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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.

Diagnosis of fetal heart failure depends primarily on fetal ultrasonography assessment. Our recent study demonstrated that plasma natriuretic peptide levels in umbilical cord blood were correlated with the severity of heart failure in fetuses with congenital heart defects or arrhythmias. However, percutaneous umbilical blood sampling is an invasive procedure, and therefore, less or noninvasive biomarkers reflecting fetal heart failure are required.The aim of this study was to investigate the possibility of whether maternal serum biomarkers can diagnose fetal heart failure in fetuses with congenital heart defects or arrhythmias.This exploratory cross-sectional study was conducted at a tertiary pediatric cardiac center. A total of 50 singletons with fetal congenital heart defects or arrhythmias and 50 controls who were registered in the National Cerebral and Cardiovascular Center Biobank from 2013 to 2016 were included. Maternal serum samples obtained during the third trimester were analyzed for 2 hormones and 36 cytokines using the Bio-Plex Pro Human Cancer Biomarker panels 1 and 2. We comprehensively analyzed the association between maternal serum biomarkers and ultrasonography findings or fetal arrhythmia status. Fetal heart failure was defined as a cardiovascular profile score ≤7.Of 37 fetuses with congenital heart defects, heart failure was found in 1 case of tricuspid valve dysplasia with moderate tricuspid regurgitation. Of 13 fetuses with arrhythmias, 5 had heart failure at 28-33 weeks of gestation. Maternal serum cytokine and hormone concentrations were compared between patients with and without fetal heart failure at 28-33 weeks of gestation (n = 6 and n = 61, respectively). Sixty-one fetuses without heart failure consisted of 10 with congenital heart defect, 6 with arrhythmia, and 45 controls. Maternal serum concentrations of tumor necrosis factor-α, interleukin-6, soluble Fas ligand, transforming growth factor-α, and vascular endothelial growth factor-D were significantly higher when fetuses had heart failure than when they did not (P.05), whereas maternal serum concentrations of heparin-binding epidermal growth factor-like growth factor were significantly lower when fetuses had heart failure than when they did not (P.05). Multivariate analysis showed that maternal serum concentrations of tumor necrosis factor-α, vascular endothelial growth factor-D, and heparin-binding epidermal growth factor-like growth factor were independently associated with fetal heart failure. The cutoff values were as follows: tumor necrosis factor-α, 68 pg/mL (sensitivity of 50.0%, specificity of 93.4%, positive likelihood ratio of 7.6, negative likelihood ratio of 0.5); vascular endothelial growth factor-D, 1156 pg/mL (sensitivity of 50.0%, specificity of 93.4%, positive likelihood ratio of 7.6, negative likelihood ratio of 0.5); and heparin-binding epidermal growth factor-like growth factor, 90 pg/mL (sensitivity of 83.3%, specificity of 83.6%, positive likelihood ratio of 5.1, negative likelihood ratio of 0.2). The combination of these 3 cytokines showed sensitivity of 100%, specificity of 80.3%, positive likelihood ratio of 5.1, and negative likelihood ratio of 0. In the absence of fetal heart failure, concentrations of all maternal serum cytokines and hormones were similar in cases of fetal congenital heart defects and controls, while maternal serum soluble CD40 ligand concentrations were increased only in fetal arrhythmias.Maternal serum concentrations of tumor necrosis factor-α, vascular endothelial growth factor-D, and heparin-binding epidermal growth factor-like growth factor were associated with fetal heart failure.

The purpose of this study was to elucidate a role for edaravone, a free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one, in neonatal hypoxic-ischemic brain damage. We determined the level of thiobarbituric acid reactive substances as an index of lipid peroxidation and nitric oxide metabolites as nitric oxide production.Seven-day-old Wistar rats were subjected to left common carotid artery ligation followed by 2 hours of 8% oxygen exposure. Then, the rats were administered edaravone (9 mg/kg) or saline solution intraperitoneally. Cerebrospinal fluid was withdrawn just before the rats were killed at 2, 5, 24, and 48 hours after hypoxia, and brains were removed. The thiobarbituric acid reactive substances and nitric oxide metabolites levels were measured in the brain tissue and cerebrospinal fluid, respectively.On the ligated side, edaravone significantly decreased thiobarbituric acid reactive substances levels at 5 and 24 hours after hypoxia, compared with saline group (P.01). Edaravone significantly decreased the nitric oxide metabolites level in the cerebrospinal fluid only at 5 hours, compared with saline group (P.01).Edaravone potently and transiently inhibited lipid peroxidation and the production of nitric oxide in the neonatal rat brain after hypoxic-ischemic insult.

