Introduction: Umbilical venous catheters (UVCs) are frequently used for clinical care in neonatal intensive care units (NICUs). Umbilical venous catheters cannot always be positioned perfectly in the inferior vena cava, and low catheters have to be used until a more stable peripherally inserted central catheter can be placed after ruling-out early onset sepsis. There are concerns that low UVCs may be associated with complications such as infection, extravasation, and thrombosis. Objectives: To determine whether UVC complications were associated with (1) low positioning of the catheter tip and (2) the postnatal age at insertion. Methods: We examined a retrospective cohort of infants with UVCs in a tertiary NICU. Neonates with major congenital anomalies, hydrops fetalis, prenatally diagnosed cardiac arrhythmias, pericardial effusion, or ascites were excluded. The position of UVCs is considered as optimum if its tip is seen on radiographs at the level between 8th and 10th thoracic vertebrae (T8–T10), to be low if below T10, and high if above T8. The primary outcome was UVC-related complications resulting in early removal of catheter. We compared the rates of UVC-related complications resulting in removal of UVCs with tips in normal (T8–T10) vs low-lying (below T10) positions at the time of insertion. We also examined the impact of postnatal age, before or after 12 hours, and the frequency of the UVC-related complication. Results: Of the 919 eligible infants, UVC tips were located optimally in 433 (47%) and were low in 415 (45%). The UVC was positioned at an abnormally high position in 71 (8%) infants. Of the 919 infants, UVC-related complication was seen in 54 (5.9%) infants. Low-lying UVCs were removed due to complications in 27 of 415 (6.5%) compared with 20 of 433 (4.6%) optimally position catheters [adjusted odds ratio (aOR) = 1.16; 95% confidence interval (CI): (0.62–2.17)]. High-placed UVCs were associated with a higher rate of cardiac complications (aOR = 6.09, 95% CI [2.03–18.28]) compared with optimally position UVCs. There was also no difference in UVC-related complications between early and late insertion of UVC (6.3% vs 4.7%, p = 0.34). Conclusions: The frequency of complications and consequent need for removal did not differ in UVCs with a tip position traditionally perceived to be optimal or low or by the time of insertion after birth.

Background: Body composition assessment using noninvasive air displacement plethysmography (ADP) can help determine the quality of postnatal growth in infants. The accretion rates of fat mass (FM) and fat-free mass (FFM), both are known to change in various clinicopathological situations in a discordant fashion, can also help evaluate the short-term impacts of nutritional interventions on body composition. Objectives: To determine the FM and FFM accretion rates from 30 to 45 weeks’ postmenstrual age (PMA) and whether these rates are different between male and female infants. Methods: We used previously published normative data with median FM and FFM values for infants at 30–45 weeks’ PMA (Norris et al., 2019). Weekly gains in FM and FFM in g/week and g/kg/week were calculated using early one-point and average two-point methods. Results: FM and FFM accretion rates calculated by the early one-point method were higher than the average two-point method. Male and female infants had similar FM and FFM accretion rates. Constant accretion rates of FM and FFM were not aligned with individual weekly accretion rates, which showed a twofold–fourfold change. A composite index (FFM/FM accretion rate ratio), which we named the “body composition accretion ratio” (BCAR), was more sensitive than the individual weekly accretion rates and showed a ninefold change during the study period. Conclusions: Weekly FM and FFM accretion rates can help assess quality of postnatal growth in young infants, but BCAR can be a more useful, sensitive index for early identification of body composition changes and may possibly guide nutritional interventions.

