Special Issue: Prematurity, Preterm-Born Adults, and Long-Term Effects on Children and Adults.

The incidence of preterm births is increasing globally, with increasing survival into adulthood [...].

Special Issue: Advances in Healthcare for Neonates.

We are delighted to present an editorial for the Special Issue 'Advances in Healthcare for Neonates' [...].

Cardiovascular Morbidities in Adults Born Preterm: Getting to the Heart of the Matter!

Advances in perinatal and neonatal care have led to improved survival of preterm infants into adulthood. However, the shift in focus to long-term health in adults born preterm requires a clear understanding of the impact of prematurity on developing organ systems and the development of adult-oriented disease. A less well-recognized area of risk for surviving preterm infants is their cardiometabolic health. Epidemiologic evidence has linked preterm birth to the development of systemic hypertension, type 2 diabetes, metabolic syndrome, heart failure, and ischemic heart disease. Of more significant concern is that the risk of cardiometabolic disorders is higher in adults born preterm compared to full-term infants. The interconnected nature of the cardio-pulmonary system means worsening morbidity and mortality in adults born preterm. Addressing the problems of adults born preterm holistically would help promote cardiovascular health, wellness, and quality of life over their lifetime. Recognizing that adults born preterm are a unique subset of the population is a challenge in the current healthcare environment. Addressing issues relevant to adults born preterm in the clinically and research domain, using technology to characterize cardiopulmonary physiology and exercise tolerance, developing screening tools for early diagnosis and treatment, and robust follow-up of these infants with access to longitudinal data would improve both the quality and longevity of life in adults born preterm.

Respiratory Failure in an Extremely Premature Neonate with COVID-19.

Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in mild infection in infants and children. However, children with risk factors such as chronic lung disease and immunosuppression have higher risk of severe illness from COVID-19. We report a case of a 27-week-gestation extremely premature infant born to a mother with COVID-19 infection. The infant, initially treated for surfactant deficiency, developed worsening hypoxic respiratory failure on the fifth day of life requiring escalating ventilatory support, an elevated level of C-reactive protein, thrombocytopenia, and an elevated level of d-dimer. The infant was positive for SARS-CoV-2 by RT-PCR from Day 1 to Day 42 of his life. The infant responded to a seven-day course of dexamethasone with a gradually decreasing oxygen requirement and could be extubated to non-invasive ventilation by the end of the fifth week after birth. The infant is currently on home oxygen by nasal cannula. Prolonged shedding of the virus may be a unique feature of the disease in premature infants. Extreme prematurity, immature lungs, and an immunocompromised status may predispose these infants to severe respiratory failure and a prolonged clinical course. Instituting appropriate COVID-19 protocols to prevent the spread of the disease in the neonatal intensive care unit (NICU) is of utmost importance. Infection with SARS-CoV-2 may have implications in the management of extremely premature infants in the NICU.

Glucose Levels during the First 24 Hours following Perinatal Hypoxia.

OBJECTIVE: Hypoglycemia is a significant risk factor for perinatal brain injury and adverse outcomes, particularly in infants requiring resuscitation following hypoxic ischemic (HI) insult. We aimed to study blood glucose (BG) levels in physiologically stressed infants in the presence or absence of epinephrine (Epi) administration at resuscitation in the first 24 hours after birth. STUDY DESIGN: A retrospective chart review of all infants with heart rate (HR) < 100/min at 1 minute requiring positive pressure ventilation (PPV) at birth was performed. Infants were classified into two groups as follows: (1) PPV group: infants' HR improved with PPV only at resuscitation, and Epi group: infants received Epi at resuscitation for persistent bradycardia. Serial measurements of BG levels collected and glucose infusion rate (GIR) calculated at 24 hours. RESULTS: By design, infants in the Epi group had lower cord pH and higher base deficit. BG was significantly lower overtime in premature infants ≤32 weeks of gestation in the Epi group. The BG was markedly higher in near-term and term infants in the Epi group compared with the PPV group. Hypoglycemia was more common despite administration of higher GIR in premature infants ≤32 weeks of gestation. CONCLUSION: In the presence of physiological stress, premature infants are more at risk for hypoglycemia than term infants.

