Thomas R. Easterling

Risk of uterine rupture during labor among women with a prior cesarean delivery

Background Each year in the United States, approximately 60 percent of women with a prior cesarean delivery who become pregnant again attempt labor. Concern persists that a trial of labor may increase the risk of uterine rupture, an uncommon but serious obstetrical complication. Methods We conducted a population-based, retrospective cohort analysis using data from all primiparous women who gave birth to live singleton infants by cesarean section in civilian hospitals in Washington State from 1987 through 1996 and who delivered a second singleton child during the same period (a total of 20,095 women). We assessed the risk of uterine rupture for deliveries with spontaneous onset of labor, those with labor induced by prostaglandins, and those in which labor was induced by other means; these three groups of deliveries were compared with repeated cesarean delivery without labor. Results Uterine rupture occurred at a rate of 1.6 per 1000 among women with repeated cesarean delivery without labor (11 women), 5.2 ...

Are We Optimizing Gestational Diabetes Treatment With Glyburide? The Pharmacologic Basis for Better Clinical Practice

Glyburides pharmacokinetics (PK) and pharmacodynamics have not been studied in women with gestational diabetes mellitus (GDM). The objective of this study was to assess steady‐state PK of glyburide, as well as insulin sensitivity, β‐cell responsivity, and overall disposition indices after a mixed‐meal tolerance test (MMTT) in women with GDM (n = 40), nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 26), and healthy pregnant women (n = 40, MMTT only). At equivalent doses, glyburide plasma concentrations were ~50% lower in pregnant women than in nonpregnant subjects. The average umbilical cord/maternal plasma glyburide concentration ratio at the time of delivery was 0.7 ± 0.4. Insulin sensitivity was approximately fivefold lower in women with GDM as compared with healthy pregnant women. Despite comparable β‐cell responsivity indices, the average β‐cell function corrected for insulin resistance was more than 3.5‐fold lower in women with glyburide‐treated GDM than in healthy pregnant women. Women with GDM in whom glyburide treatment has failed may benefit from alternative medication or dosage escalation; however, fetal safety should be kept in mind.

First-birth cesarean and placental abruption or previa at second birth

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.

Effects of Pregnancy on CYP3A and P‐glycoprotein Activities as Measured by Disposition of Midazolam and Digoxin: A University of Washington Specialized Center of Research Study

The objectives of the study were to evaluate the effects of pregnancy on CYP3A and P‐glycoprotein (P‐gp) activities, as measured by disposition of midazolam and digoxin, respectively. Thirteen women received digoxin (0.25 mg p.o.) and midazolam (2 mg p.o.) in random order, separated by 1–2 weeks at 28–32 weeks gestation, and the same order was repeated at 6–10 weeks postpartum. Plasma and urine concentrations were determined by liquid chromatography–mass spectrometry and analyzed by noncompartmental methods. Midazolam CL/Funbound (593 ± 237 l/min vs. 345 ± 103 l/min; P = 0.007), digoxin CLRenal, unbound (272 ± 45 ml/min vs. 183 ± 37 ml/min; P < 0.002) and digoxin CLsecretion, unbound (109 ± 34 ml/min vs. 58 ± 22 ml/min; P < 0.002) were higher during pregnancy than postpartum. These data are consistent with increased hepatic and/or intestinal CYP3A and renal P‐gp activities during pregnancy.

Risk factors for preeclampsia in twin pregnancies: a population-based cohort study.

Objective To evaluate in twin pregnancies the characteristics parity, race, smoking, and age, known to be risk factors for preeclampsia in non-twin pregnancies. Methods All twin pregnancies (3407) and approximately twice as many singletons (8287) were assembled using Washington state birth certificates from the period 1984–1988. Results In singleton pregnancies, preeclampsia was more common in women who were younger, black, poor, nulliparous, and nonsmokers. In twin pregnancies, similar associations were found, but were only statistically significant for age, race, and parity. There were no significant differences in the risk factors between twin and singleton women. Logistic regression showed that twin pregnancy carries a relative risk (RR) of 3.5 (95% confidence interval [CI] 3.0–4.2), nulliparity an RR of 4.0 (95% CI 3.3–4.8), and black race an RR of 1.8 (95% CI 1.2–2.6) for preeclampsia. In each case, this risk is independent of the other risk factors. Conclusion Twin pregnancy carries nearly a fourfold increased risk of preeclampsia, independent of race and parity, and the risk of a nulliparous twin pregnancy is 14 times that of a parous singleton pregnancy. Risk factors in a singleton pregnancy act similarly in a twin pregnancy. Thus, any pathophysiologic model for preeclampsia needs to account for the risk twin pregnancy poses as well as other risk factors, such as parity and race.

Pharmacokinetics of Metformin during Pregnancy

Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 ± 243 ml/min, P < 0.01) and late pregnancy (625 ± 130 ml/min, P < 0.01) compared with postpartum (477 ± 132 ml/min). These changes reflected significant increases in creatinine clearance (240 ± 70 ml/min, P < 0.01 and 207 ± 56 ml/min, P < 0.05 versus 165 ± 44 ml/min) and in metformin net secretion clearance (480 ± 190 ml/min, P < 0.01 and 419 ± 78 ml/min, P < 0.01 versus 313 ± 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (<5 ng/ml) and 1263 ng/ml. The daily infant intake of metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was <0.5% of the mother’s weight-adjusted dose. Our results indicate that metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

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.

Recent changes in delivery site of low-birth-weight infants in Washington: impact on birth weight-specific mortality.

OBJECTIVES Our purpose was to ascertain whether the proportion of low-birth-weight infants delivered in Washington at tertiary hospitals changed between 1980 and 1991 and whether mortality differed by level of birth hospital. STUDY DESIGN A retrospective cohort study was performed of 500 to 2499 gm infants born to Washington residents between 1980 and 1991 (n = 43,228). RESULTS Overall, the percentage of low-birth-weight infants born at tertiary centers rose from 1980 to 1982 through 1986 to 1988 and subsequently declined significantly. Among infants weighing < 2000 gm nontertiary delivery was associated with greater potentially preventable mortality (500 to 999 gm, relative risk 1.5, 95% confidence interval 1.3 to 1.8; 1000 to 1499 gm, relative risk 2.1, 95% confidence interval 1.3 to 3.3; 1500 to 1999 gm, relative risk 1.6, 95% confidence interval 1.0 to 2.6). Nontertiary delivery of 2000 to 2499 gm infants was associated with lower overall mortality (relative risk 0.5, 95% confidence interval 0.3 to 0.8), but higher-risk deliveries in this birth weight range were apparently concentrated at tertiary hospitals. CONCLUSIONS In light of the apparent benefit of tertiary center birth for infants weighing < 2000 gm, the possible erosion of effective regionalized perinatal care networks should be monitored closely.

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.