Objective We examined whether progenitor neural stem cells can differentiate successfully into mature neurons and astrocytes in a rat model of neonatal hypoxic-ischemic encephalopathy. Study design Seven-day-old Wistar rats were subjected to hypoxic-ischemic stress. At days 5 to 7 after hypoxic-ischemic stress, 5-bromodeoxyuridine (an early marker of cell proliferation) was injected, and the brains were retrieved at 14, 28, and 42 days after hypoxic-ischemic stress. Immunohistochemical and immunofluorescent studies were carried out for 5-bromodeoxyuridine, neuronal nuclear antigen (a marker protein of matured neuron), and glial fibrillary acidic protein (a protein marker of mature astrocytes). Results Only 1% of neuronal nuclear antigen–positive and 4.6% of glial fibrillary acidic protein–positive cells could be detected among the 5-bromodeoxyuridine-immunopositive cells in the peri-infarcted area of the cortex and the striatum, respectively, at 14 days after hypoxic-ischemic stress. There were no such double-staining cells at 28 and 42 days after hypoxic-ischemic stress. Conclusion The intrinsic ability for neurologic self-repair was limited at the maturation step after hypoxic-ischemic stress in the neonatal rat brain.

Objective There are no established therapies for preventing or rescuing perinatal infection or inflammation-induced perinatal brain damage. We administered dexamethasone (DEX), a synthetic corticosteroid anti-inflammatory drug, to neonatal rats in a model of such damage induced by a combination of lipopolysaccharide (LPS) and hypoxia-ischemia (HI), which produces characteristic histologic and behavioral abnormalities. Study design Four hours after the injection of LPS (1 mg/kg, i.p.), 7-day-old Wistar rat pups were subjected to unilateral HI for 1 hour according to Levine's procedure. Injections of 0.5 mg/kg of dexamethasone (DEX-treated group, n = 15) or saline (saline-treated group, n = 15) were given 4 hours before HI. A sham-operated control group received neither LPS nor HI (n = 15). We chose rats of this age because their stage of brain maturation is similar to the human neonate. Over the 7 to 16 weeks after treatment, a choice reaction time (CRT) task was used for assessment of attention processes in each group, an 8-arm radial maze task was used to test short-term memory, and a water maze task was used to test long-term memory. In the CRT task, the reward food was released when the tested animal correctly pressed a lever on the side of an illuminating lamp. The correct and incorrect lever pressings were counted. In the 8-arm radial maze task, rats were allowed to move freely, seeking a reward of food placed at the end of 1 arm. An error was defined as the choice of an arm that had already been visited. In the water maze, rats had to swim to seek a concealed platform as aversive escape motivation. At 19 weeks, the rats were euthanized, the brain was removed, sectioned coronally, and the volume of each part was measured. Results The striatum, cortex, and hippocampus showed reductions in volume in the saline-treated group (42.7%, 49.2%, and 34.9% decreases compared with the sham-operated controls, respectively), but this was not observed in the DEX-treated group. All learning and memory processes were impaired with the combination of LPS and HI treatment, but these deficits were almost completely prevented by DEX treatment. Conclusion Dexamethasone is a promising candidate for prevention of infection and inflammation-induced perinatal brain damage. The impact of dexamethasone identifies potential therapeutic pathways once the mechanism of dexamethasone's protection is determined.

Objective We assessed the long-term effects of perinatal hypoxia-ischemia and endotoxin on attention and short- and long-term memory in neonatal rats with the use of behavioral tasks and brain histologic results. Study design Four hours after injections of lipopolysaccharide (1 mg/kg, intraperitoneally) or saline solution, 7-day-old Wistar rat pups were subjected to unilateral hypoxia-ischemia for 1 hour. We studied 4 groups: controls (n = 43 rats), lipopolysaccharide alone (n = 12 rats), hypoxia-ischemia alone (n = 29 rats), and combined lipopolysaccharide + hypoxia-ischemia treatment (n = 34 rats). Seven to 16 weeks after the treatment, we measured attention with a choice reaction time task, short-term memory with an 8-arm radial maze task, and long-term memory with a water maze task. At 19 weeks of age, the brain was removed, fixed, and sectioned coronally; and the volume of each part was measured. Results A loss of volume in the hippocampus was observed in the lipopolysaccharide, hypoxia-ischemia, and lipopolysaccharide + hypoxia-ischemia groups; a loss of striatum was observed in the hypoxia-ischemia and lipopolysaccharide + hypoxia-ischemia groups, but loss of cortex was observed only in the lipopolysaccharide + hypoxia-ischemia group. The lipopolysaccharide, hypoxia-ischemia, and lipopolysaccharide + hypoxia-ischemia groups showed significantly poorer performance (attention deficit) than controls in the choice reaction time task. Correct choices decreased, and error increased in the lipopolysaccharide + hypoxia-ischemia group compared with the other groups in the radial maze task, which shows short-term memory impairment. Swimming distance was significantly greater in the hypoxia-ischemia and lipopolysaccharide + hypoxia-ischemia groups than in the other 2 groups in the water maze test, which shows long-term memory impairment. Conclusion Combined lipopolysaccharide and hypoxia-ischemia treatment synergistically induced short-term memory impairment that is associated with loss of cortical volume.