Effects of Neonatal Caffeine Administration on Vessel Reactivity in Adult Mice.

OBJECTIVE: The effects of neonatal caffeine therapy in adults born preterm are uncertain. We studied the impact of neonatal caffeine on systemic blood pressure, vessel reactivity, and response to stress in adult mice. STUDY DESIGN: Mice pups were randomized to caffeine (20 mg/kg/d) or saline by intraperitoneal injection for 10 days after birth. We performed tail-cuff BP (8/12 weeks), urinary 8-hydroxydeoxyguanosine and fecal corticosterone (14 weeks), and vessel reactivity in aortic rings (16 weeks) in adult mice. RESULTS: No differences were noted in systolic, diastolic, and mean blood pressures between the two groups at 8 and 12 weeks of age. However, norepinephrine-induced vasoconstriction was substantially higher in aortic rings in CAF-treated male mice. More significant vasodilator responses to nitric oxide donors in aortic rings in female mice may suggest gender-specific effects of caffeine. Female mice exposed to caffeine had significantly lower body weight over-time. Caffeine-treated male mice had substantially higher fecal corticosterone and urinary 8-hydroxydeoxyguanosine at 14 weeks, suggestive of chronic stress. CONCLUSION: We conclude sex-specific vulnerability to the heightened vascular tone of the aorta in male mice following neonatal caffeine therapy. Altered vessel reactivity and chronic stress in the presence of other risk factors may predispose to the development of systemic hypertension in adults born preterm.

Short-term perinatal oxygen exposure may impair lung development in adult mice.

BACKGROUND: Hyperoxia at resuscitation increases oxidative stress, and even brief exposure to high oxygen concentrations during stabilization may trigger organ injury with adverse long-term outcomes in premature infants. We studied the long-term effects of short-term perinatal oxygen exposure on cell cycle gene expression and lung growth in adult mice. METHODS: We randomized mice litters at birth to 21, 40, or 100%O2 for 30 min and recovered in room air for 4 or 12 weeks. Cell cycle gene expression, protein analysis, and lung morphometry were assessed at 4 and 12 weeks. RESULTS: The principal component analysis demonstrated a high degree of correlation for cell cycle gene expression among the three oxygen groups. Lung elastin was significantly lower in the 100%O2 groups at 4 weeks. On lung morphometry, radial alveolar count, alveolar number, and septal count were similar. However, the mean linear intercept (MLI) and septal length significantly correlated among the oxygen groups. The MLI was markedly higher in the 100%O2 groups at 4 and 12 weeks of age, and the septal length was significantly lower in the 100%O2 groups at 12 weeks. CONCLUSION: Short-term exposure to high oxygen concentrations lead to subtle changes in lung development that may affect alveolarization. The changes are related explicitly to secondary crest formation that may result in alteration in lung elastin. Resuscitation with high oxygen concentrations may have a significant impact on lung development and long-term outcomes such as BPD in premature infants.

Protection from systemic pyruvate at resuscitation in newborn lambs with asphyxial cardiac arrest.

