Ursodeoxycholic acid in the treatment of pregnancy cholestasis: a data-set available for Meta-analyses.

BACKGROUND: The recent literature on intrahepatic cholestasis of pregnancy raises questions on the best management of such a disease. Improved evidence might be achieved by meta-analyses. AIM: Providing data for allowing individual patients meta-analyses and aggregate data meta-analyses. METHODS: Data were collected retrospectively at the Fabia Mater Hospital of Rome (Italy), between 2013 and 2018. Several variables were collected and analyzed according to low-level bile acid (less than 40 µmol/L) and high-level bile acid (at least 40 µmol/L). Eighty-three cases of pregnancy cholestasis, diagnosed according to itching symptoms and excluding bile diseases, were collected and analyzed, both descriptively and inferentially. CONCLUSION: The analyzed data do not provide significant evidence supporting the use of ursodeoxycholic acid to prevent composite adverse fetal outcomes but they can be included in further meta-analyses.

Perspectives of Italian pregnant women on pregnancy examinations and pregnancy care: is the caregiver more important than the care?

AIM: Assessing awareness of Italian low-risk pregnant patients on low-risk pregnancy care and what do they feel about their own pregnancy. METHODS: A questionnaire was administered to 382 low-risk pregnant women. This questionnaire assessed general knowledge of low-risk pregnancy, low-risk pregnancy care, and how much patients rated ten topics of low-risk pregnancy care. It would be expected that the knowledge of each topic would associates with the patient's perceived importance of that topic. RESULTS: Poor knowledge of pregnancy care was proven. Patients seem to incorrectly overrate vaginal examinations and obstetric and gynecologist-led care, while they attribute appropriate importance to midwife-led care. The more examinations performed (vaginal examinations, sonographic checks, cardiotocographies), the higher their rating. CONCLUSIONS: In Italy, expectations of pregnant women about their own pregnancy are incorrectly trusted in the obstetrics and gynecologists. Both poor knowledge of pregnancy care and cultural perspectives on the birth process amongst Italian people explain the finding. Referring low-risk pregnant women to midwives would help them to rate more the care than the caregiver.

Cesarean section in the absence of labor and risk of respiratory complications in newborns: a case-control study.

AIM: To establish if labor and gestational age have an additive effect on the likelihood of newborn respiratory complications. METHODS: Case-control study on singleton pregnancies, delivered between 34 and 41 weeks. Cases were collected among newborns discharged with diagnoses of respiratory complications, as codified by ICD 9 1997. Subsequently, pneumonias, meconium aspiration syndromes, and pulmonary hemorrhage were excluded. Controls were all other newborns without respiratory complications. Multivariate analyses were performed hypothesizing and not hypothesizing a relationship between gestational age, labor and newborn adverse respiratory outcomes. RESULTS: Twenty thousand three hundred and ninety-seven living babies born at term or near-term between January 2006 and December 2010 were assessed. 16,084 infants were included in the analyses. 304 experienced a respiratory complication (cases group). Delivering by cesarean not in labor increases the odds ratio of adverse respiratory outcome by about 2, independently from other variables, among which is gestational age. The same increase of odds ratio of 2 is constantly observed at each week of gestation, from 35 to 39 gestational weeks. CONCLUSIONS: Cesarean not in labor adds a constant risk of newborn respiratory complications at any gestational age near-term and early-term. The more the planned cesarean is delayed, the better is newborn respiratory outcome.

Risk factors for fatality in amniotic fluid embolism: a systematic review and analysis of a data pool.

PURPOSE: Investigating risk factors for amniotic fluid embolism (AFE)-induced fatality. METHODS: A systematic review of cases of AFE available on PubMed, Scielo, Scopus and AJOL databases that occurred from 1990 to 2015 was carried out. After careful reading of titles, abstracts and full texts, case reports of AFE were reviewed. Risk factors for AFE were considered as independent variables in logistic regression models. The first model was built on the whole data pool. The second model was built on typical cases of AFE, according to the classical triad of symptoms (heart, lungs, coagulopathy). The dependent variable was fatality in both models. RESULTS: 177 cases of AFE were assessed in the first model, while 121 typical cases of AFE were assessed in the second model. Among typical cases of AFE, only oxytocin infusion during labour increases the likelihood of death (odds ratio 2.890, 95% confidence interval 1.166-7.164, p = 0.022). No risk factors for fatality were found in the whole data pool. CONCLUSIONS: Further research on national registries should focus on the behaviour of oxytocin infusion during labour in AFE cases.

