Activin A Plasma Levels at Birth: An Index of Fetal Hypoxia in Preterm Newborn

Abstract

Activin-A is a growth factor involved in cell growth and differentiation, neuronal survival, early embrionic development and erythropoiesis. Hypoxemia is a specific trigger for increasing activin-A in fetal lamb circulation. We tested the hypothesis that fetal hypoxia induces activin-A secretion in preterm newborn infants. Fifty newborn infants with gestational ages ranging from 26 to 36 wk were enrolled in a prospective study performed at the Pediatrics, Obstetrics and Reproductive Medicine Department, University of Siena, Italy. Heparinized blood samples were obtained from the umbilical vein after cord clamping, immediately after delivery. Activin A, hypoxanthine (Hx), xanthine (Xa) plasma levels and absolute nucleated red blood cell (NRBC) count were measured. Activin-A levels (p Ͻ 0.0001) and NRBC (p Ͻ 0.0001) were significantly higher in hypoxic than in non hypoxic preterm newborns. Cord activin A levels were significantly related with Hx ( a ϭ0.64, b ϭ0.64, p Ͻ 0.0001) and Xa Activin A is a growth factor (␤A/␤A dimer) mainly produced by the placenta, decidua and fetal membranes and secreted in large amounts in maternal circulation (1-7). Inhibin/activin subunits are expressed in a variety of tissues, including ovary, testis, placenta, adrenal, kidney, brain and pituitary gland. Inhibin A and Activin A have been reported to regulate various physiologic functions, including ACTH and GH secretion, neuronal survival, hypothalamic oxytocin secretion, erythropoiesis, early embryonic development and gonad function (8 -11). Activin A concentrations significantly increase in maternal serum with advancing gestation (12), whereas umbilical cord blood serum do not significantly differ from midpregnancy to term gestation (7) and are significantly lower than in maternal serum (6, 7). Disorders of pregnancy due to reduced placental perfusion and various degrees of feto-placental hypoxemia, such as preeclampsia and fetal growth restriction (13) are characterized by increased levels of maternal and umbilical cord activin A (12), and feto-placental and/or maternal isocapnic hypoxemia are specific triggers for an increase in activin A. Indeed, cord blood Activin A levels increase in the sheep after induction of hypoxia, remain elevated throughout hypoxia and return to control values when normal blood flow is restored (14). Activin A subunit mRNA expression is up-regulated during hypoxic ischemia in the adult brain and cerebral hypoxia stimulates Activin A secretion in rat newborns as well as in adult animals (15,16). No human study to date has determined whether this protein is altered in babies with clinical signs of hypoxia at birth. Perinatal hypoxia set in motion a cascade of biochemical events commencing with a shift from oxidative to anaerobic metabolism, which leads to a rapid rise in the levels of lactic acid and of oxygen free radicals (17). During hypoxia the cutback in oxidative phosphorilation rapidly diminishes reservers of high-energy phopshate. High levels of adenosine and hypoxanthine accumulate in a few minu...

Activin-A exerts a crucial anti-inflammatory role in neonatal infections

“…Moreover, activin-A is increased in the cerebrospinal fluid during meningitis in animal models and adults (22,23). Serum levels of activin-A vary with certain studies reporting high levels (11,29) and other studies reporting similar levels, or even, reporting lower levels to our study (9,28,30,31). This discordance could be due to the differences in the experimental set up, including the age of the neonates studied, the disease context, the methodology employed, the time point of analysis, etc.…”

“…The diagnosis of suspected sepsis was established when at least three clinical signs and two laboratory findings of infection were present. Activin-A is increased during perinatal asphyxia/hypoxia and intraventricular hemorrhage (11)(12)(13)(14)29,38). In addition, maternal activin-A levels are associated with preeclampsia (39) and the use of antidepressants (30).…”

“…Increased activin-A levels have been observed in the placenta and in the maternal and fetal serum of intrauterine growth retardation pregnancies (9,10). Furthermore, Florio et al have demonstrated significantly increased activin-A in preterm newborns with signs of perinatal hypoxia at birth (11). Activin-A was also upregulated in the cerebrospinal fluid of asphyxiated full-term newborns (12).…”

Cerebrospinal Fluid Activin A Measurement in Asphyxiated Full-Term Newborns Predicts Hypoxic Ischemic Encephalopathy

“…The role of such an increased secretion warrants considerations because it was proposed that the up-regulation of activin A in brain injury might serve as a neuroprotective factor: activin A enhances the survival of midbrain and hippocampal neurons (11,12 ); decrease ischemic brain injury in infant rats (8 ); and shields striatal and midbrain neurons against neurotoxic damage (12,14 ). However, increased activin A concentrations have been reported in amniotic fluid of a patient who subsequently died from intrauterine fetal hypoxia (23 ) and in the plasma of hypoxic preterm newborns (21 ), suggesting a role for activin A in the events cascade leading to hypoxic ischemic brain damage. Indeed, activin A release forms part of the CNS response to challenges involved in modulating inflammatory processes in the brain (24,25 ), the main mechanisms involved in brain damage attributable to hypoxia/asphyxia (4 ), and it prevents apoptosis (26 ) and inhibits caspase (27 ), two important pathways of neuronal death (28 ).…”

Within-Person, Among-Finger Variability of Capillary Blood Glucose Measurements

“…The role of such an increased secretion warrants considerations because it was proposed that the up-regulation of activin A in brain injury might serve as a neuroprotective factor: activin A enhances the survival of midbrain and hippocampal neurons (11,12 ); decrease ischemic brain injury in infant rats (8 ); and shields striatal and midbrain neurons against neurotoxic damage (12,14 ). However, increased activin A concentrations have been reported in amniotic fluid of a patient who subsequently died from intrauterine fetal hypoxia (23 ) and in the plasma of hypoxic preterm newborns (21 ), suggesting a role for activin A in the events cascade leading to hypoxic ischemic brain damage. Indeed, activin A release forms part of the CNS response to challenges involved in modulating inflammatory processes in the brain (24,25 ), the main mechanisms involved in brain damage attributable to hypoxia/asphyxia (4 ), and it prevents apoptosis (26 ) and inhibits caspase (27 ), two important pathways of neuronal death (28 ).…”