High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses.

Context: Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus-pituitary-adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated. Objective: We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses. Methods: Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq. Results: The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log2FC 1.75), CYP 17 subfamily A member 1 (log2FC 3.41), 3ß-hydroxysteroid dehydrogenase type I (log2FC 1.13), steroidogenic acute regulatory protein (log2FC 1.09), and CYP 21 (log2FC 0.89). Conclusion: Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.

Characteristics of Heart Rate Tracings in Preterm Fetus.

Background and Objectives: Prematurity is currently a serious public health issue worldwide, because of its high associated morbidity and mortality. Optimizing the management of these pregnancies is of high priority to improve perinatal outcomes. One tool frequently used to determine the degree of fetal wellbeing is cardiotocography (CTG). A review of the available literature on fetal heart rate (FHR) monitoring in preterm fetuses shows that studies are scarce, and the evidence thus far is unclear. The lack of reference standards for CTG patterns in preterm fetuses can lead to misinterpretation of the changes observed in electronic fetal monitoring (EFM). The aims of this narrative review were to summarize the most relevant concepts in the field of CTG interpretation in preterm fetuses, and to provide a practical approach that can be useful in clinical practice. Materials and Methods: A MEDLINE search was carried out, and the published articles thus identified were reviewed. Results: Compared to term fetuses, preterm fetuses have a slightly higher baseline FHR. Heart rate is faster in more immature fetuses, and variability is lower and increases in more mature fetuses. Transitory, low-amplitude decelerations are more frequent during the second trimester. Transitory increases in FHR are less frequent and become more frequent and increase in amplitude as gestational age increases. Conclusions: The main characteristics of FHR tracings changes as gestation proceeds, and it is of fundamental importance to be aware of these changes in order to correctly interpret CTG patterns in preterm fetuses.

Posterior urethral valve in fetuses: evidence for the role of inflammatory molecules.

BACKGROUND: The aim of this cross-sectional study was to investigate inflammatory biomarkers in urine samples of 24 fetuses with posterior urethral valve (PUV) collected at 22 ± 4 weeks of gestation and to compare the findings with measurements in urine samples of 22 male healthy preterm neonates at 23 ± 4 weeks (control group). METHODS: Inflammatory biomarkers in urine were measured using a cytometric bead array [interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ, soluable tumor necrosis factor receptor (TNFR) 1, sTNFR2, monocyte chemoattractant protein-1/chemokine ligand 2 (MCP-1/CCL2), eotaxin/CCL11 and interferon gamma-induced protein/10/C-X-C motif chemokine 10 (IP-10/CXCL10)] and ELISA assays [TNF, IL-8/CXCL8 and transforming growth factor-beta (TGF-ß)]. The Mann-Whitney test was used to compare medians. Markers of glomerular (creatinine) and tubular [beta 2 (ß2)-microglobulin, uromodulin, osmolality] functions were correlated with inflammatory biomarkers (Spearman test). RESULTS: An intense inflammatory profile was identified, with significantly increased concentrations of urinary IL-2, IL-4, IL-6, TNF, sTNFRI, sTNFRII, IFN-γ, MCP-1/CCL2, eotaxin/CCL11 and IL-8/CXCL8 in the PUV group compared to the controls. The same was observed for the anti-inflammatory cytokine IL-10 and for the fibrogenic mediator TGF-ß. In the correlation analysis, ß2-microglobulin positively correlated with the presence of MCP-1/CCL2, sTNFRI and eotaxin/CCL11 and negatively correlated with the presence of creatinine. CONCLUSIONS: This study shows that inflammatory molecules are already increased in fetuses with PUV at the mean gestational age of 22 weeks, suggesting a physiopathological role for inflammation just after the embryological formation of the urethral membrane.

Magnesium sulfate reduces EEG activity but is not neuroprotective after asphyxia in preterm fetal sheep.

Magnesium sulfate is now widely recommended for neuroprotection for preterm birth; however, this has been controversial because there is little evidence that magnesium sulfate is neuroprotective. Preterm fetal sheep (104 days gestation; term is 147 days) were randomly assigned to receive sham occlusion (n = 7), i.v. magnesium sulfate (n = 10) or saline (n = 8) starting 24 h before asphyxia until 24 h after asphyxia. Sheep were killed 72 h after asphyxia. Magnesium sulfate infusion reduced electroencephalograph power and fetal movements before asphyxia. Magnesium sulfate infusion did not affect electroencephalograph power during recovery, but was associated with marked reduction of the post-asphyxial seizure burden (mean ± SD: 34 ± 18 min vs. 107 ± 74 min, P < 0.05). Magnesium sulfate infusion did not affect subcortical neuronal loss. In the intragyral and periventricular white matter, magnesium sulfate was associated with reduced numbers of all (Olig-2+ve) oligodendrocytes in the intragyral (125 ± 23 vs. 163 ± 38 cells/field) and periventricular white matter (162 ± 39 vs. 209 ± 44 cells/field) compared to saline-treated controls ( P < 0.05), but no effect on microglial induction or astrogliosis. In conclusion, a clinically comparable dose of magnesium sulfate showed significant anticonvulsant effects after asphyxia in preterm fetal sheep, but did not reduce asphyxia-induced brain injury and exacerbated loss of oligodendrocytes.

nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep.

