Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe.
OBJECTIVE
Our purpose was to determine whether the fetal acidosis and hypoxia previously demonstrated in animal models with maternal nifedipine infusion is the result of a decrease in uteroplacental or fetoplacental blood flow and whether this effect is exacerbated by a higher drug concentration and duration of infusion.


METHODS
Ten chronically instrumented pregnant ewes (gestational age 0.9 term, term = 145 days) received nifedipine infusions (n = 7) or vehicle (95% ethanol/water, 3:7) (n = 3). Three 90-minute periods were evaluated: 5 microg/kg/min infusion (low-dose nifedipine), no infusion, and 10 microg/kg/min (high-dose nifedipine). Paired maternal and fetal blood gases, glucose, lactate, and nifedipine levels were obtained every 30 minutes while hemodynamic parameters were monitored. We determined maternal and fetal blood flows using the radioactive microsphere technique.


RESULTS
Although maternal placental blood flows decreased by 25% during low-dose nifedipine (p < 0.05), this was only transient and there were no other decreases in uteroplacental or fetoplacental blood flow. Fetal blood flow increased to the adrenals and diaphragm with high-dose nifedipine (p < 0.05). Maternal and fetal lactate levels increased with both doses (p < 0.05). In addition, fetuses exhibited significant hypoxia (oxygen content fell 0.46 mmol/L) and acidosis (pH fell 0.06 units) throughout the nifedipine infusion and recovery period. Maternal heart rate increased transiently with both doses (p < 0.05); however, there were no changes in either fetal or maternal mean arterial pressure. Infusion of the vehicle alone did not alter maternal or fetal hemodynamics. Maternal and fetal plasma nifedipine levels reached steady-state by 30 minutes, and maternal/fetal ratios were 0.4 to 0.55. The maternal metabolic clearance rates for low- and high-dose nifedipine were 80.0 and 79.8 ml/min/kg, respectively. Maternal half-life calculation revealed a two-compartment model with a calculated half-life of 2.87 +/- 3.15 and 63.57 +/- 154.03 (+/-SD) minutes for the alpha and beta components, respectively.


CONCLUSIONS
Maternal nifedipine infusion is associated with hypoxia and acidosis in the sheep fetus, without persistent decreases in uteroplacental or fetoplacental blood flows or blood pressures. These fetal blood gas changes are more severe with high-dose nifedipine and longer duration of infusion and continue to deteriorate even when recovery is allowed. The deterioration of fetal blood gases is out of proportion to the transient decreases in uteroplacental blood flow and demonstrates that another mechanism for this fetal acidosis and hypoxia exists during nifedipine infusion.
Blea
C W
CW
Department of Obstetrics and Gynecology, University of Wisconsin-Madison, 53715, USA.
Barnard
J M
JM
Magness
R R
RR
Phernetton
T M
TM
Hendricks
S K
SK
D000138:Acidosis / Q000139:chemically induced; D000818:Animals; D001639:Bicarbonates / Q000097:blood; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005315:Fetal Diseases / Q000139:chemically induced; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects*; D000860:Hypoxia / Q000139:chemically induced; D008657:Metabolic Clearance Rate; D009543:Nifedipine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000187:drug effects* / Q000378:metabolism; D012756:Sheep
D001639:Bicarbonates; D009543:Nifedipine; D010100:Oxygen