Neonatal Time Period Research Articles

Georacial Epidemiological Estimates of Glucose-6-Phosphate Dehydrogenase Deficiency among Newborns in the United States.

Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is the most common inherited enzyme deficiency disorder worldwide and a major risk factor for the development of severe hyperbilirubinemia. Racial diversity of phenotypes and genotypes in affected individuals is likely to exist in the United States because of changing population demographics. The aim of the present study was to predict an empirical estimate of annual prevalence of G6PDd in newborns adjusted for geography (state of birth), maternal racial identity, and sex of the infant. Birth statistics (2019) from National Center for Vital Statistics and CDC-WONDER data and race-specific prevalence of G6PDd in the United States were evaluated from published sources. We developed Simpson's diversity index (DI) for each State and correlated these to rates of G6PDd in neonates. Descriptive statistics including modeled prevalence and its association with DI were assessed using the Spearman's rho correlation test. We modeled state-specific prevalence for six states (California, Washington DC, Illinois, Massachusetts, New York, and Pennsylvania) using population-level allele frequencies and race, based on Hardy-Weinberg equilibrium. We estimated 78,010 (95% confidence interval: 76,768-79,252) newborns had G6PDd at birth in 2019 with cumulative median prevalence of 17.3 (interquartile range: 12.4-23.2) per 1,000 live births for United States. A strong association was noted for DI and prevalence of G6PDd (p < 0.0005). Five states (Washington DC, Mississippi, Louisiana, Georgia, and Maryland) have the highest projected G6PDd prevalence, with a range of 35 to 48 per 1,000 live births. The probability of G6PDd for female heterozygotes, based on male prevalence, ranged from 1.1 to 7.5% for each cohort in the select six states. States with diverse populations are likely to have higher rates of G6PDd. These prevalence estimates exceeded by several-fold when compared with disorders screened by existing state mandated newborn screening panels. These discrepancies are further confounded by known risk of severe neonatal hyperbilirubinemia that results with G6PDd and the life-long risk of hemolysis. Combined universal newborn predischarge screening for G6PDd and bilirubin could alert and guide a clinician's practices for parental education and closer medical surveillance during the vulnerable neonatal time period. · G6PDd is a common X-linked disorder that can present with varied phenotypes among newborns.. · Prevalence of G6PDd and genotype distribution varies with sex, race, and ethnicity.. · We present regional race- and sex-based estimates of G6PDd in the United States..

Metabolomics and adductomics of newborn bloodspots to retrospectively assess the early-life exposome.

Exposomics studies can measure health-relevant chemical exposures during a lifetime and estimate the 'internal' environment. However, sampling limitations make these features difficult to capture directly during the critical neonatal time period. We review the use of newborn dried bloodspots (DBS) archived from newborn screening programs for exposomic analysis in epidemiological children's health studies. Emerging 'omics technologies such as adductomics and metabolomics have been adapted for DBS analysis, and these technologies can now provide valuable etiological information on the complex interplay between exposures, biological response, and population phenotypes. Adductomics and metabolomics of DBS can provide robust measurements for retrospective epidemiological investigations. With extensive bioarchiving programs in the United States and other countries, DBS are poised to substantially aid epidemiological studies, particularly for rare and low-frequency childhood diseases and disorders.

Neonatal Venous Thromboembolism.

Neonates are the pediatric population at highest risk for development of venous thromboembolism (VTE), and the incidence of VTE in the neonatal population is increasing. This is especially true in the critically ill population. Several large studies indicate that the incidence of neonatal VTE is up almost threefold in the last two decades. Central lines, fluid fluctuations, sepsis, liver dysfunction, and inflammation contribute to the risk profile for VTE development in ill neonates. In addition, the neonatal hemostatic system is different from that of older children and adults. Platelet function, pro- and anticoagulant proteins concentrations, and fibrinolytic pathway protein concentrations are developmentally regulated and generate a hemostatic homeostasis that is unique to the neonatal time period. The clinical picture of a critically ill neonate combined with the physiologically distinct neonatal hemostatic system easily fulfills the criteria for Virchow’s triad with venous stasis, hypercoagulability, and endothelial injury and puts the neonatal patient at risk for VTE development. The presentation of a VTE in a neonate is similar to that of older children or adults and is dependent upon location of the VTE. Ultrasound is the most common diagnostic tool employed in identifying neonatal VTE, but relatively small vessels of the neonate as well as frequent low pulse pressure can make ultrasound less reliable. The diagnosis of a thrombophilic disorder in the neonatal population is unlikely to change management or outcome, and the role of thrombophilia testing in this population requires further study. Treatment of neonatal VTE is aimed at reducing VTE-associated morbidity and mortality. Recommendations for treating, though, cannot be extrapolated from guidelines for older children or adults. Neonates are at risk for bleeding complications, particularly younger neonates with more fragile intracranial vessels. Developmental alterations in the coagulation proteins as well as unique pharmacokinetics must also be taken into consideration when recommending VTE treatment. In this review, epidemiology of neonatal VTE, pathophysiology of neonatal VTE with particular attention to the developmental hemostatic system, diagnostic evaluations of neonatal VTE, and treatment guidelines for neonatal VTE will be reviewed.

