Daily ethanol exposure during late ovine pregnancy: physiological effects in the mother and fetus in the apparent absence of overt fetal cerebral dysmorphology

Abstract

High levels of ethanol (EtOH) consumption during pregnancy adversely affect fetal development; however, the effects of lower levels of exposure are less clear. Our objectives were to assess the effects of daily EtOH exposure (3.8 USA standard drinks) on fetal-maternal physiological variables and the fetal brain, particularly white matter. Pregnant ewes received daily intravenous infusions of EtOH (0.75 g/kg maternal body wt over 1 h, 8 fetuses) or saline (8 fetuses) from 95 to 133 days of gestational age (DGA; term ∼145 DGA). Maternal and fetal arterial blood was sampled at 131-133 DGA. At necropsy (134 DGA) fetal brains were collected for analysis. Maternal and fetal plasma EtOH concentrations reached similar maximal concentration (∼0.11 g/dl) and declined at the same rate. EtOH infusions produced mild reductions in fetal arterial oxygenation but there were no changes in maternal oxygenation, maternal and fetal Pa(CO(2)), or in fetal mean arterial pressure or heart rate. Following EtOH infusions, plasma lactate levels were elevated in ewes and fetuses, but arterial pH fell only in ewes. Fetal body and brain weights were similar between groups. In three of eight EtOH-exposed fetuses there were small subarachnoid hemorrhages in the cerebrum and cerebellum associated with focal cortical neuronal death and gliosis. Overall, there was no evidence of cystic lesions, inflammation, increased apoptosis, or white matter injury. We conclude that daily EtOH exposure during the third trimester-equivalent of ovine pregnancy has modest physiological effects on the fetus and no gross effects on fetal white matter development.

Third trimester-equivalent ethanol exposure causes micro-hemorrhages in the rat brain

“…The neuronal death caused by the micro-hemorrhages was associated with a reactive astrocytic response around the area of the lesion. This finding is similar to that of Kenna et al, (2011) who detected areas of reactive gliosis around subarachnoid hemorrhages in brains of third trimester ethanol exposed fetal sheep. (Goodlett et al, 1993) also described focal areas of high intensity GFAP immunoreactivity in the cerebral cortex of P10 rats that were exposed to ethanol via artificial rearing between P4 and P9 (blood ethanol levels approximately 0.3 g/dl).…”

“…Binge exposure of ewes to relatively high levels of ethanol during the equivalent to the second trimester of human pregnancy blunted the responsiveness of the fetal cerebral vasculature to hypoxia later in pregnancy (Mayock et al, 2007). Similarly, exposure of ewes to high (but not low) doses of ethanol in a binge-like manner during the last trimester of pregnancy induced fetal tachycardia, hypotension, acidemia, and hypercapnia, as well as increased blood flow in the cerebellum, an effect that was associated with loss of Purkinje neurons (Cudd et al, 2001, Parnell et al, 2007, Kenna et al, 2011). Kenna et al, (2011) reported the presence of small subarachnoid hemorrhages in the forebrain and cerebellum in approximately 40% of fetal sheep exposed to lower levels of ethanol during late pregnancy.…”

“…Similarly, exposure of ewes to high (but not low) doses of ethanol in a binge-like manner during the last trimester of pregnancy induced fetal tachycardia, hypotension, acidemia, and hypercapnia, as well as increased blood flow in the cerebellum, an effect that was associated with loss of Purkinje neurons (Cudd et al, 2001, Parnell et al, 2007, Kenna et al, 2011). Kenna et al, (2011) reported the presence of small subarachnoid hemorrhages in the forebrain and cerebellum in approximately 40% of fetal sheep exposed to lower levels of ethanol during late pregnancy. In a subsequent study from the same group of investigators, it was reported that this ethanol exposure paradigm increased stiffness of arteries in several fetal organs, including the brain (Parkington et al, 2014).…”

Effects of l-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol

“…Ultrasound imaging studies have shown that binge-like alcohol exposure (3 g/kg body weight) in a murine second trimester equivalent model did not alter fetal HR (Bake et al 2012). Kenna and colleagues also reported that prenatal alcohol exposure (0.75 g/kg body weight) during the third trimester-equivalent period (from GD 95 to 133) in sheep did not affect fetal HR (Kenna et al 2011). These reports support our findings that repeated maternal alcohol exposure had no significant effect on fetal HR.…”

Meconium Fatty Acid Ethyl Esters as Biomarkers of Late Gestational Ethanol Exposure and Indicator of Ethanol-Induced Multi-Organ Injury in Fetal Sheep

“…In this study, pregnant ewes received one-hour daily ethanol infusion during the third-trimester-equivalent that produced maximal maternal and fetal plasma ethanol concentrations (PEC) of 0.11–0.12 g/dL, which approximated blood ethanol concentration measured in non-pregnant women drinking socially (equivalent to a 55–70 kg woman consuming 3–4 standard drinks over one hour) [16]. This maternal ethanol exposure regimen did not result in overt fetal dysmorphology, but ethanol-induced changes were found in several fetal organs examined, including the heart [17], kidney [18], lung [19], brain and placenta [20]. As meconium was collected from these fetuses, our objective was to determine whether meconium FAEE concentration is a biomarker of repeated fetal exposure to this ethanol regimen in the third-trimester-equivalent of ovine pregnancy.…”