Major Complication Of Prematurity Research Articles

Germinal matrix hemorrhage induces immune responses, brain injury, and motor impairment in neonatal rats.

Germinal matrix hemorrhage (GMH) is a major complication of prematurity that causes secondary brain injury and is associated with long-term neurological disabilities. This study used a postnatal day 5 rat model of GMH to explore immune response, brain injury, and neurobehavioral changes after hemorrhagic injury. The results showed that CD45high/CD11b+ immune cells increased in the brain after GMH and were accompanied by increased macrophage-related chemokine/cytokines and inflammatory mediators. Hematoma formed as early as 2 h after injection of collagenase VII and white matter injury appeared not only in the external capsule and hippocampus, but also in the thalamus. In addition, GMH caused abnormal motor function as revealed by gait analysis, and locomotor hyperactivity in the elevated plus maze, though no other obvious anxiety or recognition/memory function changes were noted when examined by the open field test and novel object recognition test. The animal model used here partially reproduces the GMH-induced brain injury and motor dysfunction seen in human neonates and therefore can be used as a valid tool in experimental studies for the development of effective therapeutic strategies for GMH-induced brain injury.

Neurodevelopmental Outcomes of Extremely Low Birth Weight Survivors in Johannesburg, South Africa.

Background:Improved survival in extremely low birth weight infants (ELBWI) in Sub-Saharan Africa has raised the question whether these survivors have an increased chance of adverse neurodevelopmental outcomes.ObjectivesTo describe neurodevelopmental outcomes of ELBWI in a neonatal unit in South Africa.MethodsThis was a prospective follow-up study. All ELBWI who survived to discharge between 1 July 2013 and 31 December 2017 were invited to attend the clinic. Bayley Scales of Infant and Toddler Development (version III) were conducted at 9 to 12 months and 18 to 24 months.ResultsThere were 723 ELBWI admissions during the study period, 292 (40.4%) survived to hospital discharge and 85/292 (29.1%) attended the neonatal follow up clinic. The mean birth weight was 857.7 g (95% CI: 838.2–877.2) and the mean gestational age was 27.5 weeks (95% CI 27.1–27.9). None of the infants had any major complication of prematurity. A total of 76/85 (89.4%) of the infants had a Bayley-III assessment at a mean corrected age of 17.21 months (95% CI: 16.2–18.3). The mean composite scores for cognition were 98.4 (95% CI 95.1–101.7), language 89.9 (95% CI 87.3–92.5) and motor 97.6 (95% CI 94.5–100.6). All mean scores fell within the normal range, The study found 28 (36.8%) infants to be “at risk” for neurodevelopmental delay.ConclusionOur study demonstrates good neurodevelopmental outcome in a small group of surviving ELBWI, but these results must be interpreted in the context of the high mortality in this group of infants.

White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies.

Intraventricular haemorrhage (IVH) continues to be a major complication of prematurity that can result in cerebral palsy and cognitive impairment in survivors. No optimal therapy exists to prevent IVH or to treat its consequences. IVH varies in severity and can present as a bleed confined to the germinal matrix, small-to-large IVH or periventricular haemorrhagic infarction. Moderate-to-severe haemorrhage dilates the ventricle and damages the periventricular white matter. This white matter injury results from a constellation of blood-induced pathological reactions, including oxidative stress, glutamate excitotoxicity, inflammation, perturbed signalling pathways and remodelling of the extracellular matrix. Potential therapies for IVH are currently undergoing investigation in preclinical models and evidence from clinical trials suggests that stem cell treatment and/or endoscopic removal of clots from the cerebral ventricles could transform the outcome of infants with IVH. This Review presents an integrated view of new insights into the mechanisms underlying white matter injury in premature infants with IVH and highlights the importance of early detection of disability and immediate intervention in optimizing the outcomes of IVH survivors.

Fresh Frozen Plasma Transfusion: An Independent Risk Factor for Hemodynamically Significant Patent Ductus Arteriosus in Premature Infants.

