TY - JOUR
T1 - Sex differences in modulation of fetoplacental vascular resistance in growth-restricted mouse fetuses following betamethasone administration
T2 - comparisons with human fetuses
AU - Cahill, Lindsay S.
AU - Shinar, Shiri
AU - Whitehead, Clare L.
AU - Hobson, Sebastian R.
AU - Stortz, Greg
AU - Ayyathurai, Viji
AU - Ravi Chandran, Anjana
AU - Rahman, Anum
AU - Kingdom, John C.
AU - Baschat, Ahmet
AU - Murphy, Kellie E.
AU - Serghides, Lena
AU - Macgowan, Christopher K.
AU - Sled, John G.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1
Y1 - 2021/1
N2 - Background: Maternally administered corticosteroids are routinely used to accelerate fetal lung maturation in pregnancies at risk of early preterm delivery. Although, among the subgroup with growth restriction, a majority show a temporary improvement in umbilical artery Doppler waveforms that may be sustained up to 7 days, a minority will acutely decompensate in response to corticosteroids in association with deteriorating umbilical and fetal Doppler waveforms. The basis for such acute Doppler changes is presently unknown. Our group has developed a noninvasive ultrasound methodology to measure wave reflections in the umbilical artery and have established that wave reflection metrics are sensitive to structural changes in the placental vasculature and to acute changes in vascular tone. Using this approach, we demonstrated in healthy pregnant mice that fetoplacental vascular resistance decreased in betamethasone-treated mice compared with saline-treated controls. Objective: This study aimed to investigate the effects of betamethasone administration on the wave reflection metrics in a mouse model of fetal growth restriction and to compare these findings with equivalent measurements in human fetuses. Study Design: Pregnant CD-1 mice were housed from embryonic day 14.5 to embryonic day 17.5 in either a normoxic (21% O2, n=24) or hypoxic environment (11% O2, n=22), the latter being an established mouse model of fetal growth restriction. To investigate the effect of maternally administered betamethasone on the fetoplacental vasculature, ultrasound imaging was performed at baseline and 4 hours after treatment (either betamethasone or sterile saline). Umbilical artery wave reflection metrics were compared between the groups and for the effect of fetal sex. In addition, a cohort of 10 pregnant women with elevated umbilical artery pulsatility index and evidence of fetal growth restriction and 6 controls were imaged before and after corticosteroid administration. Results: In the mouse model, after betamethasone administration, the female fetuses from the hypoxia group showed a 15% increase in umbilical artery diameter, a 98% increase in umbilical artery blood flow, and a 27% decrease in umbilical artery reflection coefficient, whereas the males from the hypoxia group showed no substantial changes. In agreement with our mouse findings, umbilical artery reflections were found to be larger in human growth-restricted fetuses than controls in women at risk of preterm birth. Conclusion: Our studies provide insight into the mechanism whereby the human growth-restricted fetus may exhibit a temporary favorable fetoplacental vascular response to maternally administered corticosteroids. Further investigations are needed to understand why the male growth-restricted fetus seems unable to mount this favorable vascular response.
AB - Background: Maternally administered corticosteroids are routinely used to accelerate fetal lung maturation in pregnancies at risk of early preterm delivery. Although, among the subgroup with growth restriction, a majority show a temporary improvement in umbilical artery Doppler waveforms that may be sustained up to 7 days, a minority will acutely decompensate in response to corticosteroids in association with deteriorating umbilical and fetal Doppler waveforms. The basis for such acute Doppler changes is presently unknown. Our group has developed a noninvasive ultrasound methodology to measure wave reflections in the umbilical artery and have established that wave reflection metrics are sensitive to structural changes in the placental vasculature and to acute changes in vascular tone. Using this approach, we demonstrated in healthy pregnant mice that fetoplacental vascular resistance decreased in betamethasone-treated mice compared with saline-treated controls. Objective: This study aimed to investigate the effects of betamethasone administration on the wave reflection metrics in a mouse model of fetal growth restriction and to compare these findings with equivalent measurements in human fetuses. Study Design: Pregnant CD-1 mice were housed from embryonic day 14.5 to embryonic day 17.5 in either a normoxic (21% O2, n=24) or hypoxic environment (11% O2, n=22), the latter being an established mouse model of fetal growth restriction. To investigate the effect of maternally administered betamethasone on the fetoplacental vasculature, ultrasound imaging was performed at baseline and 4 hours after treatment (either betamethasone or sterile saline). Umbilical artery wave reflection metrics were compared between the groups and for the effect of fetal sex. In addition, a cohort of 10 pregnant women with elevated umbilical artery pulsatility index and evidence of fetal growth restriction and 6 controls were imaged before and after corticosteroid administration. Results: In the mouse model, after betamethasone administration, the female fetuses from the hypoxia group showed a 15% increase in umbilical artery diameter, a 98% increase in umbilical artery blood flow, and a 27% decrease in umbilical artery reflection coefficient, whereas the males from the hypoxia group showed no substantial changes. In agreement with our mouse findings, umbilical artery reflections were found to be larger in human growth-restricted fetuses than controls in women at risk of preterm birth. Conclusion: Our studies provide insight into the mechanism whereby the human growth-restricted fetus may exhibit a temporary favorable fetoplacental vascular response to maternally administered corticosteroids. Further investigations are needed to understand why the male growth-restricted fetus seems unable to mount this favorable vascular response.
KW - chronic hypoxia
KW - corticosteroids
KW - fetal sex
KW - growth restriction
KW - mouse
KW - placenta
KW - pregnancy
KW - ultrasound
KW - wave reflection
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U2 - 10.1016/j.ajogmf.2020.100251
DO - 10.1016/j.ajogmf.2020.100251
M3 - Article
C2 - 33451599
AN - SCOPUS:85100279894
SN - 2589-9333
VL - 3
JO - American Journal of Obstetrics and Gynecology MFM
JF - American Journal of Obstetrics and Gynecology MFM
IS - 1
M1 - 100251
ER -