Cerebral Palsy In Preterm Infants Research Articles

Heart rate patterns predicting cerebral palsy in preterm infants.

Heart rate (HR) patterns can inform on central nervous system dysfunction. We previously used highly comparative time series analysis (HCTSA) to identify HR patterns predicting mortality among patients in the neonatal intensive care unit (NICU) and now use this methodology to discover patterns predicting cerebral palsy (CP) in preterm infants. We studied NICU patients <37 weeks' gestation with archived every-2-s HR data throughout the NICU stay and with or without later diagnosis of CP (n = 57 CP and 1119 no CP). We performed HCTSA of >2000 HR metrics and identified 24 metrics analyzed on HR data from two 7-day periods: week 1 and 37 weeks' postmenstrual age (week 1, week 37). Multivariate modeling was used to optimize a parsimonious prediction model. Week 1 HR metrics with maximum AUC for CP prediction reflected low variability, including "RobustSD" (AUC 0.826; 0.772-0.870). At week 37, high values of a novel HR metric, "LongSD3," the cubed value of the difference in HR values 100 s apart, were added to week 1 HR metrics for CP prediction. A combined birthweight + early and late HR model had AUC 0.853 (0.805-0.892). Using HCTSA, we discovered novel HR metrics and created a parsimonious model for CP prediction in preterm NICU patients. We discovered new heart rate characteristics predicting CP in preterm infants. Using every-2-s HR from two 7-day periods and highly comparative time series analysis, we found a measure of low variability HR week 1 after birth and a pattern of recurrent acceleration in HR at term corrected age that predicted CP. Combined clinical and early and late HR features had AUC 0.853 for CP prediction.

Does Antenatal MgSO 4 Administration to the Mother in the Event of Imminent Premature Birth Reduce the Occurrence of Infantile Cerebral Palsy in the Child? - An Umbrella Review.

Introduction Premature births have a significantly increased risk of developing cerebral palsy. This clinical picture involves great restrictions and impairments in the lives of the children and their families. Its prevention is therefore of great importance. One method of neuroprotection to reduce the rate of infantile cerebral palsy is the antenatal administration of magnesium sulfate to the mother. The aim of this paper is to present the current state of research of existing reviews and meta-analyses on the topic and to review the evidence for this intervention. Material and Methods A literature search was conducted within the framework of an umbrella review in the electronic database PubMed in February 2022 to identify all relevant publications on the topic. The search was structured using the PRISMA statement. The important methodological characteristics and the results of the studies were then extracted. In addition, a quality assessment of the studies was performed using the AMSTAR score. Results Two systematic reviews with meta-analysis, one systematic review, and one individual participant data meta-analysis were included in this study. The total number of subjects was n=6178. The publications conclude that the antenatal administration of magnesium sulfate to the mother significantly reduces the risk of cerebral palsy in preterm infants. Due to the high quality of 3 of the 4 studies, a high level of evidence can be assumed. Conclusion The evidence for antenatal magnesium sulfate administration for the prophylaxis of cerebral palsy in preterm infants is high. However, further research is needed to determine which doses of magnesium and up to which gestational age the administration is useful.

Association of Cystic Periventricular Leukomalacia and Postnatal Epilepsy in Very Preterm Infants

Introduction: Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics. Methods: This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5. Results: A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8–38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age. Discussion/Conclusion: Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.

The association of γδT lymphocytes with cystic leukomalacia in premature infants.