Symphysis-fundal height predicts difficult evolution of induced labours.

BACKGROUND AND AIM: Symphysis-fundal-height (SFH) could be prove useful for the management of labour. This study aims to assess the behaviour of induced labours in relationship with SFH values. METHODS: Prospective observational study in a sample of 158 women underwent induction with intravaginal dinoprostone for different indications. SFH, SFH corrected for station, gestational age and parity were considered independent variables in multivariable models. Vaginal delivery, operative vaginal delivery, Cesarean section, Cesarean section for dystocia, Cesarean section for cardiotochographyc abnormalities, oxytocin infusion (for potentiating labour), need of Kristeller's maneuvre, epidural anesthesia (on demand), episiotomy, time from the first dose of dinoprostone to delivery, and time of active phase of labour were considered dependent variables in multivariable models. RESULTS: SFH >34 cm (both uncorrected and corrected for station) independently associates with an increase of odds ratio for operative vaginal birth, Kristeller's maneuver, oxytocin use, episiotomy. Additionally, SFH >34 cm (corrected for station) seems to correlate with increasing time of active phase of labour. CONCLUSIONS: SFH >34 cm (both corrected and uncorrected for station) predicts difficult vaginal deliveries and operative vaginal deliveries in induced labours.

Neurological abnormalities in full-term asphyxiated newborns and salivary S100B testing: the "Cooperative Multitask against Brain Injury of Neonates" (CoMBINe) international study.

BACKGROUND: Perinatal asphyxia (PA) is a leading cause of mortality and morbidity in newborns: its prognosis depends both on the severity of the asphyxia and on the immediate resuscitation to restore oxygen supply and blood circulation. Therefore, we investigated whether measurement of S100B, a consolidated marker of brain injury, in salivary fluid of PA newborns may constitute a useful tool for the early detection of asphyxia-related brain injury. METHODS: We conducted a cross-sectional study in 292 full-term newborns admitted to our NICUs, of whom 48 suffered PA and 244 healthy controls admitted at our NICUs. Saliva S100B levels measurement longitudinally after birth; routine laboratory variables, neurological patterns, cerebral ultrasound and, magnetic resonance imaging were performed. The primary end-point was the presence of neurological abnormalities at 12-months after birth. RESULTS: S100B salivary levels were significantly (P<0.001) higher in newborns with PA than in normal infants. When asphyxiated infants were subdivided according to a good (Group A; n = 15) or poor (Group B; n = 33) neurological outcome at 12-months, S100B was significantly higher at all monitoring time-points in Group B than in Group A or controls (P<0.001, for all). A cut-off >3.25 MoM S100B achieved a sensitivity of 100% (CI5-95%: 89.3%-100%) and a specificity of 100% (CI5-95%: 98.6%-100%) as a single marker for predicting the occurrence of abnormal neurological outcome (area under the ROC curve: 1.000; CI5-95%: 0.987-1.0). CONCLUSIONS: S100B protein measurement in saliva, soon after birth, is a useful tool to identify which asphyxiated infants are at risk of neurological sequelae.

Regulation by hypoxia of adrenomedullin output and expression in human trophoblast cells.

OBJECTIVES: Plasma adrenomedullin concentrations are increased in the fetal circulation in acute and chronic hypoxic conditions. The effect of hypoxia in regulating adrenomedullin synthesis and secretion was investigated in human placental trophoblast cells. STUDY DESIGN: Human trophoblast cells obtained from term placentas (n = 7) were cultured in hypoxic condition (3% oxygen). Cytotrophoblast cells were cultured for up to 48 h and syncytiotrophoblasts for 2, 8 and 24 h. Changes in adrenomedullin output compared to normoxic conditions were measured by radioimmunoassay. Protein expression was evaluated with Western blot and immunocytochemistry. RESULTS: Hypoxia induced a time-dependent increase in adrenomedullin output and protein expression by placental trophoblast cells. CONCLUSIONS: Hypoxia regulates adrenomedullin secretion and expression by human placenta, thereby promoting increased adrenomedullin concentration in the fetal circulation in clinical circumstances characterized by reduced oxygen levels.

Intrafollicular concentration of adrenomedullin is associated with IVF outcome.

