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Objective:Both excess and insufficient levels of glucocorticoid in extremely low birth weight (ELBW) infants have been associated with adverse hospital outcomes, whereas excess glucocorticoid exposure has been associated with long-term adverse neurodevelopment. Our objective was to evaluate the relationship between neonatal cortisol concentrations and long-term outcomes of growth and neurodevelopment.Study Design:As part of a multicenter randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency, cortisol concentrations were obtained at 12 to 48 h of postnatal age and at days 5 to 7 on 350 intubated ELBW infants, of whom 252 survived and returned for neurodevelopmental follow-up at 18 to 22 months corrected age. Cortisol values from each time point were divided into quartiles. Growth and neurodevelopmental outcome were compared for each quartile.Result:Median cortisol value was 16.0 μg per 100 ml at baseline for all infants, and 13.1 μg per 100 ml on days 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or at days 5 to 7 were not associated with impaired growth or neurodevelopment at 18 to 22 months corrected age. High cortisol values were associated with an increase in cerebral palsy, related to the increased incidence of severe intraventricular hemorrhage (IVH) and periventricular leukomalacia.Conclusion:Low cortisol concentrations were not predictive of adverse long-term outcomes. High cortisol concentrations, although predictive of short-term adverse outcomes such as IVH and periventricular leukomalacia, did not additionally predict adverse outcome. Further analysis into identifying factors that modulate cortisol concentrations shortly after birth could improve our ability to identify those infants who are most likely to benefit from treatment with hydrocortisone. [ABSTRACT FROM AUTHOR]

There are no standardized procedures for the resuscitation of micropreemies but respiratory and circulatory stabilization immediately after birth should be prioritized. Without aggressive support by positive pressure ventilation, establishing effective respiration among micropreemies is not possible. The first step in postnatal stabilization is initiated by positive airway pressure with a bag and mask. Once the heart rate increases above 100 beats/m, intratracheal intubation should be achieved because it is unusual for a micropreemie to breathe spontaneously or by non-invasive respiratory support for a protracted duration. Until further information is available, initial FiO2 should be between 0.3 and 0.6, and titrated to achieve SpO2 obtained from healthy term infants for the first 10 min of life. Temperature control of infants is also critical for successful resuscitation and heat-loss minimizing procedures should be used e.g. with insulating bags. After securing the intratracheal tube, the infants should be transferred to the NICU for further procedures, including pulmonary surfactant installation and umbilical cord catheterization. Procedures in a delivery room under a radiant warmer should be limited to the initial resuscitation. In NICUs, the infants should be placed into a closed incubator to maintain high environmental temperature and humidity as well as decrease exposure to intervention and noise. Increased number of staff will also be needed to stabilize the infants further in the NICU. Finally, appropriate equipment (e.g. appropriate sized laryngoscopes) should be made readily available, along with regular practical training and education, whether in person or through SIM courses which are essential for all staff to achieve competence in successful resuscitation of the newborn micropreemie. [ABSTRACT FROM AUTHOR]

OBJECTIVE. Relative adrenal insufficiency in extremely low birth weight infants may contribute to significant morbidity and death. Our objective was to evaluate the relationship between cortisol concentrations and short-term outcomes. METHODS. Cortisol concentrations were obtained for 350 intubated, extremely low birth weight infants at postnatal age of 12 to 48 hours and at day 5 to 7, as part of a multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency. Death and short-term morbidity were monitored prospectively. Cortisol levels at each time point were divided into quartiles. The incidence rates of outcomes were determined for each quartile and for infants with cortisol values of <10th percentile or >90th percentile. RESULTS. Median cortisol values were 16.0 μg/dL at baseline and 13.1 μg/dL on day 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or day 5 to 7 were not associated with increased morbidity or mortality rates and were not predictive of open-label hydrocortisone use. In fact, vasopressor use was lower for infants with lower cortisol values at baseline. Severe intraventricular hemorrhage was more frequent in infants with cortisol levels in the upper quartile at baseline, and values of >90th percentile were significantly associated with higher rates of death, severe intraventricular hemorrhage, periventricular leukomalacia, gastrointestinal perforation, and severe retinopathy of prematurity. CONCLUSIONS. Low cortisol concentrations were not predictive of adverse short-term outcomes, but high cortisol concentrations were associated with severe intraventricular hemorrhage, and extremely elevated values were associated with morbidity and death. Low cortisol concentrations alone at these 2 time points did not identify the infants at highest risk for adverse outcomes. In contrast, high cortisol values were associated with increased morbidity and mortality rates. [ABSTRACT FROM AUTHOR]

Summary: Despite a widespread myth of parental autonomy in decision-making for extremely preterm neonates, families in the United States are often not given access to accurate information about the consequences of preterm birth, resuscitation and treatment, or about their ethical options. Professional, philosophical, and financial incentives for hospitals and neonatologists to provide intensive treatment may trump parental wishes in delivery rooms and neonatal units. Parents may also be intimidated by the atmosphere of intensive care and by the behavior of committed staff. Prenatal advance directives allow parents to receive information on outcomes, treatments, and options, including palliative care, ‘on their own turf’ and as a part of routine prenatal counseling. The use of directives and other techniques for transparency in obstetric and neonatal care could improve the process of informed parental choice. [Copyright &y& Elsevier]

