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Background It is crucial to interpret fetal heart rate patterns with a focus on the pattern evolution during labor to estimate the relationship between cerebral palsy and delivery. However, nationwide data are not available. Objective The aim of our study was to demonstrate the features of fetal heart rate pattern evolution and estimate the timing of fetal brain injury during labor in cerebral palsy cases. Study Design In this longitudinal study, 1069 consecutive intrapartum fetal heart rate strips from infants with severe cerebral palsy at or beyond 34 weeks of gestation, were analyzed. They were categorized as follows: (1) continuous bradycardia (Bradycardia), (2) persistently nonreassuring, (3) reassuring-prolonged deceleration, (4) Hon’s pattern, and (5) persistently reassuring. The clinical factors underlying cerebral palsy in each group were assessed. Results Hypoxic brain injury during labor (those in the reassuring-prolonged deceleration and Hon’s pattern groups) accounted for 31.5% of severe cerebral palsy cases and at least 30% of those developed during the antenatal period. Of the 1069 cases, 7.86% were classified as continuous bradycardia (n=84), 21.7% as persistently nonreassuring (n=232), 15.6% as reassuring-prolonged deceleration (n=167), 15.9% as Hon’s pattern (n=170), 19.8% as persistently reassuring (n=212), and 19.1% were unclassified (n=204). The overall interobserver agreement was moderate (kappa 0.59). Placental abruption was the most common cause (31.9%) of cerebral palsy, accounting for almost 90% of cases in the continuous bradycardia group (64 of 73). Among the cases in the Hon’s pattern group (n=67), umbilical cord abnormalities were the most common clinical factor for cerebral palsy development (29.9%), followed by placental abruption (20.9%), and inappropriate operative vaginal delivery (13.4%). Conclusion Intrapartum hypoxic brain injury accounted for approximately 30% of severe cerebral palsy cases, whereas a substantial proportion of the cases were suspected to have either a prenatal or postnatal onset. Up to 16% of cerebral palsy cases may be preventable by placing a greater focus on the earlier changes seen in the Hon’s fetal heart rate progression.

Background: The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood. Methods: To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function. Results: In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy–lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin–nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti–interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice. Conclusions: These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system plays an important role in protecting the maternal heart from interleukin-6–induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.

OBJECTIVES Outborn (born outside tertiary centers) infants, especially extremely preterm infants, are at an increased risk of mortality and morbidity in comparison to inborn (born in tertiary centers) infants. Extremely preterm infants require not only skilled neonatal healthcare providers but also highly specialized equipment and environment surroundings. Maternal transport at an appropriate timing must be done to avoid the delivery of extremely preterm infants in a facility without the necessary capabilities. Cases of unexpected deliveries at birth centers or level I maternity hospitals need to be attended emergently. We compared the differences in short- and long-term outcomes between outborn and inborn infants to improve our regional perinatal system. DESIGN Retrospective cohort study. SETTING Neonatal Research Network of Japan database. PATIENTS Extremely preterm infants (gestational age between 22 + 0 and 27 + 6 wk) in the Neonatal Research Network of Japan database between 2003 and 2011. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 12,164 extremely preterm infants, who were divided into outborn (n = 785, 6.5%) and inborn (n = 11,379, 93.5%) groups, were analyzed. Significant differences were observed in demographic and clinical factors between the two groups. Outborn infants had higher short-term odds of severe intraventricular hemorrhage (adjusted odds ratio, 1.49; 95% CI, 1.11-2.00; p < 0.01), necrotizing enterocolitis (adjusted odds ratio, 1.49; 95% CI, 1.11-2.00; p < 0.01), and focal intestinal perforation (adjusted odds ratio, 1.58; 95% CI, 1.09-2.30; p = 0.02). There were no significant differences in long-term outcomes between the two groups, except in the rate of cognitive impairment (adjusted odds ratio, 1.49; 95% CI, 1.01-2.20; p = 0.04). CONCLUSIONS The frequency of severe intraventricular hemorrhage, necrotizing enterocolitis or focal intestinal perforation, and cognitive impairment was significantly higher in outborn infants. Thus, outborn/inborn birth status may play a role in short- and long-term outcomes of extremely preterm infants. However, more data and evaluation of improvement in the current perinatal environment are needed.

