Clonidine pharmacokinetics in pregnancy.

The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n = 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 +/- 168 ml/min during pregnancy compared with 245 +/- 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r = 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 +/- 0.1 (arterial) and 1.0 +/- 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.

Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies.

Amoxicillin is recommended for anthrax prevention in pregnancy. The objective of this study was to evaluate the pharmacokinetics of amoxicillin during pregnancy and postpartum (PP). Sixteen women received amoxicillin during gestation (18-22 weeks (T2) and 30-34 weeks (T3)) as well as 3 months postpartum (PP) to evaluate single-dose pharmacokinetics. Amoxicillin compartmental pharmacokinetic parameters were used to simulate amoxicillin concentration-time profiles following different dosage strategies. Amoxicillin CL(renal) (T2: 24.8+/-6.7 l/h, P<0.001; T3: 24.0+/-3.9 l/h, P<0.001; and PP: 15.3+/-2.6 l/h) and renal CL(secretion) (T2: 280+/-105 ml/min, P<0.002; T3: 259+/-54 ml/min, P<0.001; and PP: 167+/-47 ml/min) were higher during pregnancy than postpartum. Simulations suggest that amoxicillin concentrations adequate to prevent anthrax may be difficult to achieve during pregnancy and postpartum. Increases in amoxicillin CL(renal) and renal CL(secretion) reflect increases in filtration and secretory transport or diminished reabsorption in the kidneys. Amoxicillin may not be an appropriate antibiotic for post-anthrax exposure prophylaxis.

The effects of oral nifedipine on hepatic blood flow in humans.

Duplex ultrasonography was used to measure changes in hepatic blood flow in 13 healthy volunteers after they received single doses of 10 mg oral nifedipine and placebo. Blood flow was measured in the hepatic artery and branches of the portal and hepatic veins at baseline and 0.3, 0.6, 1, 1.5, 2, 3, 4, and 5 hours after drug administration. Cardiac output was also measured at baseline and 1, 2, and 3 hours after dosing. Blood flow initially increased in all three vessels 0.6 hour after administration of nifedipine (29%, 56%, and 31% in the hepatic artery, hepatic vein, and portal vein, respectively) compared with placebo. Flow rapidly returned to baseline in the hepatic artery and hepatic vein, whereas it appeared to remain elevated through 3 hours in the portal vein. Nifedipine administration resulted in an increase in cardiac output of 26%, 22%, and 14% above placebo at 1, 2, and 3 hours, respectively. No significant differences were detected in the systolic, diastolic, or mean arterial blood pressures after nifedipine or placebo. This study demonstrates that nifedipine increases hepatic blood flow in a transient nature and systemic hemodynamic parameters do not necessarily reflect specific organ responses. The nifedipine-induced change in blood flow should be considered when nifedipine is coadministered with high-clearance drugs, because systemic availability may be increased.

Duplication (6q) syndrome diagnosed in utero.

We report on a case of partial duplication 6q detected ultrasonographically. The clinical picture noted in utero is consistent with the adult phenotype previously reported in the literature.

Fusobacterium: anaerobic occult amnionitis and premature labor.

Fusobacterium species are well established pathogens. Before the advent of effective anaerobic antimicrobial therapy, they were associated with prolonged, often fatal courses. Previously, fusobacterium had not been identified as a common perinatal pathogen. Three cases of occult amnionitis due to Fusobacterium are presented. Review of five series of occult amnionitis revealed 23 cases. In seven (30.4%), Fusobacterium was isolated. In 14 (60.8%), an anaerobic species was isolated. The average gestational age of patients from whom anaerobes were grown was 29.0 weeks. Of those that grew no anaerobes, the average gestational age was 32.3 weeks (P less than .05). The overall rate of maternal febrile morbidity was 35%. Fusobacterium accounted for 50% of the febrile cases while accounting for only 30.4% of the total cases.

The hemodynamic effects of orthostatic stress during pregnancy.