Background: Extremely preterm infants, especially those <24 weeks of gestation, displayed extremes in changes of fluid/electrolyte balance. The purpose of the present study was to retrospectively investigate abnormalities in fluid/electrolyte balance during the first postnatal week. Methods: Of 32 subjects admitted during 20 years, 17 infants with no severe complications were examined, and 72 appropriate-for-dates infants at 24–28 weeks of gestation were taken as controls. The subjects were managed in closed incubators in a highly humidified environment and fluid/electrolyte balances were monitored in retrospect. Results: The subjects had higher urine contents, while the insensible water loss was higher than in controls. As for weight loss, no remarkable changes were noted between the two groups. On day 4 and thereafter, serum Na+ levels were high, indicating a high complication rate of hypernatremia without differences in hyperkalemia. The decrease in blood base excess was rapid, requiring supplementation of sodium bicarbonate up to postnatal day 5 in all preterm infants. Conclusion: Due to the relatively higher urine output and insensible water loss in extremely preterm infants during postnatal week 1, higher water intake was required. As such, metabolic acidosis was bound to have occurred. [ABSTRACT FROM AUTHOR]

Abstract: Advances in pharmacology and technology have pushed back the limits of viability to 23−24 weeks of gestation at the expense of an increasing number of survivors with disabilities. Treatment of these extremely preterm infants should be based on a thorough determination of diagnosis and prognosis, followed by decision-making on the basis of futility of treatment or quality-of-life issues and the counselling of parents. This paper reviews the survival rates and outcome of infants under 26 weeks of gestation born in Europe and the rest of the world, and discusses the role of parents and the influence of condition at birth, gender and birth weight on ethical decision-making on behalf of these infants. Dutch guidelines on the treatment of extremely preterm infants at birth are presented to assist clinicians facing the challenging ethical, moral, legal and emotional dilemmas that surround this hot topic in perinatology. [Copyright &y& Elsevier]

Aim: To evaluate if different resuscitation and ventilatory styles exist between two neonatal units, and if the less aggressive approach has a beneficiary effect on BPD outcome. Method: Inborn infants delivered at a gestational age <28 weeks were retrospectively studied (Boston = 70 and Stockholm = 102). Data were collected from birth to discharge or to 40 weeks. Results: The study groups were similar with regard to gestational age, birth weight, gender and CRIB score, whereas SNAPPE-II score was greater in Stockholm and prenatal steroids were given less frequently in Boston. In Stockholm, continuous positive airway pressure (CPAP) was applied in the delivery room for 56% of the infants and the prevalence of infants not requiring intubation or mechanical ventilation (MV) during the first week of life was 22%. In Boston all infants were initially intubated. Subsequently, CPAP was used less often, and higher mean airway pressures (MAWPs) were applied during the first 4 weeks of life. Mortality and moderate/severe BPD at 36 weeks were similar; however, at 40 weeks oxygen supplementation was more frequent in Boston. Site was a predictor for moderate/severe BPD or death at 40 weeks. Conclusion: Practice style differences exist and the less aggressive approach with more CPAP administration was successful. It did not decrease the risk for BPD at 36 weeks; however, at 40 weeks, fewer infants were on oxygen support, and a strong association was found between site, MAWP or MV with pulmonary morbidity indicating that CPAP could have a beneficiary role in outcome. [ABSTRACT FROM AUTHOR]

BACKGROUND. Neurodevelopmental impairment of extremely low birth weight infants increased in the 1990s. Modern therapeutic changes may have influenced more recent neonatal outcomes. OBJECTIVE. We sought to compare neonatal therapies and outcomes among all extremely low birth weight infants born in 2000-2002 (period III) to 2 previous periods: 1982-1989 (period I) and 1990-1999 (period II). METHODS. The population included 496 extremely low birth weight infants born at our perinatal center during period 1, 749 during period 11, and 233 during period III. Therapies, rates of death, and survival with and without impairment at 20 months' corrected age were compared. RESULTS. Between periods I and II, survival increased from 49% to 68% as did neonatal morbidity. This resulted in increased survival without impairment but also increased survival with impairment. Changes in therapy during period III included an increase in antenatal steroid use and a decrease in postnatal steroid use, although the rate of chronic lung disease did not change. Sepsis decreased, as did severe intraventricular hemorrhage. On follow-up, the rate of cerebral palsy decreased from 13% to 5%, resulting in a decrease in neurodevelopmental impairment from 35% to 23%. As a result, during period III versus II, survival without impairment increased, whereas survival with impairment decreased. CONCLUSION. Since 2000, neurodevelopmental impairment has decreased among extremely low birth weight infants. A variety of perinatal and neonatal factors were associated with the improved outcomes including increased antenatal steroid use and cesarean section delivery, as well as decreased sepsis, severe cranial ultrasound abnormalities, and postnatal steroid use despite no change in the rate of chronic lung disease. [ABSTRACT FROM AUTHOR]