Periventricular leukomalacia (PVL) is an essential cause of cerebral palsy in preterm infants, and cystic PVL (cPVL) is the most severe form of the disease. The pathogenesis of cPVL is complex, and immune imbalances and inflammatory responses may play an essential role in it. This study aimed to investigate the correlation between peripheral blood lymphocyte subsets, especially γδT cells with the pathogenesis of cPVL in preterm infants. Peripheral blood from preterm infants with GA < 32 weeks and BW < 1,500 g was used in this study and was collected at 34 weeks corrected gestational age and within 24 h after the diagnosis with cranial MRI or cranial ultrasound. The infants were divided into cPVL groups and control groups. Flow cytometry was used to detect peripheral blood γδT, CD3+, CD4+, CD8+, and the proportion of total lymphocytes. Multiplex cell assays were used to detect the concentration of extracellular serum cytokines IL-6, IL-2, IL-8, IL-17A, IL-10, IL-1RA, eotaxin (CCL11), MCP-1 (CCL2), CXCL1, G-CSF, and IFNγ. A follow-up visit was carried out when the patient was 3 years old. After correcting for confounding factors, the proportion of peripheral blood γδT in the cPVL group was significantly lower than that in the control group (β: 0.216; 95% CI: 0.058-0.800, P < 0.022). Peripheral blood γδT (AUC: 0.722, P=0.006) and multivariate binary regression model (AUC: 0.865, P < 0.000) have good diagnostic values for cPVL. Peripheral blood γδT has some predictive power for neurodevelopmental outcomes in preterm infants (AUC: 0.743, P = 0.002). It seems that peripheral blood γδT cells are inversely correlated with cPVL, which is not only a risk factor for cPVL disease but also neurodevelopmental outcomes in preterm infants. However, the causality of cPVL and various lymphocytes is unclear and needs further study.

Fetal heart rate evolution and brain imaging findings in preterm infants with severe cerebral palsy

Cerebral palsy is more common among preterm infants than among full-term infants. Although there is still no clear evidence that fetal heart rate monitoring effectively reduces cerebral palsy incidence, it is helpful to estimate the timing of brain injury leading to cerebral palsy and the causal relationship with delivery based on the fetal heart rate evolution patterns. Understanding the relationship between the timing and the type of brain injury can help to identify preventive measures in obstetrical care. This study aimed to examine the relationship between the timing of insults and the type of brain injury in preterm infants with severe cerebral palsy. This longitudinal study was based on a nationwide database for cerebral palsy. The data of infants with severe cerebral palsy (equivalent to levels 3-5 of the Gross Motor Function Classification System-Expanded and Revised), born between 2009 and 2014 at 28 to 33 weeks of gestation, were included. The intrapartum fetal heart rate evolution patterns were evaluated by 3 obstetricians blinded to clinical information other than gestational age at birth, and these were categorized after agreement by at least 2 of the 3 reviewers into (1) continuous bradycardia, (2) persistently nonreassuring (prenatal onset), (3) reassuring-prolonged deceleration, (4) Hon's pattern (intrapartum onset), (5) persistently reassuring (pre- or postnatal onset), and (6) unclassified. Infant brain magnetic resonance imaging findings at term-equivalent age were assessed by a pediatric neurologist blinded to the background details, except for gestational age at birth and corrected age at image acquisition, and these were categorized as (1) basal ganglia-thalamus, (2) white matter, (3) watershed cortex or subcortex, (4) stroke, (5) normal, and (6) unclassified based on the predominant site involved. The risk factors for the basal ganglia-thalamus group were compared with those of the combined white matter and watershed injuries group. Among 1593 infants with severe cerebral palsy, 231 were born at 28 to 33 weeks of gestation, and 140 met the eligibility criteria. Fetal heart rate evolution patterns were categorized as bradycardia (17% [24]); persistently nonreassuring (40% [56]); reassuring-prolonged deceleration (7% [10]); reassuring-Hon (6% [8]); persistently reassuring (7% [10]); and unclassified (23% [32]). Cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in 13% of infants. Magnetic resonance imaging showed that 34% (n=48) of infants developed basal ganglia-thalamus-dominant brain injury. Of the remaining 92 infants, 43% (60) showed white matter injuries, 1% (1) showed watershed injuries, 4% (5) showed stroke, 1% (1) had normal findings, and 18% (25) had unclassified findings. Infants with continuous bradycardia (adjusted odds ratio, 1033.06; 95% confidence interval, 15.49-68,879.92) and persistently nonreassuring fetal heart rate patterns (61.20; 2.09-1793.12) had a significantly increased risk for basal ganglia-thalamus injury. Severe cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in only 13% of infants born at 28 to 33 weeks of gestation. Although the white matter-watershed injury was predominant in the study populations, severe acute hypoxia-ischemia may be an important prenatal etiology of severe cerebral palsy in preterm infants.

