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Dopamine is often used to treat hypotension in preterm infants who are at risk of hypoxic-ischemic (HI) brain injury due to cerebral hypoperfusion and impaired autoregulation. There is evidence that systemically administered dopamine crosses the preterm blood-brain barrier. However, the effects of exogenous dopamine and cerebral HI on dopaminergic signaling in the immature brain are unknown. We determined the effect of HI and dopamine on D1 and D2 receptor binding and expressions of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum of the preterm fetal sheep. Fetal sheep (99 days of gestation, term=147days) were unoperated controls (n = 6) or exposed to severe HI using umbilical cord occlusion and saline infusion (UCO + saline, n = 8) or to HI with dopamine infusion (UCO + dopamine, 10 microg/kg/min, n = 7) for 74 h. D1 and D2 receptor densities were measured by autoradiography in vitro. DAT, TH, and cell death were measured using immunohistochemistry. HI resulted in cell death in the caudate nucleus and putamen, and dopamine infusion started before HI did not exacerbate or ameliorate these effects. HI led to reduced D1 and D2 receptor densities in the caudate nucleus and reduction in DAT protein expression in the caudate and putamen. Fetal brains exposed to dopamine in addition to HI were not different from those exposed to HI alone in these changes in dopaminergic parameters. We conclude that dopamine infusion does not alter the striatal cell death or the reductions in D1 and D2 receptor densities and DAT protein expression induced by HI in the preterm brain.NEW & NOTEWORTHY This is the first study on the effects of hypoxia-ischemia and dopamine treatment on the dopaminergic pathway in the preterm brain. In the striatum of fetal sheep (equivalent to ~26-28 wk of human gestation), we demonstrate that hypoxia-ischemia leads to cell death, reduces D1 and D2 receptors, and reduces dopamine transporter. Intravenous dopamine infusion at clinical d

Dopamine is often used to treat hypotension in preterm infants who are at risk of hypoxic-ischemic (HI) brain injury due to cerebral hypoperfusion and impaired autoregulation. There is evidence that systemically administered dopamine crosses the preterm blood-brain barrier. However, the effects of exogenous dopamine and cerebral HI on dopaminergic signaling in the immature brain are unknown. We determined the effect of HI and dopamine on D1 and D2 receptor binding and expressions of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum of the preterm fetal sheep. Fetal sheep (99 days of gestation, term=147days) were unoperated controls (n = 6) or exposed to severe HI using umbilical cord occlusion and saline infusion (UCO + saline, n = 8) or to HI with dopamine infusion (UCO + dopamine, 10 microg/kg/min, n = 7) for 74 h. D1 and D2 receptor densities were measured by autoradiography in vitro. DAT, TH, and cell death were measured using immunohistochemistry. HI resulted in cell death in the caudate nucleus and putamen, and dopamine infusion started before HI did not exacerbate or ameliorate these effects. HI led to reduced D1 and D2 receptor densities in the caudate nucleus and reduction in DAT protein expression in the caudate and putamen. Fetal brains exposed to dopamine in addition to HI were not different from those exposed to HI alone in these changes in dopaminergic parameters. We conclude that dopamine infusion does not alter the striatal cell death or the reductions in D1 and D2 receptor densities and DAT protein expression induced by HI in the preterm brain.NEW & NOTEWORTHY This is the first study on the effects of hypoxia-ischemia and dopamine treatment on the dopaminergic pathway in the preterm brain. In the striatum of fetal sheep (equivalent to ~26-28 wk of human gestation), we demonstrate that hypoxia-ischemia leads to cell death, reduces D1 and D2 receptors, and reduces dopamine transporter. Intravenous dopamine infusion at clinical d

Purpose: To evaluate differences in diagnostic yield of intra-uterine foetal (iuMR) and post-mortem MRI (PMMR) for complex brain malformations, using autopsy as the reference standard. Method(s): In this retrospective, multicentre study spanning 2 years, we reviewed 13 terminated singleton pregnancies with a prenatal ultrasound finding of complex foetal cerebral abnormalities, referred for both iuMR and PMMR. The iuMR and PMMR studies of the brain were reported independently by two groups of radiologists, blinded to each other's reports. Descriptive statistics were used to compare differences in intracranial abnormalities with autopsy (and genetic testing, where present) as reference standard. Result(s): The median gestational age at termination was 24.6 weeks (IQR 22-29) with median time between delivery and PMMR of 133 h (IQR 101-165). There was full concordance between iuMR and PMMR findings and autopsy in 2/13 (15.3%) cases. Partial concordance between both imaging modalities was present in 6/13 (46.2%) and total discordance in the remainder (5/13, 38.5%). When compared to autopsy, PMMR missed important key findings specifically for neuronal migration and cerebellar anomalies, whereas iuMR appeared to overcall CSF space abnormalities which were less crucial to reaching the final overall diagnosis. Conclusion(s): iuMR should be performed to improve foetal phenotyping where there is a prenatal ultrasound for complex foetal brain abnormalities. Reliance on PMMR alone is likely to result in misdiagnosis in a majority of cases.Copyright © 2019, The Author(s).