Abstract: Advances in pharmacology and technology have sharply reduced mortality of extremely preterm infants at the expense of an increasing number of survivors with handicaps and disabilities. The EURONIC study among neonatal intensive care units across Europe demonstrates that treatment of infants born at the limits of viability raises challenging ethical, moral, legal, and emotional dilemmas among neonatologists, nurses, and parents alike. When is it wise to withhold or withdraw intensive care and, if so, what are the needs of the nonviable or dying infant, family, and neonatal staff to provide a humane and compassionate death? This process begins with a thorough determination of diagnosis and prognosis, followed by decision making on the basis of futility of treatment or quality-of-life issues, and counseling of parents. Withholding or withdrawing of intensive care should be synonymous with palliative care. Perinatal audit and after-care of the family complete the process. The Dutch viewpoint and practice guidelines on withholding and withdrawing of neonatal intensive care are presented. [Copyright &y& Elsevier]

Objective. Increasing survival of extremely low birth weight (ELBW; birth weight <1000 g) infants raises a concern regarding the risks of adverse long-term outcome such as cognitive dysfunction. Few studies have reported long-term follow-up of representative regional cohorts. The objective of this study was to assess the 5-year outcome of a prospectively followed national ELBW infant cohort. Methods. Of all live-born ELBW infants (n = 351) who were delivered in the 2-year period 1996-1997 in Finland, 206 (59%) survived until the age of 5 years. Of these, 103 were born at <27 gestational weeks (GW). A total of 172 children were assessed with neurocognitive tests (Wechsler Preschool and Primary Scale of Intelligence-Revised and a Developmental Neuropsychological Assessment [NEPSY]). Nine children with cognitive impairment and inability to cooperate in testing were not assessed. Motor development was assessed with a modified Touwen test. Results. The rate of cognitive impairment in the ELBW survivors was 9%. The rate of cerebral palsy was 14% (19% of ELBW infants who were born at <27 GW). The mean full-scale IQ of the assessed children was 96 ± 19 and in children of GW <27 was 94 ± 19. Attention, language, sensorimotor, visuospatial, and verbal memory values of NEPSY assessment were significantly poorer compared with normal population means. Four percent needed a hearing aid, and 30% had ophthalmic findings. Of 21 children who had been treated with laser/cryo for retinopathy of prematurity, 17 (81%) had abnormal ophthalmic findings. Of the whole cohort, 41 (20%) exhibited major disabilities, 38 (19%) exhibited minor disabilities, and 124 (61%) showed development with no functional abnormalities but subtle departures from the norm. Only 53 (26%) of the total ELBW infant cohort were classified to have normal outcome excluding any abnormal ophthalmic, auditory, neurologic, or developmental findings. Being small for gestational age at birth was associated with suboptimal growth at least until age 5. Conclusions. Only one fourth of the ELBW infants were classified as normally developed at age 5. The high rate of cognitive dysfunction suggests an increased risk for learning difficulties that needs to be evaluated at a later age. Extended follow-up should be the rule in outcome studies of ELBW infant cohorts to elucidate the impact of immaturity on school achievement and social behavior later in life. [ABSTRACT FROM AUTHOR]

Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks' gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O2) for ≥228 days but not at 36 weeks' postmenstrual age (PMA) or discharge, moderate BPD as O2 for ≥28 days plus treatment with <30% O2 at 36 weeks' PMA, and severe BPD as O2 for ≥28 days plus ≥30% O2 and/or positive pressure at 36 weeks' PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD. Methods. Data from 4866 infants (birth weight ≤1000 g, GA <32 weeks, alive at 36 weeks' PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months' corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks' PMA (36 weeks' definition), and with the consensus definition of BPD. Results. A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months' corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions. [ABSTRACT FROM AUTHOR]

Objective. To understand mothers' and counselors' perceptions of their roles in decision-making about resuscitation of extremely premature infants at delivery and to assess mothers' and counselors' satisfaction with the counseling and decision-making process. Methods. Mothers who delivered an infant between 22 and 27 completed weeks of gestation and their self-identified counselor were interviewed using a structured interview format. Mothers' and counselors' perceptions of the content, tone, and directiveness of predelivery counseling and their satisfaction with the decision-making process were compared. Demographic data were collected for the mothers, infants, and counselors. Simple descriptive statistics described demographic characteristics of mothers, counselors, and infants. Pearson's correlation coefficient was used to determine agreement within individual mother-counselor pairs about the content and directiveness of counseling. Results. Thirty-three counselors and 15 mother-counselor pairs were interviewed. The majority (66.7%) of mothers stated that the counselor had made a treatment recommendation, and 60% stated that they had no choice in how their infant would be treated. Only 27.3% of counselors stated that they had made a recommendation, saying instead that they had described the treatment plan or offered options. Counselors believed that mothers were given a treatment choice in 57.6% of encounters. Specific mother-counselor pairs showed little correlation in their perceptions of whether a treatment recommendation had been made (R = 0.0) or a choice had been given about resuscitation (R = 0.07). Despite a lack of perceived choice, mothers generally believed that they were included in treatment decisions (66.7%) and were satisfied with the amount of influence that they had in the decision-making process (73.3%). Conclusions. The decision-making process in this study conforms most closely to a model of informed assent. Mothers may have been satisfied... [ABSTRACT FROM AUTHOR]

