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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 weight <10th 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, 45 via SLPCV and nine via UCO. Of the 45 SLPCV cases, there were 16 (35.6%) with SIUGR twin (and dual) survival. SIUGR twin survival appeared associated with middle cerebral artery (MCA) peak systolic velocity (psv) <1.5 multiples of the median, and forward atrial systolic flow in the ductus venosus (DV). In a post hoc analysis, we subsequently categorized patients as: SIUGR type IIa (N = 32 (71.1%)): normal MCA psv, and normal DV waveform, versus SIUGR type IIb (N = 13 (28.9%)): MCA psv ≥1.5 multiples of the median, and/or DV with absent or reversed atrial systolic flow. Thirty-day survival of the SIUGR twin was 50% for type IIa and 0% for type IIb. Over 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. Post hoc exploration and subclassification of SIUGR type II patients by preoperative Doppler indices created two groups, one (type IIa) with 50% survival and one (type IIb) with 0% survival of the SIUGR twin after laser surgery. Upon further confirmation, these findings may provide guidance for counseling patients and conducting fetal therapy. [ABSTRACT FROM AUTHOR]

Introduction: 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.Objective: To evaluate clinical management options and perinatal outcomes of sIUGR in MC pregnancies monitored in a single tertiary center.Methods: 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; n = 25), type II [persistently absent or reversed end-diastolic flow (AREDF); n = 5] and type III [intermittently absent or reversed end-diastolic flow (iAREDF); n = 25]. Types II and III were then merged together as severe sIUGR cases. Subsequently, two possible approaches were considered: expectant management (EM) with elective preterm delivery in case of fetal deterioration, or in-utero therapy via fetoscopic laser photocoagulation (FLP) of intertwin anastomosis or selective umbilical cord occlusion (CO) of the growth-restricted fetus.Results: 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, p = .028. A significantly higher proportion of twins was admitted in NICU in severe cases when compared to type I [87% (33/38) versus 47% (18/38), p < .001]. In addition, brain damage at birth was also found to be more prevalent in this group [21% (8/38) versus 11% (4/38), p = .346], especially in the larger twin, when comparing any short-term neurological sequel [30% (7/23) versus 0% (0/19), p = .011] or specifically periventricular leukomalacia [PVL; 22% (5/23) versus 0% (0/19), p = .053]. Although the overall mortality rate was significantly higher in severe sIUGR that underwent CO instead of EM [58% (7/12) versus 11% (4/36), p = .002], NICU admissions were higher in the latter [94% (17/18) versus 40% (2/5), p = .021]. Neurological sequels at birth were similar in both groups [39% (7/18) versus 40% (2/5), p = 1.000], similarly when considering only the larger twin for any brain lesion [28% (5/18) versus 40% (2/5), p = .621] or just PVL [22% (4/18) versus 20% (1/5), p = 1.000].Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective: To determine if a model of acidosis caused by occlusion of the umbilical cord could be repeated in the same sheep in ethicaly order to reduce the number of animals needed. Method: To obtain fetal acidosis, 1 min of total umbilical cord occlusion (UCO) every 2.5 min was performed on fetal sheep (n=7) until pH reached 7.10. Chronic instrumentation regularly recorded arterial blood gas and hemodynamic parameters. The occlusions were repeated to compare the data between the 2 days for each animal. Results: At the end of the UCO period, fetal acidosis was obtained with a pH 7.14 on day 1 (D1) and 7.06 on day 2 (D2). At baseline, fetuses were more hypotensive at D2 (41 mmHg vs 44 mmHg on D1, p < 0.05). During the UCO period, there was no significant difference in blood gas and hemodynamic data between D1 and D2. Conclusion: To reduce the number of animals needed, performing a second experiment on the same animal appears possible even if results must be interpreted cautiously when severe acidosis is reached.