Several studies have shown that abnormal intrapartum fetal heart rate patterns are the results from pre-existing fetal brain damage. We evaluated intrapartum fetal heart rate pattern of cytomegalovirus-infected fetuses and correlated the patterns with neurologic outcomes.Between 1991 and 2001, there were 20 cytomegalovirus-infected fetuses. We selected 40 fetuses as control subjects that were matched for gestational age and birth weight. Fetal heart rate was interpreted according to the guidelines of the National Institute for Child and Human Development. The incidence of abnormal fetal heart rate pattern and umbilical blood gases were compared between both groups. We also investigated the factors that contributed to abnormal fetal heart rate pattern in the cytomegalovirus group.Nonreassuring fetal heart rate patterns (prolonged deceleration and recurrent late deceleration) were observed in 8 of 20 fetuses (prolonged deceleration, 7 fetuses; recurrent late deceleration, 1 fetus) in the cytomegalovirus group and in 3 of 41 fetuses (prolonged deceleration, 1 fetus; recurrent late deceleration, 2 fetuses) in the control group (P.05, Fisher test). Baseline fetal heart rate variability was minimal in 4 of the 7 prolonged deceleration cases in the cytomegalovirus group. Umbilical pH7.1 was found for 1 fetus in the cytomegalovirus group. The average umbilical arterial pH values were similar in both the groups. In the cytomegalovirus group, there were no differences in the incidence of contributing factors between 8 fetuses with abnormal fetal heart rate pattern (prolonged deceleration and recurrent late deceleration) and 8 fetuses with no change. There were 3 fetuses with cerebral palsy: 2 fetuses in the no change group and 1 fetus in the prolonged deceleration group. Antigenemia was positive exclusively in 4 cases with abnormal fetal heart rate pattern (P.05).Cytomegalovirus-infected fetuses are more likely to show abnormal intrapartum fetal heart rate patterns than low-risk control fetuses, which suggests that the perinatal detection of cytomegalovirus is necessary to distinguish hypoxic-ischemic encephalopathy.

Our purpose was to evaluate the clinical validity of electronic fetal heart rate monitoring to detect fetal acidemia and to evaluate the prevalence of cerebral palsy in unselected low-risk pregnancies.We selected two secondary and two tertiary level institutions in which 10,030 infants were born. Among them, 5546 of the pregnancies were low-risk pregnancies by antepartum evaluation. The fetal heart rate patterns were interpreted according to the guidelines of the National Institute of Child Health and Human Development. The correlations between the fetal heart rate pattern and umbilical blood gases and the fetal heart rate pattern and cerebral palsy were studied. Spastic cerebral palsy was diagnosed ator =1 year by pediatric neurologists. Statistics included unpaired t test, contingency table with chi(2) and Fisher tests, and one-way analysis of variance with Bonferroni/Dunn test.On the basis of the severity of decelerations, frequency of decelerations, and decreased variability, umbilical pH, and Po(2) level were decreased accordingly, and incidence of pH7.1 was increased. Sensitivity and false-positive rate of nonreassuring fetal heart rate patterns for fetal acidemia were 63% and 89%. There were nine cerebral palsy cases: six of the cases were preexisting asphyxia before monitoring was initiated, two of the cases were cytomegaloviral infections, and one of the cases was a maternal amniotic fluid embolism.In low-risk pregnancies, intrapartum fetal heart rate monitoring was useful to detect fetal acidemia. Cerebral palsy caused by intrapartum asphyxia was restricted to unavoidable accidents under continuous fetal heart rate monitoring.