Objective. Severe abnormalities of the head ultrasound (HUS) are important predictors of cerebral palsy (CP) and mental retardation, and a normal HUS usually ensures the absence of major impairments. With the increasing survival of extremely low birth weight (ELBW) infants (birth weight <1000 g), the prognostic significance of a normal HUS may differ. This study examined the prevalence of and risk factors for CP and impaired mental development among ELBW infants with a normal HUS. Methods. Study infants were ELBW infants who were cared for in Neonatal Research Network centers in the years 1995-1999, had a normal early and late HUS, survived to discharge, and returned for follow-up assessments at 18 to 22 months' corrected age. The outcomes of interest were a score <70 on the Bayley Scales of Infant Development-II Mental Developmental Index (MDI) and CP. Risk factors included maternal demographics; infant characteristics; and interventions or morbidities related to the lung, infection, and nutrition. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A time-oriented approach was used to select variables for inclusion in logistic models. Results. Of 1749 infants with a normal early and late HUS (performed at a mean age of 6 and 47 days, respectively), 1473 (84%) returned for follow-up assessment. Infants had a birth weight of 792 ± 134 g (mean ± SD) and gestational age of 26 ± 2 weeks. Rates of CP and MDI <70 were 9.4% and 25.3%, respectively, and 29.2% of infants had either CP or MDI <70. In multivariate analyses, factors associated with CP were male gender (OR: 1.8; 95% CI: 1.2-2.6), multiple birth, (OR: 1.6; 95% CI: 1.1-2.5), decreasing birth weight (OR: 1.3 for each 100-g decrease; 95% CI: 1.1-1.5), pneumothorax (OR: 2.3; 95% CI: 1.2-4.4), and days of conventional ventilation (OR: 1.2 for each additional 10 days; 95% CI: 1.1-1.3). With the exception of pneumothorax, these same factors... [ABSTRACT FROM AUTHOR]

Aim: To determine major neonatal morbidity in surviving infants born at 23-25 weeks, and to identify maternal and infant factors associated with major morbidity. Methods: The medical records of 224 infants who were delivered at two tertiary care centres in 1992-1998 were reviewed retrospectively. At these centres, policies of active perinatal and neonatal management were universally applied. Of the 213 liveborn infants, 140 (66%) survived to discharge. Data were analysed by gestational age and considered in three time periods. Logistic regression models were used to identify factors associated with morbidity. Results: Of the survivors, 6% had intraventricular haemorrhage grade ≥3 (severe IVH) or periventricular leukomalacia (PVL), 15% retinopathy of prematurity ≥stage 3 (severe ROP) and 36% bronchopulmonary dysplasia (BPD). On logistic regression analysis, severe IVH or PVL was associated with duration of mechanical ventilation (odds ratio, OR: 1.53 per 1-wk increment in duration; 95% confidence interval, CI: 1.01-2.33). Severe ROP was associated with the presence of a patent ductus arteriosus (PDA) (OR: 3.31; 95% CI: 1.11-9.90) and birth in time period 3 versus time periods 1 and 2 combined (OR: 6.28; 95% CI: 2.10-18.74). BPD was associated with duration of mechanical ventilation (OR: 2.71 per 1-wk increment in duration; 95% CI: 1.76-4.18) and with the presence of any obstetric complication (OR: 2.67; 95% CI: 1.07-6.65). Gestational age and birthweight were not associated with major morbidity. Of all survivors, 81% were discharged home without severe IVH, PVL or severe ROP. Conclusions: Increased survival as a result of active perinatal and neonatal management was associated with favourable morbidity rates compared with those in recent studies. Among survivors born at 23-25 weeks, neither gestational age nor birthweight was a significant determinant of major morbidity. [ABSTRACT FROM AUTHOR]

Shaeffer and Avery's textbook, Diseases of the Newborn (1971), estimated the limit of viability to be around 28 weeks' gestation and/or 1000 g. Contemporarily, however, attempts are being made to resuscitate infants as early as 22 weeks' gestation. Clearly the "limit of viability" is a moving target, and the acceptable risk of intervening to attempt to "save" these small infants/fetuses is a value judgment and not one that can be answered by science. Even though the dilemma is not one that can be resolved empirically, the emphasis on resolution continues to be one of demands for "further research" by critics as well as advocates for the care of these small infants. Patrick Romanell (1912-2002) was a major philosopher in the critical naturalist movement in the United States and internationally. His observations on the tragic quality of human life and the dilemmas associated between the conflicts of good vs good rather than the epic quality of good vs evil lend themselves well to understanding the conflicts involved in determining the limits of viability of extremely preterm infants., (Copyright © 2022 Baylor University Medical Center.)

