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Direct fetal creatine supplementation increased plasma and cerebral creatine concentrations but did not alter fetal body weight, basal cardiovascular output, or blood chemistry. Creatine-treated fetuses displayed changes to arterial oxygenation 24–72 h after acute global hypoxia. An increase in striatum total creatine levels following UCO was also noted and suggests that increasing creatine tissue availability may be an adaptive response against the effects of hypoxia.

Impaired cardiac preload secondary to umbilical cord occlusion (UCO) has been hypothesized to contribute to intrapartum decelerations, brief falls in fetal heart rate (FHR), through activation of the Bezold-Jarisch reflex. This cardioprotective reflex increases parasympathetic and inhibits sympathetic outflows triggering hypotension, bradycardia, and peripheral vasodilation, but its potential to contribute to intrapartum decelerations has never been systematically examined. In this study, we performed bilateral cervical vagotomy to remove the afferent arm and the efferent parasympathetic arm of the Bezold-Jarisch reflex. Twenty-two chronically instrumented fetal sheep at 0.85 of gestation received vagotomy ( n = 7) or sham vagotomy (control, n = 15), followed by three 1-min complete UCOs separated by 4-min reperfusion periods. UCOs in control fetuses were associated with a rapid fall in FHR and reduced femoral blood flow mediated by intense femoral vasoconstriction, leading to hypertension. Vagotomy abolished the rapid fall in FHR ( P < 0.001) and, despite reduced diastolic filling time, increased both carotid ( P < 0.001) and femoral ( P < 0.05) blood flow during UCOs, secondary to carotid vasodilation ( P < 0.01) and delayed femoral vasoconstriction ( P < 0.05). Finally, vagotomy was associated with an attenuated rise in cortical impedance during UCOs ( P < 0.05), consistent with improved cerebral substrate supply. In conclusion, increased carotid and femoral blood flows after vagotomy are consistent with increased left and right ventricular output, which is incompatible with the hypothesis that labor-like UCOs impair ventricular filling. Overall, the cardiovascular responses to vagotomy do not support the hypothesis that the Bezold-Jarisch reflex is activated by UCO. The Bezold-Jarisch reflex is therefore mechanistically unable to contribute to intrapartum decelerations.

There is increasing evidence that administration of many types of stem cells, including human amnion epithelial cells (hAECs), can reduce hypoxic‐ischemic injury, including in the perinatal brain. However, the therapeutic window for single dose treatment is not known. We compared the effects of early and delayed intracerebroventricular administration of hAECs in fetal sheep at 0.7 gestation on brain injury induced by 25 minutes of complete umbilical cord occlusion (UCO) or sham occlusion. Fetuses received either 1 × 106 hAECs or vehicle alone, as an infusion over 1 hour, either 2 or 24 hours after UCO. Fetuses were killed for brain histology at 7 days post‐UCO. hAEC infusion at both 2 and 24 hours had dramatic anti‐inflammatory and anti‐gliotic effects, including significantly attenuating the increase in microglia after UCO in the white and gray matter and the number of astrocytes in the white matter. Both protocols partially improved myelination, but had no effect on total or immature/mature numbers of oligodendrocytes. Neuronal survival in the hippocampus was increased by hAEC infusion at either 2 or 24 hours, whereas only hAECs at 24 hours were associated with improved neuronal survival in the striatum and thalamus. Neither protocol improved recovery of electroencephalographic (EEG) power. These data suggest that a single infusion of hAECs is anti‐inflammatory, anti‐gliotic, and neuroprotective in preterm fetal sheep when given up to 24 hours after hypoxia‐ischemia, but was associated with limited white matter protection after 7 days recovery and no improvement in the recovery of EEG power., Human amnion epithelial cells normalize microgliosis and astrogliosis after asphyxia.

Optimal surgical management of monochorionic diamniotic twins complicated by selective intrauterine growth restriction (SIUGR) type II is unknown. Surgical management may involve selective laser photocoagulation of communicating vessels (SLPCV), which offers the possibility of dual twin survivors versus umbilical cord occlusion (UCO) of the SIUGR twin.To identify patient characteristics associated with SIUGR twin survival for those undergoing SLPCV.All patients studied were those who underwent fetal treatment for SIUGR type II at our center from 2006-2018. SIUGR type II was defined as an estimated fetal weight10th percentile with persistent absent and/or reversed end diastolic flow in the umbilical artery of the SIUGR twin, in the absence of twin-twin transfusion syndrome. Patients were offered SLPCV versus UCO, and those undergoing SLPCV, patient characteristics associated with 30-day survival of the SIUGR twin were examined using bivariate analysis and multiple logistic regression models.Fifty-four consecutive SIUGR type II patients were treated, 45Over one-third of SIUGR type II patients experienced dual survival after treatment with laser surgery. Normal MCA psv and normal DV waveforms were associated with SIUGR type II survival of the SIUGR twin.

Sensitive biomarkers are needed to rapidly identify high-risk infants after hypoxia-ischemia for neuroprotective treatment. Hypotension is a key determinant of hypoxic-ischemic neural injury, and a potent stimulus of humoral pressors including angiotensin-II and arginine vasopressin. We therefore aimed to quantify the relationship between vasopressin and angiotensin-II levels in the latent phase after hypoxia-ischemia induced by umbilical cord occlusion (UCO) with both the severity of preceding hypotension and subsequent neuronal injury.Chronically instrumented near-term fetal sheep underwent sham-UCO or UCO for either 15 min or until mean arterial pressure was8 mmHg. Neuronal injury was assessed after 72 h recovery.Umbilical cord occlusion was associated with severe hypotension that recovered after UCO; two fetuses developed profound secondary hypotension within 6 h and died. Vasopressin levels but not angiotensin-II were significantly elevated 1-3 h after UCO and were closely associated with the severity of hypotension during UCO and the subsequent severity of neuronal loss in the parasagittal and lateral cortex, caudate nucleus and putamen. The Youden cut-point for vasopressin at 1 h was 180.0 pmol/L, with sensitivity 100% and specificity 92.3% for severe neuronal injury or death.Vasopressin levels shortly after moderate-severe hypoxia-ischemia may be a useful early biomarker to guide the timely implementation of neuroprotective treatment.It can be difficuIt to rapidly identify infants who might benefit from therapeutic hypothermia. We investigated whether increases in plasma pressor hormones early after hypoxia-ischemia were biomarkers for neonatal hypoxic-ischemic encephalopathy using near-term fetal sheep. Arginine vasopressin levels were elevated at 1-3 h after hypoxia-ischemia and were predictive of the severity of preceding hypotension and subsequent risk of severe neuronal injury or death after hypoxia-ischemia. Arginine vasopressin may help identify neonates at high risk of hypoxic-ischemic encephalopathy early within the therapeutic window for hypothermia.