The incidence of patent ductus arteriosus (PDA), a major complication of prematurity, may be reduced by restricting fluid administration. Prophylactic fresh frozen plasma (FFP) transfusion may reduce the incidence of intraventricular hemorrhage in these infants, but risks transfusion-related volume overload. We conducted a retrospective study to investigate whether FFP transfusion is a risk factor for hemodynamically significant PDA (hsPDA) in very low birth weight (BW) premature infants. From January 2009 to December 2014, 102 premature infants with gestational age (GA) less than or equal to 30 weeks were admitted to a level III neonatal intensive care unit, and 88 patients were enrolled. Patients were further divided into non-hsPDA (n = 29) and hsPDA groups (n = 59). We retrospectively reviewed demographic characteristics and various perinatal and postnatal variables. Univariate and multivariable analyses were performed to identify risk factors for hsPDA. Compared with non-hsPDA patients, hsPDA patients had lower mean BW and GA, a higher incidence of severe respiratory distress symptoms, perinatal infection, use of surfactant, and need for FFP transfusion. However, multivariable logistic regression analysis showed that only FFP transfusion remained an independent risk factor for hsPDA (adjusted odds ratio = 3.880, 95% confidence interval: 1.214-12.402, p = 0.022) after adjusting for confounding factors. FFP transfusion is a significant risk factor for the subsequent development of hsPDA in our study population. FFP transfusion may complicate the fluid management of premature infants and increase the risk of hsPDA. · Hemodynamic significant PDA is an important complication of preterm infant.. · FFP transfusion may complicate the fluid management of premature infants.. · FFP transfusion is an independent risk factor for hsPDA in very low birth weight premature infants..

Intraventricular hemorrhage in preterm babies.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is a major complication of prematurity and inversely associated with gestational age and birth weight. The hemorrhage originates from the germinal matrix with an immature capillary bed where vascularization is intense and active cell proliferation is high. It occurs in around 20% of very low-birth-weight preterm neonates. Germinal matrix-intraventricular hemorrhage is less common in females, the black race, and with antenatal steroid use, but is more common in the presence of mechanical ventilation, respiratory distress, pulmonary bleeding, pneumothorax, chorioamnionitis, asphyxia, and sepsis. Ultrasonography is the diagnostic tool of choice for intraventricular hemorrhage and its complications. Approximately 25–50% of the germinal matrix-intraventricular hemorrhage cases are asymptomatic and diagnosed during routine screening. These cases are usually patients with low-grade hemorrhage. Neurologic findings are prominent in severe intraventricular hemorrhage cases. The major complications of the germinal matrix-intraventricular hemorrhage in preterm babies are periventricular hemorrhagic infarction, posthemorrhagic ventricular dilatation, periventricular leukomalacia, and cerebellar hemorrhage. It is an important cause of mortality and morbidity. The management of hemodynamics and ventilation of patients, appropriate follow-up, and early diagnosis and treatment can minimize morbidity. Prognosis in intraventricular hemorrhage is related to the severity of bleeding, parenchymal damage, and the presence of seizures and shunt surgery. The main determinant of prognosis is periventricular hemorrhagic infarction and its severity. Moderate-severe intraventricular hemorrhage can cause posthemorrhagic hydrocephalus, cerebral palsy, and mental retardation. Even mild germinal matrix-intraventricular hemorrhage can result in developmental disorders. Long-term problems such as neurodevelopmental disorders and cerebral palsy are as important as short-term problems. Improving the quality of life of these babies should be aimed through appropriate treatment and follow-up. In this review, intraventricular hemorrhage and complications are discussed.

IS BEING A PREMATURE OR HAVING ABNORMAL BIRTH WEIGHT ASSOCIATED WITH DEPRESSION AMONG 6 - 17 YEARS OLD U.S. CHILDREN?