The effects of orthostatic stress on cardiac output and systemic vascular resistance have not been previously studied in pregnancy. A Doppler technique of measuring cardiac output was used to study 15 nonpregnant women, 14 pregnant women in the first trimester, and 16 pregnant women in the third trimester. Subjects were studied in recumbent, sitting, and standing positions. In each group, the change from recumbent to standing positions resulted in a fall in cardiac output of 1.7-1.8 L/minute (P = .001). Systemic vascular resistance rose in each group (P = .001). The magnitude of the rise was greatest in nonpregnant women and smallest in the third trimester (P = .005). The observed fall in cardiac output and rise in systemic vascular resistance may be clinically significant in pregnancies complicated by uteroplacental insufficiency.

Pulmonary hypertension in pregnancy: treatment with pulmonary vasodilators.

OBJECTIVE: To describe the clinical course of pregnancies complicated by pulmonary hypertension and treated with the pulmonary vasodilators nifedipine and prostacyclin. METHODS: Four pregnant women with pulmonary hypertension were treated with pulmonary vasodilators. Therapy with oral nifedipine and intravenous prostacyclin was guided by right pulmonary artery catheterization and Doppler measurements of cardiac output. RESULTS: Three of four women responded to vasodilator therapy and successfully completed their pregnancies. Two who conceived at least 1 year after successful treatment and normalized right ventricle function carried three uncomplicated pregnancies. The woman who did not respond died. Delay in diagnosis contributed to her outcome. Noninvasive measurement of cardiac output helped diagnosis of right ventricular failure and offered reassurance in women who remained compensated. Postpartum decompensation in one woman was characterized by a negative Starling response as central venous pressure increased from 4 to 11 mmHg. She responded positively to diuresis. CONCLUSION: Early diagnosis of pulmonary hypertension is critical. Volume overload postpartum might significantly contribute to decompensation. We recommend a year of successful therapy after a response to vasodilator therapy and near-normal right ventricular function before pregnancy is considered. In complicated pregnancies, women must balance the best estimate of risk with the value they put on pregnancy.

Measurement of cardiac output during pregnancy: validation of Doppler technique and clinical observations in preeclampsia.

In 12 patients requiring pulmonary artery catheterization, cardiac output was measured using Doppler and thermodilution techniques. The Doppler technique accurately predicted measurements made by thermodilution (r = 0.91; P less than .001). Eighteen normal patients in the third trimester and 36 preeclamptics who had not been treated with medications other than magnesium sulfate were evaluated with Doppler alone. Of note was the heterogeneity among preeclamptics. Although their mean systemic vascular resistance was elevated, it ranged from 2256-648 dyne X sec X cm-5. Cardiac output ranged from 13.2-3.9 L/minute.

Aortic stenosis in pregnancy.

Aortic stenosis is uncommon during pregnancy. Five cases are described in which clinical management was facilitated by the use of Doppler echocardiography to assess the severity of disease and pulmonary artery catheterization to manage maternal hemodynamics. Regional anesthesia was used without complication. In patients with severe stenosis, significant morbidity and mortality were experienced when aortic valve replacement was delayed beyond the postpartum period.

Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study.

Preeclampsia is a disease unique to pregnancy that contributes substantially to maternal and fetal morbidity and mortality. The condition has been thought to be one of hypoperfusion in which increased vascular resistance characterizes the associated hypertension. This study was designed to test an alternative hypothesis, that preeclampsia is characterized by high cardiac output. In a blinded longitudinal study of nulliparas with uncomplicated pregnancies, cardiac output was measured serially by Doppler technique. Cardiac output was elevated throughout pregnancy in patients who became preeclamptic (P = .006). Six weeks postpartum, the hypertension of the preeclamptic subjects had resolved but cardiac output remained elevated (P = .001) and peripheral resistance remained lower than in the normotensive subjects (P = .001). This study demonstrates that preeclampsia is not a disease of systemic hypoperfusion and challenges most current models of the disease based on that assumption.

The maternal hemodynamic effect of indomethacin in normal pregnancy.