Objective: This study was intended to investigate the temporal changes in heat shock protein 72 expression and microtubule-associated protein 2 disappearance in rat brain at 2 different ages after hypoxic-ischemic insult. Study Design: Both 5-day-old and 14-day-old Wistar rats were subjected to unilateral common carotid artery ligation and hypoxia in 8% oxygen for 2 hours at 33°C. Brain sections were examined sequentially for heat shock protein 72 expression at 0.5, 3, 6, 12, 24, 48, and 72 hours of recovery after hypoxia-ischemia and for microtubule-associated protein 2 disappearance at 0, 24, 48, and 72 hours of recovery and at 7 days of recovery after hypoxia-ischemia. Results of immunohistochemical staining for heat shock protein 72 and microtubule-associated protein 2 were used as markers for detection of early hypoxic-ischemic brain damage. Permanent neuronal damage was assessed with hematoxylin and eosin staining at 7 days after hypoxia. Results: In 5-day-old rats microtubule-associated protein 2 expression was lost as early as 0 hours after hypoxia-ischemia in the cerebral cortex and hippocampus, with a peak at 48 hours after which expression recovered. Expression of heat shock protein 72 was detected in the ligated hemisphere at 0.5 hours after hypoxia-ischemia and peaked at 6 to 24 hours of recovery. In 14-day-old rats microtubule-associated protein 2 was stained in the cortex at 0 hours after hypoxia-ischemia but gradually disappeared in the cerebral cortex and hippocampus after 24 hours of recovery. The expression of heat shock protein 72 was not detected by 6 hours of recovery in the cerebral cortex and by 3 to 12 hours of recovery in the hippocampus, but heat shock protein 72 was persistently expressed in the cortex and hippocampus after 48 hours of recovery. Neuronal damage was significantly less in 5-day-old rats than in 14-day-old rats. Conclusion: In 5-day-old rats hypoxia-ischemia causes earlier changes in heat shock protein 72 and microtubule-associated protein 2 immunostaining results and causes less severe brain damage than in 14-day-old rats. (Am J Obstet Gynecol 1999;180:1254-62.)

Objectives: The study analyzed the phase relationship between fetal heart rate and arterial blood pressure fluctuation during sinusoidal heart rate patterns in fetal lambs. Study Design: Thirty-two fetal lambs were placed on extracorporeal membrane oxygenation after cesarean delivery at ages ranging between 113 and 133 days' gestation. Sinusoidal heart rate patterns persisting for >10 minutes were analyzed. The relationships between the sinusoidal heart rate cycles and the arterial blood pressure cycles were quantitatively expressed in degrees by timing the zenith and the nadir of each and assigning a phase-angle index (with 0 [360] and 180 degrees being synchronized and reciprocal, respectively). Simultaneous blood samples were taken from the 4 different sites of the fetal circulation for blood gas and acid-base analysis when the sinusoidal heart rate pattern appeared. Regional cerebral blood flow was determined by means of the colored microsphere technique in 8 fetuses with sinusoidal patterns and 7 control fetuses. Results: Sinusoidal heart rate patterns were observed in 13 (40.6%) of the 32 fetal lambs. Two types of fetal heart rate and arterial blood pressure relationship could be recognized during sinusoidal pattern, the reciprocal type (n = 7) and the synchronized type (n = 9). A reciprocal type of sinusoidal pattern preceded a synchronized type pattern in 3 lambs that showed sinusoidal patterns at different stages of the experiment. The reciprocal type was associated with a higher baseline heart rate and amplitude of the sinusoidal heart rate pattern than was the synchronized type. The synchronized type was associated with a lower pH and base excess than was the reciprocal type. The cerebral blood flow in the medulla oblongata was significantly lower during the synchronized type pattern than during the reciprocal type pattern. Conclusion: There are 2 types of sinusoidal heart rate pattern. A synchronized type sinusoidal heart rate pattern may indicate more advanced fetal compromise than is associated with a reciprocal type pattern. (Am J Obstet Gynecol 1999;180:462-8.)

Objective: The aim of this study was to examine the production of 2 types of heat shock protein 70 in the organs of neonatal rats during an episode of mild hypoxic stress that was insufficient to produce histologic changes. Study Design: Seven-day-old rats were subjected to hypoxia (inspired gas of 8% oxygen and 92% nitrogen) at 33°C for 2 hours (n = 5), 3 hours (n = 5), and 4 hours (n = 5). Control rats (n = 5) inspired room air for 4 hours. The brains, hearts, and livers were removed after 4 hours of recovery. The levels of heat shock protein 70 and heat shock cognate protein 70 messenger ribonucleic acid were measured by Northern blot analysis. Arterial pH, Pao 2 , PACO 2 , and brain temperature were measured before, during, and at 4 hours of hypoxia in another 16 animals. Histologic examinations were carried out in these 16 animals 7 days after hypoxic stress. Results: PaO 2 , PACO 2 , and brain temperature decreased during the hypoxic stress and returned to prehypoxic values at recovery time. Arterial pH did not change. No histologic changes were observed in any areas of the brain. Heat shock cognate protein 70 messenger ribonucleic acid was normally expressed in the brain, heart, and liver and was further induced after hypoxia in the brain and the heart. There was, however, no additional increase of heat shock cognate protein 70 messenger ribonucleic acid in the liver. there were no increments of the stress-induced form of heat shock protein 70 messenger ribonucleic acid in these organs. Conclusion: Mild hypoxia selectively induced messenger ribonucleic acid of heat shock cognate protein 70, which may play an important role in protecting the brain and the heart against stress. (Am J Obstet Gynecol 1999;180:457-61.)