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 < 0.05 indicated a significant difference.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. [ABSTRACT FROM AUTHOR]

Background: Umbilical cord occlusion via radiofrequency ablation (RFA) is utilized to maximize outcomes of the co-twin in complicated multifetal monochorionic (MC) gestations. However, post-procedure co-twin fetal demise is of concern.Objective: The aim of this study was to determine risk factors for co-twin fetal demise following RFA.Methods: This is a retrospective study of MC multiples that underwent RFA. Indications for RFA included twin reversed arterial perfusion (TRAP) sequence, selective fetal growth restriction (sFGR) type II, discordant lethal anomalies, and twin-twin transfusion syndrome (TTTS) with proximate placental cord insertion sites. The primary outcome was co-twin fetal demise. Bivariate analyses and multiple logistic regression modeling of identified risk factors were conducted.Results: Of 36 patients studied, surgical indications were: TRAP (n = 15, 41.7%), sFGR (n = 10, 27.8%), discordant anomalies (n = 9, 25.0%), and TTTS (n = 2, 5.6%). Nine patients (25.0%) experienced a co-twin fetal demise. In multiple logistic regression analysis, fetal growth restriction (FGR) of one co-twin was associated with increased risk of co-twin fetal demise (OR = 10.85, 95% CI 1.03-114.48, p = 0.0474) and a preoperative diagnosis of TRAP was protective against fetal demise (OR = 0.06, 95% CI 0.00-0.84, p = 0.0368).Conclusion: Co-twin FGR was associated with an increased risk of post-RFA demise. When compared to other indications, patients with TRAP sequence were less likely to have a co-twin demise. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

Key points: The cerebral response to fetal asphyxia is characterized by an upregulation of nucleic acid and chromatin modification processes, as well as a downregulation of metabolic processes at 1 h post‐umbilical cord occlusion (UCO).Twenty‐four hours post UCO, there was an upregulation of metabolic processes and protein modifications.UCO did not alter bacterial gene expression levels, nor did it produce a robust inflammatory response compared to maternal hypoxia.The administration of ketamine produced minimal effects on the fetal response to UCO in the cerebral cortex. Umbilical cord occlusion (UCO) is known to cause neurological disorders in the neonate. Previously, we have reported that hypoxic hypoxia (HH) stimulates the appearance of bacteria in the fetal brain and upregulates the expression of inflammatory markers in fetal cerebral cortex (CTX) and also that ketamine attenuates these responses. In the present study, we aimed to test the hypothesis that UCO, similar to HH, produces an inflammatory response in the fetal CTX and also that treatment with ketamine reduces these effects. In chronically instrumented fetal sheep (∼125 days), 30 min of partial UCO decreased fetal PaO2 levels by ∼50%. Half of the fetuses received ketamine (3 mg kg–1) 10 min prior to UCO (n = 4 per group). Fetal brains were collected 1 and 24 h after the experiment and mRNA was extracted and hybridized for microarray analyses. Differentially‐expressed genes were analysed for significant association with gene ontologies and pathways. After 1 h, UCO upregulated nucleic acid processing and chromatin modification and downregulated metabolic processes compared to control. After 24 h, UCO upregulated metabolic and protein modification processes. Ketamine produced minimal effects. UCO did not alter the abundance of bacterial DNA in fetal brain, nor did it upregulate inflammation pathways compared to HH. We conclude that UCO produced time‐dependent responses that did not include bacterial invasion or upregulation of inflammation pathways in fetal CTX. This contrasts with the response to HH, which resulted in the appearance of bacteria in the CTX and upregulated inflammation pathways. These responses in fetal CTX to oxygen deprivation are therefore modified by the maternal or placental response to the stimulus. Key points: The cerebral response to fetal asphyxia is characterized by an upregulation of nucleic acid and chromatin modification processes, as well as a downregulation of metabolic processes at 1 h post‐umbilical cord occlusion (UCO).Twenty‐four hours post UCO, there was an upregulation of metabolic processes and protein modifications.UCO did not alter bacterial gene expression levels, nor did it produce a robust inflammatory response compared to maternal hypoxia.The administration of ketamine produced minimal effects on the fetal response to UCO in the cerebral cortex. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