Validation of eligibility criteria for the Japan Obstetric Compensation System for Cerebral Palsy in preterm infants: A case-control cohort study.

To verify validity of the criteria used for the Japan Obstetric Compensation System for Cerebral Palsy (JOCS-CP) in preterm infants, the association between the criteria and the development of CP was studied using a neonatal database. Our hypothesis was that the criteria would not be sufficient due to the recent advances made in perinatal care. Preterm infants born between 2003 and 2019 and registered in the Neonatal Research Network of Japan database with a birth weight of 1500 g or less or a gestational age of less than 32 weeks were analyzed. The database included the clinical information of registered infants during their stay in NICUs and outcomes at 3 years of age. The database included 73 615 infants. After excluding those with an unknown outcome at discharge, 73 464 infants were analyzed for short-term outcomes, including mortality and morbidities. The incidence of CP at 3 years of age was analyzed in 36 151 infants. Furthermore, 16 467 infants born between 28 and 31 weeks of gestation were examined in terms of the validity of the current eligibility criteria. The mortality and incidences of severe intraventricular hemorrhage and periventricular leukomalacia significantly decreased during the study period (Cochrane-Armitage test, p < 0.01). Furthermore, the eligibility criteria were not sufficiently nor strongly associated with indicators for detecting perinatal hypoxia-ischemia resulting in CP. The existing eligibility criteria of the JOCS-CP used for preterm infants born between 28 and 31 weeks were no longer suitable because of the advances in perinatal care in Japan.

Tumour necrosis factor blockade after asphyxia in foetal sheep ameliorates cystic white matter injury.

Cystic white matter injury is highly associated with severe neurodevelopmental disability and cerebral palsy in preterm infants, yet its pathogenesis remains poorly understood and there is no established treatment. In the present study, we tested the hypothesis that slowly evolving cystic white matter injury after hypoxia-ischaemia is mediated by programmed necrosis initiated by tumour necrosis factor. Tumour necrosis factor blockade was begun 3 days after hypoxia-ischaemia to target the tertiary phase of injury, when most secondary cell death is thought to be complete. Chronically instrumented preterm foetal sheep (0.7 gestation) received 25 min of hypoxia-ischaemia induced by complete umbilical cord occlusion or sham-umbilical cord occlusion (controls, n = 10), followed by intracerebroventricular infusion of the soluble TNF inhibitor, Etanercept, at 3, 8 and 13 days after umbilical cord occlusion (n = 9) or vehicle (n = 9). Foetal brains were processed for histology at 21 days after umbilical cord occlusion. Umbilical cord occlusion with vehicle was associated with a spectrum of macroscopic white matter degeneration, including white matter atrophy, ventriculomegaly and overt temporal lobe cystic white matter injury. Oligodendrocyte maturational arrest and impaired labelling of myelin proteins, characteristic of diffuse white matter injury, was observed in the parietal lobe and surrounding the cystic lesions in the temporal lobe. Etanercept markedly attenuated cystic white matter injury on the side of the intracerebroventricular infusion, with partial contralateral protection. Further, Etanercept improved oligodendrocyte maturation and labelling of myelin proteins in the temporal and parietal lobes. The present study shows that cystic white matter injury reflects late-onset tertiary cell death mediated by delayed neuroinflammation through the tumour necrosis factor pathway. Delayed tumour necrosis factor blockade markedly attenuated cystic white matter injury and restored oligodendrocyte maturation and deficits in myelin protein expression. These data suggest that delayed tumour necrosis factor blockade may represent a viable therapeutic strategy to reduce the risk of cystic and diffuse white matter injury and potentially cerebral palsy after preterm birth, with a surprisingly wide therapeutic window.

Assessing the Utility of Neonatal Screening Assessments in Early Diagnosis of Cerebral Palsy in Preterm Infants.