Basal ganglia injury after hypoxia-ischemia remains common in preterm infants, and is closely associated with later cerebral palsy. In the present study we tested the hypothesis that a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10, would improve survival of striatal phenotypic neurons after profound asphyxia, and that the subsequent seizure burden and recovery of EEG are associated with neural outcome. 24 chronically instrumented preterm fetal sheep were randomized to either JI-10 (3 ml of 0.022 mg/ml, n = 8) or saline (n = 8) infusion 15 min before 25 min complete umbilical cord occlusion, or saline plus sham-occlusion (n = 8). Umbilical cord occlusion was associated with reduced numbers of calbindin-28k-, GAD-, NPY-, PV-, Calretinin- and nNOS-positive striatal neurons (p < 0.05 vs. sham occlusion) but not ChAT-positive neurons. JI-10 was associated with increased numbers of calbindin-28k-, GAD-, nNOS-, NPY-, PV-, Calretinin- and ChAT-positive striatal neurons (p < 0.05 vs. saline + occlusion). Seizure burden was strongly associated with loss of calbindin-positive cells (p < 0.05), greater seizure amplitude was associated with loss of GAD-positive cells (p < 0.05), and with more activated microglia in the white matter tracts (p < 0.05). There was no relationship between EEG power after 7 days recovery and total striatal cell loss, but better survival of NPY-positive neurons was associated with lower EEG power. In summary, these findings suggest that selective nNOS inhibition during asphyxia is associated with protection of phenotypic striatal projection neurons and has potential to help reduce basal ganglia injury in some premature babies.

Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep.

Preterm brain injury is partly associated with hypoxia-ischemia starting before birth. Excessive nitric oxide production during HI may cause nitrosative stress, leading to cell membrane and mitochondrial damage. We therefore tested the hypothesis that therapy with a new, selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10 (0.022mg/kg bolus, n=8), given 30min before 25min of complete umbilical cord occlusion was protective in preterm fetal sheep at 101-104day gestation (term is 147days), compared to saline (n=8). JI-10 had no effect on fetal blood pressure, heart rate, carotid and femoral blood flow, total EEG power, nuchal activity, temperature or intracerebral oxygenation on near-infrared spectroscopy during or after occlusion. JI-10 was associated with later onset of post-asphyxial seizures compared with saline (p<0.05), and attenuation of the subsequent progressive loss of cytochrome oxidase (p<0.05). After 7days recovery, JI-10 was associated with improved neuronal survival in the caudate nucleus (p<0.05), but not the putamen or hippocampus, and more CNPase positive oligodendrocytes in the periventricular white matter (p<0.05). In conclusion, prophylactic nNOS inhibition before profound asphyxia was associated with delayed onset of seizures, slower decline of cytochrome oxidase and partial white and gray matter protection, consistent with protection of mitochondrial function.

Modificaciones en el flujo sanguíneo del tronco de la arteria pulmonar en fetos prematuros que recibieron corticoides

Objetivos: Evaluar las modificaciones de la velocimetría Doppler en el flujo sanguíneo del tronco de la arteria pulmonar en fetos prematuros expuestos a corticoesteroides. Diseño: Estudio prospectivo. Institución: Instituto Latinoamericano de Salud reproductiva (ILSAR), Lima, Perú. Participantes: Madres con 29 a 36 semanas de edad gestacional y sus fetos. Intervenciones: En gestantes con 29 a 36 semanas de gestación que habían recibido corticoides para madurez pulmonar fetal, se hizo velocimetría Doppler del flujo sanguíneo del tronco de la arteria pulmonar de sus fetos. Principales medidas de resultados: Correlación de los cambios de la velocimetría Doppler con la madurez pulmonar en el neonato. Resultados: Los fetos prematuros que recibieron corticoides no tuvieron complicaciones respiratorias neonatales cuando el índice tiempo de aceleración/tiempo de desaceleración sistólico (TA/TD) fue igual o mayor a 0,57, cuyo valor se alcanzó en fetos con 33 semanas o más y con peso desde 2 000 g. Los valores de TA/TD luego de corticoides tuvieron una correlación estadística alta con las complicaciones respiratorias del RN (p<0,0001). Conclusiones: Después de aplicar corticoides para madurar el pulmón en fetos prematuros, se observó modificaciones en el flujo del tronco de la arteria pulmonar medidos con el índice TA/TD, con valores superiores a los observados para la misma edad gestacional en fetos sin corticoides. La diferencia fue altamente significativa desde la semana 33. El índice TA/TD del tronco de la arteria pulmonar es una herramienta útil para determinar madurez pulmonar.

Objectives: To determine changes in pulmonary artery blood flow Doppler velocimetry in preterm fetuses exposed to corticosteroids. Design: Prospective study. Setting: Instituto Latinoamericano de Salud Reproductiva (ILSAR), Lima, Peru. Participants: Mothers 29-36 weeks of gestation and their fetuses. Interventions: In fetuses of mothers 29-36 weeks of gestation who had received corticosteroids for maturation pulmonary artery blood flow Doppler velocimetry was performed. Main outcome measures: Correlation of Doppler velocimetry changes and neonate lung maturity. Results: Preterm fetuses that received corticosteroids did not present neonatal respiratory complications when systolic acceleration time/deceleration time (AT/DT) index was equal or over 0,57, value obtained in fetuses 33 weeks or more and weight over 2 000 g. AT/DT values following corticosteroids showed high statistical correlation with newborn respiratory complications (p<0,0001). Conclusions: Pulmonary artery blood flow measured with AT/DT index was modified after corticosteroids administration for preterm fetal lung maturation; values were superior to those observed for same gestational age fetuses without corticosteroids. Difference was highly significant starting at week 33. AT/DT index of the pulmonary artery stem is a useful tool to determine pulmonary maturity.