Background: Neurovascular coupling (NVC) leads to increased local cerebral blood flow and oxygenation to meet the increased metabolic demand of neural activity. Immature NVC in the preterm newborn may predispose the brain to cerebral hypoxia when neural activity is increased. We reported that prolonged somatosensory stimulation in fetal sheep reduced cerebral oxygenation (negative cerebral haemodynamic response) (Nakamura et al. 2017). We now characterise the cerebral haemodynamic response after somatosensory stimulation in the preterm newborn lamb, by measuring changes in cerebral oxy- and deoxy-haemoglobin (DELTAoxyHb, DELTAdeoxyHb) using near infrared spectroscopy (NIRS). Method(s): Preterm lambs (126-128 days gestation) were delivered and ventilated under isoflurane anaesthesia. Scalp EEG and NIRS optodes were positioned bilaterally over the somatosensory cortex. Using a cuff electrode, the left median nerve was stimulated by trains (1.8, 4.8, 7.8 s duration) of pulses (3-8 mA, 2 msec). The DELTAoxyHb and DELTAdeoxyHb were recorded. Result(s): Stimulation for 1.8 s, 4.8 s and 7.8 s durations increased DELTAoxyHb in the contralateral cortex in 9 of 10 (90%), 8 of 11 (73%) and 9 of 10 (90%) preterm lambs respectively, while the remaining lambs showed decreased DELTAoxyHb. The DELTAoxyHb did not correlate with changes in arterial blood pressure. Conclusion(s): Somatosensory stimulation increased cerebral oxygenation in the preterm newborn brain, contrasting with our published findings in age-matched fetal sheep in which prolonged stimulation decreased cerebral oxygenation. Ex-utero NVC responses in the postnatal and fetal brain may be different because of loss of endogenous neurosteroids (e.g.progesterone, allopregnanolone) of placental origin which contribute to fetal sleep and suppress somatosensory neural responses.

Purpose: To evaluate differences in diagnostic yield of intra-uterine foetal (iuMR) and post-mortem MRI (PMMR) for complex brain malformations, using autopsy as the reference standard. Method(s): In this retrospective, multicentre study spanning 2 years, we reviewed 13 terminated singleton pregnancies with a prenatal ultrasound finding of complex foetal cerebral abnormalities, referred for both iuMR and PMMR. The iuMR and PMMR studies of the brain were reported independently by two groups of radiologists, blinded to each other's reports. Descriptive statistics were used to compare differences in intracranial abnormalities with autopsy (and genetic testing, where present) as reference standard. Result(s): The median gestational age at termination was 24.6 weeks (IQR 22-29) with median time between delivery and PMMR of 133 h (IQR 101-165). There was full concordance between iuMR and PMMR findings and autopsy in 2/13 (15.3%) cases. Partial concordance between both imaging modalities was present in 6/13 (46.2%) and total discordance in the remainder (5/13, 38.5%). When compared to autopsy, PMMR missed important key findings specifically for neuronal migration and cerebellar anomalies, whereas iuMR appeared to overcall CSF space abnormalities which were less crucial to reaching the final overall diagnosis. Conclusion(s): iuMR should be performed to improve foetal phenotyping where there is a prenatal ultrasound for complex foetal brain abnormalities. Reliance on PMMR alone is likely to result in misdiagnosis in a majority of cases.Copyright © 2019, The Author(s).