The first hours after birth entail a window of opportunity to decrease morbidity and mortality among extremely preterm infants. The availability of staff and its tiredness vary depending on the timing and day of the week. We hypothesized that these circumstances may impact neonatal outcomes. We have conducted a multicenter cohort study with data obtained from the Spanish neonatal network database SEN1500, where staff doctors are in the house 24/7. The main study exposure was the time of birth; secondary exposures were cumulative work hours from the medical and nurses' shifts and day of the week. The primary outcome was survival to hospital discharge. Secondary outcomes included common preterm infants' in-hospital complications. Univariate and multivariate analysis adjusting for potential confounders was performed. All extremely preterm infants (N = 8798) born between 2011 and 2019 were eligible; 35.7% of them were admitted during the night shift. No differences were found between day and night births regarding survival or morbidity. No differences were found between weekdays and weekends or when considering cumulative worked hours in the shifts. Infants born during the night shift were more likely to be intubated at birth (OR 1.20, CI95% 1.06-1.37), receive surfactant (OR 1.24, CI95% 1.08-1.44), and having anemia requiring transfusion (OR 1.23, CI 95% 1.08-1.42)., Conclusion: the time of birth did not seem to affect mortality and morbidity of extremely preterm infants., What Is Known: • The first hours after birth in extremely preterm infants are a very valuable opportunity to decrease mortality and morbidity. • Time and day of birth have long been linked to outcomes in preterm infants, with night shifts and weekends classically having higher rates of mortality and morbidity., What Is New: • In this study, no differences were found between day and night births regarding survival or major morbidity. • Infants born during the night shift were more likely to be intubated at birth, receive surfactant and having anemia requiring transfusion., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Artificial placenta therapy (APT) is an experimental care strategy for extremely preterm infants born at 21-24 weeks' gestation. In our previous studies, blood taken from the maternal ewe was used as the basis of priming solutions for the artificial placenta circuit. However, the use of maternal blood as a priming solution is accompanied by several challenges. We explored the use of synthetic red cells (hemoglobin vesicles; HbV) as the basis of a priming solution for APT used to manage extremely early preterm ovine fetuses., Methods: Six ewes with singleton pregnancies at 95 d gestation (term = 150 d) were adapted to APT and maintained with constant monitoring of key vital parameters. The target maintenance period was 72 h in duration. A synthetic red cell solution consisting of HbV, sheep albumin and electrolytes was used as priming solutions for the APT circuit. Fetuses were evaluated on gross appearance, physiological parameters and bleeding after euthanasia., Results: Two out of six APT fetuses were successfully maintained for the targeted 72 h experimental period with controllable anemia (>10 g/dl) and methemoglobinemia (<10%) using an infusion of blood transfusion and nitroglycerin delivered >1 h after APT commencement, a sufficient period of time to cross-match blood products and screen for viral agents of concern., Conclusions: Extremely preterm sheep fetuses were maintained for a period of up to 72 h using APT in combination with circuit priming using a synthetic red cell (HbV) preparation. Although significant further refinements are required, these findings demonstrated the potential clinical utility of synthetic blood products in the eventual clinical translation of artificial placenta technology to support extremely preterm infants., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Symptomatic patent ductus arteriosus (sPDA) is common among preterm infants, and can lead to several complications. This is particularly true for extremely preterm infants, as closure of the ductus arteriosus using cyclooxygenase inhibitors is often difficult. A recent study using a preterm sheep model showed that intimal thickening-required for anatomical closure of the ductus arteriosus-is less developed in twins than in singletons. Therefore, this study primarily aimed to prove that the ductus arteriosus of extremely preterm twins is more resistant to cyclooxygenase inhibitors than those of extremely preterm singletons. Its secondary aim was to assess whether the resistance against cyclooxygenase inhibitors differed according to chorionicity. In this retrospective case-control study, medical records of 162 extremely preterm infants (gestational age < 28 weeks) were reviewed, and the treatment course of sPDA was subsequently compared between singletons (n = 131) and twins (n = 31). The median indomethacin doses for sPDA and the necessity for surgical ligation were significantly higher in twins than in singletons (5 vs 2 [p < 0.001] and 42% vs 21% [p = 0.018], respectively). No significant differences in sPDA treatment, including the number of indomethacin doses and the necessity for surgical ligation, were observed between monochorionic diamniotic and dichorionic diamniotic twins. This study confirms that the ductus arteriosus of extremely preterm twins is more resistant to cyclooxygenase inhibitors than those of singletons. However, there was no significant difference in sPDA treatment by chorionicity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Optimal management of haemodynamically significant patent ductus arteriosus (HsPDA) in premature babies remains controversial. Our aim is to compare death and/or adverse neurodevelopmental outcomes in extremely low birth weight (ELBW) infants with HsPDA who were managed with conservative [C], medical [M] and/or surgical [S] treatment, with secondary aim to examine short-term morbidities among [S] and [C] groups. The study also compared outcomes in very low birth weight (VLBW) infants with HsPDA and non-HsPDA.Methods: A retrospective study of VLBW preterm infants born before 29 weeks in Singapore from 2007 to 2016 was conducted.Results: A total of 474 VLBW infants were admitted in NUH from 2007 to 2016. Infants aged between 24 + 0 and 28 + 6 weeks of gestation, weighing ≤1500 g and diagnosed with patent ductus arteriosus (PDA) were included in the study, of which 172 infants (124 HsPDA and 48 non-HsPDA) were analyzed. Among infants with HsPDA, 17 infants were managed with [C], 83 with [M] and 24 with [S]. Mortality was not increased regardless of the presence of HsPDA or treatment received. Infants with non-HsPDA were less likely to have isolated speech delay (p < 0.05), but not global developmental delay (GDD). No significant differences in neurodevelopmental outcomes such as hearing loss, cerebral palsy (CP) and speech delay were found. [M + S] infants were at a higher risk of developing chronic lung disease (CLD) (OR 6.83, p < 0.05) and short-term growth failure compared to [C] infants. They were significantly shorter and had a smaller head circumference at discharge (p < 0.05). [M + S] infants also had elevated creatinine compared to those in group [C] (81.1 ± 24.1 vs 48.3 ± 11.8 umol/L, p < 0.000).Conclusions: Compared to conservative management, infants requiring [M + S] treatment for HsPDA were more likely to have short-term complications such as CLD, elevated creatinine, and poorer growth. Despite a more turbulent postnatal course, death and/or adverse neurodevelopmental outcomes were not worse in infants managed with [M + S]. [ABSTRACT FROM AUTHOR]