Brain Tumors in the Neonate.

Brain tumors can develop in the prenatal and neonatal time periods. Neuroimaging studies are crucial for the early detection of prenatal and neonatal brain tumors. Imaging allows for characterization of morphology, as well as the detection of hydrocephalus, local invasion, and distant spread. The imaging features of the more common neonatal brain tumors, including teratomas, choroid plexus tumors, ATRTs, and neoplasm mimics are described.

Pediatric spinal trauma.

Pediatric spinal trauma is unique. The developing pediatric spinal column and spinal cord deal with direct impact and indirect acceleration/deceleration or shear forces very different compared to adult patients. In addition children are exposed to different kind of traumas. Moreover, each age group has its unique patterns of injury. Familiarity with the normal developing spinal anatomy and kind of traumas is essential to correctly diagnose injury. Various imaging modalities can be used. Ultrasound is limited to the neonatal time period; plain radiography and computer tomography are typically used in the acute work-up and give highly detailed information about the osseous lesions. Magnetic resonance imaging is more sensitive for disco-ligamentous and spinal cord injuries. Depending on the clinical presentation and timing of trauma the various imaging modalities will be employed. In the current review article, a summary of the epidemiology and distribution of posttraumatic lesions is discussed in the context of the normal anatomical variations due to progressing development of the child.

Effect of fluoxetine on disease progression in a mouse model of ALS

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models.

Perinatal Addiction

Perinatal addiction is being seen with increasing frequency and is a complex issue. It involves the patient, her environment, partner, prenatal care, labor, delivery, and neonatal time periods. There are no quick solutions. These patients do require compassionate and competent care regardless of how their care provider may feel about their particular situation. This article can assist the clinicians in managing and trying to understand the conditions of the patient who has been identified with addiction issues and needs help and support after delivery. The aim of the clinician must be to provide competent care with compassion and patience and to formulate a plan of care that will support and benefit the mother and her neonate.

Neonatal neuroimaging findings in inborn errors of metabolism

Individually, metabolic disorders are rare, but overall they account for a significant number of neonatal disorders affecting the central nervous system. The neonatal clinical manifestations of inborn errors of metabolism (IEMs) are characterized by nonspecific systemic symptoms that may mimic more common acute neonatal disorders like sepsis, severe heart insufficiency, or neonatal hypoxic-ischemic encephalopathy. Certain IEMs presenting in the neonatal period may also be complicated by sepsis and cardiomyopathy. Early diagnosis is mandatory to prevent death and permanent long-term neurological impairments. Although neuroimaging findings are rarely specific, they play a key role in suggesting the correct diagnosis, limiting the differential diagnosis, and may consequently allow early initiation of targeted metabolic and genetic laboratory investigations and treatment. Neuroimaging may be especially helpful to distinguish metabolic disorders from other more common causes of neonatal encephalopathy, as a newborn may present with an IEM prior to the availability of the newborn screening results. It is therefore important that neonatologists, pediatric neurologists, and pediatric neuroradiologists are familiar with the neuroimaging findings of metabolic disorders presenting in the neonatal time period.

