Intra-amniotic infection and/or inflammation is associated with fetal cardiac concentric hypertrophy and diastolic dysfunction in preterm labor and preterm prelabor rupture of membranes.

BACKGROUND: Preterm delivery is associated with cardiovascular remodeling and dysfunction in children and adults. However, it is unknown whether these effects are caused by the neonatal consequences of preterm birth or if these are already present in utero. OBJECTIVE: We evaluated fetal cardiac morphology and function in fetuses of mothers admitted for preterm labor or preterm prelabor rupture of membranes and the association of these changes with the presence of intra-amniotic infection and/or inflammation. STUDY DESIGN: In this prospective cohort study, fetal echocardiography and amniocentesis were performed at admission in singleton pregnant women with preterm labor and/or preterm prelabor rupture of membranes between 24.0 and 34.0 weeks' gestation with (intra-amniotic infection and/or inflammation group, n=41) and without intra-amniotic infection and/or inflammation (non-intra-amniotic infection and/or inflammation, n=54). Controls (n=48) were outpatient pregnant women without preterm labor or preterm prelabor rupture of membranes. Intra-amniotic infection was defined by a positive amniotic fluid culture or positive 16S ribosomal RNA gene. Intra-amniotic inflammation was defined by using the amniotic fluid interleukin-6 cutoff levels previously reported by our group being >1.43 ng/mL in preterm prelabor rupture of membranes and >13.4 ng/mL in preterm labor. Fetal cardiac morphology and function was evaluated using echocardiography, and troponin-I and N-terminal pro-brain natriuretic peptide concentrations were measured in amniotic fluid from women with preterm labor or preterm prelabor rupture of membranes and compared with 20 amniotic fluid Biobank samples obtained for reasons other than preterm labor or preterm prelabor rupture of membranes or cardiac pathology. The data were adjusted for the estimated fetal weight below the 10th percentile and for preterm prelabor rupture of membranes at admission and also for gestational age at amniocentesis when amniotic fluid biomarkers were compared. RESULTS: From 2018 to 2021, 143 fetuses were included; 95 fetuses were from mothers admitted with a diagnosis of preterm labor or preterm prelabor rupture of membranes, and among those, 41 (28.7%) were in the intra-amniotic infection and/or inflammation group and 54 (37.8%) were in the non-intra-amniotic infection and/or inflammation group. A total of 48 (33.6%) fetuses were included in the control group. Fetuses with preterm labor and/or preterm prelabor rupture of membranes had signs of subclinical cardiac concentric hypertrophy (median left wall thickness of 0.93 [interquartile range, 0.72-1.16] in the intra-amniotic infection and/or inflammation group; 0.79 [0.66-0.92] in the non-intra-amniotic infection and/or inflammation group; and 0.69 [0.56-0.83] in controls; P<.001) and diastolic dysfunction (tricuspid A duration 0.23 seconds [0.21-0.25], 0.24 [0.22-0.25], and 0.21 [0.2-0.23]; P=.007). Systolic function was similar among groups. Higher values of amniotic fluid troponin I (1413 pg/mL [927-2334], 1190 [829-1636], and 841 [671-959]; P<.001) and N-terminal pro-brain natriuretic peptide were detected (35.0%, 17%, and 0%; P=.005) in fetuses with preterm labor or preterm prelabor rupture of membranes when compared with the control group. The highest N-terminal pro-brain natriuretic peptide concentrations were found in the intra-amniotic infection and/or inflammation group. CONCLUSION: Fetuses with preterm labor or preterm prelabor rupture of membranes showed signs of cardiac remodeling and subclinical dysfunction, which were more pronounced in those exposed to intra-amniotic infection and/or inflammation. These findings support that the cardiovascular effects observed in children and adults born preterm have, at least in part, a prenatal origin.

Evidence of brain injury in fetuses of mothers with preterm labor with intact membranes and preterm premature rupture of membranes.