Background: The prognosis in surgical necrotizing enterocolitis (NEC) has focused on the total length of the resected bowel; the relative impact of small intestinal vs colonic resection is not well studied. Objective: We hypothesized that intestinal resections may reduce mortality and length of hospital stay (LOS) more likely in infants who have NEC extending into the colon than in those with disease limited to the small intestine. We also investigated the relationship between gestational maturation and NEC-related mortality. Methods: A retrospective study of 153 patients compared demographic, clinical, and histopathological information in infants who had NEC limited to the small intestine vs disease with colonic involvement. Results: Our 153 infants had a mean (±standard deviation) gestational age of 27.4 ± 3.4 weeks and a birth weight of 987 ± 505 g. NEC was limited to the small intestine in 103 (67.3%) infants and extended into the colon in 50 (32.7%). Infants with small intestinal NEC needed shorter bowel resections of 28 ± 31.9 cm than 42.2 ± 40.7 cm in those with colonic involvement (p = 0.02). The LOS was longer in NEC limited to the small intestine than in disease with colonic lesions (96 ± 88.1 vs 69.7 ± 19.1 days; p <0.05). In small intestinal NEC, mortality decreased to <50% beyond a gestational age (GA) >37 weeks. In contrast, infants with NEC that involved the colon had mortality <50% mortality beyond 27.3 weeks’ GA (p = 0.008). Conclusions: Bowel resections may be more likely associated with shorter LOS in surgical NEC that involves both the small bowel and colon, even when longer segments of the gastrointestinal tract are removed, than in disease limited to the small intestine.

Objective: The objective of the study is to evaluate the utility of real-time echocardiography (RTE) to provide objective hemodynamic guidance during decannulation of neonates from extracorporeal membrane oxygenation (ECMO). Design: Retrospective case series. Patients: Neonates with respiratory and circulatory failure who underwent venoarterial ECMO (VA-ECMO). Interventions: Use of RTE to assess cardiac function, pulmonary hypertension (PH), and readiness for decannulation from ECMO. Outcome measures: Data abstracted included clinical parameters, RTE data, and management decisions during weaning from VA-ECMO. Results: We used RTE during weaning in 12 of 33 patients between 2016 and 2019. Findings prompted inotrope titration in 10 (83%) patients and volume resuscitation in 10 patients. PH was present in 12 (100%) patients and prompted initiation of prostaglandin infusion (in 3 (25%) patients. Ten of 12 patients were successfully weaned off; in 2, RTE was instrumental in halting decannulation. Conclusions: RTE may serve as a valuable tool in clinical decision-making while weaning neonates from VA-ECMO and providing data to choose appropriate support for successful decannulation.

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. NEC is characterized by intestinal tissue inflammation and necrosis. The intestinal barrier is altered in NEC, which potentially contributes to its pathogenesis by promoting intestinal bacterial translocation and stimulating the inflammatory response. In premature infants, many components of the intestinal barrier are immature. This article reviews the different components of the intestinal barrier and how their immaturity contributes to intestinal barrier dysfunction and NEC.

In both fetal and neonatal physiologic and pathologic processes in most organs, endothelial cells are known to play critical roles. Although the endothelium is one of the most ubiquitous cell type in the body, the tight adherence to the blood vessel wall has made it difficult to study their diverse function and structure. In this article, we have reviewed endothelial cell origins and explored their heterogeneity in terms of structure, function, developmental changes, and their role in inflammatory and infectious diseases. We have also attempted to evaluate the untapped therapeutic potentials of endothelial cells in neonatal disease. This article comprises various peer-reviewed studies, including ours, and an extensive database literature search from EMBASE, PubMed, and Scopus.

Ductus arteriosus is a critically important vascular structure that functions as an extracardiac shunt in fetal life between the pulmonary and systemic circulations for optimal utilization of the placenta as a gas exchange organ and fetal well-being. While morbidities and mortality are well known to be associated with persistence of patent ductus arteriosus (PDA) in postnatal life, the treatment options have concerns for adverse outcomes. Additionally, high spontaneous closure rates, lack of clear definition of hemodynamically significant PDA (hs-PDA), ideal diagnostic tools, conflicting evidence regarding timing of treatment, and lack of clear benefits of PDA treatment from randomized trial in reducing adverse outcomes continue to pose challenges for clinicians managing preterm infants with PDA. This review focuses on the pathophysiology, current diagnostic and management practices, as well as the potential of utilizing unique diagnostic tools to support precision medicine for preterm infants with hs-PDA.