International audience; Background: The autonomic nervous system has a major role in fetal adaptation to hypoxia. Its activity might be assessed using heart rate variability and heart rate deceleration analyses.Objective: To evaluate the ability of different heart rate variability and morphological deceleration analyses to predict fetal acidosis during labor in an experimental fetal sheep model.Study design: Repeated 1-minute total umbilical cord occlusions were performed at mild (1minute every 5 min), moderate (1 min every 3 min), and severe (1 min every 2 min) umbilical cord occlusion periodicities until arterial pH reached 7.10. Hemodynamic,blood gas analysis, morphological analysis of decelerations (magnitude, slope, and area ofdecelerations), and heart rate variability parameters were recorded throughout the experiment.Heart rate variability analysis included temporal analysis (root mean square of successivedifferences between adjacent RR intervals, standard deviation of normal to normal RR intervals, short term variability), spectral analysis (low frequencies, high frequencies,normalized high frequencies), and a new index developed by our team, the Fetal Stress Index.We defined and compared three pH groups: >7.20, 7.10-7.20, and

Perinatal asphyxia is a major cause of severe brain damage and death. For its prenatal identification, Doppler ultrasound has been used as a surrogate marker of fetal hypoxia. However, Doppler evaluation cannot be performed continuously. We have evaluated the performance of a miniaturized multiparametric sensor aiming to evaluate tissular oxygen and pH changes continuously in an umbilical cord occlusion (UCO) sheep model. The electrochemical sensors were inserted in fetal hindlimb skeletal muscle and electrochemical signals were recorded. Fetal hemodynamic changes and metabolic status were also monitored during the experiment. Additionally, histological assessment of the tissue surrounding the sensors was performed. Both electrochemical sensors detected the pO2 and pH changes induced by the UCO and these changes were correlated with hemodynamic parameters as well as with pH and oxygen content in the blood. Finally, histological assessment revealed no signs of alteration on the same day of insertion. This study provides the first evidence showing the application of miniaturized multiparametric electrochemical sensors detecting changes in oxygen and pH in skeletal muscular tissue in a fetal sheep model., This research was funded by CELLEX FOUNDATION. This work was financially supported by The Cellex Foundation and the Agència de Gestió d’Ajuts Universitaris i de Recerca (Grant 2017 SGR 1531). Additionally, E.E. has received support from the Departament de Salut (Grant SLT008/18/00156). The Nanobioengineering group at the Institute of Bioengineering of Catalonia (IBEC) has received support from the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (No. 2017 SGR 1079) and is part of the CERCA Programme / Generalitat de Catalunya and is supported by the Severo Ochoa programme of the Spanish Ministry of Science and Competitiveness (Grant SEV-2014-0425 (2015–2019)). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. L.R. would also like to acknowledge her support within the BEST Postdoctoral Programme, funded by the European Commission under Horizon 2020’s Marie Skłodowska-Curie Actions COFUND scheme (Grant Agreement No. 712754).

Objective We aimed to compare perinatal outcomes between umbilical cord occlusion techniques in monochorionic pregnancies, including umbilical cord ligation, fetoscopic laser coagulation, interstitial laser coagulation, bipolar cord occlusion, radiofrequency ablation, and microwave ablation. Methods This study was registered with PROSPERO (CRD42020158861). PubMed, Web of Science, Cochrane Library, and Embase were searched for studies published up to May 2020. The DerSimonian-Laird random-effects model was used for the meta-analysis. Subgroup analyses were performed to compare the outcomes among the six techniques. Meta-regression was used to adjust for confounders. Results Thirty-four studies with 1,646 participants were included. The overall survival was 76.5% after umbilical cord ligation, 78.8% after fetoscopic laser coagulation, 60.3% after interstitial laser coagulation, 79.2% after bipolar cord occlusion, 77.5% after radiofrequency ablation, and 75.0% after microwave ablation. Subgroup comparison showed the rates of overall survival and preterm premature rupture of membranes were not significant different among six techniques. However, rates of fetal loss, premature birth, live birth, and neonatal death differed significantly among the six groups. Conclusions The choice of umbilical cord occlusion techniques will affect perinatal outcomes. We suggested that the choice of umbilical cord occlusion techniques should fully consider these differences among techniques. This article is protected by copyright. All rights reserved.

Objective: To determine hemodynamic changes by Doppler ultrasound of the living fetus during 24 h after umbilical cord occlusion (UCO) in monochorionic diamniotic (MCDA) twin pregnancies. Method: We conducted a prospective observational study on fetuses undergoing UCO from 2015 to 2017. Doppler parameters peak systolic velocity (PSV) and umbilical pulsatility index (PI) were obtained in the middle cerebral artery (MCA), umbilical artery (UA) and ductus venosus (DV) before and right after UCO, and at 1, 3, 6, 12, and 24 h after. We used multiple of the median (MoM) to adjust for gestational age. Spaghetti plots visualized flow changes over time. Mixed model adjusting for paired longitudinal data compared the values at different time points. Results: A total of 16 women were included. MCA-PSV dropped within the first hour after surgery from 0.91 to 0.82 MoM (p = 0.08). MCA-PI and UA-PI increased in the first hour from 0.75 to 0.91 MoM (p = 0.02) and 0.94 to 0.98 MoM (p = 0.22), respectively. The DV-PIV increased to 1.14 MoM 3 h after surgery (p = 0.07). The spaghetti plots illustrated the small changes within the first hours and showed a stabilization of flow measurements near initial values 24 h after UCO. Conclusion: Within the first hours after UCO the circulation of the survivor twin undergoes small hemodynamic changes.

The timing of hypoxia-ischemia (HI) in preterm infants is often uncertain and there are few biomarkers to determine whether infants are in a treatable stage of injury. We evaluated whether epileptiform sharp waves recorded from the parietal cortex could provide early prediction of neuronal loss after HI. Preterm fetal sheep (0.7 gestation) underwent acute HI induced by complete umbilical cord occlusion for 25 minutes (n = 6) or sham occlusion (control, n = 6). Neuronal survival was assessed 7 days after HI by immunohistochemistry. Sharp waves were quantified manually and using a wavelet-type-2-fuzzy-logic-system during the first 4 hours of recovery. HI resulted in significant subcortical neuronal loss. Sharp waves counted by the automated classifier in the first 30 minutes after HI were associated with greater neuronal survival in the caudate nucleus (r = 0.80), whereas sharp waves between 2–4 hours after HI were associated with reduced neuronal survival (r = −0.83). Manual and automated counts were closely correlated. This study suggests that automated quantification of sharp waves may be useful for early assessment of HI injury in preterm infants. However, the pattern of evolution of sharp waves after HI was markedly affected by the severity of neuronal loss, and therefore early, continuous monitoring is essential.

The mammalian fetus and newborn can survive far more prolonged periods of hypoxia-ischaemia without neural injury than adults. In part, this remarkable physiological resilience reflects the effecti...