We previously showed that in asphyxiated fetal lambs the duration of hypotension correlated well with the severity of histologic damage to the brain, whereas the duration of bradycardia did not. This study compares fetal heart rate patterns with the degree of histologic damage to the brain.Twelve chronically instrumented near-term fetal lambs were subjected to asphyxia by umbilical cord occlusion until fetal arterial pH was6. 9 and base excess was-20 mEq/L. An additional 4 fetuses served as sham-asphyxia controls. Fetal heart rate (from electrocardiogram), arterial blood pressure, fetal breathing movements, and electrocorticogram were continuously monitored before, during, and for 72 hours after asphyxia. Fetal brain histologic features were categorized as mild (group 1, n = 5), moderate (group 2, n = 4), and severe (group 3, n = 3). Long-term fetal heart rate variability expressed as amplitude range was assessed visually every 5 minutes from 30 minutes before asphyxia until 2 hours of recovery and at 6, 12, 24, 48, and 72 hours of recovery.Long-term fetal heart rate variability amplitude decreased from 32 +/- 17 beats/min (mean +/- SEM) preocclusion to 4 +/- 13 beats/min at the end of occlusion (P.001) without significant differences among the 3 groups. During 10 to 45 minutes of recovery, the long-term variability of group 1 was significantly greater than that of groups 2 and 3. At 24 to 72 hours of recovery, the long-term variability of groups 1 and 2 was significantly higher than that of group 3, which was almost 0. The "checkmark" and sinusoidal fetal heart rate patterns were observed during the recovery period in groups 2 and 3.Decreased long-term fetal heart rate variability and the "checkmark" and sinusoidal fetal heart rate patterns were indicators of the severity of asphyxial histologic damage in the fetal brain.

Objective: Our purpose was to determine whether hypoxic-ischemic brain damage would be protected against by advance conditioning of the animal with 4 hours of hypoxic exposure. Study Design: Neonatal rats were exposed on postnatal day 7 to (1) 4 hours of hypoxia with 8% oxygen (preconditioning hypoxic group) or (2) 4 hours of normoxia (sham-preconditioning group). At 24 hours after the conditioning, rats from both groups were exposed to left carotid artery ligation followed by 2 hours of hypoxia (8% oxygen/92% nitrogen). All the rats were killed 1 week after hypoxia-ischemia, and their brains were extracted for histologic study. Results: Two types of brain damage were histologically observed at 1 week after hypoxia-ischemia in both groups: (1) generalized infarction in the ligated hemisphere and (2) predominant neuronal loss in the hippocampal region. The total incidence of brain damage was significantly decreased in the preconditioning hypoxic group (10/24 rats, 41.7%) compared with the sham-preconditioning hypoxic group (17/22 rats, 77.3%; P Conclusion: Our results show that the hypoxic-ischemic tolerance phenomenon may be induced in the hypoxic-ischemic brain damage model by conditioning the animal before the insult with 4 hours of hypoxic exposure. (Am J Obstet Gynecol 1998;179:1075-8.)

Our purpose was to characterize the histologic changes in the asphyxiated fetal lamb brain and to correlate the severity of these changes with fetal physiologic parameters during and after asphyxia.Seventeen near-term fetuses were used for analysis: control group without manipulation (n = 4, 132 +/- 1.1 days of gestation at autopsy, mean +/- SEM), sham-asphyxia control group (n = 3, 132 +/- 1.3 days), and asphyxiated group, which successfully survived 72 hours after asphyxia (n = 10, 130 +/- 1.0 days). Asphyxia was produced by umbilical cord occlusion lasting for approximately 60 minutes until fetal arterial pH diminished to6.9 and base excess to-20 mEq/L. Fetal heart rate, blood pressure, and electrocorticographic activity were continuously monitored. The fetuses were killed 72 hours after asphyxia, and the brains were fixed in formalin and processed for histologic and immunocytochemical studies.Neuropathologic changes varied from case to case, ranging from almost total infarction of cortical and subcortical structures to extremely subtle and patchy white matter alterations characterized by slight vacuolization of the white matter or slight to moderate increases in cellularity confined to the junction of cerebral cortex and white matter. Even fetuses that showed full recovery of all physiologic parameters, including electrocorticographic activity, demonstrated subtle but distinct white matter lesions. The gray matter, including the hippocampal neurons, was generally spared in these cases. Electrocorticographic parameters, duration of hypotension during asphyxia, and delayed recovery of blood lactate concentrations correlated well with the histologic grading of brain damage.Asphyxia by partial umbilical cord occlusion in near-term fetal lambs produces variable neuropathologic changes. The mildest change is a white matter lesion characterized by vacuolization and loss of myelin or by increased cellularity in the damaged regions.

