Extrauterine Growth Restriction: Need for an Accurate Definition.

Neonates show considerable variation in growth that can be recognized through serial measurements of basic variables such as weight, length, and head circumference. If possible, measurement of subcutaneous and total body fat mass can also be useful. These biometric measurements at birth may be influenced by demographics, maternal and paternal anthropometrics, maternal metabolism, preconceptional nutritional status, and placental health. Subsequent growth may depend on optimal feeding, total caloric intake, total metabolic activity, genetic makeup, postnatal morbidities, medications, and environmental conditions. For premature infants, these factors become even more important; poor in utero growth can be an important reason for spontaneous or induced preterm delivery. Later, many infants who have had intrauterine growth restriction (IUGR) and are born small for gestational age (SGA) continue to show suboptimal growth below the 10th percentile, a condition that has been defined as extrauterine growth restriction (EUGR) or postnatal growth restriction (PNGR). More importantly, a subset of these growth-restricted infants may also be at high risk of abnormal neurodevelopmental outcomes. There is a need for well-defined criteria to recognize EUGR/PNGR, so that correctional steps can be instituted in a timely fashion.

Clinical Correlates of Cholestasis in Preterm Infants with Surgical Necrotizing Enterocolitis.

Background: We sought to investigate the clinical determinants and outcomes of cholestasis in preterm infants with surgical necrotizing enterocolitis (sNEC). Methods: Retrospective comparison of clinical information in preterm infants who developed cholestasis vs those who did not. Results: Sixty-two (62/91, 68.1%) infants with NEC developed cholestasis at any time following the onset of illness. Cholestasis was seen more frequently in those who had received ionotropic support at 24 hours following sNEC diagnosis (87.1% vs 58.6%; p = 0.002), had higher mean C-reactive protein levels 2 weeks after NEC diagnosis (p = 0.009), had blood culture-positive sepsis [25 (40.3%) vs 4 (13.8%); p = 0.011], received parenteral nutrition (PN) for longer durations (108.4 ± 56.63 days vs 97.56 ± 56.05 days; p = 0.007), had higher weight-for-length z scores at 36 weeks' postmenstrual age [-1.0 (-1.73, -0.12) vs -1.32 (-1.76, -0.76); p = 0.025], had a longer length of hospital stay (153.7 ± 77.57 days vs 112.51 ± 85.22 days; p = 0.024), had intestinal failure more often (61% vs 25.0%, p = 0.003), had more surgical complications (50% vs 27.6%; p = 0.044), and had >1 complication (21% vs 3.4%; p = 0.031). Using linear regression, the number of days after surgery when feeds could be started [OR 15.4; confidence interval (CI) 3.71, 27.13; p = 0.009] and the postoperative ileus duration (OR 11.9, CI 1.1, 22.8; p = 0.03) were independently associated with direct bilirubin between 2 and 5 mg/dL (mild-moderate cholestasis) at 2 months of age. The duration of PN was independently associated with direct bilirubin >5 mg/dL (severe cholestasis) at 2 months of age in these patients. Conclusion: Cholestasis was seen in 68% of infants following surgical NEC. The most likely contributive factors are intestinal failure and subsequent PN dependence for longer periods. Our data suggest that identification and prevention of risk factors such as sepsis and surgical complications and early feeds following NEC surgery may improve outcomes.

Point-of-care Ultrasound to Diagnose and Monitor the Course of Necrotizing Enterocolitis.

Context: Neonatal gut ultrasound (US) is an emerging clinical tool for quick diagnosis and prognosis in various abdominal pathologies. In this review, we summarize normal gut US findings and concentrate on the specifications of diagnosing necrotizing enterocolitis. Evidence: A comprehensive literature search was conducted across numerous sources with relevant keywords along with the specified age group of 0-28 days of life. Findings: This review describes the normal gut US picture with the basic technicalities needed to master the art of point-of-care (POC) abdominal US. This modality is gaining importance due to its accuracy, applicability, safety, and affordability. Key findings include altered bowel perfusion, decreased peristalsis, and bowel wall thickening with better precision compared to abdominal X-ray (AXR). Many meta-analyses and narrative reviews have already demonstrated their usefulness. The high specificity and positive predictive value could make this tool a guide for early identification and prompt surgical intervention in the dreaded diagnosis of necrotizing enterocolitis. Conclusion: Emerging evidence and expertise in the field of abdominal US will make it a valuable tool for early diagnosis and prognosis of necrotizing enterocolitis.