Prenatal and neonatal exposure to the antiandrogen flutamide alters connexin 43 gene expression in adult porcine ovary

Connexin 43 (Cx43) is the predominant gap junction protein within porcine ovary and is required for proper follicle and corpus luteum (CL) development. Recent research suggests maternally or neonatally mediated effects of antiandrogens on reproductive function during adulthood, notably those dependent on gap junctional communication. The current study was conducted to determine whether late gestational or neonatal exposure to the antiandrogen flutamide influences Cx43 gene expression in the adult porcine ovary. Flutamide was injected into pregnant gilts between days 80 and 88 of gestation and into female piglets between days 2 and 10 posnatally. After animals reached sexual maturity, the ovaries were collected from treated and nontreated (control) pigs. Expression of Cx43 mRNA and protein was determined for preantral and antral follicles and for CLs. In addition, 3β-hydroxysteroid dehydrogenase (3β-HSD) expression and progesterone concentration were determined for luteal tissues. In preantral follicles, Cx43 mRNA was down-regulated ( P < 0.01) following maternal and neonatal flutamide exposure. In large antral follicles, Cx43 mRNA was up-regulated ( P < 0.01) after neonatal flutamide administration. Immunofluorescence showed that Cx43 expression decreased ( P < 0.001) in preantral follicles and increased ( P < 0.001) in large antral follicles following flutamide exposure. In luteal tissues, Cx43 and 3β-HSD expression and progesterone concentration decreased ( P < 0.01) after postnatal flutamide treatment. Overall, these results suggest the involvement of androgens in the regulation of Cx43 expression in pig ovary. Moreover, alteration of Cx43 expression by the administration of flutamide during particular prenatal and neonatal time periods may affect porcine follicle development, as well as CL formation and function.

IGF-II and collagen expression by keratocytes during postnatal development

Keratocytes produce the extensive stromal matrix of the cornea during the late embryonic and neonatal time periods. We propose to test the hypothesis that their biosynthetic activity declines during this process. Keratocytes were isolated from corneas of 6–8-week-old rabbits and corneas of 1–2-year-old cows and their ability to proliferate and synthesize collagen in serum-free media was determined. Rabbit keratocyte cultures increased 38% in DNA content after one week and deposited collagen type I and IGF-II in the media. Bovine keratocyte cultures, in contrast, did not increase in DNA or produce detectable collagen and IGF-II. Bovine keratocytes cultured in media previously conditioned by rabbit keratocytes, however, increased 56% in DNA content, and deposited collagen type I into the media. Microarray analysis of mRNA from neonatal and adult mouse keratocytes was used to confirm these differences. Compared to adult mouse keratocytes, neonatal keratocytes showed high expression levels of IGF-I, IGF-II and collagen types III and V. Since previous studies showed that IGFs stimulate bovine keratocytes to proliferate and to synthesize procollagen type I, we therefore propose that the results of this study suggests that the IGFs may play an important role in regulating early corneal growth in vivo.

Perinatal and Neonatal Manipulation of the Intestinal Microbiome: A Note of Caution

As we learn more about interactions between microbes and the developing gastrointestinal (GI) tract, it is becoming clear that the establishment of the intestinal "microbiome" shortly after birth plays a critical role in the early origins of health and disease. Nutrition, mode of delivery, the use of maternal or postnatal antibiotics, and pre- and probiotics are factors that may alter the microbial ecology and affect lifelong gene expression. Because the neonatal period is a critical period of development when microbes become established in the GI tract, the long-term effects of manipulations of the GI microbial ecology during this time are more amplified than the effects of later manipulations. In this paper, recent research findings are reviewed with the intent of providing information about the benefits of early manipulation of the GI microbiome, but also to give a warning about its indiscriminant manipulation during the perinatal and neonatal time periods.

Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus

The human and rat hippocampus is highly susceptible to iron deficiency (ID) during the late fetal, early neonatal time period which is a peak time of regulated brain iron uptake and utilization. ID during this period alters cognitive development and is characterized by distinctive, long-term changes in hippocampal cellular growth and function. The fundamental processes underlying these changes are not entirely understood. In this study, ID-induced changes in expression of 25 genes implicated in iron metabolism, including cell growth and energy metabolism, dendrite morphogenesis, and synaptic connectivity were assessed from postnatal day (P) 7 to P65 in hippocampus. All 25 genes showed altered expression during the period of ID (P7, 15, and 30); 10 had changes on P65 after iron repletion. ID caused long-term diminished protein levels of four factors critical for hippocampal neuron differentiation and plasticity, including CamKII alpha, Fkbp1a (Fkbp12), Dlgh4 (PSD-95), and Vamp1 (Synaptobrevin-1). ID altered gene expression in the mammalian target of rapamycin (mTOR) pathway and in a gene network implicated in Alzheimer disease etiology. ID during late fetal and early postnatal life alters the levels and timing of expression of critical genes involved in hippocampal development and function. The study provides targets for future studies in elucidating molecular mechanisms underpinning iron's role in cognitive development and function.