Rationale: Identifying neonatal and post-discharge exposures among extremely low gestational age newborns (ELGANs) that drive increased pulmonary morbidity and abnormal lung function at 1 year of age proves challenging., Objective: The NIH-sponsored Prematurity and Respiratory Outcomes Program (PROP), evaluated infant pulmonary function tests (iPFTs) at 1 year corrected age to determine which demographic and clinical factors are associated with abnormal lung function., Methods: iPFTs were performed on a PROP subcohort of 135 participants following Institutional Review Board (IRB)-approved written consent. Demographic data, Neonatal Intensive Care Unit (NICU) clinical care, and post-NICU exposures were analyzed for association with iPFTs., Main Results: A significant decrease in forced expiratory volume at 0.5 s (FEV 0.5 ) and/or forced expiratory flows at 75% of forced vital capacity (FEF 75 ), were associated with male sex and African American race. Clinical factors including longer duration of ventilatory support, exposure to systemic steroids, and weight less than the 10th percentile at 36 weeks postmenstrual age were also associated with airflow obstruction, whereas supplemental oxygen requirement and bronchopulmonary dysplasia were not. Additionally, the need for respiratory medications, technology, or hospitalizations during the first year, ascertained by a quarterly survey, were the only post-NICU factors associated with decreased FEV 0.5 and FEF 75 . Only 7% of infants had reversible airflow obstruction., Conclusions: Neonatal demographic factors, respiratory support in the NICU, and a history of greater post-NICU medical utilization for respiratory disease had the strongest association with lower lung function at 1 year in ELGANs., (© 2021 Wiley Periodicals LLC.)

Background: Vitamin D (VitD) is involved in lung development but its influence on respiratory distress syndrome of extremely preterm (EPT) infants have been little investigated. In this study, we examined the influence of low vitamin D status at birth on early respiratory outcomes of this vulnerable infant population., Methods: Cord blood 25(OH)D levels ≤ 75 nmol/L were considered as Low vitamin D levels. Stepwise logistic regression and classification regression-tree analyses were used and the primary outcome was the combined outcome of death or mechanical ventilation need by the end of the first week (death or MV DoL7) as a marker od RDS severity., Results: The mean (SD) GA and birth weight were 26 (1.4) weeks and 801 (212) gr, respectively; 81/109 (74%) infants had low 25(OH)D levels. Infants with low VitD levels had 25% higher initial FiO 2 levels ( p < 0.05) and were more likely to be mechanically ventilated on DoL7 (36 vs. 7%, p < 0.05). Adjusted for gestational age, they had 10-fold higher odds of death or MV DoL7 ( p < 0.01). By regression tree analysis, the rate of death or MV DoL7 increased from 18 to 71% in infants with GA < 26 weeks and with cord blood 25(OH)D levels higher and lower than 74 nmol/L, respectively ( p < 0.05)., Conclusion: Low vitamin D levels at birth are associated with early adverse respiratory outcomes in infants with GA less 29 weeks. Further largest studies are needed to confirm this association., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Papalia, Samonini, Buffat, Gras, des Robert, Landrier, Pauly and Boubred.)