BACKGROUND: Infants with hypoxic-ischemic injury often require cardiopulmonary resuscitation. Mitochondrial failure to generate adenosine triphosphate (ATP) during hypoxic-ischemic reperfusion injury contributes to cellular damage. Current postnatal strategies to improve outcome in hypoxic-ischemic injury need sophisticated equipment to perform servo-controlled cooling. Administration of intravenous pyruvate, an antioxidant with favorable effects on mitochondrial bioenergetics, is a simple intervention that can have a global impact. We hypothesize that the administration of pyruvate following the return of spontaneous circulation (ROSC) would improve cardiac function, systemic hemodynamics, and oxygen utilization in the brain in newborn lambs with cardiac arrest (CA). METHODS: Term lambs were instrumented, delivered by C-section and asphyxia induced by umbilical cord occlusion along with clamping of the endotracheal tube until asystole; Lambs resuscitated following 5 min of CA; upon ROSC, lambs were randomized to receive pyruvate or saline infusion over 90 min and ventilated for 150 min postinfusion. Pulmonary and systemic hemodynamics and arterial gases monitored. We measured plasma pyruvate, tissue lactate, and ATP levels (heart and brain) in both groups. RESULTS: Time to ROSC was not different between the two groups. Systolic and diastolic blood pressures, stroke volume, arterial oxygen content, and cerebral oxygen delivery were similar between the two groups. The cerebral metabolic rate of oxygen was higher following pyruvate infusion; higher oxygen consumption in the brain was associated with lower plasma levels but higher brain ATP levels compared to the saline group. CONCLUSIONS: Pyruvate promotes energy generation accompanied by efficient oxygen utilization in the brain and may facilitate additional neuroprotection in the presence of hypoxic-ischemic injury.

Short-term perinatal oxygen exposure may impair lung development in adult mice

BACKGROUND: Hyperoxia at resuscitation increases oxidative stress, and even brief exposure to high oxygen concentrations during stabilization may trigger organ injury with adverse long-term outcomes in premature infants. We studied the long-term effects of short-term perinatal oxygen exposure on cell cycle gene expression and lung growth in adult mice. METHODS: We randomized mice litters at birth to 21,40, or 100%O2 for 30 min and recovered in room air for 4 or 12 weeks. Cell cycle gene expression, protein analysis, and lung morphometry were assessed at 4 and 12 weeks. RESULTS: The principal component analysis demonstrated a high degree of correlation for cell cycle gene expression among the three oxygen groups. Lung elastin was significantly lower in the 100%O2 groups at 4 weeks. On lung morphometry, radial alveolar count, alveolar number, and septal count were similar. However, the mean linear intercept (MLI) and septal length significantly correlated among the oxygen groups. The MLI was markedly higher in the 100%O2 groups at 4 and 12 weeks of age, and the septal length was significantly lower in the 100%O2 groups at 12 weeks. CONCLUSION: Short-term exposure to high oxygen concentrations lead to subtle changes in lung development that may affect alveolarization. The changes are related explicitly to secondary crest formation that may result in alteration in lung elastin. Resuscitation with high oxygen concentrations may have a significant impact on lung development and long-term outcomes such as BPD in premature infants.

Caffeine and Clinical Outcomes in Premature Neonates.

Caffeine is the most widely used drug by both adults and children worldwide due to its ability to promote alertness and elevate moods. It is effective in the management of apnea of prematurity in premature infants. Caffeine for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia in very-low-birth-weight infants and improves survival without neurodevelopmental disability at 18-21 months. Follow-up studies of the infants in the Caffeine for Apnea of Prematurity trial highlight the long-term safety of caffeine in these infants, especially relating to motor, behavioral, and intelligence skills. However, in animal models, exposure to caffeine during pregnancy and lactation adversely affects neuronal development and adult behavior of their offspring. Prenatal caffeine predisposes to intrauterine growth restriction and small growth for gestational age at birth. However, in-utero exposure to caffeine is also associated with excess growth, obesity, and cardio-metabolic changes in children. Caffeine therapy is a significant advance in newborn care, conferring immediate benefits in preterm neonates. Studies should help define the appropriate therapeutic window for caffeine treatment along with with the mechanisms relating to its beneficial effects on the brain and the lung. The long-term consequences of caffeine in adults born preterm are being studied and may depend on the ability of caffeine to modulate both the expression and the maturation of adenosine receptors in infants treated with caffeine.

Subcutaneous fat necrosis, a rare but serious side effect of hypoxic-ischemic encephalopathy and whole-body hypothermia.