The vasodilation of pregnancy is thought by many to be due to increased endothelial production of prostacyclin, a vasodilatory prostanoid. Indomethacin, a potent inhibitor of prostaglandin synthesis, is known to increase the maternal blood pressure response to angiotensin II infusion. We sought to measure directly the hemodynamic effects of a short course of indomethacin. Twenty-three healthy pregnant women with uncomplicated pregnancies between 26-32 weeks' gestation completed the study. Using Doppler technology, we determined cardiac output, stroke volume, and total peripheral resistance before and after three 25-mg doses of indomethacin. Although blood pressure did not change, peripheral resistance rose and stroke volume fell following indomethacin administration. Our findings support the hypothesis that indomethacin interferes with tonic prostaglandin-induced vasodilation in pregnancy. However, the increase in vascular resistance was very slight, suggesting that other vasodilators are also at work in pregnancy. We recommend that indomethacin be used judiciously in hypertensive pregnant patients until more information concerning possible adverse hemodynamic effects becomes available.

Renal vascular hypertension during pregnancy.

We report two women with renal artery stenosis in pregnancy. The first patient presented with severe hypertension in the first and second trimesters characterized by an extremely high vascular resistance (maximum 2455 dyne.second.cm-5). Transluminal angioplasty was performed at 20 weeks' gestation, resulting in resolution of the patient's hypertension. After angioplasty, her vascular resistance fell to 1600 dyne.second.cm-5, but did not reach normal pregnant levels. The pregnancy was carried to term without complication. The second patient's hypertension improved during pregnancy, and she delivered at term without complication. Twelve weeks postpartum, the patient again became severely hypertensive, and transluminal angioplasty was performed.

Maternal hemodynamics in pregnancies complicated by hyperthyroidism.

The hemodynamics of six pregnant women with hyperthyroidism were studied before and after therapy. Cardiac output was measured by Doppler technique, and blood pressure by automated cuff. When compared with values in euthyroid pregnant women, blood pressure (83.6 mmHg, P less than .001), heart rate (89.2 beats per minute, P less than .001), cardiac output (11.2 L/minute, P less than .001), and stroke volume (123 mL, P less than .001) were significantly elevated. Total peripheral resistance was significantly reduced (609 dyne.second.cm-5, P less than .001). Despite normalization of thyroid indices after therapy, cardiac output remained markedly elevated (9.7 L/minute, P less than .001) and vascular resistance remained reduced (708 dyne.second.cm-5, P = .01). Although the hemodynamics of pregnant thyrotoxic women normalize with therapy, they remain significantly hyperdynamic.

Maternal hemodynamics and aortic diameter in normal and hypertensive pregnancies.

The aortic diameters of 89 normotensive pregnant women were compared with those of nine rigorously defined preeclamptic women and 59 women who required antihypertensive therapy. Over the course of normal pregnancy, the diameter increased significantly; it was larger in preeclamptic than in normotensive women throughout pregnancy. The aortic diameter in women with high-resistance hypertension was smaller than that in normotensive women and in those with high-output, low-resistance hypertension, but it was larger in women with low-resistance hypertension than in normotensive women. The aortic diameter increased after treatment of high-resistance hypertension with hydralazine, but decreased after treatment of high-output, low-resistance hypertension.

A randomized controlled trial of the effect of third-trimester calcium supplementation on maternal hemodynamic function.

OBJECTIVE: To determine the effect of third-trimester calcium supplementation on maternal hemodynamic function. METHODS: Pregnant women were randomized to receive either 1.5 g of elemental calcium or placebo for 6 weeks during the third trimester. Using Doppler technique, maternal hemodynamic characteristics were measured at baseline, at 2 hours after the first dose of study drug, and at the completion of 6 weeks. Serum, dietary, and urinary calcium levels were also assessed. Power calculation indicated the need to study ten subjects in each group to detect a 1.2 L (20%) difference in cardiac output between groups, assuming a mean of 6.2 +/- 1.0 L/minute. Data were analyzed by analysis of variance for repeated measures, Student t test, Mann-Whitney U test, and Fisher exact test. RESULTS: Twenty-three women enrolled, and 18 completed the study. There were no statistically significant differences in demographic characteristics or in serum, dietary, or urinary calcium levels between the two groups. There were also no statistically significant differences in hemodynamic function over time within the calcium supplementation or placebo group (P > .05; analysis of variance for repeated measures). After 6 weeks, there were no significant differences between the calcium- and placebo-treated subjects in any hemodynamic measurement. Specifically, there was not a statistically significant difference in cardiac output (7.3 +/- 1.2 L/minute versus 8.0 +/- 0.9 L/minute; P = .09) between the calcium- and placebo-treated groups. CONCLUSION: These findings suggest that third-trimester calcium supplementation does not significantly alter cardiac output. The mechanism by which calcium supplementation lowers blood pressure remains to be elucidated.

