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

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

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.

The COVID-19 pandemic has affected maternal and infant health globally both directly from infection with the SARS-CoV-2 virus and indirectly from changes in health care resulting from social, economic, and health care policies unique to each country. The developing countries have to share the disproportionate burden on maternal and infant health. In this review, we discuss the uncertainties resulting from SARS-CoV-2 infection in pregnancy, vertical transmission of the virus, and its effects on breastfeeding of the newborn. The problems of families and communities caring for mothers with COVID-19 and its impact on breastfeeding in newborns are discussed. The challenges posed by the pandemic have forced us to think and devise innovative solutions, including telemedicine help for antenatal counseling, breastfeeding education, and lactation support. Optimal utilization of resources and technology to find creative solutions at the individual and the community level will help in facilitating maternal–infant bonding soon after birth. Appropriate health care policies to support pregnant and lactating mothers will go a long way in meeting healthy child development goals.

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.

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 (20mg/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.

BACKGROUND:Oxygen toxicity mediated by reactive oxygen species (ROS) plays an essential role in the development of bronchopulmonary dysplasia in premature infants. By reducing oxidative stress, antioxidants protect the immature lung. We studied the effects of MnTBAP, a catalytic antioxidant on angiogenesis and alveolar growth following neonatal hyperoxia.METHODS:Newborn mouse litters randomized to room air (RA) or >95% O2 for 72 hours from day 4 (D4) to D7 to receive either MnTBAP (10 mg/kg/d) or saline intraperitoneally (every 24 h for three doses). Lungs harvested for angiogenic gene expression, protein expression, and histopathology post-hyperoxia exposure. Radial alveolar count (RAC), mean linear intercept (MLI) and vessel density assessed by histopathology.RESULTS:Angiogenic gene expression was significantly lower in the hyperoxia group compared to the RA group. The protein expression for VEGF and its receptor, VEGFR1, was significantly lower following treatment with MnTBAP compared to hyperoxia alone. Expression of VEGFR2, Angiopoietin-1 and TIE2, were substantially higher in the RA groups compared to hyperoxia groups with or without MnTBAP. Hyperoxia groups demonstrated alveolar simplification. MnTBAP reduced vessel density and failed to improve alveolar growth following hyperoxia.CONCLUSIONS:MnTBAP, a catalytic antioxidant, does not offer protection from hyperoxia-induced alveolar impairment. The lack of angiogenic upregulation by MnTBAP may contribute to alveolar simplification in newborn mice.

Background: Oxygen therapy and mechanical ventilation are important predisposing factors for the development of bronchopulmonary dysplasia (BPD), leading to increased morbidity and mortality in premature infants. Oxygen toxicity mediated by reactive oxygen species (ROS) may play an important part in the development of BPD. We studied the effects of MnTBAP, a catalytic antioxidant on airway responsiveness and alveolar simplification in adult mice following neonatal hyperoxia. Methods: Mice litters were randomized to 85 %O-2 or room air (RA) on D3 for 12 days to receive either MnTBAP (10 mg/kg/d) or saline intraperitoneally. Methacholine challenge (MCC) performed at 8 and 12 weeks of age by whole-body plethysmography to assess airway reactivity. Alveolarization quantified on lung sections by radial alveolar count (RAC) and mean linear intercept (MLI). Cell counts assessed from bronchoalveolar lavage (BAL) performed at 15 weeks. Results: Mice exposed to hyperoxia and MnTBAP (OXMN) had significantly higher airway reactivity post-MCC at 8 weeks compared to RA and O-2 groups. At 12 weeks, airway reactivity was higher post-MCC in both hyperoxia and OXMN groups. MnTBAP did not attenuate hypemxia-induced airway reactivity in adult mice. Hypemxia exposed mice demonstrated large and distended alveoli on histopathology at 2 and 15 weeks. MnTBAP did not ameliorate hypemxia-induced lung injury as assessed by RAC/MLI. Absolute lymphocyte count was significantly higher in BAL in the hypemxia and OXMN groups. Conclusions: MnTBAP, a catalytic antioxidant, did not afford protection from hyperoxia-induced lung injury 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%O 2 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%O 2 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%O 2 groups at 4 and 12 weeks of age, and the septal length was significantly lower in the 100%O 2 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.

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.

BACKGROUND:Stridor is one of the rare side effects of neonatal hypothermia treatment for hypoxic-ischemic encephalopathy. We aimed to describe the clinical characteristics of the infants who underwent whole-body hypothermia and developed stridor.METHODS:We reviewed the medical records of 171 infants with moderate or severe hypoxic-ischemic encephalopathy who underwent hypothermia therapy. Demographics, as well as clinical characteristics, were documented.RESULTS:A total of 18 infants developed transient stridor out of 171 infants who underwent whole-body hypothermia (10.5%). The stridor was transient and resolved in all infants. All infants with stridor received treatment with one or more of the following: racemic epinephrine, dexamethasone, positive pressure ventilation and/or heliox. Two infants required otorhinolaryngologist (ENT) evaluation due to persistent and severe symptoms, of whom one was found to have left vocal cord paresis that improved with time.CONCLUSION:Stridor is a transient complication associated with hypoxic-ischemic encephalopathy and whole-body hypothermia in neonates. The exact mechanism is unclear and most likely multifactorial. ENT evaluation is recommended in the presence of prolonged symptoms or significant respiratory distress.

Background: Prenatal caffeine adversely affects learning and memory in adult offspring, whereas its administration to adolescent humans improves consolidation of long-term memory. The effects of postnatal caffeine on learning and memory are not known. Our objective was to assess spatial learning and memory in adult mice after caffeine therapy in newborn mice. Methods: Mice pups are randomized to receive caffeine (20 mg/kg per day) or saline intraperitoneally for 10 days after birth. Water maze test was performed at 14 weeks of age. Mice had 60 seconds of training for 3 consecutive days to find the platform. A probe trial was performed to assess time to platform quadrant and the number of passes through the target quadrant in the absence of the platform. Results: Mice treated with caffeine postnatally located the platform in shorter time for 3 days of training. Time to the platform was significantly shorter in the caffeine group over the training period. Time spent in the target quadrant was not different between the two groups. The frequency of passes through the target zone was significantly higher in the caffeine group, specifically in males. Conclusions: No adverse effects on learning and memory were noted in adult mice after postnatal caffeine. Postnatal caffeine may have beneficial effects on spatial learning, and this effect may be sex specific in adult mice.

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. 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. 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. Postnatal caffeine by modulating angiogenic gene expression early in lung development may restore the pulmonary microvasculature and alveolarization in adult lung.

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.

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 10(9)/L vs. 146 +/- 62 10(9)/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.

Persistent pulmonary hypertension of the newborn (PPHN) is an essential cause for hypoxic respiratory failure with significant morbidity and mortality in term and near-term neonates. Hydrocortisone has been shown to decrease oxygen dependency and pulmonary hypertension in neonates with meconium aspiration syndrome and animal studies, respectively. We hypothesize that hydrocortisone will improve oxygenation in term and near-term infants with pulmonary hypertension. We performed a retrospective chart review of all infant with PPHN who received intravenous hydrocortisone therapy as a rescue for severe PPHN. Clinical response was objectively measured using, oxygenation index (OI), PaO2/FiO2 ratio, and inotrope score before, during, and after the hydrocortisone course. We found that hydrocortisone administration resulted in significant improvement of systolic blood pressure, OI, and PaO2/FiO2. In conclusion, hydrocortisone increased systolic blood pressure and improved oxygenation in term and near-term infants with persistent pulmonary hypertension. Prospective randomized trials are required to evaluate these findings further.

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.