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 Pa CO2 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. [ABSTRACT FROM AUTHOR]

Melatonin has diverse physiological actions in addition to its well-recognized maintenance roles in circadian and seasonal timing. In particular, melatonin may have a direct protective action on the developing fetal brain. We examined the cellular processes by which melatonin provides protection following an acute late gestation hypoxic insult. 15 fetal sheep at 126 days' gestation were instrumented with a brachial artery catheter and a silastic cuff around the umbilical cord. At ∼130 days' gestation, the cuff was inflated for 10 min in 10 fetuses, causing complete umbilical cord occlusion (UCO). 5 UCO fetuses received intravenous melatonin maternally for 2 h, before and after UCO (UCO + melatonin). The remaining 5 fetuses had no UCO performed (sham-operated controls). At 48 h after UCO, the fetal brain was collected from each animal. Compared to controls, UCO caused significant hypoxia, hypercapnia and acidosis in UCO and UCO + melatonin fetuses. In the UCO-alone animals there were significant increases in pyknotic cell death, in the hippocampus (>7-fold) and the cerebellum (3-fold). Maternal melatonin administration ameliorated cellular pyknosis in UCO fetuses. UCO was also associated with astrogliosis, increased albumin uptake, activated microglia and lipid peroxidation. Melatonin prevented these effects. There were no significant differences in the number of brain macrophages or microglia between any of the groups. Following acute severe hypoxia in the late gestation fetus, melatonin reduces neuronal lipid peroxidation and prevents loss of blood-brain barrier integrity and astrogliosis. These are likely key mechanisms underlying the neuroprotective actions of melatonin in the fetal brain. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective To compare the outcomes of a consecutive case series of monochorionic (MC) monoamniotic (MA) discordant twins treated with umbilical cord occlusion and transection, with those of a cohort of MC diamniotic (DA) twins treated with conventional cord occlusion. Methods This study included 17 MCMA twins (12 true MA and five iatrogenic) treated with cord occlusion and transection and a control group of 72 MCDA discordant twins treated during the same period with cord occlusion in a single center. Duration of surgery, rates of preterm delivery (PTD) or preterm premature rupture of membranes (PPROM) <32 weeks and intrauterine fetal demise (IUFD), perinatal outcome and neonatal survival were prospectively recorded in both groups. Results Median durations of surgery were 28.5 (range, 14.0-74.0) min and 24.0 (3.0-60.0) min in the cord transection and control groups, respectively (P = 0.24). There were no significant differences between cord transection and control groups in the rates of PPROM (35.3% vs. 20.8%, P = 0.22), PTD (41.2% vs. 28.2%, P = 0.29), IUFD (0% vs. 2.8%, P = 1.0) and neonatal survival (76.5% vs. 80.6%, P = 1.0). Gestational age at delivery (median 35.0 (24.5-39.0) vs. 37.1 (26.2-41.0) weeks, P = 0.21) and fetal birth weight (2215 (800-3200) g vs. 2605 (588-3830) g, P = 0.51) were similar between study groups. Conclusion Cord occlusion and transection in MCMA discordant twins resulted in similar perinatal outcomes to those of MCDA discordant twins treated with cord occlusion. [ABSTRACT FROM AUTHOR]