Abstract BACKGROUND Reports in 2015 showed that premature birth rate in the United States increased when compared to 2014 data, and this was the first increment since 2007. Major complications of prematurity and birth weight abnormalities are well known, but other complications including mental health abnormalities require more investigation to understand their association well. OBJECTIVES We aimed in this study to determine if prematurity and birth weight abnormalities including very low birth weight (VLBW) and low birth weight (LBW) are associated with depression among United States children aged between six and seventeen years old. ​ DESIGN/METHODS This is a cross sectional study using data from the National Survey of Children’s Health (NSCH) 2011–2012. When we applied our selection criteria, 84,182 children out of the total 95,677 NSCH population were selected. Our exclusion criteria were: age less than six years, child’s history of cerebral palsy, and mental retardation. Multivariable logistic regression was done to control for confounding effects when studying the association of prematurity, birth weight abnormalities and depression. ​ RESULTS Our results reveal that 3.6% of our population had history of depression, 11% were born prematurely, 7.4% had low birth weight, and 1.5% had very low birth weight. Depression was more frequent in children who were born prematurely (prevalence 4.3%) when compared to children born at term. Different models were built to analyze the association between prematurity, birth weight abnormalities and depression. There was no detectable statistically significant association when controlling for demographic data (age, gender, race, family structure) and mental health risk factors (parental poor mental health, chronic health conditions) as well as other factors. Results reveal that children who had chronic health conditions or had adverse family experiences have greater odds of having depression. On the other hand, African-American, male, and younger (6–11 years old) children have lower odds of depression. ​ CONCLUSION Further longitudinal studies are required to establish a causal relationship of behavioral and psychological complications, and to determine the biological mechanisms of brain development that could be associated with depression among premature infants or those who have birth weight abnormalities.

AMPA-Kainate Receptor Inhibition Promotes Neurologic Recovery in Premature Rabbits with Intraventricular Hemorrhage.

Intraventricular hemorrhage (IVH) is a major complication of prematurity and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The development of IVH leads to inflammation of the periventricular white matter, apoptosis and arrested maturation of oligodendrocyte precursor cells, and hypomyelination. Here, we show that AMPA-kainate receptor inhibition by NBQX suppresses inflammation, attenuates apoptosis of oligodendrocyte precursor cells, and promotes myelination as well as clinical recovery in preterm rabbits with IVH. Importantly, AMPA-specific inhibition by the FDA-approved perampanel, which unlike NBQX has a low side-effect profile, also enhances myelination and neurological recovery in rabbits with IVH. Hence, the present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and identifies a novel strategy of neuroprotection, which might improve the neurological outcome for premature infants with IVH.

Neurally adjusted ventilator assist in very low birth weight infants: Current status.

Continuous improvements in perinatal care have resulted in increased survival of premature infants. Their immature lungs are prone to injury with mechanical ventilation and this may develop into chronic lung disease (CLD) or bronchopulmonary dysplasia. Strategies to minimize the risk of lung injury have been developed and include improved antenatal management (education, regionalization, steroids, and antibiotics), exogenous surfactant administration and reduction of barotrauma by using exclusive or early noninvasive ventilatory support. The most frequently used mode of assisted ventilation is pressure support ventilation that may lead to patient-ventilator asynchrony that is associated with poor outcome. Ventilator-induced diaphragmatic dysfunction or disuse atrophy of diaphragm fibers may also occur. This has led to the development of new ventilation modes including neurally adjusted ventilatory assist (NAVA). This ventilation mode is controlled by electrodes embedded within a nasogastric catheter which detect the electrical diaphragmatic activity (Edi) and transmit it to trigger the ventilator in synchrony with the patient's own respiratory efforts. This permits the patient to control peak inspiratory pressure, mean airway pressure and tidal volume. Back up pressure control (PC) is provided when there is no Edi signal and no pneumatic trigger. Compared with standard conventional ventilation, NAVA improves blood gas regulation with lower peak inspiratory pressure and oxygen requirements in preterm infants. NAVA is safe mode of ventilation. The majority of studies have shown no significant adverse events in neonates ventilated with NAVA nor a difference in the rate of intraventricular hemorrhage, pneumothorax, or necrotizing enterocolitis when compared to conventional ventilation. Future large size randomized controlled trials should be established to compare NAVA with volume targeted and pressure controlled ventilation in newborns with mature respiratory drive. Most previous studies and trials were not sufficiently large and did not include long-term patient oriented outcomes. Multicenter, randomized, outcome trials are needed to determine whether NAVA is effective in avoiding intubation, facilitating extubation, decreasing time of ventilation, reducing the incidence of CLD, decreasing length of stay, and improving long-term outcomes such as the duration of ventilation, length of hospital stay, rate of pneumothorax, CLD and other major complications of prematurity. In order to prevent barotrauma, next generations of NAVA equipment for neonatal use should enable automatic setting of ventilator parameters in the backup PC mode based on the values generated by NAVA. They should also include an upper limit to the inspiratory time as in conventional ventilation. The manufacturers of Edi catheters should produce smaller sizes available for extreme low birth weight infants. Newly developed ventilators should also include leak compensation and high frequency ventilation. A peripheral flow sensor is also essential to the proper delivery of all modes of conventional ventilation as well as NAVA.