Background: Early diagnosis of cerebral palsy (CP) in high-risk infants is possible at 3–4 months’ corrected age (CA) using standardised assessments. Aim: To assess the utility of neonatal screening assessments—writhing general movements (GMs) and the Hammersmith Neonatal Neurological Examination (HNNE)—to predict CP/high-risk status at 3–4 months’ CA in extremely preterm infants. Methods: Retrospective cohort study of high-risk preterm infants (born < 29 weeks’ gestation and/or birth weight < 1000 g) attending an Early Neurodevelopment Clinic. Data from neonatal assessments were compared with CP/high-risk diagnosis at 3–4 months’ CA, fidgety GMs, and Hammersmith Infant Neurological Examinations (HINE) using logistic regression, linear regression, and Spearman rank correlation. Results: Two hundred and two preterm infants (median gestation age at birth 27.3 (IQR 25.4–28.3) weeks, mean birth weight 870.3 (SD 248.4) grams) were included. A total of 26 (12.8%) infants received early CP/high-risk diagnoses at 3–4 months’ CA. A lower gestational age (GA) (OR = 0.78; p = 0.029, 95% CI [0.26, 0.97]) and abnormal writhing GMs (OR 1.56; p = 0.019, 95% CI [1.07, 2.27]) were predictive of CP/high-risk diagnosis. Although after adjustment for sex, GA, birth weight, and growth restriction, GA (aOR = 0.67; p = 0.068, 95% CI [0.44, 1.03]) and writhing GMs (aOR = 1.44; p = 0.087, 95% CI [0.95, 2.20]) were not significant, a strong trend still persisted. The HNNE scores significantly correlated with both the HINE evaluation (rs = 0.43, p < 0.001, 95% CI [0.31, 0.56]) and fidgety GMs (rs = −0.10, p = 0.012, 95% CI [−0.32, −0.04]). Linear regression confirmed the HNNE was highly predictive of the HINE (correlation coefficient 0.82; p < 0.001, 95% CI [0.48, 1.15]). Writhing GMs did not significantly correlate with either fidgety GMs (p = 0.723, 95% CI [−0.12, 0.17]) or the HINE (p = 0.173, 95% CI [−0.24, 0.04]). Conclusions: Abnormal writhing GMs in the neonatal period were non-significantly associated with early CP/high-risk diagnoses in extremely preterm infants in a multivariate analysis. Additionally, the HNNE significantly correlated with both fidgety GMs and the HINE.

Early detection relationship of cerebral palsy markers using brain structure and general movements in infants born

AimTo detect early brain structural and clinical functional markers of brain injury and development based on a magnetic resonance imaging (MRI) scoring system and a general movement assessment (GMA) for preterm infants later diagnosed with cerebral palsy (CP). Study designRetrospective cohort study. General movements (GMs) were scored according to a semiquantitative scoring system: the GMs optimality score (GMOS) at preterm and term ages and the Motor Optimality Score (MOS) at the corrected age of 3 months after birth. Brain magnetic resonance imaging (MRI) at term-equivalent age was scored using an MRI scoring system. We analyzed the relationship between the early degree of cerebral white matter (WM) abnormality and the GMOS and the MOS for infants born <32 weeks gestational age later diagnosed with CP in a comparison group of neurotypical controls. SubjectsSixteen preterm infants were included in this study who underwent MRI and GMs assessment. 8 out of the 16 preterm infants were later diagnosed with CP, while the other 8 infants with normal motor development (N) were placed into the control group. Their median gestational age was 30w6d and 27w6d for each group respectively. ResultsThe cerebral WM MRI scores were significantly higher in the CP group than in the control group (p < 0.01). The GMOS and MOS were significantly higher in the control group than in the CP group (p < 0.05). The MOS showed a strong correlation to the cerebral WM MRI score (r = -0.88) and the subscale of cerebral WM items (the cystic degeneration and the focal signal abnormalities) of the MRI score (r = -0.94) in the CP group. The MOS also showed a correlation with corrected biparietal diameter (cBPD) in the preterm infant group with CP (r = 0.75). Results of linear regression analyses between term MRI and GMs measures in preterm infants with CP are presented. Cerebral WM scores were associated with the MOS (β = −0.63; 95%CI = −0.97, −0.29; p < 0.01). Cerebral WM injury, including the subscale of cystic degeneration and focal signal abnormalities was closely associated with the MOS (β = −0.83; 95%CI = −1.13, −0.54; p < 0.001). ConclusionCerebral WM scores show a strong association with a decreased motor performance on the MOS in preterm infants later diagnosed with CP. Severe white matter injury and significantly decreased MOS scores may provide useful early markers and strong evidence to early predict the risk of later development of cerebral palsy in preterm infants.

