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Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β-cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed-meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age-dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity.

The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25–750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was

Aims Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. Methods A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration–time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. Results The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19–36)% (P

Aim(s) The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk. Methods Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. Results Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml−1) were 71 ± 18% (range 45–99%) of maternal concentrations (9.0 ± 3.4 ng ml−1). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml−1) and unbound drug concentrations (0.003 ± 0.001 ng ml−1) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. Conclusions Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.

Objective To compare magnesium sulphate concentrations achieved by intramuscular and intravenous regimens used for the prevention of eclampsia. Setting Low-resource obstetric hospitals in Nagpur and Vellore, India. Population Pregnant women at risk for eclampsia due to hypertensive disease. Methods A pharmacokinetic study was performed as part of a randomised trial that enrolled 300 women comparing intramuscular and intravenous maintenance regimens of magnesium dosing. Data from 258 enrolled women were analysed in the pharmacokinetic study. A single sample was drawn per woman with the expectation of using samples in a pooled data analysis. Main outcome measures Pharmacokinetic parameters of magnesium distribution and clearance. Results Magnesium clearance was estimated to be 48.1 dl/hour, volume of distribution to be 156 dl and intramuscular bioavailability to be 86.2%. The intramuscular regimen produced higher initial serum concentrations, consistent with a substantially larger loading dose. At steady state, magnesium concentrations in the intramuscular and intravenous groups were comparable. With either regimen, a substantial number of women would be expected to have serum concentrations lower than those generally held to be therapeutic. Conclusions Clinical implications were that a larger loading dose for the intravenous regimen should be considered; where feasible, individualised dosing of magnesium sulphate would reduce the variability in serum concentrations and might result in more women with clinically effective magnesium concentrations; and lower dose magnesium suphate regimens should be considered with caution.

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.

Nine healthy males participated in a double-blind, placebo-controlled, randomized, crossover study to determine the effects of verapamil and metoprolol administered alone and concurrently on blood flow through the hepatic artery and portal and hepatic veins and to detect a possible drug interaction between the two agents. Single oral doses of placebo/placebo, metoprolol (50 mg)/placebo, verapamil (80 mg)/placebo, or verapamil/metoprolol were separated by at least 14 days. Liver blood flow through individual hepatic vessels was measured up to 8 hours after dosage administration using a duplex Doppler ultrasound technique. Cardiac output, heart rate, blood pressure, stroke volume, and total peripheral resistance were measured for 3 hours after drug doses were given. In 5 subjects, pharmacokinetic parameters for total drug as well as S- and R-enantiomers were also measured. Verapamil given alone caused a rapid and intense increase in liver blood flow (hepatic artery = 50%, portal vein = 42%, hepatic vein = 55%) 0.75 to 1 hour after administration because of a decrease in total peripheral resistance and an increase in heart rate, stroke volume, and cardiac output. Metoprolol given alone caused a slow but prolonged decrease in liver blood flow (maximum decrease: hepatic artery = -54%, portal vein = -21%, hepatic vein = -27%) 4 hours after administration because of a decrease in heart rate and cardiac output. When the two agents were given together, a composite of the changes noted after separate administration was noted: a brief peak increase in liver blood flow at 0.33 to 1 hour followed by a slow, prolonged decrease that reached its maximum decline 4 to 5 hours postdose. During the combined phase, metoprolol and its enantiomers had an increased AUC and Cmax, while verapamil and its enantiomers had an increased AUC and t1/2. These pharmacokinetic changes were consistent with the magnitude and time course of liver blood flow changes through the hepatic artery and portal or hepatic veins.

The purpose of this study was to evaluate the risk of fetal aneuploidy in the presence of isolated choroid plexus cysts and to evaluate the results obtained from our institution and those reported previously in the English literature. All patients with fetal choroid plexus cysts on prenatal ultrasonography were offered genetic counseling and amniocentesis for fetal karyotyping. Seven of 274 fetuses, 2.6% (95% confidence interval = 1.0 to 5.2%), with isolated choroid plexus cysts were aneuploid. Literature analysis located 23 other reports of 1537 fetuses with isolated choroid plexus cysts; 26 were karyotypically abnormal, 1.7% (95% confidence interval = 1.0 to 2.4%). When evaluating only those patients whose indication for amniocentesis was choroid plexus cysts (i.e., eliminating those patients with advanced maternal age or abnormal serum screening) the risk of having a fetus with trisomy 18 changed little, 1.9% (95% confidence interval = 0.4 to 5.5%). Our data, combined with those of the literature, suggest that the risk of finding an abnormal fetal karyotype in the presence of isolated choroid plexus cysts is at least 1% and may be as high as 2.4%. On the basis of these results, genetic counseling and prenatal diagnosis should be offered to these patients.

Duplex sonography was used to assess the effects on hepatic blood flow after administering 0.6 mg nitroglycerin (NTG) sublingually to ten healthy volunteers. The study was a randomized, placebo-controlled, cross-over study in which subjects were studied on three separate occasions. Each visit involved administering either placebo or NTG followed by estimation of blood flow through a particular branch of the hepatic artery, portal vein, and hepatic vein every minute for 15 minutes after NTG and placebo administration. Two hours later, subjects were crossed over to the other treatment and the same vessel branch was again examined for 15 minutes. Total blood flow increased 7% in the portal vein and 27% in the hepatic vein during NTG treatment, but did not change significantly in the hepatic artery. Vascular resistance was increased in the hepatic artery and decreased in the portal and hepatic veins after NTG. Qualitatively, flow changed dramatically in the hepatic vein after NTG with the disappearance of normal retrograde flow. The results indicate that nitroglycerin effects hepatic blood flow through the portal and hepatic veins with a decrease in vascular resistance in the portal and hepatic veins and an increase in resistance in the hepatic artery.

The prenatal diagnosis of pulmonary atresia is of particular importance because the affected neonate may be dependent on ductal blood flow to the lung, requiring urgent administration of prostaglandins. We review eight cases studied by ultrasonography in utero. Severe tricuspid regurgitation was present in six fetuses. Right ventricular size varied among cases. Right atrial enlargement was present in seven, usually with tricuspid regurgitation. Failure to identify the main pulmonary artery or valve on a single examination was not specific. Doppler flow studies were most reliable for the diagnosis by establishing the existence of retrograde flow in the ductus arteriosus from the aorta.

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.

The timing of treatment for stage I-B cervical carcinoma diagnosed during pregnancy is complicated by conflicting concerns for fetal survival and control of malignancy. There were 11 pregnant women with stage I-B cervical carcinoma diagnosed prior to fetal viability since 1969. Six patients were managed with termination of pregnancy and radical hysterectomy with pelvic lymphadenectomy. In 5 patients, treatment was delayed for 6 to 17 weeks and then delivery was accomplished by cesarean section followed directly by radical hysterectomy and pelvic lymphadenectomy. Two of the infants experienced complicated neonatal courses and would have benefited from additional delay. Benefits that could be achieved by delaying delivery for the fetus were calculated from a review of 600 inborn infants without congenital anomalies admitted to the neonatal intensive care (NICU) during 1984 and 1985. Neonatal mortality decreased from 32.8% at 26–27 weeks to 2.7% at 34–35 weeks gestation. Similar improvements in neonatal morbidity were demonstrated. Although adverse maternal outcomes were not associated with delay, an evaluation of risk cannot be derived from this series. Significant fetal benefit can accrue from relatively short delays in planned delivery dates. When stage I-B cervical carcinoma is diagnosed during pregnancy and when fetal survival is desired, delivery should be delayed to achieve fetal maturity, rather than only potential viability.