Background: Neurovascular coupling (NVC) leads to increased local cerebral blood flow and oxygenation to meet the increased metabolic demand of neural activity. Immature NVC in the preterm newborn may predispose the brain to cerebral hypoxia when neural activity is increased. We reported that prolonged somatosensory stimulation in fetal sheep reduced cerebral oxygenation (negative cerebral haemodynamic response) (Nakamura et al. 2017). We now characterise the cerebral haemodynamic response after somatosensory stimulation in the preterm newborn lamb, by measuring changes in cerebral oxy- and deoxy-haemoglobin (DELTAoxyHb, DELTAdeoxyHb) using near infrared spectroscopy (NIRS). Method(s): Preterm lambs (126-128 days gestation) were delivered and ventilated under isoflurane anaesthesia. Scalp EEG and NIRS optodes were positioned bilaterally over the somatosensory cortex. Using a cuff electrode, the left median nerve was stimulated by trains (1.8, 4.8, 7.8 s duration) of pulses (3-8 mA, 2 msec). The DELTAoxyHb and DELTAdeoxyHb were recorded. Result(s): Stimulation for 1.8 s, 4.8 s and 7.8 s durations increased DELTAoxyHb in the contralateral cortex in 9 of 10 (90%), 8 of 11 (73%) and 9 of 10 (90%) preterm lambs respectively, while the remaining lambs showed decreased DELTAoxyHb. The DELTAoxyHb did not correlate with changes in arterial blood pressure. Conclusion(s): Somatosensory stimulation increased cerebral oxygenation in the preterm newborn brain, contrasting with our published findings in age-matched fetal sheep in which prolonged stimulation decreased cerebral oxygenation. Ex-utero NVC responses in the postnatal and fetal brain may be different because of loss of endogenous neurosteroids (e.g.progesterone, allopregnanolone) of placental origin which contribute to fetal sleep and suppress somatosensory neural responses.

Background: Impaired cerebral autoregulation in preterm infants makes circulatory management important to avoid cerebral hypoxic-ischemic injury. Dobutamine is frequently used as inotropic treatment in preterm neonates, but its effects on the brain exposed to cerebral hypoxia are unknown. We hypothesized that dobutamine would protect the immature brain from cerebral hypoxic injury. Method(s): In preterm (0.6 gestation) fetal sheep, dobutamine (Dob, 10 mug/kg/min) or saline (Sal) was infused intravenously for 74 h. Two hours after the beginning of the infusion, umbilical cord occlusion (UCO) was performed to produce fetal asphyxia (Sal+UCO: n = 9, Dob+UCO: n = 7), or sham occlusion (Sal+sham: n = 7, Dob+sham: n = 6) was performed. Brains were collected 72 h later for neuropathology. Result(s): Dobutamine did not induce cerebral changes in the sham UCO group. UCO increased apoptosis and microglia density in white matter, hippocampus, and caudate nucleus, and astrocyte density in the caudate nucleus. Dobutamine commenced before UCO reduced microglia infiltration in the white matter, and microglial and astrocyte density in the caudate. Conclusion(s): In preterm hypoxia-induced brain injury, dobutamine decreases neuroinflammation in the white matter and caudate, and reduces astrogliosis in the caudate. Early administration of dobutamine in preterm infants for cardiovascular stabilization appears safe and may be neuroprotective against unforeseeable cerebral hypoxic injury.Copyright © 2018, International Pediatric Research Foundation, Inc.

Background: Impaired cerebral autoregulation in preterm infants makes circulatory management important to avoid cerebral hypoxic-ischemic injury. Dobutamine is frequently used as inotropic treatment in preterm neonates, but its effects on the brain exposed to cerebral hypoxia are unknown. We hypothesized that dobutamine would protect the immature brain from cerebral hypoxic injury. Method(s): In preterm (0.6 gestation) fetal sheep, dobutamine (Dob, 10 mug/kg/min) or saline (Sal) was infused intravenously for 74 h. Two hours after the beginning of the infusion, umbilical cord occlusion (UCO) was performed to produce fetal asphyxia (Sal+UCO: n = 9, Dob+UCO: n = 7), or sham occlusion (Sal+sham: n = 7, Dob+sham: n = 6) was performed. Brains were collected 72 h later for neuropathology. Result(s): Dobutamine did not induce cerebral changes in the sham UCO group. UCO increased apoptosis and microglia density in white matter, hippocampus, and caudate nucleus, and astrocyte density in the caudate nucleus. Dobutamine commenced before UCO reduced microglia infiltration in the white matter, and microglial and astrocyte density in the caudate. Conclusion(s): In preterm hypoxia-induced brain injury, dobutamine decreases neuroinflammation in the white matter and caudate, and reduces astrogliosis in the caudate. Early administration of dobutamine in preterm infants for cardiovascular stabilization appears safe and may be neuroprotective against unforeseeable cerebral hypoxic injury.Copyright © 2018, International Pediatric Research Foundation, Inc.