Background: There is no consensus as to whether the outcomes of extremely preterm infants born <25 weeks' gestation have been constantly improving.Aims: Our study aimed to clarify changes in mortality during hospitalization among extremely preterm infants.Study Design: Comparison of mortality rates between the 2005 and 2010 retrospective nationwide surveys in Japan.Subjects: Extremely preterm infants born <25 weeks' gestation in Japan and registered in the nationwide surveys, 802 infants in 2005 and 797 in 2010, respectively.Outcomes: Mortality rates stratified by gestational age.Results and Conclusion: Mortality rates <25 weeks' gestation decreased from 36.4% to 25.6% (difference - 10.8% [95% confidence interval {CI}: -15.3%, -6.2%]) in 2010 compared to 2005. Gestational age-specific mortality rates were lower in 2010 compared to 2005, except for 24 weeks' gestation: 66.0% vs. 50.0% (difference: -16% [95% CI: -29.8%, -21.2%]) and 45.7% vs. 25.5% (difference: -20.2%, [95% CI: -28.1, -12.3%]) at 22, and 23 weeks' gestation, respectively. After adjusting for explanatory variables, the probability of death during hospitalization in 2010 was significantly lower in infants born <25 weeks' gestation (adjusted odds ratio [aOR] 0.597 [95% CI: 0.471, 0.757], but when stratified by gestational age, it was only significant for infants born at 23 weeks' gestation (aOR 0.439 [95% CI: 0.303, 0.636]). In conclusion, the mortality rates among infants born <25 weeks' gestation have been steadily improving from 2005 to 2010 in Japan, but the practice for infants born at 22 weeks' gestation is still challenging. [ABSTRACT FROM AUTHOR]

Background: Ex vivo uterine environment therapy is an experimental intensive care strategy for extremely preterm infants born between 21 and 24 weeks of gestation. Gas exchange is performed by membranous oxygenators connected by catheters to the umbilical vessels. The fetus is submerged in a bath of synthetic amniotic fluid. The lungs remain fluid filled, and pulmonary respiration does not occur. Intrauterine inflammation is strongly associated with extremely preterm birth and fetal injury. At present, there are no data that we are aware of to show that artificial placenta-based systems can be used to support extremely preterm fetuses compromised by exposure to intrauterine inflammation.Objective: To evaluate the ability of our ex vivo uterine environment therapy platform to support extremely preterm ovine fetuses (95-day gestational age; approximately equivalent to 24 weeks of human gestation) exposed to intrauterine inflammation for a period of 120 hours, the following primary endpoints were chosen: (1) maintenance of key physiological variables within normal ranges, (2) absence of infection and inflammation, (3) absence of brain injury, and (4) gross fetal growth and cardiovascular function matching that of age-matched in utero controls.Study Design: Ten ewes with singleton pregnancies were each given a single intraamniotic injection of 10-mg Escherichia coli lipopolysaccharides under ultrasound guidance 48 hours before undergoing surgical delivery for adaptation to ex vivo uterine environment therapy at 95-day gestation (term=150 days). Fetuses were adapted to ex vivo uterine environment therapy and maintained for 120 hours with constant monitoring of key vital parameters (ex vivo uterine environment group) before being killed at 100-day equivalent gestational age. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, biochemical parameters, inflammatory markers, and microbial load to exclude infection. Ultrasound was conducted at 48 hours after intraamniotic lipopolysaccharides (before surgery) to confirm fetal viability and at the conclusion of the experiments (before euthanasia) to evaluate cardiac function. Brain injury was evaluated by gross anatomic and histopathologic investigations. Eight singleton pregnant control animals were similarly exposed to intraamniotic lipopolysaccharides at 93-day gestation and were killed at 100-day gestation to allow comparative postmortem analyses (control group). Biobanked samples from age-matched saline-treated animals served as an additional comparison group. Successful instillation of lipopolysaccharides into the amniotic fluid exposure was confirmed by amniotic fluid analysis at the time of administration and by analyzing cytokine levels in fetal plasma and amniotic fluid. Data were tested for mean differences using analysis of variance.Results: Six of 8 lipopolysaccharide control group (75%) and 8 of 10 ex vivo uterine environment group fetuses (80%) successfully completed their protocols. Six of 8 ex vivo uterine environment group fetuses required dexamethasone phosphate treatment to manage profound refractory hypotension. Weight and crown-rump length were reduced in ex vivo uterine environment group fetuses at euthanasia than those in lipopolysaccharide control group fetuses (P<.05). There were no biologically significant differences in cardiac ultrasound measurement, differential leukocyte counts (P>.05), plasma tumor necrosis factor α, monocyte chemoattractant protein-1 concentrations (P>.05), or liver function tests between groups. Daily blood cultures were negative for aerobic and anaerobic growth in all ex vivo uterine environment group animals. No cases of intraventricular hemorrhage were observed. White matter injury was identified in 3 of 6 lipopolysaccharide control group fetuses and 3 of 8 vivo uterine environment group fetuses.Conclusion: We report the use of an artificial placenta-based system to support extremely preterm lambs compromised by exposure to intrauterine inflammation. Our data highlight key challenges (refractory hypotension, growth restriction, and white matter injury) to be overcome in the development and use of artificial placenta technology for extremely preterm infants. As such challenges seem largely absent from studies based on healthy pregnancies, additional experiments of this nature using clinically relevant model systems are essential for further development of this technology and its eventual clinical application. [ABSTRACT FROM AUTHOR]