Knowledge of fetal physiology during labor has been largely generated from animal models. Our team recently developed a new index to assess parasympathetic activity using different experimental protocols to obtain acidosis. The objective of the present study was to discuss the different protocols and to review other models proposed in the literature.Pregnant ewes underwent a surgical procedure at the 123±2 days gestational age (term=145 days). Three experimental protocols were used: protocol A consisted of 25%, 50% and 75% umbilical cord occlusion (UCO) for 20min. Protocol B consisted of partial 75% UCO until reaching a pH7.10. Protocol C consisted of brief, repetitive complete occlusion until severe acidosis occurred. Hemodynamic and blood gas parameters were compared to those of the stability period before UCO.Protocol A led to a progressive response depending on the degree of occlusion (decrease in fetal heart rate, arterial hypertension and pH). Protocol B led to severe acidosis, although the duration of UCO varied per animal. Protocol C also progressively led to acidosis. We observed high inter individual variability in the acidosis response.Pregnant ewes are a relevant model for exploring fetal response to acidosis. The frequency of UCO and partial or complete occlusion should be adapted to the expected effects. Knowledge of these protocols is important to respect ethical guidelines and to reduce the required number of animals. Moreover, it is important to consider the high individual variability of the acidosis response in the interpretation of the results.

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., Cystic white matter injury is the key pathological substrate of cerebral palsy in preterm infants. Lear et al. show that in fetal sheep cystic injury after severe hypoxia evolved over many weeks, raising the tantalizing possibility that substantial white matter protection may be possible with very delayed interventions., Graphical Abstract

KEY POINTS Brief episodes of severe fetal hypoxia can arise in late gestation as a result of interruption of normal umbilical blood flow Systemic parameters and blood chemistry indicate complete recovery within 1-2 hours, although the long-term effects on fetal brain functions are unknown Fetal sheep were subjected to umbilical cord occlusion (UCO) for 10 min at 131 days of gestation, and then monitored intensively until onset of labour or delivery (

Background Radiofrequency ablation (RFA) is recommended to prevent potential neurological injury or intrauterine foetal death (IUFD) of the co-twin(s) in complicated monochorionic (MC) pregnancies. However, the impacts of various indications on the pregnancy outcome following RFA remain unclear. This study aimed to determine how the indications influence the perinatal outcomes in complicated MC pregnancies undergoing radiofrequency ablation. Methods This was a retrospective cohort study performed in a single centre. All consecutive MC pregnancies treated with RFA between July 2011 and July 2019 were included. The adverse perinatal outcomes and the survival rate were analysed based on various indications. The continuous variables with and without normal distribution were compared between the groups using Student’s t-test and Mann–Whitney U test, respectively, and for categorical variables, Chi-square and Fisher’s exact tests were used. P Results We performed 272 RFA procedures in 268 complicated MC pregnancies, including 60 selective intrauterine growth restriction (sIUGR), 64 twin–twin transfusion syndrome (TTTS), 12 twin reversed arterial perfusion sequence (TRAPs), 66 foetal anomaly and 66 elective foetal reduction (EFR) cases. The overall survival rate of the co-twin was 201/272 (73.9%). The overall technical successful rate was determined at 201/263 (76.7%). The IUFD rate in the co-twin was 20/272 (7.4%). The TTTS group had recorded the lowest survival rate (37/64, 57. 8%), and the survival rate was significantly correlated with Quintero stages (P = 0.029). Moreover, the sIUGR III subgroup had a lower survival rate compared with sIUGR II (55.6%, versus 84.3%). The subgroup of foetal anomaly of gastroschisis or exomphalos had the highest IUFD rate (4/10, 40%), followed by sIUGR III (2/9, 22.2%) and dichorionic triamniotic (DCTA) subgroup (8/46, 17.9%). In EFR group, eight IUFD cases were all coming from the DCTA subgroup and received RFA before 17 weeks. Conclusions The perinatal outcome of RFA was correlated with the indications, with the lowest survival rate in TTTS IV and the highest IUFD incidence in abdominal wall defect followed by sIUGR III. Elective RFA after 17 weeks may prevent IUFD in DCTA pregnancies.

Background: The aim was to evaluate the relationship between the direction of the patent ductus arteriosus (PDA) shunt and the pre- and postductal gradient for arterial blood gas (ABG) parameters in a lamb model of meconium aspiration syndrome (MAS) with persistent pulmonary hypertension of the newborn (PPHN). Methods: PPHN was induced by intermittent umbilical cord occlusion and the aspiration of meconium through the tracheal tube. After delivery, 13 lambs were ventilated and simultaneous 129 pairs of pre- and postductal ABG were drawn (right carotid and umbilical artery, respectively) while recording the PDA and the carotid and pulmonary blood flow. Results: Meconium aspiration resulted in hypoxemia. The bidirectional ductal shunt had a lower postductal partial arterial oxygen tension ([PaO2] with lower PaO2/FiO2 ratio&mdash, 97 &plusmn, 36 vs. 130 &plusmn, 65 mmHg) and left pulmonary flow (81 &plusmn, 52 vs. 133 &plusmn, 82 mL/kg/min). However, 56% of the samples with a bidirectional shunt had a pre- and postductal saturation gradient of &lt, 3%. Conclusions: The presence of a bidirectional ductal shunt is associated with hypoxemia and low pulmonary blood flow. The absence of a pre- and postductal saturation difference is frequently observed with bidirectional right-to-left shunting through the PDA, and does not exclude a diagnosis of PPHN in this model.

Introduction: We sought to assess the incidence of severe neurodevelopmental impairment (NDI) in monochorionic twins treated for twin-twin transfusion syndrome (TTTS) and compare it to the incidence in uncomplicated monochorionic twins. Material and Methods: We included TTTS pregnancies treated by fetoscopic selective laser coagulation (FSLC) or umbilical cord occlusion (UCO) in 2004–2015. Primary outcome was severe NDI defined as cerebral palsy, bilateral blindness or bilateral deafness (ICD-10 diagnoses), and severe cognitive and/or motor delay (assessed by the Ages and Stages Questionnaires [ASQ]). Results: A total of 124 children after TTTS and 98 controls were followed up at 25 months of age (SD 11.4). Severe NDI was found in 8.9% of the TTTS children (10.5% [9/86] after FSLC; 5.3% [2/38] after UCO) compared to 3.1% in the control group (p = 0.10). The odds ratio for severe NDI was 1.8 in cases versus controls (p = 0.37). The total ASQ score was significantly lower in the TTTS group than in controls (p = 0.03) after FSLC (p = 0.03) and after UCO (p = 0.14). Discussion: Children after TTTS appear to have a higher risk of severe NDI and score significantly lower on the ASQ compared to monochorionic twins from uncomplicated pregnancies.