The goal of the study was to examine risks in pregnancy in patients with Ebstein anomaly.Data were examined retrospectively for 13 patients (27 pregnancies, 21 live births) with Ebstein anomaly during pregnancy who were treated at our institution from 1985 to 2011. The associated anomalies in these patients were atrial septal defect (ASD) (n = 4) and the Wolff-Parkinson-White syndrome (n = 6).Before pregnancy, 2 patients underwent ASD closure and 1 received tricuspid valve replacement (TVR). In all patients, the cardiothoracic ratio increased from 55.1 at conception to 57.0 during pregnancy and 58.0 postpartum (P.05). Cesarean sections were performed in 3 cases: 1 with ventricular tachycardia and orthopnea (New York Heart Association [NYHA] III) preterm; at full term, and the third in a patient with a mechanical tricuspid valve who developed maternal cerebellum hemorrhage at 27 weeks. The baby died of prematurity in the third case. In all other cases (20 of 21), neonatal prognoses were good without congenital heart diseases. There were 6 spontaneous abortions. Recurrent paroxysmal supraventricular tachycardia occurred during pregnancy in 2 cases and was treated with adenosine triphosphate or verapamil. In 17 pregnancies, NYHA remained in class I and all had full-term vaginal delivery.Maternal and fetal outcomes are good in patients with Ebstein anomaly and NYHA class I. However, pregnancy in Ebstein anomaly can be complicated with tachyarrhythmia or cardiac failure. In post-TVR cases, meticulous care is required for these complications during pregnancy and delivery.

The purpose of this study was to assess the effect of early pregnancy on maternal regional cerebral blood flow.We studied 10 pregnant women at 7 to 19 weeks' gestation by the xenon 133 washout technique by means of single-photon emission computed tomography the day before the abortion was induced and then again at a mean of 42.8 days after the abortion.Blood flow in the cerebral hemispheres decreased after the abortion, with a decline of 8.1% (p0.001). Each regional decrease was as follows: 7.6% (p0.01) in the frontal lobe, 9.1% (p0.01) in the temporal lobe, 12.9% (p0.001) in the parietal lobe, 9.8% (p0.01) in the basal ganglia, and 16.7% (p0.001) in the cerebellum. There was no significant difference in blood flow in the occipital lobe before versus after the abortion.Maternal regional cerebral blood flow was increased in early pregnancy compared with the nonpregnant state, except in the occipital lobe.

OBJECTIVE: We evaluated the intrapartum fetal heart rate (FHR) patterns in fetuses with congenital heart disease (CHD). STUDY DESIGN: One hundred sixteen cases of fetal CHD were identified at our institute between 2000-2007; 464 fetuses without CHD were used as controls. The incidences of abnormal FHR patterns and umbilical blood gases were compared. RESULTS: More fetuses with CHD showed variant FHR than did control fetuses (46.6% vs 17.7%; P < .01). Cesarean section deliveries that were based on fetal indications were performed more frequently in fetuses with CHD than in control fetuses (12.9% vs 3.2%; P < .01). Isomerism and tetralogy of Fallot were observed frequently with variant FHR. When chromosomal abnormalities and intrauterine growth restriction were excluded, the fetuses with CHD showed more variant FHR than did the control fetuses. CONCLUSION: Fetuses with CHD are more likely to show abnormal FHR patterns than are control fetuses. We suggest that cardiac abnormalities are associated with abnormalities in FHR patterns.

Objective It has been reported that an infarcted area is reduced by the injection of glial cell line–derived neurotrophic factor into brain parenchyma after hypoxic/ischemic insult in neonatal rats. For use of glial cell line–derived neurotrophic factor in humans, we have developed a system for the delivery of a constant supply of glial cell line–derived neurotrophic factor to the brain. The aim of this study was to examine the neuroprotective effect of glial cell line–derived neurotrophic factor with the use of this delivery system. Study design Baby hamster kidney cells were transfected with human glial cell line–derived neurotrophic factor complementary DNA, encapsulated in semipermeable hollow fibers, and implanted into the left cerebrum of 12-day-old Wistar rats (glial cell line–derived neurotrophic factor group, 11 rats). Nontransfected baby hamster kidney cells served as controls (control group, 9 rats). Two days after implantation, the rats received a hypoxic/ischemic stress, with a modification of Levine's method. Seven days later the rats were killed, and coronal brain slices were cut 2, 4, 6, 8, and 10 mm from the anterior pole. The cortex, hippocampus, striatum, and thalamus were evaluated for damage severity. The serum concentrations of glial cell line–derived neurotrophic factor were also determined. Results The left brain hemispheric area was significantly larger; the neuronal damage to each brain region was significantly less, and the serum glial cell line–derived neurotrophic factor concentrations were significantly higher in the glial cell line–derived neurotrophic factor group, compared with the control group. Conclusion Grafting of encapsulated glial cell line–derived neurotrophic factor–secreting cells is a promising way to protect the neonatal brain from hypoxic/ischemic insult.

Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells into brain parenchyma reduces histological brain damage following hypoxic-ischemic stress in neonatal rats. We examined the effect of glial cell line-derived neurotrophic factors on long-term learning and memory impairment and morphological changes up to 18 weeks after hypoxic-ischemic stress in neonatal rats.Baby hamster kidney cells were transfected with expression vector either including (glial cell line-derived neurotrophic factor-hypoxic-ischemic group; n = 10) or not including (control-hypoxic-ischemic group; n = 8) human glial cell line-derived neurotrophic factor cDNA, encapsulated in semipermeable hollow fibers, and implanted into the left brain parenchyma of 7-day-old Wistar rats. Two days after implantation the rats received hypoxic-ischemic stress, and their behavior was then examined in several learning tasks: the 8-arm radial maze, choice reaction time, and water maze tasks, which examine short-term working memory, attention process, and long-term reference memory, respectively. The rats were killed 18 weeks after the hypoxic-ischemic insult for evaluation of brain damage. Two additional control groups were used: the control group (n = 15), which underwent no treatment, and the glial cell line-derived neurotrophic factor group (n = 6), which underwent implantation of the glial cell line-derived neurotrophic factor capsule but did not undergo hypoxic-ischemic stress.The decrease in the size of the cerebral hemisphere was significantly less in the glial cell line-derived neurotrophic factor-hypoxic-ischemic group, compared with the control-hypoxic-ischemic group, and improved performance was observed in all three tasks for the glial cell line-derived neurotrophic factor-hypoxic-ischemic group: for the control-hypoxic-ischemic group versus the glial cell line-derived neurotrophic factor-hypoxic-ischemic group, respectively, in the 8-arm radial maze test, average number of correct choices was 6.2 +/- 0.1 versus 6.9 +/- 0.1 ( P.01); in the choice reaction time test, average reaction time for a correct response was 2.35 +/- 0.1 seconds versus 1.97 +/- 0.09 seconds ( P.01); in the water maze test, average swimming length was 1120.0 +/- 95.2 cm versus 841.6 +/- 92.1 cm ( P.01). All results for the glial cell line-derived neurotrophic factor group were similar to those for the control group.Glial cell line-derived neurotrophic factor treatment is effective in not only reducing brain damage but also inhibiting learning and memory impairment, following hypoxic-ischemic insult in neonatal rats. No adverse effects in learning and memory tests were observed in the glial cell line-derived neurotrophic factor group.

Objectives: Hypoxic-ischemic tolerance can be induced in neonatal rats through hyperthermic preconditioning. The purposes of this study were to determine the interval between hyperthermic preconditioning and a subsequent hypoxic-ischemic insult that would provide optimal neuroprotection against the insult and to examine the relationship between tolerance induction and heat shock protein expression. Study Design: On postnatal day 7 Wistar rat pups were separated into the following 2 groups: a heated group (those exposed to 15 minutes of hyperthermic pretreatment at a brain temperature of 41.5°C-42.0°C) and an unheated control group. At 6, 12, 24, 48, and 72 hours after the hyperthermic stress, rats from both groups were exposed to left carotid artery ligation followed by 2 hours of hypoxia (8% oxygen and 92% nitrogen) at 33°C. Twenty animals from each group were used at each time point. All rats were killed at 1 week after hypoxia-ischemia, at which time the brains were processed and neuronal damage in the cortex and hippocampus was assessed histologically. Another set of 7-day-old rats (n = 30) was studied immunohistochemically at 6, 12, 24, 48, and 72 hours after the same hyperthermic treatment. Expression of 72-kd heat shock protein was measured in neuronal, glial, and vascular endothelial cells. Results: Hyperthermia-induced hypoxic-ischemic tolerance was observed at 6, 12, and 24 hours but not at 48 and 72 hours after hyperthermic preconditioning. Heat shock protein 72 expression in the vascular endothelial cells, rather than in the glial or neuronal cells, was most strongly associated with hypoxic-ischemic tolerance. Conclusion: These findings suggest that heat shock protein 72 in endothelial cells plays an important role in the acquisition of hypoxic-ischemic tolerance at postnatal day 7, a time when maximal angiogenesis occurs and the blood-brain barrier is still immature. (Am J Obstet Gynecol 2000;182:380-6.)