Delayed failure of open repair of an anterior glottic web in the neonatal time period

Delayed failure of open repair of an anterior glottic web in the neonatal time period

P-635: Hypogonadism in a baby with hypospadius: Clinical and molecular findings

During the first 6 months of life, males demonstrate gonadal function with increases in both gonadotropins and testosterone, which then decline during childhood until puberty. Therefore, in a male with hypogonadism, the etiology should be able to be determined during this critical neonatal time period. The purpose of the study was to determine the molecular basis of hypospadius and hypogonadism in a three month old male.

Neonatal seizure classification: A fetal perspective concerning childhood epilepsy

Neonatal seizures are markers for time-specific etiologies during antepartum, intrapartum and neonatal time periods. Seizures with or without encephalopathic signs can represent a continuum of maternal, placental, fetal and neonatal risk factors and disease states. A multi-dimensional classification scheme for neonatal seizures is suggested that will help strategize specific therapeutic interventions to optimize neurologic outcome and anticipate later neurological morbidities including epilepsy risk. This scheme combines “epileptic” and “non-epileptic” seizure descriptions which capture time-specific and brain region-specific mechanisms for seizures. Synchronized video electroencephalographic monitoring provides the most accurate start and endpoints for cortically generated seizures. However, subcortical sites of injury may also initiate abnormal clinical signs with or without the subsequent expression of electrographic seizures. Co-registration of digital neuroimaging techniques such as magnetic resonance imaging with computational electroencephalographic datasets will provide more precise structure–function correlates for neonatal seizures that address both cortical and subcortical sites of injury. Finally, more precise definitions of neonatal status epilepticus need to be established because of the long-term harmful effects on brain development by prolonged seizures expressed as epilepsy and cognitive-behavioral deficits. With this expanded classification scheme for neonatal seizures, novel pharmacologic and surgical strategies can be designed for disease-specific rescue, repair, and regeneration strategies of damaged brain tissue that occur during fetal and neonatal periods, and are later expressed during infancy and childhood. Clinical neuroscientists must strive to develop a classification scheme that bridges bench to bedside concepts of developmental neural plasticity research, recognizing both negative and positive consequences of brain remodeling and repair of the child and adolescent brain. Developmental neural plasticity also extends into adulthood when brain remodeling mechanisms further contribute to epileptogenesis and continues to impair quality of life.

Delayed failure of open repair of an anterior glottic web in the neonatal time period

Summary Laryngeal webs are rare congenital laryngeal malformations, the management of which are fraught with controversy. A case is presented of an unusually large web for which an open repair was attempted at a young age. The literature on this topic is reviewed.

Relation of Pregnancy and Neonatal Factors to Subsequent Development of Childhood Epilepsy: A Population-Based Cohort Study

We examined the effect of pregnancy and neonatal factors on the subsequent development of childhood epilepsy in a population-based cohort study. Children born between January 1986 and December 2000 in Nova Scotia, Canada were followed up to December 2001. Data on pregnancy and neonatal events and on diagnoses of childhood epilepsy were obtained through record linkage of 2 population-based databases: the Nova Scotia Atlee Perinatal Database and the Canadian Epilepsy Database and Registry. Factors analyzed included events during the prenatal, labor and delivery, and neonatal time periods. Cox proportional hazards regression models were used to estimate relative risks and 95% confidence intervals. There were 648 new cases of epilepsy diagnosed among 124,207 live births, for an overall rate of 63 per 100,000 person-years. Incidence rates were highest among children <1 year of age. In adjusted analyses, factors significantly associated with an increased risk of epilepsy included eclampsia, neonatal seizures, central nervous system (CNS) anomalies, placental abruption, major non-CNS anomalies, neonatal metabolic disorders, neonatal CNS diseases, previous low birth weight infant, infection in pregnancy, small for gestational age, unmarried, and not breastfeeding infant at the time of discharge from hospital. Our study supports the concept that prenatal factors contribute to the occurrence of subsequent childhood epilepsy.