Selective intrauterine growth restriction (sIUGR) is a complication observed in about 10-15% of all monochorionic (MC) pregnancies, causing a significant increase in perinatal mortality and morbidity.To evaluate clinical management options and perinatal outcomes of sIUGR in MC pregnancies monitored in a single tertiary center.A retrospective study was performed on 55-MC pregnancies with sIUGR between January 2012 and May 2018 at the Fetal Medicine Unit of La Paz Hospital. Cases were classified according to the umbilical artery (UA) Doppler pattern as type I (positive end-diastolic flow;Gestational age (GA) at diagnosis was progressively lower with each type. Severe sIUGR cases delivered significantly earlier than type I, showing lower birth weights and higher intertwin biometric discordance. Unintended fetal demise occurred in 14% (6/25) of severe sIUGR pregnancies as opposed to 0% (0/19) in type I,Given the good prognosis of type I sIUGR, expectant management is the first approach to consider. However, due to the poorer clinical evolution of types II and III sIUGR, the decision-making is challenging and needs to be individualized depending on the UA Doppler pattern, GA at diagnosis, severity of growth restriction and biometric discordance, technical issues and parents' preferences.

Objective To compare outcomes between 2 umbilical cord occlusion (UCO) methods: radiofrequency ablation (RFA) versus fetoscopic-guided laser photocoagulation. Methods Retrospective study of all monochorionic diamniotic multiple gestations that underwent UCO with RFA (preferred after 2014) or laser (preferred before 2014). In bivariate analysis, patients treated with RFA were compared with laser. Risk factors for intrauterine fetal demise (IUFD) and 30-day survival of the co-twin were identified, and multiple logistic models were fitted to examine whether the UCO method was associated with these outcomes. Results Of 60 UCO cases, 18 (30%) underwent RFA and 42 (70%) underwent laser surgery. The RFA method was associated with co-twin IUFD after surgery (6/18 [33.3%] vs 1/42 [2.4%], P = 0.0021). In logistic regression models, patients who underwent RFA were more likely than patients who underwent laser to have an IUFD of the co-twin (OR 13.2, 1.23-142.62, P = 0.0331). These patients were also less likely to have 30-day survival of the co-twin, although this was not statistically significant (OR 0.20, 0.04-1.15, P = 0.0710). Conclusion Despite clear technical advantages of RFA compared with laser, we found that RFA appeared to be associated with increased risk of post-procedure fetal demise. Further studies should be conducted to confirm these findings.

We describe two cases of monochorionic twins with severe anemia in the surviving twin after cord occlusion. The first one was a case of discordant malformation (anencephalia) and the second one was a case of early severe selective intrauterine growth restriction type II in a dichorionic triamniotic triplet pregnancy. In both cases, the cord of the occluded fetus had a marginal insertion. Both of them presented hydrops 2 d after the occlusion, having measurements of the peak systolic velocity (PSV) of the middle cerebral artery (MCA) above 1.5 multiples of the median (MoM). In the first one intrauterine transfusion was performed with pretransfusion measurement of fetal hemoglobin of 3.3 g/dL. An extensive area of destruction of brain tissue at the right parietal-temporal-occipital level was diagnosed at 300 weeks. In the second one, expectant management was decided and a grade 3 intraventricular hemorrhage associated with moderate ventriculomegaly was detected at 22 weeks' gestation. We hypothesize that the surviving fetus after the occlusion can become bloodless and hypovolemic when its blood is poured into the placental and umbilical circulation of the occluded twin through the vascular anastomoses between them. It should not be assumed that cord occlusion removes the risk of transfusional brain injury in surviving-cotwins.

Objectives To compare ultrasound-derived resistive indices (RIs) obtained at the level of the thalamus via fast Doppler ultrasound with traditional anterior cerebral artery measures in a model of neonatal hypoxic-ischemic encephalopathy and to correlate each with clinical outcomes. Methods Nine nonhuman primate neonates underwent no umbilical cord occlusion (n = 3), umbilical cord occlusion without hypothermia (n = 3), or umbilical cord occlusion with hypothermia (n = 3). The RI was measured in the anterior cerebral artery and thalamus on days 0, 1, and 4 of life. Magnetic resonance imaging with spectroscopy was performed on day 4. Results Mean thalamus and anterior cerebral artery RI values in the first 36 hours of life were statistically different in neonates who died (+0.13; P = .019) or developed cerebral palsy (−0.08; P = .003). Thalamic RI values showed stronger associations with serum and spectroscopic lactate values than those in the anterior cerebral artery. The umbilical cord occlusion-with-hypothermia group showed a significant increase in the RI in the thalamus but not the anterior cerebral artery. Conclusions Resistive index measurements in the thalamus may eventually supplement other bedside measures for predicting outcomes in the HIE population, but further studies need to differentiate the effect of hypothermia from illness severity on thalamic perfusion.

Introduction: Ultrasound-guided bipolar umbilical cord occlusion (UCO) is used in complicated monochorionic multiple pregnancies in Denmark. The aim of this study was to assess a learning curve in the procedure of UCO. Materials and Methods: One hundred and two monochorionic pregnancies treated with UCO at Rigshospitalet, Denmark between 2004 and 2015 were included. The procedures were divided into period 1 (2004-2009) and period 2 (2010-2015) to determine a learning curve. Primary outcome measure was survival rate. Secondary outcome measures were time from operation to fetal loss and gestational age (GA) at delivery. Results: Period 1 included 59 cases. The median GA at procedure was 19.9 weeks (range 16.7-25.9) and at delivery 34.7 weeks (range 24.3-40.3). Period 2 included 43 cases. The median GA at procedure was 20.7 weeks (range 16.7-27.6) and at delivery 37.3 weeks (range 29.1-40.3). Survival rate increased from 78% (period 1) to 95% (period 2) (p = 0.02). GA at delivery increased as well. Fetal death within 48 h after surgery decreased from 4 (period 1) to 0 (period 2). Discussion: Our results suggest a learning curve in the procedure of UCO with improved outcome on all measures.

Umbilical vein varix (UVV) is a very rare cord anomaly associated with intrauterine fetal death and fetal anomaly. We describe a case of extra-abdominal UVV with thrombosis. UVV was diagnosed at 23 weeks of gestation for the first time by ultrasonographic screening. Peak systolic velocity (PSV) near the UVV was partially increased up to about 100 cm/s, and blood flow was not detected in one of the umbilical arteries at 28 weeks of gestation. Therefore, the mother was hospitalized to monitor alterations of the PSV of the UVV frequently. Because the PSV of the UVV showed a sudden rapid increase up to about 150 cm/s at 32 weeks of gestation, she underwent emergent cesarean section on the same day to avoid sudden umbilical cord occlusion. The infant’s birth weight was 1,744 g, and the Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. The pathological examination showed UVV with thrombosis and an occlusion in one of the umbilical arteries. The neonatal laboratory data showed no coagulopathy. Based on our experience with this case, frequent ultrasonographic examination should be performed to detect the acute thrombosis in the case of extra-abdominal UVV, especially during the preterm period.