Impact of Maternal Diabetes Mellitus on Mortality and Morbidity of Preterm Infants (24–33 Weeks' Gestation)

Data from several epidemiologic studies have demonstrated that diabetes mellitus (DM) is a risk factor for respiratory distress syndrome (RDS). Two previous studies have shown that with modern management and adequate glycemic control, the risk of RDS in near-term and term newborns of mothers with DM is not increased beyond that observed in a nondiabetic control population. Both these studies were limited by small numbers of preterm infants, and it remains unclear whether preterm infants of diabetic mothers are at increased risk for RDS. This study tested the hypothesis that maternal DM among a population of very low birth weight (VLBW) infants is associated with increased risk for mortality, RDS, and major complications of prematurity. Prospective data collected between 1995 and 2007 by the Israel Neonatal Network on VLBW Infants were analyzed with multivariable logistic regression analysis to assess the independent effect of maternal DM status (pregestational and gestational) on infant mortality, RDS, and other complications of prematurity. Because rates of major neonatal complications were very similar among infants of mothers with pregestational (n = 120) and gestational (n = 825) diabetes, their data were pooled. There was a greater likelihood that mothers with DM had received a complete course of prenatal steroids than nondiabetic mothers. Both the gestational age and birth weight were slightly increased in infants of diabetic mothers compared with infants of nondiabetic mothers. A nearly identical distribution of birth weight percentiles and mean birth weight z scores were found in both groups. Apgar scores were significantly higher among infants of diabetic mothers. With multivariate analysis, no significant differences between the 2 groups occurred in delivery room mortality, RDS, and other major complications of prematurity. Rates of total mortality and bronchopulmonary dysplasia were significantly higher among infants of nondiabetic mothers. No significant increases occurred in infants of diabetic mothers in the adjusted odds ratios for mortality, RDS, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, and patent ductus arteriosus. These findings indicate that with modern management and adequate prenatal care, VLBW infants of diabetic mothers are at no higher risk of developing RDS or other major complications of prematurity than infants of nondiabetic mothers.

Pulmonary Vascular Disease and Bronchopulmonary Dysplasia: Evaluation and Treatment of Pulmonary Hypertension

Despite major advances in perinatal medicine, bronchopulmonary dysplasia (BPD) persists as a major complication of prematurity. Pulmonary hypertension (PH) has been long-recognized as a significant problem of infants with BPD and remains strongly associated with worse outcomes and late mortality. Recent studies further suggest that the pulmonary circulation is characterized by a dysmorphic structure, which contributes to impaired gas exchange, poor tolerance of respiratory infections, increased risk for developing PH, and late exercise intolerance. Current approaches to the diagnosis and management of PH in BPD includes avoidance of hypoxia, aggressive treatment of airways disease, assessing risk for chronic aspiration, and other factors that can complicate the overall respiratory course of infants with established BPD. Echocardiograms and cardiac catheterization remain essential for the accurate assessments of the presence and severity of PH and potential therapeutic strategies. Novel pharmacologic therapies are available for the treatment of PH in BPD, but data are limited regarding optimal strategies and efficacy. Further studies are needed to better understand the incidence, risk factors, and optimal management of PH in infants with BPD.

