Chronic maternal hypercortisolemia in late gestation alters fetal cardiac function at birth

Abstract

Studies in our laboratory have shown that modest chronic increases in maternal cortisol concentrations over the last 0.20 of gestation impair maternal glucose metabolism and increase the incidence of perinatal stillbirth. Previous studies had found that an increase in maternal cortisol concentrations from 115 to 130 days of gestation in sheep increased both proliferation in fetal cardiomyocytes and apoptosis in the fetal cardiac Purkinje fibers. We hypothesized that the adverse effects of excess cortisol may result in defects in cardiac conduction during labor and delivery. In the present study, we infused cortisol (1 mg·kg^-1·day^-1) into late gestation pregnant ewes and continuously monitored fetal aortic pressure and ECG through labor and delivery. We found that, although the fetuses of cortisol infused ewes had normal late gestation patterns of arterial pressure and heart rate, there was a significant decrease in fetal aortic pressure and heart rate on the day of birth, specifically in the final hour before delivery. Significant changes in the fetal ECG were also apparent on the day of birth, including prolongation of the P wave and P-R interval. We speculate that chronic exposure to glucocorticoids alters cardiac metabolism or ion homeostasis, contributing to cardiac dysfunction, precipitated by active labor and delivery.

Keywords: ECG; cortisol; fetus; telemetry.

Fig. 1.

Plasma cortisol (A and D), glucose (B and E), and lactate (C and F) concentrations in control ewes (A–C) and their fetuses (○; D–F), or ewes that were infused with cortisol during pregnancy (1.0 mg·kg⁻¹·day⁻¹; A–C) and their fetuses (●; CORT group; D–F). *Significant overall effect of time. **Significant overall effect of maternal cortisol treatment. †Values significantly different between groups at the indicated time point. d, Days of gestation.

Fig. 2.

Blood Po₂ (A), Pco₂ (B), and pH (C) in fetuses of control ewes (○) or fetuses of ewes that were infused with cortisol during pregnancy (1.0 mg·kg⁻¹·day⁻¹; ●).

Fig. 3.

Mean aortic pressure (A, F, and K), systolic pressure (B, G, and L), diastolic pressure (C, H, and M), heart rate (D, I, and N), and rate-pressure product (E, J, and O) during late gestation (A–E), the immediate perinatal period (F–J), and 10 min after birth (K–O) in fetuses of control ewes (○) or fetuses of ewes infused with cortisol during pregnancy (1.0 mg·kg⁻¹·day⁻¹; ●). *Significant effect of time. ***Significant interaction between the effects of maternal cortisol treatment and time. †Values significantly different between groups at the indicated time point.

Fig. 4.

The duration of the P-R interval (A and C) and the P wave (B and D) during late gestation (A and B) and the immediate perinatal period (C and D) in fetuses of control ewes (○) or fetuses of ewes infused with cortisol during pregnancy (1.0 mg·kg⁻¹·day⁻¹; ●). *Significant effect of time. **Significant overall effect of maternal cortisol treatment. ***Significant interaction effect of maternal cortisol treatment and time. †Values significantly different between groups at the indicated time point.

Fig. 5.

Examples of ECG abnormalities identified in four cortisol-treated fetuses or lambs at the time of birth. A: atrioventricular (AV) block (P wave with no associated QRS complex) and elevated ST segment in a fetus during active labor. B: notched (or split) P wave in a newborn lamb. C: atrial fibrillation in a newborn lamb who later succumbed. D: abnormal ST segment and notched P waves in a newborn lamb. Note that the shape of the ECG varies with the positioning of the lead on the chest wall relative to the lead secured within the jugular. Thus the shape can vary between fetuses and also within fetus, depending on the orientation of the fetus.