The purpose of this study was to compare the regional distribution of apoptotic cells in the near term ovine fetal brain caused by prolonged moderate hypoxia, as seen in placental insufficiency, and intermittent severe hypoxia, as seen in umbilical cord compression, which may then contribute to adverse neurodevelopment in the postnatal life. We hypothesized that apoptosis in the fetal brain will be increased in response to both prolonged moderate hypoxia and intermittent severe hypoxia. Twenty-one near term (126-127 days) sheep were divided into 3 groups: control (CON; n = 7), placental embolization (EMB; n = 7), and umbilical cord occlusion (UCO; n = 8). The EMB group had microsphere injections into the umbilical arterial circulation until the oxygen content was at 50% of baseline value. The UCO group had complete cord occlusion for 2 minutes every hour, 6 times a day for 2 consecutive days. At 4 pm on day 2, the animals were euthanized; fetal brains were fixed and prepared for apoptosis staining using the terminal uridine deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay method. In the cerebellar white matter, there was a 3-fold increase in the number of TUNEL positive cells per 1000 cells in both EMB and UCO animals as compared to CON (P = .017). There was also a significant increase in the frontal cortical grey matter (layers 1-3) in EMB animals as compared to CON (P = .014). As such, apoptosis in the near term fetal sheep brain is altered with both sustained moderate hypoxia and intermittent severe hypoxia in the latter part of pregnancy, with potential for long-term neurological sequelae.

Objective The aim of fetal heart rate monitoring during labour is to identify and prevent foetal distress, but its evaluation is not perfect. Fetal scalp blood sampling for pH measurement is one of the second-line methods of monitoring when fetal heart rate is classified as suspicious. This study aims to determine when pH testing should be performed after a prolonged deceleration. Study design This was an experimental study in a fetal sheep model. A partial umbilical cord occlusion was performed for seven minutes followed by a recuperation period of 30 min. Hemodynamic parameters (heart rate, mean blood pressure and intra-amniotic pressure) and blood gases were recorded before occlusion (T0), during occlusion (T4), just after the end of occlusion (T7), and then 10, 20 and 30 min after occlusion (T17, T27 and T37 respectively). Results Ten experiments were carried out. During partial cord occlusion, the fetal pH decreased significantly to acidosis. After a prolonged deceleration with fetal acidosis, the pH recovered to a normal value, defined by a pH greater than or equal to 7.25, after 20 min of recuperation. Conclusion After a prolonged deceleration, fetal pH normalizes between 20 and 30 min thereafter. Thus, if a foetal blood sample is indicated, this delay must be respected in order to avoid inducing an unnecessary intervention decision.

Introduction The inconclusive clinical results for ST-waveform analysis (STAN) in detecting fetal hypoxemia may be caused by the signal processing of the STAN-device itself. We assessed the performance of a clinical STAN device in signal processing and in detecting hypoxemia in a fetal sheep model exposed to prolonged umbilical cord occlusion (UCO). Methods Eight fetal lambs were exposed to 25 minutes of UCO. ECG recordings were analyzed during a baseline period and during UCO. STAN-event rates and timing of episodic T/QRS rise, baseline T/QRS rise and the occurrence of biphasic ST-waveforms, as well as signal loss, were assessed. Results During baseline conditions of normoxemia, a median of 40 (IQR, 25–70) STAN-events per minute were detected, compared to 10 (IQR, 2–22) during UCO. During UCO STAN-events were detected in five subjects within 10 minutes and in six subjects after 18 minutes, respectively. Two subjects did not generate any STAN-event during UCO. Biphasic ST event rate was reduced during UCO (median 0, IQR 0–5), compared to baseline (median 32, IQR, 6–55). ST-waveforms could not be assessed in 62% of the recording time during UCO, despite a good quality of the ECG signal. Conclusions The STAN device showed limitations in detecting hypoxemia in fetal sheep after prolonged UCO. The STAN device produced high false positive event rates during baseline and did not detect T/QRS changes adequately after prolonged fetal hypoxemia. During 14% of baseline and 62% of the UCO period, the STAN-device could not process the ECG signal, despite its good quality. Resolving these issues may improve the clinical performance of the STAN device.

Magnesium sulphate is a standard therapy for eclampsia in pregnancy and is widely recommended for perinatal neuroprotection during threatened preterm labour. MgSO4 is a vasodilator and negative inotrope. Therefore the aim of this study was to investigate the effect of MgSO4 on the cardiovascular and cerebrovascular responses of the preterm fetus to asphyxia. Fetal sheep were instrumented at 98 ± 1 days of gestation (term = 147 days). At 104 days, unanaesthetised fetuses were randomly assigned to receive an intravenous infusion of MgSO4 (n = 6) or saline (n = 9). At 105 days all fetuses underwent umbilical cord occlusion for 25 min. Before occlusion, MgSO4 treatment reduced heart rate and increased femoral blood flow (FBF) and vascular conductance compared to controls. During occlusion, carotid and femoral arterial conductance and blood flows were higher in MgSO4-treated fetuses than controls. After occlusion, fetal heart rate was lower and carotid and femoral arterial conductance and blood flows were higher in MgSO4-treated fetuses than controls. Femoral arterial waveform height and width were increased during MgSO4 infusion, consistent with increased stroke volume. MgSO4 did not alter the fetal neurophysiological or nuchal electromyographic responses to asphyxia. These data demonstrate that a clinically comparable dose of MgSO4 increased FBF and stroke volume without impairing mean arterial pressure (MAP) or carotid blood flow (CaBF) during and immediately after profound asphyxia. Thus, MgSO4 may increase perfusion of peripheral vascular beds during adverse perinatal events.

Changes in fetal heart rate variability (FHRV) and ST segment elevation (measured as the T/QRS ratio) are used to evaluate fetal adaptation to labour. The sympathetic nervous system (SNS) is an important contributor to FHRV under healthy normoxic conditions, and is critical for rapid support of blood pressure during brief labour-like asphyxia. However, although it has been assumed that SNS activity contributes to FHRV during labour; this has never been tested, and it is unclear whether the SNS contributes to the rapid increase in T/QRS ratio during brief asphyxia. Thirteen chronically instrumented fetal sheep at 0.85 of gestation received either chemical sympathectomy with 6-hydroxydopamine (6-OHDA; n = 6) or sham treatment (control; n = 7), followed 4-5 days later by 2 min episodes of complete umbilical cord occlusion repeated every 5 min for up to 4 h, or until mean arterial blood pressure fell to

We have determined the change in immunoreactivity (IR) for microtubule-associated protein 2 (MAP-2) and synaptophysin (SYN) as markers for dendritic and presynaptic nerve development, respectively, in the ovine fetal brain with advancing gestation and in response to intermittent umbilical cord occlusion (UCO), which might then contribute to adverse neurodevelopment. Fetal sheep (control and experimental groups preterm at 111-115 and near term at 132-138 days of gestation; term = 145 days) were studied over 4 days with UCOs performed by inflation of an occluder cuff for 90 seconds every 30 minutes for 3 to 5 hours each day. Animals were then euthanized and fetal brains assessed for IR of MAP-2 and SYN. In control animals, the IR of SYN increased in the gray matter with advancing gestation consistent with a developmental increase in presynaptic vesicles and/or nerve terminals as expected; however, the IR of MAP-2 decreased in all brain regions studied, suggesting concurrent refinement in dendritic branching and spine development. Intermittent UCO as studied with marked but limited hypoxemia resulted in a decrease in IR of SYN for the brain regions of the preterm animals when protein turnover is higher and indicates decreased presynaptic vesicle formation; whereas, MAP-2 IR was selectively increased in the hippocampus CA1 and thalamus of the near-term animals, consistent with reactive dendritic change and heightened vulnerability for neuronal injury. As such, intermittent cord compressions in the ovine fetus can impact protein markers for dendritic and presynaptic nerve development depending on their timing, which might then lead to alterations in synapse formation and neuronal circuitry.