OBJECTIVE: To test the hypothesis that serum or intrafollicular concentrations of adrenomedullin (AM) would correlate with reproductive outcomes in in vitro fertilisation (IVF) cycles. DESIGN: Serum and follicular fluid samples were collected during transvaginal oocyte retrieval. The follicular fluid was individually aspirated, and the presence of oocyte was recorded. AM concentrations were measured using an enzyme-linked immunosorbent assay. SETTING: Department of Gynaecology, Perinatology and Child Health, 'Sapienza' University of Rome, Italy. PATIENTS: Eighty women undergoing IVF for primary infertility aged 18-45 years. MAIN OUTCOME MEASURES: AM concentrations in plasma and follicular fluid were correlated to follicular fluid volume, presence of oocyte, oocyte maturation, embryo grading, fertilisation and pregnancy rates, live-birth rate and plasma estrogen concentration. RESULTS: Monofollicular fluid AM concentrations did not differ between follicles containing oocyte and those without oocyte; however, AM concentrations were lower in follicles that resulted in pregnancy than in those that failed. Serum but not follicular fluid AM concentrations correlated with serum estrogen levels. Follicular fluid AM correlated with plasma AM levels. CONCLUSION: We conclude that higher level of AM in the follicular fluid appears to be associated with a negative outcome in IVF treatment.

Effect of corticosteroids and progesterone on adrenomedullin output and expression in human fetal membranes and placenta trophoblasts.

OBJECTIVE: Plasma adrenomedullin (AM) concentrations are increased in fetal and maternal circulation in response to exogenous glucocorticoids administration. The role of corticosteroids and progesterone in regulating AM synthesis and secretion was investigated in amnion and chorion trophoblast cells of the fetal membranes and in placental trophoblast cells. STUDY DESIGN: Cells were treated with betamethasone, hydrocortisone, and progesterone. Changes in AM output were measured with radioimmunoassay. Protein expression was evaluated with Western blot and immunohistochemistry. RESULTS: Betamethasone stimulated AM secretion and protein expression in placental trophoblast cells and in amnion cells of the fetal membranes. Hydrocortisone and progesterone did not induce any effect either on secretion or protein expression in placenta and fetal membranes cells. CONCLUSION: Glucocorticoids regulate AM secretion and expression by human placenta thereby promoting increased AM concentration in maternal and fetal circulation in circumstances characterized by increased cortisol levels.

S100 beta protein is increased in fetuses with neural tube defect.

We investigated the levels of S100 beta protein (S100B) in the serum of fetuses with neural tube defects (NTD), and their mother. Samples from 20 fetuses with NTD and 30 controls at the same gestational age, and their mothers, were studied. S100B protein levels were determined using Lia-mat Sangtec. kit. S100B concentrations were significantly higher in NTD fetuses (median 2.71 microg/L) than in control subjects (median 0.98 microg/L). Increased S100B levels were also found in mothers carrying fetuses with NTD compared to control and uncomplicated pregnancies. This study indicates that NTD is associated with increased serum concentration of S100B in fetuses and mothers. Moreover, it gives information on S100B levels in the fetal circulation in early-mid gestation.

Changes in the interrelationship between leptin, resistin and adiponectin in early neonatal life.

The aim of this study was to investigate the interrelationship between leptin,adiponectin and resistin in the fetal and early postnatal period and the association of these hormones with anthropometric and metabolic indexes. Serum concentrations of leptin, adiponectin and resistin were measured in maternal and neonatal circulation at delivery and on the 3rd day after birth in 40 healthy newborns and their mothers Serum leptin levels were significantly higher in fetuses that in newborn infants on 3rd day after delivery, whereas concentration of adiponectin and resistin were maintained in either maternal and neonatal circulation after delivery. Leptin serum concentrations correlated with those of adiponectin in the fetal circulation, but not in neonatal life. On the other hand no correlation was found between leptin and resistin levels in cord blood, whereas a positive correlation between leptin and resistin concentrations was present in the neonatal circulation on 3rd day. Fetal leptin, adiponectin and resistin levels are largely independent of maternal influences and immediately after birth, important changes in the relation among adipokines occurred compared to intrauterine life.

Biochemical markers of perinatal brain damage.

Hypoxia-ischemia constitutes a risk in infants by altering cerebral blood flow regulatory mechanisms and causing loss of cerebral vascular auto-regulation. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation leading to cell death and tissue damage. These dramatic phenomena represent a common repertoire in infants complicated by perinatal acute or chronic hypoxia. To date, despite accurate perinatal and intra-operative monitoring, the post-insult period is crucial, since clinical symptoms and monitoring parameters may be of no avail and therapeutic window for pharmacological intervention (6-12 hours) may be limited, at a time when brain damage is already occurring. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk infants. The present review is aimed at investigating the role as circulating biochemical markers such as adrenomedullin, S100B, activin A, neuronal specific enolase (NSE), glial fibrillary acid protein (GFAP), in the cascade of events leading to ischemia reperfusion injury in infants complicated by perinatal asphyxia.

