Pharmacodynamics of clonidine therapy in pregnancy: a heterogeneous maternal response impacts fetal growth.

BACKGROUND: Clonidine, a centrally acting antihypertensive agent, has been used successfully in pregnancy. We sought to describe the pharmacodynamic effects of clonidine in pregnancy and the associated impact on fetal growth. METHODS: A retrospective cohort study was performed. Maternal hemodynamics were measured before and after treatment. Responses to clonidine were categorized by the predominant hemodynamic effect: decreased vascular resistance, decreased cardiac output (CO), or mixed. Multinomial logistic regression was used to evaluate predictors of hemodynamic response to clonidine and association between response group and birth weight. RESULTS: Sixty-six pregnant women were studied. Treatment was associated with a reduction of mean arterial pressure (MAP) (-9.2 mm Hg, P < 0.001), a reduction in total peripheral resistance (TPR) (-194 dyne·cm·sec⁻5, P < 0.001), and an increase in CO (+0.5 l/min, P < 0.001). The hemodynamic response was characterized by decreased resistance in 34 women; decreased CO in 22; and mixed effect in 10. No maternal demographic characteristics were associated with a reduction in CO. Mean birth weight percentile was lower in the group that experienced a reduction in CO compared to the group with a reduction in vascular resistance (26.1 vs. 43.6, P = 0.02). The rate of birth weight <10th percentile was also higher in the group experiencing decreased CO (41 vs. 8.8%, P = 0.008). CONCLUSIONS: The hemodynamic effect of clonidine in pregnancy is heterogeneous. The category of effect, reduction in vascular resistance vs. reduction in CO, significantly impacts fetal growth. A reduction in heart rate (HR) after therapy identifies pregnancies at risk for reduced fetal growth.

Atenolol pharmacokinetics and excretion in breast milk during the first 6 to 8 months postpartum.

The objectives were to evaluate the time course for atenolol pharmacokinetics in lactating women postpartum and to quantify atenolol plasma concentrations in the women's 3- to 4-month-old nursing infants. Data were collected during 1 dosing interval from lactating women treated with atenolol for therapeutic reasons, at 2 to 4 weeks (n = 32), 3 to 4 months (n = 22), and 6 to 8 months (n = 17) postpartum. A single blood sample was collected from 15 nursing infants (3-4 months of age) of the mothers participating in the study. At 2 to 4 weeks, 3 to 4 months, and 6 to 8 months postpartum, atenolol infant doses, relative to the mother's weight-adjusted dose, were 14.6% ± 7.6%, 8.3% ± 5.2% and 5.9% ± 2.9%, respectively. Over this time, maternal atenolol pharmacokinetics did not change to a clinically significant extent. Atenolol concentrations were below assay quantification limits (<10 ng/mL) in the plasma of all 3- to 4-month-old nursing infants studied. These findings support the careful use of atenolol during breastfeeding, because in the vast majority of healthy, term infants, atenolol concentrations will be too low to be clinically relevant. Premature infants and those with kidney disease require further study. Infant exposure depends on maternal dose and decreases during the first 6 to 8 months postpartum.

Hemodynamically-directed atenolol therapy is associated with a blunted rise in maternal sFLT-1 levels during pregnancy.

OBJECTIVE: Cardiac output and sFlt-1 are elevated prior to clinical evidence of preeclampsia. Early treatment of high cardiac output with atenolol decreases the risk for preeclampsia. We hypothesized that atenolol would impact circulating sFlt-1. METHODS: Cardiac output and plasma sFlt-1 were measured

Maternal hemodynamic changes associated with furosemide treatment.

OBJECTIVE: To assess the pharmacodynamic effects of furosemide in pregnancy. METHODS: Twenty-one pregnant women who received furosemide 20 mg daily had cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR) measured by Doppler technique before and after treatment. RESULTS: Furosemide was initiated at 22.4 +/- 6.0 weeks gestation. CO and SV decreased (mean +/- SD: 1.2 +/- 0.2 L/min and 17+/-3 mL, respectively), whereas TPR increased (101+/-26 dyne.sec.cm(-5); p < 0.001 for all) after 2.9+/-1.4 weeks. Hemodynamics did not approach the expected mean for pregnancy. CONCLUSIONS: While furosemide improved the hyperdynamic circulation in pregnancy, it did not lower blood pressure or cause clinically significant vasoconstriction.

Diabetic nephropathy in pregnancy: suboptimal hypertensive control associated with preterm delivery.

BACKGROUND: Nephropathy complicates 5% to 10% of pregnancies in women with diabetes and is associated with adverse outcomes. Given the importance of blood pressure (BP) control in reducing cardiovascular and renal complications outside of pregnancy, we hypothesized that poorly controlled hypertension in early pregnancy among women with diabetic nephropathy would be associated with adverse outcomes. METHODS: To examine the impact of hypertensive control in early pregnancy on perinatal outcomes, we performed a retrospective cohort study of pregnancies complicated by diabetic nephropathy with "Above Target" mean arterial pressure (> or = 100 mm Hg; N = 21) and "Below Target" mean arterial pressure (< 100 mm Hg; N = 22), which approximates the American Diabetes Association and the Seventh Report of the Joint National Committee recommended target of 130/80 mm Hg, measured at < 20 weeks' gestation. RESULTS: There were no differences in maternal age (mean +/- SEM: 27.2 +/- 1.2 v 29.5 +/- 1.0 years), duration of diabetes (median, range: 17.5, 13 to 24 v 16, 1 to 25 years), or glucose control (glycosylated hemoglobin [HbA1c] 8.0% +/- 0.3% v 8.1% +/- 0.4%) between the Above and Below Target groups. The Above Target group had more proteinuria (4.69 +/- 1.08 v 1.65 +/- 0.43 g/24 h; P = .007) and higher serum creatinine levels (1.23 +/- 0.17 v 0.85 +/- 0.06 mg/dL; P = .02). The Above Target group was more likely to deliver at < 32 weeks' gestation (38.1% v 4.6%; P = .007). The increased risk of preterm delivery remained significant after adjusting for duration of diabetes and glucose control. CONCLUSIONS: Suboptimal control of hypertension in early pregnancy in women with diabetic nephropathy is associated with a significant risk of preterm delivery. Improved preconceptional control of hypertension may reduce adverse perinatal outcomes in women with diabetic nephropathy.

Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum.

Preexisting hypertension complicates 5% of all pregnancies. The objective of this study was to evaluate steady-state atenolol pharmacokinetics and pharmacodynamics (n = 17) during the second trimester (2nd T), third trimester (3rd T), and 3 months postpartum. Pregnancy as compared to 3 months postpartum (nonpregnant control) resulted in significant (P < .05) changes, including the following: 42% (2nd T) and 50% (3rd T) increase in creatinine clearance, 38% (2nd T) and 36% (3rd T) increase in atenolol renal clearance, 12% (2nd T) and 11% (3rd T) decrease in atenolol half-life, 20% (2nd T) and 28% (3rd T) increase in cardiac output, 15% (2nd T) and 23% (3rd T) increase in resting heart rate, and 22% (2nd T) and 21% (3rd T) decrease in total peripheral resistance in subjects on steady-state oral atenolol for treatment of hypertension in pregnancy. In conclusion, the renal clearance of atenolol along with creatinine clearance is increased during pregnancy. However, this does not translate into an increase in apparent oral clearance of atenolol, possibly related to the high variability in bioavailability. Atenolol administration did not appear to change the pattern of the increase in cardiac output and the decrease in total peripheral resistance, which normally occurs during pregnancy.