Apgar Score and Risk of Cerebral Palsy in Preterm Infants: A Population-Based Cohort Study.

A low Apgar score is associated with increased risk of cerebral palsy (CP) in term infants, while such association remains controversial in preterm neonates. The objective of this study was to assess association between 5-minute Apgar scores and CP in different subcategories of preterm birth based on gestational age. The Slovenian National Perinatal Information System was used to identify singleton children without congenital malformations live-born at 22 to 37 weeks of gestation between 2002 and 2010. Data were linked to the Slovenian Registry of Cerebral Palsy in children born between 2002 and 2010. CP was diagnosed at a minimum of 5 years of age. Of 11,924 children included, 241 (2.0%) died before discharge and 153 (1.3%) were diagnosed with CP. Five-minute Apgar scores <7 were significantly associated with higher risk of death or CP (compared with scores ≥9) at all preterm gestations. CP alone was associated with Apgar scores <7 only at moderately or late preterm gestation (32-36 weeks) (adjusted relative risk [aRR]: 8.27; 95% confidence interval [CI]: 1.87-36.64 for scores 0-4 and aRR: 4.96; 95% CI 1.89-13.06 for scores 5-6). In conclusion, a low 5-minute Apgar score was associated with combined outcome of neonatal death or CP in all preterm births, while in surviving preterm infants at >32 weeks a low 5-minute Apgar score was associated with CP.

Tertiary cystic white matter injury as a potential phenomenon after hypoxia-ischaemia in preterm f sheep

White matter injury, including both diffuse and cystic elements, remains highly associated with neurodevelopmental disability and cerebral palsy in preterm infants, yet its pathogenesis and evolution are still poorly understood and there is no established treatment. We examined the long-term evolution of white matter injury in chronically instrumented preterm fetal sheep (0.7 gestation) after 25 min of complete umbilical cord occlusion or sham occlusion. Fetal brains were processed for histology after 3 days (n = 9, sham n = 9), 7 days (n = 8, sham n = 8), 14 days (n = 9, sham n = 8) and 21 days (n = 9, sham n = 9) of recovery. At 3 and 7 days recovery, umbilical cord occlusion was associated with diffuse white matter injury, with loss of total and mature oligodendrocytes and reduced myelination in both the parietal and temporal lobes. At 14 days after umbilical cord occlusion, extensive microglial and astrocytic activation were observed in the temporal lobe. At 21 days recovery a spectrum of severe white matter degeneration was observed, including white matter atrophy, ventriculomegaly and overt cystic white matter lesions. The most severe injury was observed in the temporal lobe after 21 days recovery, including the majority of cystic lesions, persistent oligodendrocyte maturational arrest and impaired myelination. The spatial distribution of delayed white matter degeneration at 21 days recovery was closely related to the location of dense microglial aggregates at earlier time-points, implicating a role for exuberant inflammation originating from microglial aggregates in the pathogenesis of cystic white matter injury. The delayed appearance of cystic injury is consistent with continuing tertiary evolution of necrotic cell death. This slow evolution raises the tantalizing possibility that there may a relatively long therapeutic window to mitigate the development of cystic white matter injury. Delayed anti-inflammatory treatments may therefore represent a promising strategy to reduce neurodevelopmental disability in the preterm infants.

Assessment of risk factors for cystic periventricular leukomalacia.