New markers of neonatal neurology.

Hypoxia-ischemia (H-I) constitutes the main phenomenon responsible for brain-blood barrier permeability modifications leading to cerebral vascular auto-regulation loss in newborns. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation loss leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents, of calcium mediated effects could be responsible for reperfusion injury (R-I), which, in turns, leads to cerebral hemorrhage and damage. These phenomena represent a common repertoire in newborns complicated by perinatal acute or chronic hypoxia treated by risky procedures such as mechanical ventilation, nitric oxide supplementation, brain cooling, and extracorporeal membrane oxygenation (ECMO). Despite accurate monitoring, the post-insult period is crucial, as clinical symptoms and standard monitoring parameters may be silent at a time when brain damage is already occurring and the therapeutic window for pharmacological intervention is limited. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk newborns. The present review is aimed at investigating the role of biochemical markers such as adrenomedullin, a vasoactive peptide; S100B, a calcium binding protein, activin A, a glycoprotein, in the cascade of events leading to I-R injury in newborns complicated by perinatal asphyxia.

Circulating biochemical markers of brain damage in infants complicated by ischemia reperfusion injury.

Hypoxia-ischemia constitutes a risk in infants by altering cerebral blood flow regulatory mechanisms and causing loss of cerebral vascular auto-regulation. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents of calcium mediated effects could be responsible for reperfusion injury, which, in turns, leads to cerebral hemorrhage and damage. These dramatic phenomena represent a common repertoire in infants complicated by perinatal acute or chronic hypoxia or cardiovascular disorders treated by risky procedures such as open heart surgery and cardiopulmonary by-pass (CPB). To date, despite accurate perinatal and intra-operative monitoring, the post-insult period is crucial, since clinical symptoms and monitoring parameters may be of no avail and therapeutic window for pharmacological intervention (6-12 hours) may be limited, at a time when brain damage is already occurring. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk infants. The present review is aimed at investigating the role as circulating biochemical markers such as adrenomedullin, a vasoactive peptide; S100B, a calcium binding protein, activin A, a glycoprotein; neuronal specific enolase (NSE), a dimeric isoenzyme; glial fibrillary acid protein (GFAP), a astroglial protein, in the cascade of events leading to ischemia reperfusion injury in infants complicated by perinatal asphyxia or cardiovascular disorders requiring risky therapeutic strategies such as CPB and/or extracorporeal membrane oxygenation.

Effect of calcium ionophore A23187 on prostaglandin synthase type 2 and 15-hydroxy-prostaglandin dehydrogenase expression in human chorion trophoblast cells.

OBJECTIVE: Prostaglandins induce parturition in humans. Prostaglandin output is regulated by the synthetic and metabolic enzymes, prostaglandin synthase type 2 (PTGS2) and 15-hydroxyprostaglandin dehydrogenase (PGDH). The role of calcium in regulating PTGS2 and PGDH expression was investigated in chorion trophoblasts. STUDY DESIGN: Cells were treated with calcium ionophore A23187 in the presence or absence of calcium chelators; changes in messenger ribonucleic acid expression were measured with real-time polymerase chain reaction and analyzed with analysis of variance. Protein expression was evaluated with Western blot and dual immunofluorescence. RESULTS: A23187 stimulated PTGS2 and suppressed PGDH expression. Effects of A23187 were reversed by calcium chelators. PTGS2 had perinuclear and cytosolic distribution, whereas PGDH was cytosolic. Some cells expressed both enzymes, some neither enzyme, and some either PTGS2 or PGDH. CONCLUSION: Chorion cells showed heterogeneity in the expression of PTGS2 and PGDH. Calcium influx regulates PTGS2 and PGDH expression, thereby promoting coordinated increased prostaglandin output in circumstances such as term and preterm labor.

Effects of prenatal betamethasone administration on leptin and adiponectin concentrations in maternal and fetal circulation.