Allopregnanolone and related steroids are potent γ-aminobutyric acid receptor-A receptor agonistic allosteric modulators that suppress central nervous system (CNS) activity; in some species, these neurosteroids regulate normal CNS activity before birth. The aims of this study were to determine the effect of suppressing allopregnanolone production on behavioral responses to transient asphyxia in late gestation fetal sheep using the 5α-reductase (R)-2 inhibitor, finasteride. Specificity of the effects of finasteride was assessed by co-infusion of alfaxalone, a synthetic analog of allopregnanolone. Fetal catheters and electrodes for measurement of the electrocorticogram (ECoG) and nuchal electromyogram were implanted at 125 days of gestation, and an inflatable occluder was placed to allow umbilical cord occlusion (UCO). At of gestation, fetuses received carotid arterial infusion of vehicle (2-hydroxypropyl-β-cyclodextrin; 40% w/vol), finasteride (40 mg/kg/h), alfaxalone (5 mg/kg/h), or finasteride+alfaxalone. A further three groups of fetuses were subjected to 5 min UCO at 30 min after the start of each infusion regime. Finasteride treatment alone increased the incidence of arousal-like activity; this was reduced by co-infusion of alfaxalone. After UCO, finasteride treatment caused a prolongation of sub-low voltage (LV) ECoG activity and increase in aberrant ECoG spike activity when compared to vehicle-treated UCO fetuses. After UCO, alfaxalone treatment reduced the incidence of sub-LV, reduced the number of aberrant EEG spikes, and restored ECoG activity to the pattern observed after UCO in vehicle-treated fetuses. These results confirm that neurosteroids significantly modulate normal CNS activity in the late gestation fetus, modify, and limit the effects of asphyxia on the brain. [ABSTRACT FROM AUTHOR]

The aim of this study was to review literature concerning selective feticide (SF) in monochorionic pregnancies complicated with twin-twin transfusion syndrome, twin reversed arterial perfusion, severe malformation, and discordant growth. The remaining twins'' outcomes were stratified for indication and surgical technique. Three hundred forty-five cases of SF were reviewed. Premature rupture of membranes was described in all the procedures and complicated 76/345 (22%) pregnancies within 4 postoperative weeks (59%) or later (41%; P = .52). Fetal demise accounted for 51/345 (15%), more frequently within 2 postoperative weeks (79%) than thereafter (21%; P = .004; odds ratio [OR], 6.12; 95% confidence interval [CI], 1.81-20.70). Improved survival rate was achieved in surgeries after 18 weeks (89%) than earlier (69%; P = .02; OR, 0.28; 95% CI, 0.10-0.80) without differences for indication. Survivors were 86% after radiofrequency ablation, 82% after bipolar cord coagulation, 72% after laser cord coagulation, 70% after cord ligation. In spite of favorable outcomes, the optimal surgical approach remains undetermined. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: Allopregnanolone (AP) is a potent GABAergic agonist that suppresses CNS activity, seizure threshold, and excitotoxicity in the adult brain. AP is present in the fetal sheep brain and increases rapidly after asphyxial insult due to increased 5α-reductase type-2 (5αR-2) expression. The aim of this study was to use finasteride to suppress fetal neurosteroid synthesis, and then determine the effect on brain injury, particularly in the hippocampus, of asphyxia induced in utero by brief occlusion of the umbilical cord. Catheters and an inflatable umbilical cord cuff were implanted in fetal sheep at ∼125 days gestation. Five days later the fetuses received either finasteride (20 mg/kg/h) or vehicle (40% hydroxypropyl-β-cyclodextrin) for 2 h. The umbilical cord was occluded (UCO) for 5 min at 30 min after starting the infusion. The fetal brain was obtained 24 h later for examination of activated caspase-3 expression as an index of apoptosis, and to measure AP content. Finasteride treatment alone significantly reduced AP content and increased the number of caspase-3 positive cells in the hippocampus, cerebellum, and the subcallosal bundle, indicating that AP modulates the normal rate of apoptosis in the developing brain. UCO in vehicle and finasteride-treated fetuses produced a similar, marked decrease in O2 saturation (5.8±0.6%), but after finasteride treatment UCO caused a significantly greater increase in the number of caspase-3 positive cells in the hippocampal cornu ammonis 3 (CA3) (57.3±1.6%) compared with the vehicle-treated fetuses. Thus, 5α-reduced steroids such as AP may be protective in reducing cell death following acute fetal asphyxia. Perturbation of normal fetal neurosteroid levels in late gestation (e.g. due to preterm birth, or maternal synthetic steroid treatment to induce fetal lung maturation) could adversely affect brain development and increase its vulnerability to injury. [Copyright &y& Elsevier]