Neurological Manifestations of Perinatal Dengue.

Dengue viruses (DENVs) are single-stranded RNA viruses belonging to the family Flaviviridae. There are four distinct antigenically related serotypes, DENVs types 1, 2, 3, and 4. These are all mosquito-borne human pathogens. Congenital dengue disease occurs when there is mother-to-fetus transmission of the virus and should be suspected in endemic regions in neonates presenting with fever, maculopapular rash, and thrombocytopenia. Although most of the infected infants remain asymptomatic, some can develop clinical manifestations such as sepsis-like illness, gastric bleeding, circulatory failure, and death. Neurological manifestations include intracerebral hemorrhages, neurological malformations, and acute focal/disseminated encephalitis/encephalomyelitis. Dengue NS1Ag, a highly conserved glycoprotein, can help the detection of cases in the viremic stage. We do not have proven specific therapies yet; management is largely supportive and is focused on close monitoring and maintaining adequate intravascular volume.

Use of Cryoprecipitate in Newborn Infants.

Cryoprecipitate is a transfusion blood product derived from fresh-frozen plasma (FFP), comprised mainly of the insoluble precipitate that gravitates to the bottom of the container when plasma is thawed and refrozen. It is highly enriched in coagulation factors I (fibrinogen), VIII, and XIII; von Willebrand factor (vWF); and fibronectin. In this article, we have reviewed currently available information on the preparation, properties, and clinical importance of cryoprecipitate in treating critically ill neonates. We have searched extensively in the databases PubMed, Embase, and Scopus after short-listing keywords to describe the current relevance of cryoprecipitate.

Innate Immune Memory in Macrophages.

Macrophages have been recognized as the primary mediators of innate immunity starting from embryonic/fetal development. Macrophage-mediated defenses may not be as antigen-specific as adaptive immunity, but increasing information suggests that these responses do strengthen with repeated immunological triggers. The concept of innate memory in macrophages has been described as "trained immunity" or "innate immune memory (IIM)." As currently understood, this cellular memory is rooted in epigenetic and metabolic reprogramming. The recognition of IIM may be particularly important in the fetus and the young neonate who are yet to develop protective levels of adaptive immunity, and could even be of preventive/therapeutic importance in many disorders. There may also be a possibility of therapeutic enhancement with targeted vaccination. This article presents a review of the properties, mechanisms, and possible clinical significance of macrophage-mediated IIM.

Mitochondrial Dynamics during Development.

Mitochondria are dynamic membrane-bound organelles in eukaryotic cells. These are important for the generation of chemical energy needed to power various cellular functions and also support metabolic, energetic, and epigenetic regulation in various cells. These organelles are also important for communication with the nucleus and other cellular structures, to maintain developmental sequences and somatic homeostasis, and for cellular adaptation to stress. Increasing information shows mitochondrial defects as an important cause of inherited disorders in different organ systems. In this article, we provide an extensive review of ontogeny, ultrastructural morphology, biogenesis, functional dynamics, important clinical manifestations of mitochondrial dysfunction, and possibilities for clinical intervention. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.

Mitochondria in Early Life.

Mitochondria are highly-dynamic, membrane-bound organelles that generate most of the chemical energy needed to power the biochemical reactions in eukaryotic cells. These organelles also communicate with the nucleus and other cellular structures to help maintain somatic homeostasis, allow cellular adaptation to stress, and help maintain the developmental trajectory. Mitochondria also perform numerous other functions to support metabolic, energetic, and epigenetic regulation in our cells. There is increasing information on various disorders caused by defects in intrinsic mitochondrial or supporting nuclear genes, on different organ systems. In this review, we have summarized the ultrastructural morphology, structural components, our current understanding of the evolution, biogenesis, dynamics, function, clinical manifestations of mitochondrial dysfunction, and future possibilities. The implications of deficits in mitochondrial dynamics and signaling for embryo viability and offspring health are also explored. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.

Association of Surgical Necrotizing Enterocolitis and Its Timing with Retinopathy of Prematurity.