Extra-uterine growth restriction (EUGR) is frequently seen in premature and critically ill infants. Even though advancements in neonatal intensive care have improved the survival of these high-risk infants, many new questions have emerged about the relationship between postnatal growth and neurodevelopmental outcome of these infants. EUGR has traditionally been ascribed to caloric restriction during postnatal periods of critical illness. Nutritional compromise, particularly during the first few weeks of life, may affect the overall growth and could also cause long-term neurodevelopmental impairment. The accidental and premature interruptions of pregnancy could also alter the normal mobilization and utilization of major nutrients from the ways that would have otherwise occurred during the last trimester of pregnancy, which is normally a period of maximal in utero growth. In this article, we review our current understanding of defining EUGR, various risk factors for EUGR, its pathophysiology, and possible ways with which our current healthcare protocols could prevent EUGR.

Imaging of congenital heart disease (CHD) starts in the intrauterine period by fetal echocardiography. The anatomy and physiology are confirmed postnatally by transthoracic echocardiogram. However, complex CHDs require further imaging to delineate anatomy for further management and surgical intervention. Cardiac magnetic resonance imaging (MRI) and cardiac chest tomography (CT) complement the role of transthoracic echocardiogram in delineating further details of anatomy and physiology in the neonatal period. This review covers the basic sequences and terminologies used in cardiac MRI and cardiac CT. A brief description of the indications and the ideal modality of imaging is described, including the limitations of each modality of imaging.

Periodontitis is an often overlooked but important risk factor for both preterm birth and adverse neonatal outcomes. With preterm birth being the leading cause of mortality for all children under the age of 5, any potentially modifiable risk factor associated with preterm birth must be fully evaluated. Periodontal disease is due to bacterial infection of the gingivae with resulting localized and systemic inflammation that can have profound effects in both nonpregnant and pregnant individuals. In pregnancy, several studies have demonstrated an association between periodontitis and preterm birth. Furthermore, extensive evidence demonstrates that fetal exposure to systemic inflammation during gestation predisposes to brain injury and neurodevelopmental delay. Thus, periodontitis and the resulting inflammatory cascade not only affect the pregnant individual but also have significant lifelong consequences on the development and well-being of future offspring. In this review, we will first discuss the epidemiology, prevalence, and pathophysiology of periodontitis. We will then explore the medical literature evaluating the association between periodontitis and preterm birth prior to delving into the potential for neurodevelopmental delay and brain injury among offspring. Finally, we will conclude by discussing future directions and unanswered questions related to periodontitis and its relationship with preterm birth and adverse neonatal outcomes.

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity and carries increased respiratory morbidity into childhood and adulthood. Systemic administration of dexamethasone during the preterm period has been shown to decrease the incidence of BPD in this population. However, enthusiasm about its use has been tempered by early evidence that suggested potential adverse neurodevelopmental outcomes. More recent studies suggest that the timing, dosing, and duration of therapy may have a significant impact on the safety and efficacy of dexamethasone administration and that side effects and harms may be minimized if its use is appropriately targeted. Focusing on studies published since the 2010s American Academy of Pediatrics (AAP) statement on dexamethasone, this review seeks to examine the evidence from recent clinical trials to present the current state of knowledge regarding the systemic dexamethasone administration to prevent BPD in extremely premature infants and how dose, duration, and timing might impact its safety and efficacy in this vulnerable population.

Iron deficiency can exist at birth. Even if iron is sufficient at birth, deficiency can develop during the neonatal period, or during infancy, or during childhood. Iron deficiency can exist despite a normal hematocrit and a normal blood hemoglobin concentration, because anemia is a very late manifestation of iron deficiency. It is likely that adverse neurodevelopmental consequences occur during perinatal biochemical iron deficiency, despite a normal hematocrit and hemoglobin. Consequently, measuring those parameters is a very insensitive method for perinatal iron deficiency screening. This review focuses on potentially better practices for diagnosing perinatal iron deficiency, including recent advances in understanding the pathogenesis of this condition, and also on practical means of treatment, and on global rewards of so doing.