Objective To describe the clinical characteristics and risk factors in infants with subcutaneous fat necrosis (SFN) following therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). Methods A case-control study was performed by a retrospective chart review of infants with moderate or severe HIE admitted to a level IV regional perinatal center and who underwent whole-body cooling. Results A total of 14 (8.1%) of 171 infants with moderate or severe HIE who underwent whole-body cooling developed SFN during hospitalization. There were more females [71% (10/14)] and large-for-gestational age (LGA) infants [28% (4/14)] in the SFN group vs. 36% females (57/157) and 8% LGA infants (13/157) in the group without SFN (P-values of 0.009 and 0.015, respectively). The mean lowest platelet count was lower 108 ± 55 109/L vs. 146 ± 62 109/L and the mean highest calcium level was higher 11.3 ± 2.5 vs. 10.6 ± 0.8 mg/dL in infants with SFN vs. infants without SFN, respectively (P-values of 0.0078 and 0.006, respectively). Distribution of skin lesions followed distinctive patterns representing the areas with direct contact with the cooling blanket. One infant developed severe, life-threatening hypercalcemia that required aggressive management, including diuretics, corticosteroids and bisphosphonates. Conclusion Although SFN is a rare complication of therapeutic hypothermia, it can be a life-threatening condition if complicated by severe hypercalcemia. Infants who undergo therapeutic hypothermia for HIE need regular skin examinations to evaluate for SFN. If SFN is identified, monitoring of serum calcium levels to prevent life-threatening hypercalcemia is recommended.

Caffeine is associated with improved alveolarization and angiogenesis in male mice following hyperoxia induced lung injury.

BACKGROUND: Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia (BPD) in premature neonates. Several mechanisms, including improvement in pulmonary mechanics underly beneficial effects of caffeine in BPD. As vascular development promotes alveologenesis, we hypothesized that caffeine might enhance angiogenesis in the lung, promoting lung growth, thereby attenuating BPD. METHODS: C57Bl/6 mice litters were randomized within 12 h of birth to room air (RA) or 95%O2 to receive caffeine (20 mg/kg/day) or placebo for 4 days and recovered in RA for 12wks. The lung mRNA and protein expression for hypoxia-inducible factors (HIF) and angiogenic genes performed on day 5. Lung morphometry and vascular remodeling assessed on inflation fixed lungs at 12wks. RESULTS: Caffeine and hyperoxia in itself upregulate HIF-2α and vascular endothelial growth factor gene expression. Protein expression of HIF-2α and VEGFR1 were higher in hyperoxia/caffeine and angiopoietin-1 lower in hyperoxia. An increase in radial alveolar count, secondary septal count, and septal length with a decrease in mean linear intercept indicate an amelioration of hyperoxic lung injury by caffeine. An increase in vessel surface area and a significant reduction in smooth muscle thickness of the pulmonary arterioles may suggest a beneficial effect of caffeine on vascular remodeling in hyperoxia, especially in male mice. CONCLUSIONS: Postnatal caffeine by modulating angiogenic gene expression early in lung development may restore the pulmonary microvasculature and alveolarization in adult lung.

Continued Enteral Feeding Is Beneficial in Hypoglycemic Infants Admitted to Intensive Care for Parenteral Dextrose Therapy.

There is variability in practice among care providers on feeding infants admitted with neonatal hypoglycemia (NH) for parenteral dextrose. We compared clinical outcomes in infants who were fed (NH-Fed) and hypoglycemic infants who were kept nothing per os (NPO) (NH-NPO) at the time of initiation of intravenous (IV) dextrose. We performed a retrospective review of all newborn infants admitted to the neonatal intensive care unit with NH for IV dextrose. Infants were grouped as per the feeding approach at initiation of IV dextrose: NH-Fed or NH-NPO infants. We found that infants in the NH-Fed group had lower maximum glucose infusion rate, less duration of glucose infusion therapy compared with the NH-NPO group, and significantly less number of days of hospital stay compared with the NH-NPO group (5.87 ± 1.4 days vs 4.9 ± 1.4 days, P < .006). In conclusion, feeding infants with hypoglycemia who require IV dextrose offers tangible benefits of shorter duration of parenteral dextrose and shorter length of hospitalization.

Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates.

Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services.

Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia, cardiac dysfunction and pulmonary hypertension. Inhaled nitric oxide (iNO) and milrinone are commonly used pulmonary vasodilators in CDH. We studied the hemodynamic effects of iNO and milrinone in infants with CDH. METHODS: A retrospective chart review was performed of all CDH infants admitted to two regional perinatal centers and infants classified into three groups: No-iNO group; iNO-responders and iNO-nonresponders. Oxygenation and hemodynamic effects of iNO and milrinone were assessed by blood gases and echocardiography. RESULTS: Fifty-four percent (39/72) of infants with CDH received iNO and 31% of these infants (12/39) had complete oxygenation response to iNO. Oxygenation response to iNO was not associated with a decrease in right ventricular pressures (RVP) or ECMO use. Four infants (33%) in the iNO-responder group and eight infants (30%) in the iNO-nonresponder group received milrinone. Milrinone lowered RVP and improved ejection fraction (EF). Response to iNO was associated with improved oxygenation to milrinone and increased survival following ECMO (67 vs. 20% among nonresponders). CONCLUSIONS: Response to inhaled nitric oxide in combination with milrinone may be associated with improved oxygenation and better survival after ECMO in infants with CDH.

Liver Failure and Conjugated Hyperbilirubinemia in a Preterm Neonate: Role of Early IVIG and Exchange Transfusion.

Neonatal liver failure (NLF) is a rare diagnosis but carries with it significant risks of mortality and morbidity. Common etiologies for NLF include metabolic causes, gestational alloimmune liver disease (GALD or neonatal hemochromatosis), and viral infections. We report a case of liver failure in a premature infant with abnormal iron profile within 48 hours of birth. Lack of accepted guidelines for the initial management of severe jaundice with a high direct component in the first week after birth made treatment challenging. The infant underwent intensive phototherapy along with four exchange transfusions (ET) and two courses of intravenous immunoglobulins (IVIG). The clinical goals were to keep total bilirubin values ≤ 20 mg/dL in this premature neonate and to minimize the risk of bilirubin-induced neurologic dysfunction and decompensated liver failure. Abnormal iron studies and later magnetic resonance imaging were suggestive of GALD. Liver functions improved over time with normal neurodevelopmental assessment at 3 years of age. To conclude, in infants with NLF soon after birth, earlier consideration of IVIG/ET in the first few days may be beneficial. Larger multicenter data analyses are required to formulate treatment guidelines and indications for phototherapy, ET, and IVIG in sick neonates with NLF.

Adaptive immune responses are altered in adult mice following neonatal hyperoxia.

Premature infants with bronchopulmonary dysplasia (BPD), are at risk for frequent respiratory infections and reduced pulmonary function. We studied whether neonatal hyperoxia disrupts adaptive immune responses in adult mice, contributing to higher respiratory-related morbidities seen in these infants. Newborn mice litters were randomized at 3 days to 85% O2 or room air (RA) for 12 days. Whole lung mRNA was isolated in both the groups at 2 weeks and 3 months. Gene expression for T-cell and B-cell adaptive immune response was performed by real-time PCR and qRT-PCR; protein expression (p21, IL4, IL10, IL27, cd4) was performed by enzyme immunoassay along with p21 immunohistochemistry. Hyperoxia increased expression of p21 and decreased expression of 19 genes representing T/B-cell activation by ≥ fourfold; three of them significantly (Rag1, Cd1d1, Cd28) compared to the RA group at 2 weeks. Despite RA recovery, the expression of IFNγ, IL27, and CD40 was significantly reduced at 3 months in the hyperoxia group. Expression of p21 was significantly higher and IL27 protein lower at 2 weeks following hyperoxia. Adult mice exposed to neonatal hyperoxia had lower IL4 and IL10 in the lung at 3 months. Adaptive immune responses are developmentally regulated and neonatal hyperoxia suppresses expression of genes involved in T-/B-cell activation with continued alterations in gene expression at 3 months. Dysfunction of adaptive immune responses increases the risk for susceptibility to infection in premature infants.