Hemodynamic observations during paroxysmal hypertension in a pregnancy with pheochromocytoma.

A patient with pheochromocytoma diagnosed at 17 weeks' gestation was studied at rest, during an episode of paroxysmal hypertension, and during phenoxybenzamine treatment. Cardiac output was estimated noninvasively by Doppler technique. During paroxysmal hypertension, the mean blood pressure was 102 mmHg, cardiac output fell by 40%, and systemic vascular resistance rose by 250%. Phenoxybenzamine treatment did not change the resting cardiac output or systemic vascular resistance. These observations suggest that serious fetal compromise might occur even with mild episodes of hypertension associated with pheochromocytoma.

Cesarean delivery and postpartum mortality among primiparas in Washington State, 1987-1996(1).

OBJECTIVE: To examine the association between delivery method and mortality within 6 months of delivery among primiparas. METHODS: We conducted a population-based, retrospective cohort analysis using statewide, maternally linked birth certificate, hospital discharge, and death certificate data. The present cohort was all primiparas who gave birth to live-born infants in civilian hospitals in Washington State from January 1, 1987 through December 31, 1996 (n = 265,471). Odd ratios (OR) and 95% confidence intervals (CI) were calculated for overall mortality, pregnancy-related mortality, and pregnancy-unrelated mortality associated with delivery method. RESULTS: Thirty-two women (12.1 per 100,000 singleton live births) died within 6 months of delivery of their first child. Eleven of 32 deaths were pregnancy related (4.1 per 100,000 singleton live births, 95% CI 1.6, 6.5), and 21 of the 32 deaths were not pregnancy related (7.9 per 100,000 singleton live births, 95% CI 4.5, 11.3). The pregnancy-related mortality rate was higher among women delivered by cesarean (10.3/100,000) than among women delivered vaginally (2.4/100,000). In logistic regression analyses, women who had cesarean delivery were not at significantly higher risk of death overall after adjustment for maternal age (OR 1.7, 95% CI 0.3, 3.6), pregnancy-related death after adjustment for maternal age and severe preeclampsia (OR 2.2, 95% CI 0.6, 7.9), or pregnancy-unrelated death after adjustment for maternal age and marital status (OR 0.9, 95% CI 0.3, 2.7), relative to women who had vaginal delivery. CONCLUSION: Cesarean delivery might be a marker for serious preexisting morbidities associated with increased mortality risk rather than a risk factor for death in and of itself. Data from additional sources such as medical records and autopsy reports are necessary to disentangle preexisting mortality risk from risk associated solely with delivery method.

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.

First-birth cesarean and placental abruption or previa at second birth(1).

OBJECTIVE: To assess the association between first-birth cesarean delivery and second-birth placental abruption and previa. METHODS: We conducted a population-based, retrospective cohort analysis using data from the Washington State Birth Events Record Database. The study cohort included all primiparas who gave birth to live singleton infants in nonfederal short-stay hospitals from January 1, 1987, through December 31, 1996, and who had second singleton births during the same period (n = 96,975). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for placental abruption or previa at second births associated with first-birth cesareans. RESULTS: Among our study cohort, abruptio placentae complicated 11.5 per 1000 and placenta previa 5.2 per 1000 singleton deliveries at second births. In logistic regression analyses adjusted for maternal age, women with first-birth cesareans had significantly increased risk of abruptio placentae (OR 1.3, 95% CI 1.1, 1.5), and placenta previa (OR 1.4, 95% CI 1.1, 1.6) at second births, compared with women with prior vaginal deliveries. CONCLUSION: We found moderately increased risk of placental abruption and previa as a long-term effect of prior cesarean delivery on second births.

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.