OBJECTIVE: The study aimed to determine the association of surgical necrotizing enterocolitis (NEC) and its timing, with the development and timing of retinopathy of prematurity (ROP). STUDY DESIGN: This was a secondary data analysis of 7,483 preterm infants from the Postnatal Growth and Retinopathy of Prematurity Study. Associations between infants with surgical NEC, early-onset surgical NEC (8-28 days), and late-onset surgical NEC (over 28 days) with ROP were evaluated by using multivariable logistic regression models, controlling for birth weight, gestational age, small for gestational age status, chronic lung disease, intraventricular hemorrhage, hydrocephalus, patent ductus arteriosus, and periventricular leukomalacia. RESULTS: Three hundred fifty-six (4.8%) infants had surgical NEC, with 56% having early surgical NEC. Infants with surgical NEC had a higher risk of any ROP and severe ROP (adjusted odds ratio [OR]: 2.7; 95% CI: 1.9-3.7) and 2.5 (95% CI: 1.9-3.3), respectively; p < 0.001) compared with infants without surgical NEC. Infants with early surgical NEC were at the highest risk of developing ROP and severe ROP (adjusted OR: 3.1 [95% CI: 2.1-4.8], and 3.3 [95% CI: 2.3-4.7] respectively, p < 0.001). Infants with late surgical NEC were also at increased risk of developing ROP and severe ROP (adjusted OR: 2.1 [95% CI: 1.3-3.4], and 1.9 [95% CI: 1.3-2.8] respectively, p < 0.001) compared with infants without surgical NEC. CONCLUSION: Infants with surgical NEC, especially early surgical NEC, are at higher risk of ROP and severe ROP. KEY POINTS: · Infants with surgical NEC are at higher risk of ROP and severe ROP than those without surgical NEC.. · Increased ROP risk is seen in infants with both early- or later onset surgical NEC.. · Early-onset surgical NEC is associated with a higher ROP risk compared with later onset surgical NEC..

Respiratory Syncytial Virus Infections in Neonates: A Persisting Problem.

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in young infants. It is an enveloped, single-stranded, nonsegmented, negative-strand RNA virus, a member of the family Pneumoviridae. Globally, RSV is responsible for 2.3% of deaths among neonates 0-27 days of age. Respiratory syncytial virus infection is most common in children aged below 24 months. Neonates present with cough and fever. Respiratory syncytial virus-associated wheezing is seen in 20% infants during the first year of life of which 2-3% require hospitalization. Reverse transcriptase polymerase chain reaction (RT-PCR) gives fast results and has higher sensitivity compared with culture and rapid antigen tests and are not affected by passively administered antibody to RSV. Therapy for RSV infection of the LRT is mainly supportive, and preventive measures like good hygiene and isolation are the mainstay of management. Standard precautions, hand hygiene, breastfeeding and contact isolation should be followed for RSV-infected newborns. Recent AAP guidelines do not recommend pavilizumab prophylaxis for preterm infants born at 29-35 weeks without chronic lung disease, hemodynamically significant congenital heart disease and coexisting conditions. RSV can lead to long-term sequelae such as wheezing and asthma, associated with increased healthcare costs and reduced quality of life.

CMV-induced Hearing Loss.

Congenital cytomegalovirus (cCMV) infection is the most common fetal viral infection and contributes to about 25% of childhood hearing loss by the age of 4 years. It is the leading nongenetic cause of sensorineural hearing loss (SNHL). Infants born to seroimmune mothers are not completely protected from SNHL, although the severity of their hearing loss may be milder than that seen in those whose mothers had a primary infection. Both direct cytopathic effects and localized inflammatory responses contribute to the pathogenesis of cytomegalovirus (CMV)-induced hearing loss. Hearing loss may be delayed onset, progressive or fluctuating in nature, and therefore, a significant proportion will be missed by universal newborn hearing screening (NHS) and warrants close monitoring of hearing function at least until 5-6 years of age. A multidisciplinary approach is required for the management of hearing loss. These children may need assistive hearing devices or cochlear implantation depending on the severity of their hearing loss. In addition, early intervention services such as speech or occupational therapy could help better communication, language, and social skill outcomes. Preventive measures to decrease intrauterine CMV transmission that have been evaluated include personal protective measures, passive immunoprophylaxis and valacyclovir treatment during pregnancy in mothers with primary CMV infection. Several vaccine candidates are currently in testing and one candidate vaccine in phase 3 trials. Until a CMV vaccine becomes available, behavioral and educational interventions may be the most effective strategy to prevent maternal CMV infection.

Congenital and Perinatal Varicella Infections.