Objective: This study aimed to determine the additional diagnostic information provided by prenatal (fetal) magnetic resonance imaging (pMRI) following tertiary ultrasound (US) for fetal cranial abnormalities in complicated monochorionic gestations. Method(s): Women with complicated monochorionic gestations complicated by twin-twin transfusion syndrome, co-twin demise (CD), selective intrauterine growth restriction, and/or twin anaemia-polycythaemia sequence who were referred for pMRI after tertiary US were included. Additional diagnostic information by pMRI that changed prognostic counselling was the primary outcome. Result(s): Thirty-three women with 48 live fetuses had pMRI at a median of 25 weeks (range: 21-29). Three of ten survivors of spontaneous CD, one of eight survivors of CD after twin-twin transfusion syndrome and 1/30 co-survivors had diagnostic information added by pMRI that altered counselling; US was normal in two and in the other three underrepresented parenchymal injury (5/33 = 15%; 95% confidence interval +/-0.27-0.03). Additional findings included occipital lobe infarction, hemispheric injury, dural sinus thrombosis, ischaemia-producing polymicrogyria and intraventricular haemorrhage. Another 8/33 women had additional information provided by pMRI that did not alter counselling. Conclusion(s): Prenatal magnetic resonance imaging resulted in changed prognostic counselling in 5/33 pregnancies. Evaluation of incorporation of pMRI into routine surveillance of complicated monochorionic gestations is needed. © 2017 John Wiley & Sons, Ltd.

Fetal growth restriction (FGR) is a common complication of pregnancy and, in severe cases, is associated with elevated rates of perinatal mortality, neonatal morbidity, and poor neurodevelopmental outcomes. The leading cause of FGR is placental insufficiency, with the placenta failing to adequately meet the increasing oxygen and nutritional needs of the growing fetus with advancing gestation. The resultant chronic fetal hypoxia induces a decrease in fetal growth, and a redistribution of blood flow preferentially to the brain. However, this adaptation does not ensure normal brain development. Early detection of brain injury in FGR, allowing for the prediction of short- and long-term neurodevelopmental consequences, remains a significant challenge. Furthermore, in FGR infants the detection and diagnosis of neuropathology is complicated by preterm birth, the etiological heterogeneity of FGR, timing of onset of growth restriction, its severity, and coexisting complications. In this review, we examine existing and emerging diagnostic tools from human and preclinical studies for the detection and assessment of brain injury in FGR fetuses and neonates. Increased detection rates, and early detection of brain injury associated with FGR, will offer opportunities for developing and assessing interventions to improve long-term outcomes.Copyright © 2017 International Pediatric Research Foundation, Inc.

Objective: This study aimed to determine the additional diagnostic information provided by prenatal (fetal) magnetic resonance imaging (pMRI) following tertiary ultrasound (US) for fetal cranial abnormalities in complicated monochorionic gestations. Method(s): Women with complicated monochorionic gestations complicated by twin-twin transfusion syndrome, co-twin demise (CD), selective intrauterine growth restriction, and/or twin anaemia-polycythaemia sequence who were referred for pMRI after tertiary US were included. Additional diagnostic information by pMRI that changed prognostic counselling was the primary outcome. Result(s): Thirty-three women with 48 live fetuses had pMRI at a median of 25 weeks (range: 21-29). Three of ten survivors of spontaneous CD, one of eight survivors of CD after twin-twin transfusion syndrome and 1/30 co-survivors had diagnostic information added by pMRI that altered counselling; US was normal in two and in the other three underrepresented parenchymal injury (5/33 = 15%; 95% confidence interval +/-0.27-0.03). Additional findings included occipital lobe infarction, hemispheric injury, dural sinus thrombosis, ischaemia-producing polymicrogyria and intraventricular haemorrhage. Another 8/33 women had additional information provided by pMRI that did not alter counselling. Conclusion(s): Prenatal magnetic resonance imaging resulted in changed prognostic counselling in 5/33 pregnancies. Evaluation of incorporation of pMRI into routine surveillance of complicated monochorionic gestations is needed. © 2017 John Wiley & Sons, Ltd.

Fetal growth restriction (FGR) is a common complication of pregnancy and, in severe cases, is associated with elevated rates of perinatal mortality, neonatal morbidity, and poor neurodevelopmental outcomes. The leading cause of FGR is placental insufficiency, with the placenta failing to adequately meet the increasing oxygen and nutritional needs of the growing fetus with advancing gestation. The resultant chronic fetal hypoxia induces a decrease in fetal growth, and a redistribution of blood flow preferentially to the brain. However, this adaptation does not ensure normal brain development. Early detection of brain injury in FGR, allowing for the prediction of short- and long-term neurodevelopmental consequences, remains a significant challenge. Furthermore, in FGR infants the detection and diagnosis of neuropathology is complicated by preterm birth, the etiological heterogeneity of FGR, timing of onset of growth restriction, its severity, and coexisting complications. In this review, we examine existing and emerging diagnostic tools from human and preclinical studies for the detection and assessment of brain injury in FGR fetuses and neonates. Increased detection rates, and early detection of brain injury associated with FGR, will offer opportunities for developing and assessing interventions to improve long-term outcomes.Copyright © 2017 International Pediatric Research Foundation, Inc.