In this study, we tested the hypothesis that cerebral hypoperfusion after asphyxia and induced hypothermia is associated with reduced circulating nitrite levels as an index of nitric oxide synthase (NOS) activity. The preterm fetal sheep at 0.7 gestation (103-104 days, term = 147 days) received 25-minute umbilical cord occlusion, followed by mild whole-body cooling from 30 minutes to 72 hours after occlusion. Occlusion and induced hypothermia were independently associated with reduced carotid vascular conductance (CaVC) from 2 to 72 hours, and with transiently suppressed plasma nitrite levels at 6 hours. There was a significant within-subjects correlation (r(2) = 0.33, P = .002) between CaVC and plasma nitrite values in the first 24 hours after occlusion but not after sham occlusion. These findings suggest that in preterm fetal sheep, changes in NOS activity are an important mediator of changes in carotid vascular tone in the early recovery phase after asphyxia and may help mediate some of the vascular effects of induced hypothermia.

Melatonin (MLT) is an endogenous hormone that controls circadian cycle. MLT has additional important properties that make it appealing as a neuroprotective agent—it is a potent anti-oxidant, with anti-apoptotic and anti-inflammatory properties. MLT is safe for administration during pregnancy or to the newborn after birth, and can reduce white matter brain injury under conditions of chronic fetal hypoxia. Accordingly, in the current study, we examined whether an intermediate dose of MLT could restore white matter brain development when administered after an acute hypoxic ischemic (HI) insult in preterm fetal sheep. Fifteen fetal sheep at 95–98 days gestation were instrumented with femoral artery and vein catheters, and a silastic cuff placed around the umbilical cord. At 102 days gestation, the cuff was inflated, causing complete umbilical cord occlusion for 25 min in 10 fetuses, to induce acute severe HI. Five HI fetuses received intravenous MLT for 24 h beginning at 2 h after HI. The remaining five fetuses were administered saline alone. Ten days after HI, the fetal brain was collected from each animal and white and gray matter neuropathology assessed. HI caused a significant increase in apoptotic cell death (TUNEL+), activated microglia (Iba-1+), and oxidative stress (8-OHdG+) within the subventricular and subcortical white matter. HI reduced the total number of oligodendrocytes and CNPase+ myelin density. MLT administration following HI decreased apoptosis, inflammation and oxidative stress within the white matter. MLT had intermediate benefits for the developing white matter: it increased oligodendrocyte cell number within the periventricular white matter only, and improved CNPase+ myelin density within the subcortical but not the striatal white matter. MLT administration following HI was also associated with improved neuronal survival within the cortex. Neuropathology in preterm infants is complex and mediated by multiple mechanisms, including inflammation, oxidative stress and apoptotic pathways. Treatment with MLT presents a safe approach to neuroprotective therapy in preterm infants but appears to have brain region-specific benefits within the white matter.

Selective intrauterine growth restriction (sIUGR) occurs in 10 to 15% of monochorionic (MC) twins, and it is associated with a substantial increase in perinatal mortality and morbidity. Clinical evolution is largely influenced by the existence of intertwin placental anastomoses: pregnancies with similar degrees of fetal weight discordance are associated with remarkable differences in clinical behavior and outcome. We have proposed a classification of sIUGR into three types according to umbilical artery (UA) Doppler findings (I-normal, II-absent/reverse end-diastolic flow, III-intermittent absent/reverse end-diastolic flow), which correlates with distinct clinical behavior, placental features and may assist in counseling and management. In terms of prognosis, sIUGR can roughly be divided in two groups: type I cases, with a fairly good outcome, and types II and III, with a substantial risk for a poor outcome. Management of types II and III may consist in expectant management until deterioration of the IUGR fetus is observed, with the option of cord occlusion if this occurs before viability. Alternatively, active management can be considered electively, including cord occlusion or laser coagulation. Both therapies seem to increase the chances of intact survival of the larger fetus, while they entail, or increase the chances of, intrauterine demise of the IUGR fetus. Copyright © 2010 John Wiley & Sons, Ltd., E.E. is supported by a Rio Hortega research fellowship from the Spanish Fondo de Investigaciones Sanitarias.

BACKGROUNDWhite matter brain injury in preterm infants can induce neurodevelopmental deficits. Umbilical cord blood (UCB) cells demonstrate neuroprotective properties, but it is unknown whether cells obtained from preterm cord blood (PCB) vs. term cord blood (TCB) have similar efficacy. This study compared the ability of TCB vs. PCB cells to reduce white matter injury in preterm fetal sheep.METHODSHypoxia-ischemia (HI) was induced in fetal sheep (0.7 gestation) by 25 min umbilical cord occlusion. Allogeneic UCB cells from term or preterm sheep, or saline, were administered to the fetus at 12 h after HI. The fetal brain was collected at 10-day post HI for assessment of white matter neuropathology.RESULTSHI (n=7) induced cell death and microglial activation and reduced total oligodendrocytes and CNPase+myelin protein in the periventricular white matter and internal capsule when compared with control (n=10). Administration of TCB or PCB cells normalized white matter density and reduced cell death and microgliosis (P0.05). PCB prevented upregulation of plasma tumor necrosis factor (TNF)-a, whereas TCB increased anti-inflammatory interleukin (IL)-10 (P0.05). TCB, but not PCB, reduced circulating oxidative stress.CONCLUSIONSTCB and PCB cells reduced preterm HI-induced white matter injury, primarily via anti-inflammatory actions. The secondary mechanisms of neuroprotection appear different following TCB vs. PCB administration.