The preterm fetus is capable of surviving prolonged periods of severe hypoxia without neural injury for much longer than at term. To evaluate the hypothesis that regulated suppression of brain metabolism contributes to this remarkable tolerance, we assessed changes in the redox state of cytochrome oxidase (CytOx) relative to cerebral heat production, and cytotoxic edema measured using cerebral impedance, during 25 min of complete umbilical cord occlusion or sham occlusion in fetal sheep at 0.7 gestation. Occlusion was followed by rapid, profound reduction in relative cerebral oxygenation and EEG intensity and an immediate increase in oxidized CytOx, indicating a reduction in electron flow down the mitochondrial electron transfer chain. Confirming rapid suppression of cerebral metabolism there was a loss of the temperature difference between parietal cortex and body at a time when carotid blood flow was maintained at control values. As occlusion continued, severe hypotension/hypoperfusion developed, with a further increase in CytOx levels to a plateau between 8 and 13 min and a progressive rise in cerebral impedance. In conclusion, these data strongly suggest active regulation of cerebral metabolism during the initial response to severe hypoxia, which may help to protect the immature brain from injury. [ABSTRACT FROM AUTHOR]

Objectives To assess the ability and safety of radiofrequency (RF) to induce cord thermal lesions using in-vitro perfused umbilical cords. Methods Nineteen human term umbilical cords were cannulated at both ends and perfused continuously with saline serum in a saline serum bath (37°C). The RF electrode was then inserted into the cord close to the umbilical vein. Different RF power and temperature controls were applied to determine the optimal RF procedure in terms of cord tissue injury and safety in nine experiments. The safety of RF procedures was investigated in ten cords by measuring temperature changes at different sites close to the RF electrode insertion and the impact of RF on cord narrowing was evaluated by continuous monitoring of intraluminal pressure. Subsequent histopathological analysis was carried out in all cases. Results The optimal RF procedure reached a temperature of 100°C in 10 min. RF produced a significant increase in intraluminal pressure (from 54.2 ± 16.4 mmHg at baseline to 118.3 ± 42.7 mmHg after 10 min, P < 0.057. There was no significant increase in temperature next to the site of insertion during the RF procedure. Histopathological analysis confirmed a > 30% decrease in cord and vein diameter. Cord tissue lesions were characterized by damage in the vessel walls and in the surrounding Wharton's jelly. Conclusion Our results suggest that RF might be a feasible and safe technique to induce occlusion of umbilical vessels. Further in-vivo experiments are needed to assess its ability to induce a complete occlusion of the umbilical cord. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to review our experience in the management of twin reversed arterial perfusion sequence to derive management recommendations. Study design: All patients with twin reversed arterial perfusion sequence who were seen for consultation between 1993 and 2004 were studied. Criteria for umbilical cord occlusion included abdominal circumference of the twin reversed arterial perfusion fetus that was more than or equal to the pump twin, polyhydramnios (maximum vertical pocket > 8 cm), abnormal Doppler studies or hydrops of the pump twin, or monoamniotic twins. Various surgical and access techniques for umbilical cord occlusion were used as they were developed. Results: Seventy-four patients with twin reversed arterial perfusion sequence were studied. Sixty-five patients were considered surgical candidates, of which 51 patients underwent umbilical cord occlusion attempt. The overall perinatal survival for surgical candidates who had umbilical cord occlusion was 65% (33/51 patients) versus 42.9% (6/14 patients) for the surgical candidates who did not undergo umbilical cord occlusion (P = .1). However, perinatal outcomes in surgical patients were significantly better than expectantly treated surgical candidates if the dividing membrane was not disrupted purposely (22/28 patients; 78.5%; P = .02). Surgery within the sac of the twin reversed arterial perfusion fetus was feasible in 23.5% of patients and was associated with no incidence of premature rupture of membranes, with 83% perinatal survival, and with a significantly greater gestational age at delivery (36 weeks). There were no significant differences in perinatal outcome relative to the specific surgical technique that was used. Conclusion: Surgical management of twin reversed arterial perfusion sequence is indicated in high-risk patients. The surgical approach and the surgical technique should be tailored to the specific clinical presentation, preferably by performing the surgery within the sac of the twin reversed arterial perfusion sequence fetus and avoiding disruption of the dividing membrane. [ABSTRACT FROM AUTHOR]