Impact of Maternal Diabetes Mellitus on Mortality and Morbidity of Preterm Infants (24–33 Weeks' Gestation)

We hypothesized that maternal diabetes mellitus (DM) increases the risk for mortality, respiratory distress syndrome (RDS), and major complications of prematurity. Analysis of prospectively collected (1995-2007) Israel National Very Low Birth Weight Infant Database. Maternal DM was recorded as pregestational or gestational. Multivariable logistic regression analysis was used to assess the independent effect of maternal DM status on infant mortality, RDS, and other complications of prematurity. Infants of mothers with pregestational (n = 120) and gestational (n = 825) DM were similar, and their data were pooled for analyses. Mothers with DM were more likely to have received a complete course of prenatal steroids than control mothers. Infants of diabetic mothers (IDM) had a slightly higher gestational age and birthweight than non-IDM's. Distribution of birthweight percentiles and the mean birthweight z scores were similar. Apgar scores were statistically higher in the IDM group. There were no significant differences between the 2 groups in terms of delivery room mortality, RDS, and other major complications of prematurity. Total mortality and bronchopulmonary dysplasia rates were significantly higher in the nondiabetic group. The adjusted odds ratios for mortality, RDS, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, and patent ductus arteriosus were not significantly increased in the IDM group. With modern management and adequate prenatal care, IDM born very low birthweight do not seem to be at an excess risk of developing RDS or other major complications of prematurity compared with non-IDM.

Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition

Intraventricular haemorrhage is a major complication of prematurity that results in neurological dysfunctions, including cerebral palsy and cognitive deficits. No therapeutic options are currently available to limit the catastrophic brain damage initiated by the development of intraventricular haemorrhage. As intraventricular haemorrhage leads to an inflammatory response, we asked whether cyclooxygenase-2, its derivative prostaglandin E2, prostanoid receptors and pro-inflammatory cytokines were elevated in intraventricular haemorrhage; whether their suppression would confer neuroprotection; and determined how cyclooxygenase-2 and cytokines were mechanistically-linked. To this end, we used our rabbit model of intraventricular haemorrhage where premature pups, delivered by Caesarian section, were treated with intraperitoneal glycerol at 2 h of age to induce haemorrhage. Intraventricular haemorrhage was diagnosed by head ultrasound at 6 h of age. The pups with intraventricular haemorrhage were treated with inhibitors of cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α; and cell-infiltration, cell-death and gliosis were compared between treated-pups and vehicle-treated controls during the first 3 days of life. Neurobehavioural performance, myelination and gliosis were assessed in pups treated with cyclooxygenase-2 inhibitor compared to controls at Day 14. We found that both protein and messenger RNA expression of cyclooxygenase-2, prostaglandin E2, prostanoid receptor-1, tumour necrosis factor-α and interleukin-1β were consistently higher in the forebrain of pups with intraventricular haemorrhage relative to pups without intraventricular haemorrhage. However, cyclooxygenase-1 and prostanoid receptor 2-4 levels were comparable in pups with and without intraventricular haemorrhage. Cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α inhibition reduced inflammatory cell infiltration, apoptosis, neuronal degeneration and gliosis around the ventricles of pups with intraventricular haemorrhage. Importantly, cyclooxygenase-2 inhibition alleviated neurological impairment, improved myelination and reduced gliosis at 2 weeks of age. Cyclooxygenase-2 or prostanoid receptor-1 inhibition reduced tumour necrosis factor-α level, but not interleukin-1β. Conversely, tumour necrosis factor-α antagonism did not affect cyclooxygenase-2 expression. Hence, prostanoid receptor-1 and tumour necrosis factor-α are downstream to cyclooxygenase-2 in the inflammatory cascade induced by intraventricular haemorrhage, and cyclooxygenase-2-inhibition or suppression of downstream molecules--prostanoid receptor-1 or tumour necrosis factor-α--might be a viable neuroprotective strategy for minimizing brain damage in premature infants with intraventricular haemorrhage.