T/QRS ratio monitoring is used to help identify fetal asphyxia. However, immature animals have greater capacity to maintain blood pressure during severe asphyxia, raising the possibility that they may show an attenuated T/QRS increase during asphyxia. Chronically instrumented fetal sheep at 0.6 of gestation (0.6 GA;n= 12), 0.7 GA (n= 12), and 0.8 GA (n= 8) underwent complete umbilical cord occlusion for 30 min, 25 min, or 15 min, respectively. Cord occlusion was associated with progressive metabolic acidosis and initial hypertension followed by severe hypotension, with a more rapid fall in mean arterial blood pressure (MAP) and carotid blood flow (CaBF) with advancing gestation. T/QRS ratio rose after occlusion more rapidly at 0.8 GA than in immature fetuses, to a similar final peak at all ages, followed by a progressive fall that was slower at 0.8 GA than in the immature fetuses. The increase in T/QRS ratio correlated with initial hypertension at 0.8 GA (P<0.05,R2= 0.38), and conversely, its fall correlated closely with falling MAP in all gestational groups (P<0.01,R2= 0.67). In conclusion, elevation of the T/QRS ratio is an index of onset of severe asphyxia in the last third of gestation, but not of fetal compromise.

BackgroundIn neonates requiring chest compression (CC) during resuscitation, neonatal resuscitation program (NRP) recommends against relying on a single feedback device such as end-tidal carbon dioxide (ETCO2) or saturations (SpO2) to determine return of spontaneous circulation (ROSC) until more evidence becomes available.MethodsWe evaluated the role of monitoring ETCO2 during resuscitation in a lamb model of cardiac arrest induced by umbilical cord occlusion (n = 21). Lambs were resuscitated as per NRP guidelines. Systolic blood pressure (SBP), carotid and pulmonary blood flows along with ETCO2 and blood gases were continuously monitored. Resuscitation was continued for 20 min or until ROSC (whichever was earlier). Adequate CC was arbitrarily defined as generation of 30 mmHg SBP during resuscitation. ETCO2 thresholds to predict adequacy of CC and detect ROSC were determined.ResultsSignificant relationship between ETCO2 and adequate CC was noted during resuscitation (AUC-0.735, P < 0.01). At ROSC (n = 12), ETCO2 rapidly increased to 57 ± 20 mmHg with a threshold of ≥32 mmHg being 100% sensitive and 97% specific to predict ROSC.ConclusionIn a large mammalian model of perinatal asphyxia, continuous ETCO2 monitoring predicted adequacy of CC and detected ROSC. These findings suggest ETCO2 in conjunction with other devices may be beneficial during CC and predict ROSC.

The current guidelines recommend the use of 100% O2 during resuscitation of a neonate requiring chest compressions (CC). Studies comparing 21% and 100% O2 during CC were conducted in postnatal models and have not shown a difference in incidence or timing of return of spontaneous circulation (ROSC). The objective of this study is to evaluate systemic oxygenation and oxygen delivery to the brain during CC in an ovine model of perinatal asphyxial arrest induced by umbilical cord occlusion. Pulseless cardiac arrest was induced by umbilical cord occlusion in 22 lambs. After 5 min of asystole, lambs were resuscitated with 21% O2 as per Neonatal Resuscitation Program (NRP) guidelines. At the onset of CC, inspired O2 was either increased to 100% O2 (n = 25) or continued at 21% (n = 9). Lambs were ventilated for 30 min post ROSC and FiO2 was gradually titrated to achieve preductal SpO2 of 85&ndash, 95%. All lambs achieved ROSC. During CC, PaO2 was 21.6 &plusmn, 1.6 mm Hg with 21% and 23.9 &plusmn, 6.8 mm Hg with 100% O2 (p = 0.16). Carotid flow was significantly lower during CC (1.2 &plusmn, 1.6 mL/kg/min in 21% and 3.2 &plusmn, 3.4 mL/kg/min in 100% oxygen) compared to baseline fetal levels (27 &plusmn, 9 mL/kg/min). Oxygen delivery to the brain was 0.05 &plusmn, 0.06 mL/kg/min in the 21% group and 0.11 &plusmn, 0.09 mL/kg/min in the 100% group and was significantly lower than fetal levels (2.1 &plusmn, 0.3 mL/kg/min). Immediately after ROSC, lambs ventilated with 100% O2 had higher PaO2 and pulmonary flow. It was concluded that carotid blood flow, systemic PaO2, and oxygen delivery to the brain are very low during chest compressions for cardiac arrest irrespective of 21% or 100% inspired oxygen use during resuscitation.

Background and Purpose— Electroencephalographic recovery is predictive of outcome after perinatal hypoxia–ischemia, but it is unknown whether early changes in electroencephalographic can predict the response to therapeutic hypothermia in the preterm brain. Methods— 0.7 gestation fetal sheep received umbilical cord occlusion or sham occlusion for 25 minutes, followed by sham hypothermia or whole-body cooling started either 30 minutes or 5 hours after occlusion and continued for 72 hours. Results— Early but not delayed hypothermia reduced neuronal loss and microglial induction in the striatum, with faster recovery of spectral edge frequency, reduced seizure burden, and less suppression of electroencephalographic amplitude ( P Conclusions— Recovery of higher electroencephalographic frequencies may be a biomarker of effective hypothermic neuroprotection in the preterm-equivalent brain.

During labor and delivery, variable decelerations in the fetal heart rate (FHR) are commonly seen on the cardiotocogram (CTG) that is used to monitor fetal welfare. These decelerations are often induced by umbilical cord compression from uterine contractions. Via changes in oxygenation and blood pressure, umbilical cord compression activates the chemo- and baroreceptor reflex, and thus affects FHR. Since the relation between the CTG and fetal oxygenation is complex, assessment of fetal welfare from the CTG is difficult. We investigated umbilical cord compression-induced variable decelerations with a mathematical model. For this purpose, we extended our model for decelerations originating from caput compression and reduced uterine blood flow with the possibility to induce umbilical venous, arterial and total cord occlusion. Model response during total occlusion is evaluated for varying contractions (duration and amplitude) and sensitivity of the umbilical resistance to the uterine pressure. A clinical scenario is used to simulate a labor CTG with variable decelerations. Simulation results show that fetal mean arterial pressure increases during umbilical cord occlusion, while fetal oxygenation drops. There is a clear relation between these signals and the resulting FHR. The extent of umbilical compression and thus FHR deceleration is positively related to increased contraction duration and amplitude, and increased sensitivity of the umbilical resistance to uterine pressure. No relation is found between contraction interval and FHR response, which can probably be ascribed to the lack of catecholamines in the model. The simulation model provides insight into the complex relation between uterine pressure, umbilical cord compression, fetal oxygenation, blood pressure and heart rate. The model can be used for individual learning, and incorporated in a simulation mannequin, be used to enhance obstetric team training.

