity included respiratory distress syndrome (57.1 %), infection (100 %, including all cases (direct postpartum and during admission), one case of sepsis), pulmonary hypoplasia (42.9 %), pulmonary hypertension (28.6 %), bronchopulmonary dysplasia (14.3 %), and sepsis combined pneumonia (14.3 %). 57.1 % of the infants could be discharged without severe morbidity and 80 % of the survivors had normal development at two and four years. CONCLUSION: Anhydramnios combined with low gestational age at PPROM appear to negatively influence neonatal outcome after pre-viable preterm premature rupture of membranes. The incidence of neonatal complications decreased with increasing gestational age. Survival without long term severe morbidity is possible. Maximal therapy is an interdisciplinary decision and the patients should be counseled accordingly. Delivery in centers where potential postnatal complications including pulmonary hypoplasia, severe bronchopulmonary dysplasia and respiratory distress syndrome can be aggressively treated is recommended.

Obstetric and fetal short- and long-term outcomes of delayed-interval delivery in multiple pregnancies.

INTRODUCTION: Multiple pregnancies are at higher risk of preterm birth. However, both children do not necessarily have to be born and exposed to the morbidity of prematurity. One option is a delayed-interval delivery with reduction of morbidity and mortality for the second twin. The present case series demonstrates the feasibility and safety of this procedure including the long-term outcome of the surviving children compared to the overall outcome of premature born children at the same perinatal center. MATERIAL: Retrospective evaluation of all cases of delayed-interval deliveries in multiple pregnancies from 2003 to 2020 at the Women's and Children's Hospital of the University Hospital Ulm. RESULTS: In 17 cases, the delivery of the second twin could be delayed, on average by 36 days. Pregnancies with delivery of the first twin before 22 weeks of gestation had a longer prolongation than pregnancies with delivery of the first twin after 22 weeks (53 vs. 22 days). If a cerclage was placed after the delivery of the first twin a longer prolongation interval could be achieved (45 vs. 19 days). No severe maternal morbidity occurred, and the short- and long-term outcome of the second twin did not differ from age-matched controls. CONCLUSIONS: In multiple pregnancies with extremely preterm birth of the first twin, delivery of the second twin can in some cases be successfully postponed without serious maternal morbidity or additional fetal complications. Delivery of the first twin before 22 weeks of gestation and placement of a cerclage is associated with a longer prolongation interval.

Invasive Group B Streptococcus Disease With Recurrence and in Multiples: Towards a Better Understanding of GBS Late-Onset Sepsis.

Group B Streptococcus (GBS) is a common intestinal colonizer during the neonatal period, but also may cause late-onset sepsis or meningitis in up to 0.5% of otherwise healthy colonized infants after day 3 of life. Transmission routes and risk factors of this late-onset form of invasive GBS disease (iGBS) are not fully understood. Cases of iGBS with recurrence (n=25) and those occurring in parallel in twins/triplets (n=32) from the UK and Ireland (national surveillance study 2014/15) and from Germany and Switzerland (retrospective case collection) were analyzed to unravel shared (in affected multiples) or fixed (in recurrent disease) risk factors for GBS disease. The risk of iGBS among infants from multiple births was high (17%), if one infant had already developed GBS disease. The interval of onset of iGBS between siblings was 4.5 days and in recurrent cases 12.5 days. Disturbances of the individual microbiome, including persistence of infectious foci are suggested e.g. by high usage of perinatal antibiotics in mothers of affected multiples, and by the association of an increased risk of recurrence with a short term of antibiotics [aOR 4.2 (1.3-14.2), P=0.02]. Identical GBS serotypes in both recurrent infections and concurrently infected multiples might indicate a failed microbiome integration of GBS strains that are generally regarded as commensals in healthy infants. The dynamics of recurrent GBS infections or concurrent infections in multiples suggest individual patterns of exposure and fluctuations in host immunity, causing failure of natural niche occupation.

Risk Indicators for Air Leaks in Preterm Infants Exposed to Restrictive Use of Endotracheal Intubation.

OBJECTIVES: To identify perinatal risk indicators for air leaks in preterm infants treated with a policy of restrictive use of endotracheal intubation based on sustained inflations followed by noninvasive ventilation in the delivery room. METHODS: Perinatal variables and variables of respiratory support in the delivery room were analyzed retrospectively in a cohort of 297 inborn preterm infants with a gestational age <29 weeks born in 2005-2009 in a tertiary care center with respect to their associations with air leaks. Multivariate logistic regression analysis was performed to analyze independent risk indicators. RESULTS: Gestational age was 26 weeks + 0 days (22+3 to 28+6), birth weight was 790 g (265-1,660) and 270/297 survived (91.0%). A total of 63 (21.2%) developed air leaks, 32 (10.8%) pneumothorax, 44 (14.8%) pulmonary interstitial emphysema, and 1 (0.3%) pneumopericardium. The infants with air leaks had a higher risk of death (p < 0.01) and of intraventricular hemorrhage grade 3/4 (p < 0.05). Air leaks were associated with less use of prenatal steroids (p < 0.01), more frequent use of cardiac compressions (p < 0.01), use of a pressure of 30 cm H2O for sustained inflations (p < 0.05), and intubation in the delivery room (p < 0.01). After multivariate logistic regression only prenatal steroids (OR 0.41, 0.20-0.85), epinephrine (OR 3.56, 1.55-8.15) and surfactant use (OR 12.03, 3.39-42.72) remained significant. CONCLUSIONS: Our approach resulted in a high survival rate but was associated with a substantial rate of air leaks, which were associated with death and severe intraventricular hemorrhage. Prenatal steroids were protective, and epinephrine and surfactant use were significant risk indicators, whereas the use of sustained inflations was not a risk factor.