Periventricular leukomalacia (PVL) is an important cause of cerebral palsy in premature infants, and cystic PVL is the most serious form of the disease. The risk factors for cystic PVL in singleton fetuses at a gestational age of <35 weeks are unclear. This study included 2013 singleton birth infants delivered at a gestational age of <35 weeks in Kagoshima City Hospital between 2006 and 2017. The findings for 30 infants with cystic PVL were compared with those for 63 matched control infants by gestational age and birth weight. The cystic PVL was associated with increased incidence of recurrent late deceleration (L/D) (43.4% vs. 15.9%, P = 0.004) and loss of variability (LOV) (10.0% vs. 0.0%, P = 0.03) in fetal heart rate monitoring and late-onset circulatory dysfunction (LCD) (33.3% vs. 11.1%, P = 0.02). Logistic regression analysis revealed that recurrent L/D (odds ratio [OR] = 3.57, 95% confidence interval [CI]: 1.29-10.15, P = 0.01) and LCD (OR = 3.41, 95% CI: 1.09-11.04, P = 0.03) were risk factors associated with cystic PVL. LOV was not included in the multivariate analysis as there were too few cases in both the cystic PVL and control groups. Recurrent L/D, LOV and LCD are strongly associated with cystic PVL. In cases of fetal acidosis related to recurrent L/D or loss of variability, cystic PVL may occur.

Prenatal Tobacco Exposure and Childhood Neurodevelopment among Infants Born Prematurely.

Nicotine is an established neuroteratogen, and prenatal tobacco exposure alters the structure of the developing nervous system. An association between prenatal tobacco exposure and impaired neurologic function is less well established. We examine the association between prenatal tobacco exposure and childhood neurodevelopment among infants born preterm. Secondary analysis of a multicenter randomized controlled trial assessing the benefits of magnesium sulfate for the prevention of cerebral palsy in preterm infants. Women were included if they delivered a singleton and nonanomalous infant before 37 weeks. Exposure was any self-reported prenatal tobacco use. Primary outcome was the original trial composite outcome of moderate or severe cerebral palsy at 2 years of age, or stillbirth, or infant death by 1 year of age. Secondary outcomes included components of the composite and mild cerebral palsy at 2 years, Bayley Scales of Infant Development II motor and mental scores, death before two years, and use of auditory aids or corrective lenses. Multivariable logistic regression models were performed to estimate adjusted odds ratios (aOR) with 95% confidence intervals. Of 1,826 women included, 503 (27.5%) used tobacco. Tobacco users were more likely to be older, unmarried, and white; have a prior preterm birth; have received no prenatal care; and to use illicit drugs or alcohol. Gestational age at delivery, betamethasone exposure, and magnesium exposure were not different between groups. There were no differences in the composite primary outcome or in rates of cerebral palsy by tobacco use. Moderate developmental delay was more common among tobacco exposed in bivariate but not adjusted analysis (20.5 vs. 15.9%, p = 0.035). In adjusted analysis, tobacco exposure was associated with increased use of corrective lenses (5.0 vs. 2.9%, aOR: 2.28, 95% confidence interval: 1.28-4.07). Prenatal tobacco exposure is not associated with neurodevelopmental impairment in infants born preterm. However, tobacco exposure may be associated with impaired vision. · Tobacco exposure is not associated with impaired neurodevelopment in this preterm population.. · Prenatal tobacco exposure is associated with increased need for corrective lenses.. · Tobacco use in pregnancy may be a risk factor for poorer visual acuity in children..

Cerebral palsy after very preterm birth - an imaging perspective

Neonatal brain imaging undoubtedly can provide the most accurate information from which to determine whether cerebral palsy is likely to affect an individual infant born preterm. The sensitivity and specificity of that information is different between cranial ultrasound and MRI, depending on what approaches and sequences are used and the timing of the examinations. In this chapter we highlight the changing incidence of different patterns of brain injury in the preterm newborn and present a comparison of cranial ultrasound and MRI for predicting cerebral palsy in preterm infants affected by the commoner intracranial pathologies.