Hypoxia can significantly contribute to the development of permanent brain injury in the term neonate; however the response of cerebral blood vessels is not well understood. This study aimed to quantitatively measure vascular density and morphology using laminin immunohistochemistry as a marker of blood vessels, and determine the effects of a single, severe bout of hypoxia (umbilical cord occlusion, UCO) late in gestation on the developing cerebrovasculature in fetal sheep. At 124-126 days gestation singleton fetal sheep underwent surgery for implantation of catheters and placement of an inflatable cuff around the umbilical cord. A 10 min UCO or sham UCO (n=5) occurred at 132 days gestation. Fetal brains were collected at 24 h (n=5) or 48 h (n=4) after UCO for vascular density and morphology analysis of laminin immunohistochemistry. 48 h following a single, brief bout of severe hypoxia late in gestation decreased vascular density was seen in the caudate nucleus and no changes in vascular morphology occurred. However closer analysis revealed a significant shift in the frequency of smaller (≤10 μm) to larger (≤100 μm) perimeter blood vessels in periventricular and subcortical white matter. Close examination of the frequency distribution of vascular perimeter highlights that alterations in vascular morphology persist in the near term fetal brain for up to 48 h following a brief (10 min) hypoxia in white but not gray matter. These findings suggest that the near term brain may still be vulnerable to white matter injury following in utero hypoxia.

New Findings • What is the central question of this study? Dopamine is commonly used for blood pressure support in the neonate, but there is limited empirical evidence that it prevents hypotension or improves survival after asphyxia. • What is the main finding and its importance? Dopamine infusion delayed but did not prevent terminal hypotension after severe asphyxia in near-term fetal sheep. We also demonstrate that hypotension is directly associated with exacerbated brain swelling, strongly supporting the concept that better ways of protecting the brain from hypotension during recovery from asphyxia are essential. Dopamine is commonly used for blood pressure support in the neonate, but has limited empirical evidence to support its use. We tested the hypothesis that after near-terminal asphyxia in utero, dopamine infusions would prevent secondary hypotension. Fetal sheep (122–129 days of gestation; term is 147 days) received umbilical cord occlusion for 15 min or sham occlusion (n = 5). If the mean arterial blood pressure fell below 90% of baseline within 6 h after occlusion, fetuses were randomized to either dopamine infusion starting at 4 μg kg−1 min−1 and titrated according to mean arterial blood pressure up to a maximum of 40 μg kg−1 min−1 (n = 5) or to the same volume of normal saline (n = 5). Dopamine infusion, initiated at a median of 180 min after occlusion (range 96–280 min), was associated with a marked but transient increase in mean arterial blood pressure and fall in femoral blood flow compared with saline. Terminal hypotension developed later in four of the five fetuses that received maximal dopamine infusions than in five of five receiving saline infusion [517 (range 240–715) versus 106 min (range 23–497) after the start of infusions, P

Umbilical cord occlusion (UCO) is a hypoxic insult that has been used to model birth asphyxia and umbilical cord compression in utero. UCO triggers vigorous neural and endocrine responses that include increased plasma ACTH and cortisol concentrations, increased blood pressure (BP), and decreased heart rate (HR). We have previously reported that ketamine, a noncompetitive N‐methyl‐D‐aspartate receptor antagonist, can modify the fetal hemodynamic and ACTH responses to ventilatory hypoxia and cerebral ischemia‐reperfusion. We performed the present experiments to test the hypothesis that ketamine has similar effects on the neuroendocrine and cardiovascular responses to UCO. Fetal sheep were chronically catheterized at gestational day 125. Ketamine (3 mg/kg) was administered intravenously to the fetus 10 min prior to the insult. UCO was induced for 30 min by reducing the umbilical vein blood flow until fetal PaO2 levels were reduced from 17 ± 1 to 11 ± 1 mm Hg. UCO produced an initial increase on fetal BP in both control and ketamine groups ( P = 0.018 time), followed by a decrease in the control group, but values remained higher with ketamine. HR decreased after UCO ( P = 0.041 stimulus*time) in both groups, but the reduction was greater initially in control compared to ketamine groups. Fetal PaCO2 levels increased after UCO ( P < 0.01 stimulus*time), but values were higher in the control versus ketamine groups. UCO significantly decreased fetal pH values ( P < 0.01 stimulus*time) with a greater effect on the control versus ketamine group. Ketamine delayed the cortisol responses to UCO ( P < 0.001 stimulus*time), and UCO produced a robust increase in ACTH levels from 19 ± 2 to 280 ± 27 pg/mL ( P < 0.001 stimulus*time), but there were no differences in ACTH levels between UCO groups. We conclude that ketamine augmented the cardiovascular response to UCO, but did not alter the ACTH response to UCO.

Introduction: Umbilical cord occlusion (UCO) utilizing laser photocoagulation is often not considered an option for selective termination after 20 weeks of gestation due to reported limitations of the procedure because of umbilical cord size. We compared outcomes after laser umbilical cord occlusion (L-UCO) before and after 20 weeks of gestation. Materials and Methods: We examined all patients with monochorionic- diamniotic twins and higher-order multiples (monoamniotic excluded) that underwent L-UCO at our facility between 2006 and 2014. Statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests as appropriate. Results: Of 43 L-UCO cases, 11 cases (25.6%) had a discordant anomaly, and 32 cases (74.4%) had twin reversed arterial perfusion (TRAP) sequence. We achieved complete vascular occlusion in 100% (43/43) of cases of attempted L-UCO. There were 22 cases (51.2%) with gestational age ≤20 weeks, and 21 cases (48.8%) with gestational age >20 weeks. Perioperative patient characteristics and outcomes did not differ between the two groups. Survival rates were 90.9% (20/22) and 100% (21/21) at ≤20 weeks of gestation and >20 weeks of gestation, respectively. Discussion: The results of this study suggest that L-UCO is a reasonable surgical modality for patients prior to and beyond 20 weeks of gestation.

Infants born very preterm are at high risk for neurological deficits including cerebral palsy. In this study we assessed the neuroprotective effects of umbilical cord blood cells (UCBCs) and optimal administration timing in a fetal sheep model of preterm brain injury. 50 million allogeneic UCBCs were intravenously administered to fetal sheep (0.7 gestation) at 12h or 5d after acute hypoxia-ischemia (HI) induced by umbilical cord occlusion. The fetal brains were collected at 10d after HI. HI (n=7) was associated with reduced number of oligodendrocytes (Olig2+) and myelin density (CNPase+), and increased density of activated microglia (Iba-1+) in cerebral white matter compared to control fetuses (P

Twin–twin transfusion syndrome is characterized by unequal blood exchange from the donor twin to the recipient co-twin through placental vascular anastomoses. Treatment of twin–twin transfusion syndrome consists of serial amnioreduction, septostomy, laser photocoagulation of placental vessels and umbilical cord occlusion of the apparently sick twin. Amnioreduction reduces maternal discomfort due to polyhydramnios and improves fetal circulation by reducing amniotic fluid pressure on the placenta. Septostomy equalizes amniotic fluid pressure between the two gestational sacs. Laser therapy interrupts intertwin blood shunting and restores two independent circulations. Umbilical cord occlusion is offered when signs of imminent death are present, such as hydrops and cardiac failure. Laser therapy is associated with increased neonatal survival rates and lower risk of adverse outcomes compared with other treatments.