Background: In 2013 German infection surveillance guidelines recommended weekly colonization screening for multidrug-resistant (MDRO) or highly epidemic organisms for neonatal intensive care units (NICUs) and extended hygiene measures based on screening results. It remains a matter of debate whether screening is worth the effort. We therefore aimed to evaluate sepsis related outcomes before and after the guideline update. Methods: The German Neonatal Network (GNN) is a prospective cohort study including data from extremely preterm infants between 22 + 0 and 28 + 6 gestational weeks born in 62 German level III NICUs. Results: Infants treated after guideline update (n = 8.903) had a lower mortality (12.5% vs. 13.8%, p = 0.036), reduced rates for clinical sepsis (31.4 vs. 42.8%, p < 0.001) and culture-proven sepsis (14.4% vs. 16.5%, p = 0.003) as compared to infants treated before update (n = 3.920). In a multivariate logistic regression analysis, nine pathogens of culture-proven sepsis were associated with sepsis-related death, e.g. Pseudomonas aeruginosa [OR 59 (19–180), p < 0.001)]. However, the guideline update had no significant effect on pathogen-specific case fatality, total sepsis-related mortality and culture-proven sepsis rates with MDRO. While the exposure of GNN infants to cefotaxime declined over time (31.1 vs. 40.1%, p < 0.001), the treatment rate with meropenem was increased (31.6 vs. 26.3%, p < 0.001). Conclusions: The introduction of weekly screening and extended hygiene measures is associated with reduced sepsis rates, but has no effects on sepsis-related mortality and sepsis with screening-relevant pathogens. The high exposure rate to meropenem should be a target of antibiotic stewardship programs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Neonatal AKI in the preterm population is an under-recognized morbidity. Detecting AKI in preterm infants is important for their long-term kidney health. We aimed to examine the yearly trends of incidence and the related morbidities and care practices affecting the occurrence of neonatal AKI in extremely preterm (gestational age <29 weeks) and very preterm (gestational age 29-32 weeks) infants., Design, Setting, Participants, & Measurements: The trends and the related risk factors and care practices of AKI were examined in the extremely preterm ( n =434) and very preterm ( n =257) infants who were admitted within 14 days after birth from 2005 to 2018 to the University Hospital and had at least two serum creatinine measurements during hospitalization. We defined AKI as a serum creatinine rise of 0.3 mg/dl or more within 48 hours or a 1.5-fold increase within 7 days., Results: The extremely preterm group had a three-fold higher incidence of AKI (30% versus 10%) than the very preterm group. Among preterm infants with AKI, 92% had one episode of AKI, and 45% experienced stage 2 or 3 AKI; the mean duration of AKI was 12±9 days. Across the 14-year period, the crude incidence of AKI declined markedly from 56% to 17% in the extremely preterm group and from 23% to 6% in the very preterm group. After adjustment, a significant decline of AKI incidence was still observed in the extremely preterm group. The declining AKI in the extremely preterm infants was related to the trends of decreasing incidences of neonatal transfer, prolonged aminoglycoside exposure, prophylactic use of nonsteroidal anti-inflammatory drugs, and sepsis., Conclusions: We observed a declining trend in the incidence of neonatal AKI among extremely preterm infants from 2005 to 2018, which may be related to improvement of care practices., (Copyright © 2021 by the American Society of Nephrology.)

Objectives: To compare the efficacy of intra-tracheal (IT) surfactant/budesonide (SB) with that of surfactant alone (S) in reducing the rate of bronchopulmonary dysplasia (BPD) at 36 weeks post-menstrual age (PMA), we included extremely preterm very low birth weight (VLBW) infants with severe respiratory distress syndrome (RDS) in our tertiary neonatal level of care unit (Padua, Italy)., Study Design: A retrospective chart review of two cohorts of extremely preterm VLBW neonates (<28 +0  gestation weeks, birth weight [BW] < 1500 g) born in two consequent epochs (2017-2018/2018-2019) were compared. The SB group received surfactant (200 mg/kg 1st dose) and budesonide (0.25 mg/kg), while the S group received surfactant alone., Results: Among 68 neonates with RDS Grades III-IV, FiO 2  ≥ 0.3 within 12 h of life, 18 were included in each group after matching for perinatal, clinical, and laboratory characteristics. IT SB did not affect the rate of BPD (Vermont Oxford Network, Jensen's, and National Institute of Child Health and Human Development BPD Workshop 2018 definitions), death, BPD, or death at 36 weeks PMA. Hypotension requiring inotropic support within the first 5 days was lower in those receiving the combined treatment (p = .03). The SB group had fewer admissions to pediatric ward due to respiratory causes up to 12 months of corrected age (p = .03)., Conclusion: The preliminary results of this retrospective study suggest that in extremely preterm VLBW infants, IT SB for severe RDS did not affect the incidence of BPD, death, and BPD or death at 36 weeks PMA, compared to surfactant alone. The combined therapy proved to be safe in this population. Further studies are warranted to explore the role of early IT steroids on respiratory morbidity in preterm infants., (© 2021 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Of 308 surviving children, born at 25 or fewer weeks of gestation in the United Kingdom and Ireland, 283 (92%) were examined at a median age of 30 months, and results reported from the School of Human Development, University of Nottingham, UK.