BACKGROUND: Brain injury and poor neurodevelopment have been consistently reported in infants and adults born before term. These changes occur, at least in part, prenatally and are associated with intra-amniotic inflammation. The pattern of brain changes has been partially documented by magnetic resonance imaging but not by neurosonography along with amniotic fluid brain injury biomarkers. OBJECTIVE: This study aimed to evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm premature rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a risk mediator. STUDY DESIGN: In this prospective cohort study, fetal brain remodeling and injury were evaluated using neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm premature rupture of membranes between 24.0 and 34.0 weeks of gestation, with (n=41) and without (n=54) intra-amniotic inflammation. The controls for neurosonography were outpatient pregnant patients without preterm labor or preterm premature rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm premature rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin 6 concentrations of >13.4 ng/mL in preterm labor and >1.43 ng/mL in preterm premature rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. Neuron-specific enolase, protein S100B, and glial fibrillary acidic protein were selected as amniotic fluid brain injury biomarkers. Data were adjusted for cephalic biometrics, fetal growth percentile, fetal sex, noncephalic presentation, and preterm premature rupture of membranes at admission. RESULTS: Fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes showed signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in the intra-amniotic inflammation, non-intra-amniotic inflammation, and control groups, the transcerebellar diameter measurements were 32.7 mm (interquartile range, 29.8-37.6), 35.3 mm (interquartile range, 31.2-39.6), and 35.0 mm (interquartile range, 31.3-38.3), respectively (P=.019), and the vermian height measurements were 16.9 mm (interquartile range, 15.5-19.6), 17.2 mm (interquartile range, 16.0-18.9), and 17.1 mm (interquartile range, 15.7-19.0), respectively (P=.041). Second, they presented a lower corpus callosum area (0.72 mm2 [interquartile range, 0.59-0.81], 0.71 mm2 [interquartile range, 0.63-0.82], and 0.78 mm2 [interquartile range, 0.71-0.91], respectively; P=.006). Third, they showed delayed cortical maturation (the Sylvian fissure depth-to-biparietal diameter ratios were 0.14 [interquartile range, 0.12-0.16], 0.14 [interquartile range, 0.13-0.16], and 0.16 [interquartile range, 0.15-0.17], respectively [P<.001], and the right parieto-occipital sulci depth ratios were 0.09 [interquartile range, 0.07-0.12], 0.11 [interquartile range, 0.09-0.14], and 0.11 [interquartile range, 0.09-0.14], respectively [P=.012]). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes had higher concentrations of neuron-specific enolase (11,804.6 pg/mL [interquartile range, 6213.4-21,098.8], 8397.7 pg/mL [interquartile range, 3682.1-17,398.3], and 2393.7 pg/mL [interquartile range, 1717.1-3209.3], respectively; P<.001), protein S100B (2030.6 pg/mL [interquartile range, 993.0-4883.5], 1070.3 pg/mL [interquartile range, 365.1-1463.2], and 74.8 pg/mL [interquartile range, 44.7-93.7], respectively; P<.001), and glial fibrillary acidic protein (1.01 ng/mL [interquartile range, 0.54-3.88], 0.965 ng/mL [interquartile range, 0.59-2.07], and 0.24 mg/mL [interquartile range, 0.20-0.28], respectively; P=.002). CONCLUSION: Fetuses with preterm labor with intact membranes or preterm premature rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in fetuses with intra-amniotic inflammation.

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy.

The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 - and Abcd1 - /Abcd2 -/- mice) and X-ALD patient's fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 - /Abcd2 -/- mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.

Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1 (-) /Abcd2 (-/-) mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients.

Outpatient management of preterm prelabor rupture of membranes before 34 weeks: Maternal and neonatal outcomes.

OBJECTIVE: To evaluate the maternal, fetal, and neonatal outcomes of pregnant women complicated with preterm prelabor rupture of membranes (PPROM) eligible for outpatient care. METHODS: This study included a retrospective cohort of patients with singleton pregnancies with PPROM between 23+0 to 34+0 weeks who remained pregnant after the first 72 h. Outpatient management was considered in women with clinical, ultrasound and analytical stability, and easy access to hospital. Maternal, fetal, and neonatal results were compared between women managed as inpatients versus those managed as outpatients. RESULTS: Women eligible for the outpatient management had a better prognostic profile (no anhydramnios, longer cervical length, less intraamniotic infection, and clinical, ultrasound, and analytical stability) and presented a lower gestational age at admission and longer latency to delivery, resulting in a similar gestational age at delivery as the inpatient group. Postpartum curettage, uterine atony, respiratory distress syndrome, and bronchopulmonary dysplasia were less frequent in the outpatient group. Composite maternal-fetal morbidity and mortality outcomes were similar in both groups, while composite neonatal morbidity and mortality outcomes were significantly lower in the outpatient group. CONCLUSION: Outpatient management may be an option for women presenting stable PPROM before 34 weeks when adequate selection criteria are fulfilled. Differences in perinatal outcomes in the outpatient group compared with the inpatient group are probably attributable to baseline characteristics. Further prospective randomized studies are needed to confirm the benefits of outpatient management in PPROM.