Intraventricular Hemorrhage in Premature Infants: Mechanism of Disease

Intraventricular hemorrhage (IVH) is a major complication of prematurity. IVH typically initiates in the germinal matrix, which is a richly vascularized collection of neuronal-glial precursor cells in the developing brain. The etiology of IVH is multifactorial and is primarily attributed to the intrinsic fragility of the germinal matrix vasculature and the disturbance in the cerebral blood flow (CBF). Although this review broadly describes the pathogenesis of IVH, the main focus is on the recent development in molecular mechanisms that elucidates the fragility of the germinal matrix vasculature. The microvasculature of the germinal matrix is frail because of an abundance of angiogenic blood vessels that exhibit paucity of pericytes, immaturity of basal lamina, and deficiency of glial fibrillary acidic protein (GFAP) in the ensheathing astrocytes endfeet. High VEGF and angiopoietin-2 levels activate a rapid angiogenesis in the germinal matrix. The elevation of these growth factors may be ascribed to a relative hypoxia of the germinal matrix perhaps resulting from high metabolic activity and oxygen consumption of the neural progenitor cells. Hence, the rapid stabilization of the angiogenic vessels and the restoration of normal CBF on the first day of life are potential strategies to prevent IVH in premature infants.

Free radical generation in germinal matrix hemorrhage

Germinal matrix hemorrhage‐Intraventricular hemorrhage (GMH‐IVH) is a major complication of prematurity. In adult animal model, intracerebral hemorrhage is attended by free radical generation resulting from activation of NADPH oxidase, which contributes to brain injuries. Therefore, we hypothesized that there might be greater generation of reactive oxygen species (ROS) in brain with IVH than controls and that suppression of NADPH oxidase might attenuate free radical formation. We tested our hypotheses in a rabbit pup model. We delivered pups prematurely and induced IVH by producing intracranial hypotension with IP glycerol at 2h age. We measured production of O2. ‐ and H2O2 in the periventricular and the cerebral cortical area at 6h postnatal age. To determine the source of free radical generation, we used inhibitors for NADPH oxidase (apocynin), xanthine oxidase, COX‐2 or NO synthase. We found that O2. ‐ and H2O2 generation were significantly greater in both the periventricular area and cortex of pups with IVH than controls (P<0.05). Only apocynin inhibited ROS generation in both brain areas (P<0.05). Our data suggest that free radicals are generated more in the periventricular area than in the cortical mantle in IVH and that the activation of NAPDH oxidase is the predominant mechanism of oxidative stress. Suppression of ROS production by NADPH oxidase inhibitor might reduce brain injuries in premature infants.

Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants

Our objective was to test the hypothesis that prenatal maternal corticosteroids would improve the subsequent response of infants to surfactant treatments. We used the data bases of two recently published large multicenter trials of multidose surfactant treatments to retrospectively evaluate the possible interactions between maternal corticosteroids and randomized surfactant treatments on short-term ventilatory effects, complications of respiratory distress syndrome and prematurity, and 28-day death rates. The combined use of corticosteroids and surfactant significantly decreased overall death and death caused by respiratory distress syndrome relative to either treatment alone. Ventilatory variables at 72 hours were improved in those infants receiving both treatments, and other major complications of prematurity also tended to have decreased incidences. The combined use of prenatal corticosteroids, when indicated, and postnatal surfactant improves neonatal outcome.