OBJECTIVE: We sought to determine the relationship between the degree of histologic changes in the brain, heart, kidney, and liver in fetal lambs after severe asphyxia and to analyze the role of oxidative stress in the pathogenesis of fetal multiple organ failure. STUDY DESIGN: Eight chronically instrumented near-term fetal lambs were asphyxiated by partial umbilical cord occlusion for approximately 60 minutes until the fetal arterial pH reached

OBJECTIVES: The purpose of this study was to explain the role of oxidative stress in the pathogenesis of brain damage caused by intrauterine fetal asphyxia. STUDY DESIGN: Six chronically instrumented near-term fetal lambs were subjected to asphyxia by partial umbilical cord occlusion for approximately 60 minutes until fetal arterial pH diminished to less than 6.9 and base excess to less than –20 mEq. Another six fetuses surgically prepared but not occluded were used as control. Fetuses were killed after 72 hours and eight different brain regions (frontal and parietal gray matter, frontal and parietal white matter, basal ganglia, thalamus, hippocampus, and cerebellum) were dissected and assayed for thiobarbituric acid reactive substances, glutathione, and superoxide dismutase. RESULTS: Thiobarbituric acid reactive substance levels in asphyxiated animals were elevated in frontal and parietal white matter, basal ganglia, and thalamus compared with those in controls. The concentrations of superoxide dismutase in the asphyxiated group were also higher in frontal and parietal white matter, basal ganglia, and cerebellum compared with those in the control group. Between the two groups, however, glutathione concentrations did not differ significantly. CONCLUSION: These results suggest that oxidative stress may be a major contributing factor to the development of brain damage in intrauterine fetal asphyxia. (Am J Obstet Gynecol 1998;178:474-8.)

Objective: Our purpose was to study the neuronal responses of heat shock protein-72 (a stress-inducible protein) and microtubule-associated protein-2 (a constitutive protein of the neuronal cytoskeleton) after hypoxia-ischemia and their relationship with permanent damage in the newborn rat brain. Study design: Seven-day-old rats were exposed to unilateral carotid artery ligation followed by 2 hours of hypoxia (8% oxygen/92% nitrogen) and then killed at time points ranging from 1 to 72 hours after injury. Brains were removed for immunohistochemical and routine staining. Results: Heat shock protein-72 appearance and microtubule-associated protein-2 disappearance occurred from 1 hour after injury, mainly in the dentate gyrus of the hippocampal formation and the cerebral cortex. Such alterations reached maximal levels at 24 hours for both proteins. Microtubule-associated protein-2 staining recovered in almost all parts of the brain. However, the hippocampal CA3 showed a delay in the responses for both proteins, and microtubule-associated protein-2 did not recover the response to immunostaining. Histologic evaluation at 72 hours after hypoxia by routine methods showed predominant damage in the hippocampal CA3. Conclusion: Our results show that delayed responses of heat shock protein-72 and microtubule-associated protein-2 are related to a high incidence of neuronal cell loss in the hippocampal CA3 region.

classified as obese. Comorbid conditions included gestational diabetes (6%) and chronic hypertension (8%). Among the cohort, 12% had SSD. Women with SSD compared to those without were more likely to have prepregnancy obesity (71 vs. 31%, p 0.04) but had a similar delivery gestational age (38 1.2 weeks vs. 39 1, p 0.21), similar birthweight (3330 429 vs. 3141 491, p 0.36) and similar ponderal index (2.8 0.3 vs. 2.84 4, p 0.8). Obese women when compared to normal weight women had neonates with similar birthweight (3416 646 vs. 3251 386gm, p 0.2) but higher ponderal index (2.9 0.3 vs. 2.7 0.3, p 0.02). Neonatal birthweight was predicted by gestational age ( 0.53, p 0.001) and prepregnancy obesity ( 0.28, p 0.02) but not SSD ( .121, p n.s.) After controlling for comorbid conditions, prepregnancy obesity ( 0.32, p 0.02) but not SSD ( .117, p n.s.) was predictive of neonatal ponderal index. CONCLUSION: Obesity is associated with severe sleep disturbance. In this cohort of full term neonates, it is obesity rather than sleep disturbance that appears to affect neonatal adiposity.

Objective The purpose of this study was to classify fetal heart rate (FHR) monitor patterns according to risk of fetal acidemia and risk of evolution to a more serious pattern and to use this information to construct a standardized process for FHR pattern management, with the ultimate aim of minimizing newborn infant acidemia without excessive obstetric intervention. Study Design We have identified 134 FHR patterns that have been classified by baseline rate, baseline variability, and type of deceleration. Based on the best available evidence, we have assigned a risk of newborn infant acidemia or low 5-minute Apgar score to these patterns. We have also evaluated each pattern for the risk that the pattern would evolve further into a pattern with a higher risk of acidemia. Results Each FHR pattern has been color-coded, from no threat of fetal acidemia (green, no intervention required) to severe threat of acidemia (red, rapid delivery recommended). Three intermediate categories (blue, yellow, and orange) require escalated informing of appropriate individuals for intervention and resuscitation (obstetrician, anesthesiologist, and neonatal resuscitator) and preparation for urgent delivery (eg, staff and surgical suite availability and conservative techniques to ameliorate the FHR patterns). Conclusion This framework is applicable potentially to the institutions where it was developed and will need to be modified for other situations, depending on the logistics, facilities, and personnel available. This may provide a framework for developing algorithms for the standardized management of FHR patterns during labor, which can be tested for validity.