Preterm infants spend much of their time in the neonatal intensive care unit (NICU) learning to orally feed. Attempts to support the preterm infant in acquiring oral skills have evolved greatly over the past decades, including the increasing involvement of speech, physical, and occupational therapists. Interventions have included modified positioning, specialized nipples, external pacing, sensorimotor exercises, oral motor skills programs, and cue-based feeding programs. While many infants seem to have benefited from these methods, a subset of babies continues to require supplemental feeding methods via nasogastric or gastrostomy tube. In particular, infants with aerodigestive complications are at high risk for needing supplemental feeding methods. Additionally, the neurodevelopmental implications of having significant feeding difficulties early on is not fully known. Studies have brought about concerns that children with early oral feeding difficulties may be at risk for the presence of neurodevelopmental delays and continued feeding issues later in childhood. Further research is needed to better understand which infants will struggle with oral feeding, as well as identify appropriate therapeutic options and optimal time periods of implementation.

Despite significant advances in preventive and therapeutic approaches, Group B streptococcus (GBS) still remains one of the most common causes of sepsis and meningitis in neonates. There is considerable variability in the immune responses that is related to microbial virulence, bacterial load, and immaturity of immune response system of the host. In this review, the mechanisms of GBS invasion and host–pathogen interactions are described. Understanding the host immune response to various bacterial components of GBS could help in refining our future strategies to mitigate the immune response and improve neonatal outcomes due to GBS sepsis.

The incomplete understanding of the etiopathogenesis of necrotizing enterocolitis (NEC) contributes to the lack of timely diagnosis and limited therapeutic options. Non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression in various pathways that can modulate various physiological and pathological processes. Despite several studies revealing the role of ncRNAs in intestinal inflammatory diseases in adults, these remain largely unexplored in NEC. In this article, we review the information on ncRNAs that have been specifically identified in NEC or have been noted in other inflammatory bowel disorders that share some of the histopathological abnormalities seen frequently in NEC. We have assimilated the most current research findings on ncRNAs in intestinal diseases. This is an attempt to explore a novel field that has immense potential for future translational and clinical research in preventing, detecting, and treating NEC.

Mitochondria are highly dynamic organelles of bacterial origin in eukaryotic cells. These play a central role in metabolism and adenosine triphosphate (ATP) synthesis and in the production and regulation of reactive oxygen species (ROS). In addition to the generation of energy, mitochondria perform numerous other functions to support key developmental events such as fertilization during reproduction, oocyte maturation, and the development of the embryo. During embryonic and neonatal development, mitochondria may have important effects on metabolic, energetic, and epigenetic regulation, which may have significant short- and long-term effects on embryonic and offspring health. Hence, the environment, epigenome, and early-life regulation are all linked by mitochondrial integrity, communication, and metabolism.

Rotavirus is the primary cause of acute, frequently severe gastroenteritis among growing premature neonates, young infants, and children under the age of five globally. It contains a double-stranded ribonucleic acid genome is a member of the Reoviridae family. In this review, we have discussed the structure and characteristics of the virus, the pathogenesis of rotaviral diarrhea, clinical features, methods of diagnosis, clinical management, and available vaccines. This article combines peer-reviewed evidence from our own clinical studies with results of an extensive literature search in the databases PubMed, EMBASE, and Scopus.

Hypoglycemia is the most common metabolic problem in the neonatal period with a potential to cause brain injury. However, there are controversies in diagnosis, significance, and treatment of neonatal hypoglycemia. Several large-scale prospective and retrospective studies have reported the impact of neonatal hypoglycemia on neurodevelopment in high-risk infants. Significance of short-term hypoglycemia on neurodevelopment in healthy infants remains unresolved. There are also concerns that rapid correction of hypoglycemia may worsen brain injury. Conflicting recommendations from professional societies have further muddied the field. This review examines the current knowledge on the epidemiology of neonatal hypoglycemia, its impact on neurodevelopment, current screening and treatment recommendations, and the emerging role of dextrose gel for management of neonatal hypoglycemia.