OBJECTIVE: The aim of this study was to determine the effects of in vivo administration of prenatal betamethasone on leptin and adiponectin concentration in maternal and fetal circulation. STUDY DESIGN: Blood samples were collected from 35 pregnant women receiving betamethasone for threatened preterm delivery before and at different time points after drug administration. Cord blood was collected at delivery in infants born from mothers treated with betamethasone and in 15 infants who delivered at the same gestational age not receiving betamethasone. RESULTS: Betamethasone caused an approximately 170% increase in maternal leptin at 24 hours after betamethasone, whereas it had no effects on adiponectin concentration. Betamethasone affects neonatal leptin and adiponectin levels in a time-dependent manner. The glucocorticoid-induced changes in the relationship between these adipokines in maternal and fetal circulation was long lasting. CONCLUSION: These results provide the first evidence for in vivo effects of glucocorticoids on maternal and fetal adipokines relationship in human pregnancy.

Opposite effect of phorbol ester PMA on PTGS2 and PGDH mRNA expression in human chorion trophoblast cells.

Prostaglandins (PGs) induce the mechanism of labor in humans. The enzymes responsible for PG synthesis and metabolism are prostaglandin-endoperoxide synthase 2 (PTGS2) and 15-hydroxyprostaglandin dehydrogenase (PGDH). In human chorion trophoblast cells, calcium ionophore A23187 upregulates PTGS2 and downregulates PGDH protein and mRNA. The authors hypothesize that this regulation requires activation of protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs). Human chorion trophoblasts were incubated with A23187 or phorbol 12-myristate 13-acetate (PMA) in the absence or presence of inhibitors of PKC, c-Jun N-terminal kinase, p38, and MEK1/2. PTGS2 and PGDH mRNA were measured by real-time reverse-transcription polymerase chain reaction. PMA upregulated PTGS2 and downregulated PGDH. The PMA effect was reversed by the inhibition of PKC. The p38 inhibitor reduced the stimulatory effect of PMA and A23187 on PTGS2. MEK1/2 inhibitor reduced the effect of PMA on PTGS2. All MAPK inhibitors failed to reverse the effect of either A23187 or PMA on PGDH. The authors conclude that upon stimulation with the same upstream signals, different downstream intracellular pathways regulate PTGS2 and PGDH mRNA expression.

Adrenomedullin blood concentrations in infants subjected to cardiopulmonary bypass: correlation with monitoring parameters and prediction of poor neurological outcome.

BACKGROUND: Brain injury is a major adverse event after cardiac surgery, especially when extracorporeal circuits are used. We evaluated whether cardiopulmonary bypass (CPB) affects cerebrovascular resistance and plasma concentrations of adrenomedullin (AM), a vasoactive peptide regulating cerebral blood flow. METHODS: We evaluated 50 infants (age <1 year) with congenital heart defects, matched according to a 2-year follow-up; 40 infants had no overt neurological injury, and 10 had brain damage. Blood samples were taken before surgery, during surgery before CPB, at the end of CPB, at the end of surgery, and at 12 h after surgery. Neurological outcome was evaluated before surgery, on postoperative day 7, and 2 years after surgery. We measured AM concentrations and used Doppler velocimetry to measure middle cerebral artery (MCA) pulsatility index (PI). RESULTS: The highest MCA PI values and lowest AM concentrations occurred at the end of CPB and of the surgical procedure. Infants who developed abnormal neurologic sequelae had significantly (P <0.001 for both) higher MCA PI values and lower AM concentrations than patients with normal neurologic outcome at the end of CPB and after surgery. As single markers for predicting neurological abnormalities, AM (cutoff: 17.4 ng/L) achieved a sensitivity of 100% and a specificity of 73.0% and MCA PI (cutoff value: 1.8) a sensitivity of 100% and a specificity of 56.8%. CONCLUSIONS: AM concentrations and MCA PI patterns change during CPB, mainly in infants with brain damage, and may be useful for early identification of infants at risk for brain damage.

Localization and distribution of adrenomedullin receptor in the human placenta: changes with gestational age.

OBJECTIVE: To examine the distribution and localization of adrenomedullin (AM) receptor (AM-R) in human placenta and fetal membranes to assess any change during pregnancy or with labor. STUDY DESIGN: Immunohistochemistry was performed by the avidin/biotin immunoperoxidase method using an antibody specific to AM-R on intrauterine tissues collected from 7-41 weeks of gestation (n=73). RESULTS: AM-R was localized in the placenta and fetal membranes in all 3 trimesters. The distribution of AM-R in the villous and extravillous trophoblast cells of the placenta and in chorion and decidua cells of the fetal membranes changed with gestational age but not with labor. CONCLUSION: AM is secreted by decidua and trophoblast cells that also possess AM-R, suggesting that placental tissues function in both the synthesis and action of AM. Changes in AM-R in the placenta during pregnancy may reflect changes in AM function throughout gestation.