The Effects of Maternal Betamethasone Administration on the Intrauterine Growth-Restricted Fetus

Abstract

Intrauterine growth restriction (IUGR) is associated with altered fetal cardiovascular function to ensure adequate perfusion of essential organs. IUGR fetuses are at risk of preterm delivery and so are likely to receive antenatal glucocorticoids to promote lung maturation. Because glucocorticoids alter vascular tone, we questioned whether such treatment may induce fetal cardiovascular alterations. Using pregnant sheep carrying twins, we induced IUGR at approximately 0.7 gestation by single umbilical artery ligation in one twin, using the other twin as a control. In each fetus, we monitored carotid blood flow and arterial blood gases. We administered 11.4 mg betamethasone (n = 5) or vehicle (n = 4) to the ewe on d 5 (BM1) and 6 (BM2) postsurgery. On d 7, fetal brains were collected for immunohistochemistry. In control fetuses, carotid blood flow decreased 3.5 h post-BM1 by 24% (P < 0.001), returning to baseline at 5.5 h. In IUGR fetuses, carotid flow decreased 2.5 h post-BM1 by 27% and then increased by 25% over baseline, peaking at 11 h (P < 0.001). Compared to control + saline, we observed a significant increase in oxidative damage (4-hydroxynonenal-positive cells) in the fetal hippocampus and subcallosal area of all treatment groups (IUGR + BM > IUGR + saline = control + BM). There was a significant correlation between carotid blood flow reperfusion after betamethasone and the number of 4-hydroxynonenal-positive cells in the cortex and hippocampus. These data suggest that antenatal betamethasone may induce brain injury in the IUGR fetus but not in the normally grown fetus.

The effects of intrauterine growth restriction and antenatal glucocorticoids on ovine fetal lung development

“…The duration of SUAL in this study was relatively short (1 wk) but was associated with the key features of human IUGR, namely altered fetal growth, fetal hypoxemia, and increased levels of circulating cortisol, reflecting SUAL-induced IUGR as an appropriate model of human IUGR (15)(16)(17). Despite increased cortisol concentrations, 1 wk of SUAL-induced IUGR alone did not alter fetal lung morphology.…”

“…The time course undertaken in this study-1 wk between the onset of SUAL-induced IUGR and postmortem, incorporating BM administration on d 5 and d 6-was chosen because we had previously demonstrated that this results in asymmetric growth restriction and fetal hypoxemia (15,17) and because we wished to replicate a common clinical scenario, the preterm IUGR baby that is exposed to glucocorticoids for a short period before birth (35). We also did not want our animals to deliver in response to BM-which occurs in sheep (36), nor did we want to confound experimental outcomes with the administration of progestogen to prevent preterm labor (36).…”

Antenatal Corticosteroids Increase Fetal, But Not Postnatal, Pulmonary Blood Flow in Sheep

“…Corticosteroids affect blood flow in a variety of organs, including the placenta (14), kidney (13), and cerebral circulation (15). However, the induced affect and mechanism of action varies considerably depending upon the vascular bed.…”

“…resistance (22,23) and decrease cerebral blood flow by increasing cerebral vascular resistance (15). Corticosteroids have also been shown to influence the fetal pulmonary circulation by enhancing its adaptation at birth.…”

“…Very preterm infants commonly suffer from persistent pulmonary hypertension, indicating that PVR remains high in these infants (12). However, as most of these infants are likely to have had antenatal corticosteroids, which can affect blood flow in a variety of vascular beds (13)(14)(15), it is possible that corticosteroids influence PBF and the transition of the pulmonary circulation after birth. Our aim was to examine the effects of antenatal betamethasone on PBF and PBF waveform characteristics in the fetus, during the pulmonary transition at birth and for the first 10 min after birth in very preterm lambs.…”