Debra Brateng

Treatment of hypertension in pregnancy: effect of atenolol on maternal disease, preterm delivery, and fetal growth.

OBJECTIVE To assess the impact of antihypertensive therapy initiated early in pregnancy on maternal and fetal outcomes. METHODS A retrospective review of patients treated in early pregnancy with atenolol was conducted. Therapy was directed by measurements of cardiac output. Fetal growth was analyzed with reference to prior pregnancy outcome, treatment inconsistent with standards present at the end of the study period, and year of treatment. Data were analyzed by paired and unpaired t‐test, analysis of variance for multiple comparisons, and linear regression. RESULTS Two hundred thirty‐five pregnancies at risk for preeclampsia were studied. Ten percent (n = 22) received additional therapy with furosemide; 20% (n = 48) with hydralazine. Six and one half percent had treatment inconsistencies. Fifty‐five percent had greater than 100 mg of proteinuria at baseline. One patient developed severe preeclampsia. Only 2.1% delivered before 32 weeks; 4.7% delivered before 34 weeks. Low percentile birth weight was strongly associated with a prior pregnancy with intrauterine growth restriction (P = 0.001), treatment inconsistency (P < .001), and a pregnancy earlier in our treatment experience (P < .001). Percentile birth weight increased from the 20th at the beginning of the study period to the 40th by the end (P = 0.002). CONCLUSION Early intervention with antihypertensive therapy was associated with a low rate of severe maternal hypertension and preterm delivery. The failure to adjust therapy in response to an excessive fall in cardiac output or increase in vascular resistance was associated with reduced fetal growth.

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.

Low-dose, short-acting, angiotensin-converting enzyme inhibitors as rescue therapy in pregnancy

Objective To assess the risks and potential benefits of low-dose angiotensin-converting enzyme (ACE) inhibitor treatment in pregnancies complicated by severe hypertension. Methods A retrospective review of pregnant women treated with ACE inhibitors was conducted. Hemodynamics before and after treatment were assessed by using Doppler technique to measure cardiac output. Data were analyzed by using the Wilcoxon signed-rank test. Maternal and neonatal outcomes were assessed by chart review and phone interview. Results Ten pregnancies were identified in which ACE inhibitor therapy was initiated in pregnancy for severe, unresponsive vasoconstricted hypertension; three were complicated by severe chronic hypertension, 4 by renal insufficiency, and 3 by severe preeclampsia. Treatment was limited to a low-dose, short-acting ACE inhibitor (captopril, 12.5 to 25 mg/day). Treatment was associated with an increase in cardiac output from 5.7 ± 1.5 L/minute to 7.4 ± 1.4 L/minute (P < .01) and a reduction in total peripheral resistance from 1770 ± 670 to 1222 ± 271 dyne • sec • cm−5 (P = .005). No fetal or neonatal complications were observed. The probability of observing one or more adverse neonatal outcome in this sample, based on an assumed true risk of 5% and 10%, was calculated to be 12% and 50%, respectively. Conclusion Low-dose captopril therapy was associated with improvement in maternal hemodynamics and, in cases complicated by severe hypertension and renal insufficiency, successful continuation of pregnancy. Fetal and neonatal complications were not experienced, but complication rates of 5–10% could have been missed because of the small number of exposed pregnancies.

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.

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.

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 womens 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 mothers 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.