Persistent pulmonary hypertension of the newborn (PPHN) is a significant cause of morbidity and mortality in neonates. Despite advances in medical care, mortality remains high. In the United States, inhaled nitric oxide is the gold standard treatment in patients with PPHN. However, while it decreases the need for extracorporeal membrane oxygenation, many patients do not respond to inhaled nitric oxide, and it does not improve overall mortality in those with PPHN. Furthermore, its use is cost-prohibitive in many parts of the world. Thus, there is a critical need to research alternative therapies to improve neonatal outcomes. In this review, we present the animal and human data of some emerging therapeutic targets for pulmonary hypertension, prioritizing pediatric and neonatal data when available. Specifically, we discuss the role of soluble guanylate cyclase stimulators and activators, prostacyclin and analogues, phosphodiesterase 3, 4, and 5 inhibitors, rho-kinase inhibitors, endothelin receptor blockers, PPARγ agonists, and antioxidants in the treatment of neonates with PPHN.

Necrotizing enterocolitis (NEC) is a relatively rare but devastating entity associated classically with the preterm cohort in the neonatal intensive care unit. Preterm and term babies with congenital heart disease are at risk of a number of comorbidities because of the hemodynamic derangements due to a structurally abnormal heart and the corrective procedures adopted. Necrotizing enterocolitis is one of the dreaded complications associated with this cohort and impacts the course of these babies in the hospital in a major way. A large majority of term babies with NEC are in the backdrop of a significant congenital cardiac lesion. This review article summarizes the literature and elaborates this entity including its specific features, risk factors associated with its causality, histopathology and related aspects of hemodynamics, and feeding in this vulnerable population. It also provides insight into modifiable risk factors and early markers of detection of gut necrosis to facilitate prevention and early detection. It highlights the subtle but definite difference in outcome variables to help physicians enable the parents of babies with heart disease to develop a better understanding of the entity and its expected course while counseling.

Near-infrared spectroscopy (NIRS) is a noninvasive, bedside diagnostic tool that could assist in the early diagnosis of necrotizing enterocolitis (NEC) in preterm neonates. NIRS is a safe and effective clinical tool in the neonatal intensive care unit to detect abnormal alterations in tissue perfusion and oxygenation. In addition, NIRS could also detect the complications of NEC, such as bowel necrosis and perforation. NEC is the most common gastrointestinal complication associated with preterm birth and critically ill infants. It is observed in 6–10% of preterm neonates, weighing below 1500 g, leading to considerable morbidity, mortality, and healthcare cost burden. The mortality rate ranges from 20 to 30%, highest in NEC infants undergoing surgery. NIRS is a promising diagnostic modality that could facilitate the early diagnosis of NEC and early detection of complications alone or with the imaging modalities.

Necrotizing enterocolitis (NEC) is inflammatory bowel necrosis of preterm and critically ill infants. The disease is seen in 6–10% of preterm infants who weigh less than 1500 g at birth and carries considerable morbidity, mortality, and healthcare cost burden. Efforts focused on timely mitigation remain restricted due to challenges in early diagnosis as clinical features, and available laboratory tests remain nonspecific until late in the disease. There is renewed interest in the radiological and sonographic assessment of intestinal diseases due to technological advances making them safe, cost-efficient, and supporting Web-based transmission of images, thereby reducing time to diagnosis by disease experts. Most of our experience has been with plain abdominal radiography, which shows characteristic features such as pneumatosis intestinalis in up to 50–60% of patients. Many patients with advanced disease may also show features such as portal venous gas and pneumoperitoneum. Unfortunately, these features are not seen consistently in patients with early, treatable conditions, and hence, there has been an unfulfilled need for additional imaging modalities. In recent years, abdominal ultrasound (AUS) has emerged as a readily available, noninvasive imaging tool that may be a valuable adjunct to plain radiographs for evaluating NEC. AUS can allow real-time assessment of vascular perfusion, bowel wall thickness, with higher sensitivity in detecting pneumatosis, altered peristalsis, and characteristics of the peritoneal fluid. Several other modalities, such as contrast-enhanced ultrasound (CEUS), magnetic resonance imaging (MRI), and near-infrared spectroscopy (NIRS), are also emerging. In this article, we have reviewed the available imaging options for NEC evaluation.