Understanding sleep ontogeny to assess brain dysfunction in neonates and infants.

The ontogenetic framework onto which a child's sleep is constructed undergoes significant developmental alterations during early life. Sleep state behaviors, in large part, reflect continuities from fetal through neonatal time periods. Major changes in sleep organization subsequently occur throughout infancy. Maturational expressions of sleep behaviors must be understood by the pediatric neurologist before specific physiologic phenomena can be assessed as transient sleep disturbances or clinically relevant sleep disorders. The first part of this two-part review article focuses on the major aspects of developmental sleep physiology in the first few months of life. Recognition of age-specific electroencephalographic/polysomnographic patterns will facilitate the child neurologist's evaluation of the newborn with suspected seizures and interictal encephalopathies, as well as the prediction of neurologic sequelae.

Effects of sodium ascorbate, sodium saccharin and ammonium chloride on the male rat urinary bladder.

Sodium saccharin administered at high doses to male rats beginning after 5 weeks of age produces mild urothelial hyperplasia but does not result in a significant increase in incidence of bladder cancer unless it is administered after an initiating agent. However, if it is administered in a two-generation bioassay, a significant incidence of bladder tumors is produced. The hyperplastic and tumorigenic effects are inhibited by co-administration with high doses of NH4Cl. The present experiment was designed to evaluate the effects of another sodium salt, sodium ascorbate, administered through the neonatal time period. Sodium saccharin administered as 5% of the diet produced urothelial hyperplasia and increased labeling index, and this was inhibited by co-administration with 1.23% NH4Cl. Four doses of sodium ascorbate was evaluated. The lowest dose, 0.91%, was without effect on the urinary tract. A slight effect (not statistically significant) was observed at a dose of 2.73%, and a significant proliferative response was detected at 4.56 and 6.84%. Recent studies suggest that a calcium phosphate-containing amorphous precipitate forms in the urine of rats fed high doses of sodium saccharin, producing cytotoxicity of the urothelium and consequent regenerative hyperplasia. This precipitate was observed in the present experiment in the rats administered the high dose of sodium saccharin or the higher doses of sodium ascorbate. Formation of this precipitate and induction of urothelial proliferation were inhibited by co-administration of NH4Cl, but somewhat higher doses of ammonium chloride were required for doses of sodium ascorbate compared to sodium saccharin. These results demonstrate that sodium ascorbate administered through the neonatal time period of the male rat produces urothelial hyperplasia in the dose responsive manner, with a no-effect level of 0.91% of the diet. The formation of the calcium phosphate-containing amorphous precipitate and urothelial proliferation were inhibited by co-administration with NH4Cl.

1389 SEX DIFFERENCES IN LUNG AND ADRENAL NEUROSYMPATHETIC DEVELOPMENT

Adrenergic mechanisms are known to be important in the synthesis and release of pulmonary surfactant and in the prevention of neonatal respiratory distress syndrome (RDS). We studied neuro-sympathetic development in the lung and adrenal glands in male (M) and female (F) fetal and newborn rabbits. Tissue levels of catecholamines, norepinephrine (NE), epinephrine (E), and dopamine (DA) were measured using a sensitive radioenzymatic assay. Beta adrenergic receptor development in the lung was studied using the tritiated radioligand dihydroalprenolol. Neurosympathetic innervation of the lung was assessed by measuring tissue NE levels which increased gradually from 27 day fetuses to 8 day old newborns. Sex differences were not significant. Lung β-receptor number was significantly elevated in F over M at each gestational age and throughout the neonatal time period investigated (p<0.005) Adrenal gland content of E, NE and DA increased exponentially with advancing developmental age (p<.005). Adrenal E was significantly (p<.01) elevated in F as compared to M fetuses as was the proportion of E. Adrenal NE and DA were similar in M and F fetuses. Sex differences were not significant in the newborn animals. Conclusions: 1) Lung β receptor development but not innervation is accelerated in F fetuses; 2) Adrenal maturation is accelerated in F fetuses; 3) Delayed neurosympathetic and neurohumoral development may explain the male susceptibility to RDS.