Objective: To review our experience with a minimally invasive technique for umbilical cord occlusion as a method of selective feticide in monochorionic sets. Study design: Umbilical cord occlusion was completed using 3 mm bipolar cautery under ultrasound guidance (3D/4D, n = 6; 2D, n = 6) with pre and post ligation endoscopic evaluation. Results: 12 cases of monochorionic sets where selective feticide was performed were identified during the period 2000 to present. There were four triplet and eight twin gestations in the study cohort. Median interval from intervention to delivery was 16 weeks (range, 5-19). All co-twins survived the procedure and 15 of 16 were delivered after 33 weeks. Conclusions: Umbilical cord occlusion in monochorionic sets can be accomplished in a minimally invasive manner with combined endoscopic and ultrasound guidance in both twin and triplet pregnancies. [ABSTRACT FROM AUTHOR]

Objectives: In this study we sought to determine the effect of brief repeated umbilical cord occlusions (rUCO) on surfactant protein (SP) mRNA levels in the fetal sheep lung at two different gestational ages. Methods: Fourteen fetuses at 112 to 115 days’ gestation (control n = 7, rUCO n = 7) and 15 fetuses at 130 to 133 days’ gestation (control n = 7, rUCO n = 8) were studied over 4 successive days with rUCO of 90 seconds duration performed every 30 minutes for 3 to 5 hours each day in the rUCO animals. Blood samples were collected for corticotrophin (ACTH) and cortisol measurements. Animals were killed within 1 hour of the final cord occlusion. SP-A, -B, -C, and -D mRNA levels were determined in lung tissue using a ribonuclease protection assay. Results: Cord occlusions resulted in temporary increases in circulating ACTH on day 1 with both gestational ages, but the elevations were blunted by day 4. Plasma cortisol levels increased transiently with the larger effect being observed on day 4, in particular with the near-term group. With advancing gestational age there was a significant (P <.05) increase in the level of SP-A (control 112–115 days: 0.01 ± 0.01 vs control 130–133 days: 0.07 ± 0.02 fmol/mg RNA), SP -B (control 112–115 days: 0.02 ± 0.01 vs control 130–133 days: 0.07 ± 0.01 fmol/mg RNA) and SP-C (control 112–115 days: 0.13 ± 0.09 vs control 130–133 days: 0.51 ± 0.10 fmol/mg RNA), but not SP-D mRNA levels (control 112–115 days: 0.002 ± 0.002 vs control 130–133 days: 0.01 ± 0.002 fmol/mg RNA). At 112 to 115 days, there was no significant change in any of the SP mRNA levels following rUCO compared to controls. However, the same regime of rUCO at 130 to 133 days resulted in an 85% reduction in SP-A and SP-B mRNA content and a 66% reduction in SP-C mRNA levels compared to controls. Conclusion: The surprising decrease in SP-A and SP-B mRNA levels, which contrasts with other studies, suggests intermittent asphyxial episodes impact differently on surfactant apoprotein mRNA expression than does prolonged hypoxia. [Copyright &y& Elsevier]