Hypocalcemia in neonates is defined as total serum calcium concentration less than 7.5–8 mg/dL and/or ionized calcium less than 4.4 mg/dL in neonates (>1500 g) and total serum calcium concentration less than 7 mg/dL or ionized calcium less than 3.6 mg/dL in low-birth-weight neonates (<1500 g). About 80% of the calcium transfer across the placenta occurs in the last trimester. Parathyroid hormone-related peptide (PTHrP) regulates the positive calcium balance in the placenta. Postpartum serum calcium level in neonates depends on an intricate relationship between PTH and renal and skeletal factors. Based on the timing of the presentation, hypocalcemia can be early onset (develops in the first 72 hours of life) and late onset (occurs after 72 hours of life). Causes of early-onset hypocalcemia include prematurity, SGA, IUGR, birth asphyxia, diabetes mellitus, or toxemia in the mother. Late-onset neonatal hypocalcemia may be caused by increased dietary phosphate content, neonatal vitamin D deficiency, hypomagnesemia, hypoparathyroidism, or parathyroid hormone resistance. We present a neonate with hypocalcemia due to transient hypoparathyroidism secondary to maternal adenoma. A thorough history and physical examination are essential to identify at-risk asymptomatic infants who need screening for hypocalcemia. Neonatal hypocalcemia can be a serious event and can cause serious morbidity and mortality. Majority of the early as well as transient late neonatal hypocalcemia resolves completely, while lifelong treatment may be required in some cases depending on the etiology.

A chromosomal evaluation should be used to provide better care for a child and their family, not limit it. However, in many pediatric institutions, the diagnosis of a chromosomal abnormality automatically circumscribes the medical and surgical options made available to the family. For example, alongside many other comorbidities (including severe cognitive impairment), infants diagnosed with trisomy 13 or 18 (T13/18) often have cognitive heart defects (e.g., atrial or ventricular septal defects, patent ductus arteriosus, atrioventricular septal defects) that can be successfully repaired or palliated in the general population. However, because T13/18 have historically been considered “lethal” diagnoses or “incompatible with life”, surgical correction of these defects is not frequently offered, and instead infants with these diagnoses are managed with a noninterventionist, “comfort care” approach in which the infant is simply allowed to expire after birth. In recent years, however, more data have emerged from centers that regularly pursue medical and surgical interventions in this population, demonstrating improved outcomes in both quality and quantity of life. Simultaneously, the pediatric ethics literature has argued that treatment decisions for infants with T13/18 are frequently informed by unfounded biases concerning disability and quality of life. Now that neonatology is equipped with improved medical and ethical evidence, the practice of categorically excluding infants with a T13/18 diagnosis from life-saving interventions should be challenged, and instead, parents of these infants should be offered targeted interventions, including corrective and palliative procedures, and included in the process of shared decision-making about which interventions best meet the family's goals of care.

Introduction: The association between red blood cell (RBC) transfusions and necrotizing enterocolitis (NEC), so-called transfusion-associated NEC (ta-NEC), was first described in 1987. However, further work is needed to confirm a causal relationship, elucidate underlying mechanisms, and develop possible strategies for prevention. We performed an extensive literature search in the databases PubMed, EMBASE, and Scopus. Areas covered: Although multiple retrospective human studies have strongly suggested an association between blood transfusions and subsequent occurrence of NEC, meta-analyses of randomized controlled trials (RCTs) testing RBC transfusion thresholds or the use of recombinant erythropoiesis-stimulating growth factors did not confirm an association of anemia with ta-NEC. These conflicting data necessitated the development of an animal model to elucidate mechanisms and causal factors. Data from this recent mouse model of ta-NEC highlighted the importance of sequential exposure to severe anemia followed by transfusion for development of ta-NEC. Expert opinion: This review summarizes current human and experimental data, highlights open questions, and suggests avenues for further research aimed at preventing ta-NEC in preterm infants. Further studies are required to delineate whether there is a tipping point, in terms of the level and duration of anemia, and to develop an effective strategy for blood management and the quality of RBC transfusions.