610: Effect of general anesthesia at time of cesarean delivery on perinatal outcomes and childhood neurodevelopment

In 2016, the FDA expressed concern that general anesthesia or sedation exposure in pregnancy or before 3 years of age may impact pediatric neurodevelopment and called for further research examining the impact of anesthesia, including single, short exposures. We examine the impact of general anesthesia (GA) during cesarean delivery (CD) on neurodevelopment at two years of age among infants born preterm. Secondary analysis of a multicenter RCT assessing magnesium for prevention of cerebral palsy in preterm infants. Women were included if they delivered a singleton, non-anomalous infant < 37wks by CD. The exposure of interest was general anesthesia. The primary outcome was mild to moderate developmental delay at 24 mos by Bayley Scales of Infant Development II (BSID). Secondary outcomes were BSID subdomains, periventricular leukomalacia, seizures, abnormal tone, hypotension, ventilator need, duration of oxygen use, and use of visual aids. Chi square, Fisher Exact, student’s t-test, Wilcoxon Rank Sum tests, and multivariable logistic regression models were performed. Of 557 women, 119 (21%) received GA. Women receiving GA were more likely to be unmarried, non-white, delivering more preterm (28.6 vs 29.7 wks, p< 0.01), undergoing CD for fetal distress (49% vs 36%, p=0.01), and in preterm labor >4cm (11% vs 3%, p< 0.01). Betamethasone and magnesium exposure were similar between groups, as was substance use. Mild to moderate developmental delay was not increased in those exposed to GA (Table). When BSID subdomains were analyzed individually, nominal increases in mild and moderate mental delay among infants exposed to GA did not persist after controlling for significant variables, including gestational age at delivery. Secondary outcomes did not differ significantly between groups. General anesthesia at time of CD does not appear to increase the risk of neurodevelopmental delay at two years in infants born preterm. Future studies should evaluate the impact of longer or multiple anesthetic exposures on neurodevelopment among all infants.

Genome-Wide Alteration of 5-Hydroxymethylcytosine in Hypoxic-Ischemic Neonatal Rat Model of Cerebral Palsy.

Cerebral palsy (CP) is a neurodevelopmental disorder usually occurring early in life and persisting through the whole life. Several risk factors, including perinatal hypoxia-ischemia (HI), may contribute to occurrence of CP in preterm infants. DNA hydroxymethylation has been shown to play an important role in neurodevelopment and neurodegenerative disorders. However, the effect of DNA hydroxymethylation in CP remains unknown. The aim of this study is to explore whether and how DNA hydroxymethylation is involved in CP pathogenesis. We observed that overall 5-hydroxymethylcytosine (5hmC) abundance in the cortex of the temporal lobe of rat pups was decreased significantly after hypoxic-ischemic injury, and the reduced expression of Tet1 and Tet2 enzymes might be responsible for this change. Identified differential hydroxymethylation regions (DhMRs) were richly involved in multiple signaling pathways related to neuronal development and function. Furthermore, we found that reduced 5hmC modification on the DhMRs-related genes were accompanied by decrease of their mRNA expression levels. These results suggest that 5hmC modifications are involved in the CP pathogenesis and may potentially serve as a new therapeutic target.

The prevention of cerebral palsy in preterm infants – the potential role of magnesium sulfate

The prevention of cerebral palsy in preterm infants – the potential role of magnesium sulfate

Modulation of Microglial Activation by Adenosine A2a Receptor in Animal Models of Perinatal Brain Injury.

Neuroinflammation has a key role in the pathogenesis of perinatal brain injury. Caffeine, a nonspecific antagonist of adenosine receptors (ARs), is widely used to treat apnea of prematurity and has been linked to a decrease in the incidence of cerebral palsy in premature infants. The mechanisms explaining its neuroprotective effect have not yet been elucidated. The objective of this study was to characterize the expression of adenosine and ARs in two neonatal rat models of neuroinflammation and to determine the effect of A2aR blockade on microglial activation assessed through inflammatory cytokine gene expression. We have used two rat models of microglial activation: the gestational low protein diet (LPD) model, associated with chronic brain injury, and postnatal ibotenate intracerebral injections, responsible for acute excitotoxicity injury. Adenosine blood levels have been measured by Tandem Mass Spectrometry. The expression of ARs in vivo was assessed using qPCR and immunohistochemistry. In vivo models have been replicated in vitro on primary microglial cell cultures exposed to A2aR agonist CGS-21680 or antagonist SCH-58261. The effects of these treatments have been assessed on the M1/M2 cytokine expressions measured by RT-qPCR. LPD during pregnancy was associated with higher adenosine levels in pups at postnatal day 1 and 4. A2aR mRNA expression was significantly increased in both cortex and magnetically sorted microglial cells from LPD animals compared to controls. CD73 expression, responsible for extracellular production of brain adenosine, was significantly increased in LPD cortex and sorted microglia cells. Moreover, CD73 protein level was increased in ibotenate treated animals. In vitro experiments confirmed that LPD or control microglial cells exposed to ibotenate display an increased expression, at both protein and molecular levels, of A2aR and M1 markers (IL-1β, IL-6, iNOS, TNFα). This pro-inflammatory profile was significantly reduced by SCH-58261, which reduces M1 markers in both LPD and ibotenate-exposed cells, with no effect on control cells. In the same experimental conditions, a partial increased of M1 cytokines was observed in response to A2aR agonist CGS-21680. These results support the involvement of adenosine and particularly of its receptor A2aR in the regulation of microglia in two different animal models of neuroinflammation.