Background and Purpose— Cannabidiol has been reported to be a neuroprotectant, but the neuroprotective mechanism of cannabidiol remains unclear. We studied the neuroprotective mechanism of cannabidiol in 4-hour middle cerebral artery (MCA) occlusion mice. Methods— Male MCA occluded mice were treated with cannabidiol, abnormal cannabidiol, anandamide, methanandamide, cannabidiol plus capsazepine, and cannabidiol plus WAY100135 before and 3 hours after MCA occlusion. The infarct size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Cerebral blood flow (CBF) was measured at, before and 1, 2, 3, and 4 hours after MCA occlusion. Results— Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve. Similarly, abnormal cannabidiol but not anandamide or methanandamide reduced the infarct volume. Moreover, the neuroprotective effect of cannabidiol was inhibited by WAY100135, a serotonin 5-hydroxytriptamine 1A (5-HT 1A ) receptor antagonist but not capsazepine a vanilloid receptor antagonist. Cannabidiol increased CBF to the cortex, and the CBF was partly inhibited by WAY100135 in mice subjected to MCA occlusion. Conclusions— Cannabidiol and abnormal cannabidiol reduced the infarct volume. Furthermore, the neuroprotective effect of cannabidiol was inhibited by WAY100135 but not capsazepine, and the CBF increased by cannabidiol was partially reversed by WAY100135. These results suggested that the neuroprotective effect of cannabidiol may be related to the increase in CBF through the serotonergic 5-HT 1A receptor.

Objective We sought to evaluate from a behavioral and histological viewpoint the effect of local administration of glial cell line-derived neurotrophic factor (GDNF) on neonatal preganglionic Erb's palsy in rats. Methods The Erb's palsy model was produced by transecting the anterior and posterior roots of the left C5-C7 nerves of 7-day-old rats. The rats were divided into GDNF-treated (n = 10) and vehicle-treated groups (n = 11). After we transected the roots, contact in the proximal and distal stumps of the transected nerves was maintained, and the transected point and the entire intraspinal portion of the transected roots were enclosed by Gelfoam soaked with 10 micro g GDNF or saline. The behavioral evaluation consisted of a foot-fault test and a forepaw muscle strength test, all of which were performed from the third to the seventh weeks after the operation. Seven weeks after the operation, all rats were killed, the number of anterior horn cells was counted at C5-C7, and the differences on each side were compared. Results In the vehicle-treated group, the foot-fault test indicated an abnormality in forelimb function on the root transection side. In the GDNF-treated group, however, significant improvement in forelimb function was observed on the basis of the foot-fault test results obtained in the third to sixth weeks after the operation. In the histological evaluation, the number of anterior horn cells from the side in which the operation took place in the vehicle-treated group was significantly less than that taken from the contralateral side at each segment. In the GDNF-treated group, however, there was no difference in any of the segments, regardless of the side from which they were taken. Conclusion Local administration of GDNF in a neonatal preganglionic Erb's palsy model resulted in significant improvement in deficits on the basis of behavioral and histological evaluations.

The fetal membrane (FM), which is reported to contain mesenchymal stam cells (MSC), has been regarded as an ideal source for regenerative medicine, although it is normally discarded after birth. Little information is available regarding the biological difference and therapeutic potential of MSC obtained from different layers of FM including amnion and chorion. We assessed the hypothesis that human FM-derived MSC (FM-MSC) might have therapeutic effects on hindlimb ischemia. FM was obtained following cesarean section and vaginal delivery of healthy donor mothers after obtaining informed consent. We mechanically and enzymatically separated human FM into three layers; amnion and inner and outer layers of chorion, and isolated dish-adherent cells from each layer of FM. These FM-derived cells showed similar surface antigen expression and pluripotency compared to bone marrow (BM)-derived MSC. Because cultured inner chorion-derived MSC (IC-MSC) secreted large amounts of growth factors including IGF-1(13.6 ± 0.08 ng/106cells/24hrs, p < 0.001 vs. amnion or outer chorion-derived MSC (AM-MSC or OC-MSC)) and HGF (7.94 ± 0.67 ng/106cells/24hrs, p < 0.001 vs. AM-MSC or OC-MSC) compared to AM-MSC or OC-MSC, we chose to use IC-MSC for further in vivo experiment. Hindlimb ischemia was induced in 6-week-old male NOD/SCID mice, which were divided into two groups: IC-MSC transplanted group (1 × 10 6 cells/50 μl PBS, n = 9), and control group (50 μl PBS, n = 10). IC-MSC was injected into ischemic hindlimb muscle at five different points. Laser Doppler perfusion analyses showed that the ischemic/nonischemic blood flow ratio was significantly increased in IC-MSC group compared to control group (0.468 ± 0.093 vs. 0.227 ± 0.045 respectively, p < 0.01). Transplantation of FM-MSC showed significant neovascularization in murine hindlimb ischemia model. FM-MSC might have a potential to be an ideal source for treatment of ischemic cardiovascular disease.