Varicella-zoster virus (VZV) is a human pathogen of the α-herpesvirus family. Some fetuses infected in utero around 8-20 weeks of pregnancy show signs of congenital varicella syndrome (CVS). Infants born to mothers who develop varicella within 5 days before and 2 days after delivery can experience severe disease with increased mortality. The best diagnostic modality is polymerase chain reaction (PCR), which can be done using vesicular swabs or scrapings, scabs from crusted lesions, tissue from biopsy samples, and cerebrospinal fluid. The prevention and management of varicella infections include vaccination, anti-VZV immunoglobulin, and specific antiviral drugs. In this article, we have reviewed the characteristics of VZV, clinical manifestations, management of perinatal infections, and short- and long-term prognosis.

Use of Fresh-frozen Plasma in Newborn Infants.

Nearly 10% of premature and critically ill infants receive fresh-frozen plasma (FFP) transfusions to reduce their high risk of bleeding. The authors have only limited data to identify relevant clinical predictors of bleeding and to evaluate the efficacy of FFP administration. There is still no consensus on the optimal use of FFP in infants who have abnormal coagulation parameters but are not having active bleeding. The aims of this review are to present current evidence derived from clinical studies focused on the use of FFP in neonatology and then use these data to propose best practice recommendations for the safety of neonates receiving FFP.

Enteroviral Infections in Infants.

Enteroviruses (EVs) are major pathogens in young infants. These viruses were traditionally classified into the following four subgenera: polio, coxsackie A and B, and echoviruses. Now that poliomyelitis seems to be controlled in most parts of the world, coxsackie and echoviruses are gaining more attention because (i) the structural and pathophysiological similarities and (ii) the consequent possibilities in translational medicine. Enteroviruses are transmitted mainly by oral and fecal-oral routes; the clinical manifestations include a viral prodrome including fever, feeding intolerance, and lethargy, which may be followed by exanthema; aseptic meningitis and encephalitis; pleurodynia; myopericarditis; and multi-system organ failure. Laboratory diagnosis is largely based on reverse transcriptase-polymerase chain reaction, cell culture, and serology. Prevention and treatment can be achieved using vaccination, and administration of immunoglobulins and antiviral drugs. In this article, we have reviewed the properties of these viruses, their clinical manifestations, and currently available methods of detection, treatment, and prognosis.

Intestinal Resection is More Likely to be Effective in Necrotizing Enterocolitis Extending to Colon than in Disease Limited to the Small Intestine.

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.

Role of the Endothelium in Neonatal Diseases.

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.

Non-coding RNAs in Neonatal Necrotizing Enterocolitis.

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.

Maternal Nutrition and Fetal/Infant Development.

Nutrition in pregnant mothers has long been known to be an important determinant of fetal/maternal outcomes. In general, the typical American diet shows opportunities for improvement. The intake of fruits, vegetables, whole grains, and fiber may be below recommended levels, but the relative proportion of sodium, fats, and carbohydrates seems high. In this review, we present current evidence on how the fetal/neonatal outcomes may be altered by maternal nutrition at the time of conception, fetal nutrition in utero, contribution of maternal dietary factors in fetal outcomes, weight gain during pregnancy, diabetes during pregnancy, fetal growth restriction (FGR), maternal nutritional status during later pregnancy, and pregnancy in adolescent mothers.

Human Milk Lipids Induce Important Metabolic and Epigenetic Changes in Neonates.

Lipids are a major source of energy during the fetal/neonatal period. Most are received from the mother, transplacentally during the intrauterine period or via maternal milk after birth. However, in addition to the known nutritional roles, lipids are now known to bind a variety of cellular receptors to regulate specific patterns in metabolism and gene expression. The expression of these receptors is regulated by various genetic and environmental stimuli, and ligation can activate positive-feedback loops in the expression and the activity of downstream signaling pathways. The authors summarize the role of lipid ligands, cognate receptors, epigenetic regulation, and downstream signaling.

Nutritional Management of Short Bowel Syndrome.

Short bowel syndrome (SBS) of infancy is a cause of prolonged morbidity with intolerance to enteral feeding, specialized nutritional needs, and partial/total dependence on parenteral nutrition. These infants can benefit from individualized nutritional strategies to support and enhance the process of intestinal adaptation. Early introduction of enteral feeds during the period of intestinal adaptation is crucial, even though the enteral feedings may need to be supplemented with an effective, safe, and nutritionally adequate parenteral nutritional regimen. Newer generation intravenous lipid emulsions can be effective in preventing and treating intestinal failure-associated liver disease. Prevention of infection(s), pharmaceutical interventions to enhance bowel motility and prevent/mitigate bacteria overgrowth, and specialized multidisciplinary care to minimize the injury to other organs such as the liver, kidneys, and the brain can assist in nutritional rehabilitation and lower the morbidity in SBS.