Pessary for Management of Cervical Varices Complicating Pregnancy.

BACKGROUND: Cervical varices complicating pregnancy are rare but can cause significant maternal and perinatal morbidity. There is limited evidence regarding the optimal management of bleeding caused by cervical varices during pregnancy. CASE: A 38-year-old woman was admitted to the hospital at 16 weeks of gestation due to vaginal hemorrhage in the setting of cervical varices accompanied by placenta previa. A cervical pessary was placed at 21 weeks of gestation without further bleeding. Magnetic resonance imaging demonstrated variceal reduction after pessary placement, and a cesarean delivery was performed at 36 weeks of gestation without complications. CONCLUSION: Cervical pessary should be considered as conservative option to control the bleeding associated with cervical varices during pregnancy.

Micronutrient Deficiencies in Patients with Decompensated Liver Cirrhosis.

Patients with cirrhosis often develop malnutrition and micronutrient deficiencies, leading to a worse prognosis and increased mortality. Our main goal was to assess the prevalence of micronutrient deficiencies in patients with decompensated cirrhosis. This was a prospective single-center study including 125 consecutive patients hospitalized for acute decompensation of cirrhosis (mostly of alcoholic etiology). A blood test including trace elements and vitamins was performed on admission. The main micronutrient deficiencies observed were vitamin D (in 94.5%), vitamin A (93.5%), vitamin B6 (60.8%) and zinc (85.6%). Patients in Child-Pugh class C had lower levels of vitamin A (p < 0.0001), vitamin E (p = 0.01) and zinc (p < 0.001), and higher levels of ferritin (p = 0.002) and vitamin B12 (p < 0.001) than those in Child-Pugh class A and B. Patients with a higher model of end-stage liver disease (MELD) score had lower levels of vitamin A (p < 0.0001), vitamin E (p < 0.001), magnesium (p = 0.01) and zinc (p = 0.001), and higher levels of ferritin (p = 0.002) and vitamin B12 (p < 0.0001). Severe hepatic insufficiency correlated with lower levels of zinc, vitamin E and vitamin A, and higher levels of vitamin B12 and ferritin.

Mid-trimester prediction of spontaneous preterm birth with automated cervical quantitative ultrasound texture analysis and cervical length: a prospective study.

The objective of this study was to evaluate a novel automated test based on ultrasound cervical texture analysis to predict spontaneous Preterm Birth (sPTB) alone and in combination with Cervical Length (CL). General population singleton pregnancies between 18 + 0 and 24 + 6 weeks' gestation were assessed prospectively at two centers. Cervical ultrasound images were evaluated and the occurrence of sPTB before weeks 37 + 0 and 34 + 0 were recorded. CL was measured on-site. The automated texture analysis test was applied offline to all images. Their performance to predict the occurrence of sPTB before 37 + 0 and 34 + 0 weeks was evaluated separately and in combination on 633 recruited patients. AUC for sPTB prediction before weeks 37 and 34 respectively were as follows: 55.5% and 65.3% for CL, 63.4% and 66.3% for texture analysis, 67.5% and 76.7% when combined. The new test improved detection rates of CL at similar low FPR. Combining the two increased detection rate compared to CL alone from 13.0 to 30.4% for sPTB < 37 and from 14.3 to 42.9% sPTB < 34. Texture analysis of cervical ultrasound improved sPTB detection rate compared to cervical length for similar FPR, and the two combined together increased significantly prediction performance. This results should be confirmed in larger cohorts.