Byron D. Elliott

Comparative placental transport of oral hypoglycemic agents in humans: A model of human placental drug transfer

OBJECTIVE This study compares the human placental transport of glyburide, glipizide, chlorpropamide, and tolbutamide. STUDY DESIGN The recirculating single cotyledon human placenta model tested maternal-to-fetal transport in term placentas perfused immediately after delivery. Drug levels were measured by high-performance liquid chromatography and liquid scintillation spectrometry, and transport rates were calculated by comparing maternal and fetal concentrations. RESULTS The transport of these substances differed significantly over a tenfold range (analysis of variance, p < 0.0008). A significant association exists by multiple linear regression between drug transfer and molecular weight, dissociation constant, and the octanol-water partition coefficient (R2 = 0.91, p < 0.0001). CONCLUSIONS There is significant variability in human placental transfer rates of the oral hypoglycemics, which strongly correlates with molecular properties. These data suggest that less fetal exposure may occur with second-generation sulfonylureas and anticipate that regression models may be useful in selecting agents that minimize placental transport to the fetus.

Insignificant transfer of glyburide occurs across the human placenta

No data exist concerning human placental transfer of oral hypoglycemic agents during pregnancy. This study characterizes the transport of glyburide in 10 term human placentas with the single-cotyledon placental model. Serial samples were taken from both the maternal and fetal reservoirs during each 3-hour perfusion, and the percent transport and metabolism of tritiated glyburide was calculated with liquid scintillation spectrometry and high-performance liquid chromatography. Antipyrine labeled with carbon 14 was added to the perfusate solution during these experiments as a control. Virtually no transfer of glyburide occurred, and no appreciable metabolism of the drug was detected. Neither variation in the albumin concentration nor increase in the maternal glyburide levels to 100 times therapeutic concentration materially altered the rate of transport. These data show that insignificant transport of glyburide occurs across the human placenta in vitro and suggest that fetal exposure to maternally administered glyburide likewise may be insignificant.

Do growth-retarded premature infants have different rates of perinatal morbidity and mortality than appropriately grown premature infants?

Objective To determine if perinatal morbidity and mortality differ in growth-retarded, small for gestational age (SGA), premature infants and appropriate for gestational age (AGA) infants. Methods All consecutive, singleton, nondiabetic, preterm pregnancies delivered over a 15-year period were analyzed. Infants were categorized as SGA (at or below the tenth percentile) or AGA (11th to the 89th percentiles), then stratified by birth weight and gestational age categories. Perinatal morbidity and mortality were examined. Results We studied 4183 preterm deliveries, 1012 of them SGA and 3171 of them AGA. Overall, we found significantly higher rates of fetal and neonatal death in the SGA group. Stratification by gestational age revealed significantly higher rates of neonatal death for the SGA group compared with the AGA group in each gestational age category. Overall, comparison also revealed significantly higher rates of fetal heart rate abnormality in the SGA group but no difference in neonatal sepsis, birth trauma, cesarean delivery, hyaline membrance disease, or congenital anomalies. Conclusion Growth-retarded premature infants have a significantly higher risk of morbidity and mortality, both before and after delivery, than do appropriately grown infants.

Combination antibiotics and indomethacin in idiopathic preterm labor: A randomized double-blind clinical trial

Subclinical infection may play a role in the failure of magnesium sulfate tocolysis. Using a double-blind randomized study design, we administered a combination of ampicillin-sulbactam and indomethacin or corresponding placebos to patients in preterm labor who were receiving intravenous magnesium sulfate tocolysis. The mean gestational age at enrollment was 30.1 weeks, and mean cervical dilatation was 2.15 cm. No differences were noted between placebo (n = 43) and study patients (n = 43) in gestational age at delivery, term deliveries, days gained, or neonatal outcome. Preterm delivery (less than 36 weeks) occurred in 61% of the total population. The likelihood of a beta error was 0.07 to 0.23 on the basis of outcome analysis. In our population adjunctive ampicillin-sulbactam with indomethacin did not improve the success of magnesium sulfate tocolysis.

Perinatal outcome in growth-restricted fetuses: do hypertensive and normotensive pregnancies differ?

Objective To test the hypothesis that fetal growth restriction (FGR) associated with a maternal hypertensive disorder results in worse perinatal outcome than FGR in pregnancies without maternal hypertension. Methods All consecutive, singleton, nondiabetic, small for gestational age (SGA) deliveries (birth weight at or below the tenth percentile for gestational age) in a 15-year computerized data base were analyzed for pregnancy outcome. Perinatal outcome was compared after stratification by presence or absence of hypertensive disorders and by gestational age at delivery. Results Eleven thousand two hundred twenty-seven SGA pregnancies were analyzed. The morbidity and mortality profiles differed between hypertensive and normotensive pregnancies delivered preterm and those delivered at term. Perinatal mortality was significantly higher in the normotensive than in the hypertensive group in preterm deliveries (30.3 versus 18.7%, odds ratio [OR] 1.9 [confidence interval (CI) 1.3–2.9]). At term, hypertensive pregnancies demonstrated significantly higher mortality than normotensive pregnancies (4.6 versus 1.9%, OR 2.42 [95% CI 1.7–3.4]). In both preterm and term gestations, cesarean rates were significantly higher in hypertensive pregnancies than in normotensive pregnancies. Using logistic regression analysis, hypertension was independently associated with a 39% reduction in risk of perinatal mortality preterm, compared with a twofold increased risk of perinatal mortality at term. Conclusion Before term, FGR in normotensive women resulted in significantly higher perinatal mortality than FGR in hypertensive women. In contrast, at term, FGR in pregnancies complicated by hypertension had poorer perinatal outcomes than FGR in normotensive women.

Human Placental Transfer of the Prostaglandin Inhibitor Sulindac Using an In Vitro Model

Objective: We determined whether the prostaglandin inhibitor sulindac crosses the human placenta. Methods: The recirculating single-cotyledon placenta model was used to characterize the matenal-to-fetal and fetal-to-maternal transport of 14C-labeled sulindac in normal term placentas perfused immediately after delivery. Antipyrine was added as a standard for simple diffusion. Serial samples were taken from bth reservoirs during each 3-hour perfusion. Transport was calculated using liquid scitntillation spectrometry for 14C-labeled sulindac and high-performance liquid chromatography for antipyrine. Results: There was significant maternal-to-fetal transfer of sulindac. The mean (±SD) transfer at 2 hours was 7.22 ± 2.57%. The fetal-to-maternal transfer was similar at 10.75 ± 3.80%. The mean maternal/fetal concentration ratio of sulindac was 0.42 at 3 hours. Placental uptake ranged from 24-45 ng/g of placenta. Conclusions: Sulindac crosses the human placenta in small but significant amounts. The transport is similar in both directions, implying simple diffusion.

The development and testing of new instruments for operative vaginal delivery

OBJECTIVE Little innovation has occurred in recent years in the instruments available for operative vaginal delivery. The purpose of this study is to develop a technique to test the utility of an investigational device, the obstetric bonnet, and measure the forces it places on the fetal head. STUDY DESIGN We constructed a model of the fetal head capable of measuring both compression and vacuum created by an applied device. A total of 18 devices were tested to a maximum traction of 60 pounds. RESULTS A significant linear relationship exists between the traction applied and the compression (R2 = 0.42, p = 0.0004) and vacuum (R2 = 0.85, p = 0.0001) created. Compression and vacuum recorded at maximum recommended traction were 1.1 lb/sq in and 31 cm Hg, respectively. CONCLUSION These findings explain the mechanics of this interesting device, and demonstrate forces that compare favorably with those known to occur with forceps or vacuum extraction.