Time- and sex-dependent efficacy of magnesium sulfate to prevent behavioral impairments and cerebral damage in a mouse model of cerebral palsy

Cerebral lesions acquired in the perinatal period can induce cerebral palsy (CP), a multifactorial pathology leading to lifelong motor and cognitive deficits. Several risk factors, including perinatal hypoxia-ischemia (HI), can contribute to the emergence of CP in preterm infants. Currently, there is no international consensus on treatment strategies to reduce the risk of developing CP. A meta-analysis showed that magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery reduces the risk of developing CP (Crowther et al., 2017). However, only a few studies have investigated the long-term effects of MgSO4 and it is not known whether sex would influence MgSO4 efficacy. In addition, the search for potential deleterious effects is essential to enable broad use of MgSO4 in maternity wards. We used a mouse model of perinatal HI to study MgSO4 effects until adolescence, focusing on cognitive and motor functions, and on some apoptosis and inflammation markers. Perinatal HI at postnatal day 5 (P(5)) induced (1) sensorimotor deficits in pups; (2) increase in caspase-3 activity 24 h after injury; (3) production of proinflammatory cytokines from 6 h to 5 days after injury; (4) behavioral and histological alterations in adolescent mice with considerable interindividual variability. MgSO4 prevented sensorimotor alterations in pups, with the same efficacy in males and females. MgSO4 displayed anti-apoptotic and anti-inflammatory effects without deleterious side effects. Perinatal HI led to motor coordination impairments in female adolescent mice and cognitive deficits in both sexes. MgSO4 tended to prevent these motor and cognitive deficits only in females, while it prevented global brain tissue damage in both sexes. Moreover, interindividual and intersexual differences appeared regarding the lesion size and neuroprotection by MgSO4 in a region-specific manner. These differences, the partial prevention of disorders, as well as the mismatch between histological and behavioral observations mimic clinical observations. This underlines that this perinatal HI model is suitable to further analyze the mechanisms of sex-dependent perinatal lesion susceptibility and MgSO4 efficacy.

Cost Analysis of Azithromycin versus Erythromycin in Pregnancies Complicated by Preterm Premature Rupture of Membranes.

To quantify the potential cost savings if azithromycin is substituted for erythromycin in women with preterm premature rupture of membranes (PPROM). Secondary analysis of a multicentered study investigating magnesium sulfate for the prevention of cerebral palsy in premature infants. All patients with PPROM who received antibiotics for prophylaxis were included in the analysis. The number of expected doses each patient would have received was calculated for erythromycin, multidose azithromycin, and single-dose azithromycin regimens accounting for latency from PPROM to delivery. The wholesale acquisition cost was used to calculate the expected cost of each regimen. There were 981 PPROM patients who received a penicillin class antibiotic and erythromycin. Patients would have received 7,528 intravenous doses and 10,194 oral doses of erythromycin at a combined cost of $357,169. In comparison, patients would have received 6,422 and 3,942 doses at a cost of $15,669 and $9,574 for the multidose and single-dose azithromycin regimens respectively, which represents a more than 95% cost reduction for either regimen compared with erythromycin. The use of azithromycin substituted for erythromycin in the standard antibiotic regimen of women with PPROM represents a potential for substantial cost reduction.