Search

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.

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V β ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V β /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V β /F by 28%, weight-adjusted V β /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.

The objectives of this systematic review were to examine the reproducibility of sonographic estimates of amniotic fluid volume (AFV) in twin pregnancies, compare the association of sonographic estimates of AFV with dye-determined AFV, and correlate AFV with antepartum, intrapartum, and perinatal outcomes in twin pregnancies. Studies were included if they were adequately powered and investigated antepartum, intrapartum, and/or perinatal adverse outcome parameters in twin gestations. Studies with comparable populations and exclusion criteria were merged into forest plots. Data comparing the accuracy of AFV assessment, correlation of AFV with gestational age, and adverse outcomes were tabulated. Five of the 6 studies investigating AFV by the amniotic fluid index as a function of gestational age reported data fitting a quadratic equation, with fluid volumes peaking at mid gestation and then declining. This trend was less pronounced when AFV was assessed by the single deepest pocket (2 of 4 studies reporting a quadratic fit). Polyhydramnios was associated with prematurity in 2 of 4 studies (1 amniotic fluid index and 1 single deepest pocket), and oligohydramnios was associated with prematurity in 1 single deepest pocket study. Stillbirth was the only intrapartum outcome reported in more than 1 study. Perinatal outcomes associated with polyhydramnios included neonatal death (P < .05 in 1 of 2 studies), low Apgar scores (1 of 2 studies), neonatal intensive care unit admission (1 of 2 studies), and low birth weight (2 of 3 studies).

Glycosylation of plasma proteins increases during pregnancy. Our objectives were to investigate an anti-inflammatory role of these proteins in normal pregnancies and determine whether aberrant protein glycosylation promotes monocyte adhesion in preeclampsia. Plasma was prospectively collected from nonpregnant controls and nulliparous patients in all 3 trimesters. Patients were divided into cohorts based on the applicable postpartum diagnosis. U937 monocytes were preconditioned with enzymatically deglycosylated plasma, and monocyte adhesion to endothelial cell monolayers was quantified by spectrophotometry. Plasma from nonpregnant controls, first trimester normotensives, and first trimester patients with mild preeclampsia inhibited monocyte–endothelial cell adhesion (P < .05), but plasma from first trimester patients with severe preeclampsia and second and third trimester normotensives did not. Deglycosylating plasma proteins significantly increased adhesion in all the cohorts. These results support a role of plasma glycoprotein interaction in monocyte–endothelial cell adhesion and could suggest a novel therapeutic target for severe preeclampsia.

Minimally invasive diagnostic tests are needed in obstetrics to identify women at risk for complications during delivery. The apolipoproteins fluctuate in complexity and abundance in maternal plasma during pregnancy and could be incorporated into a blood test to evaluate this risk. The objective of this study was to examine the relative plasma concentrations of apolipoproteins and their biochemically modified subtypes (i.e. proteolytically processed, sialylated, cysteinylated, dimerized) over gestational time using a targeted mass spectrometry approach. Relative abundance of modified and unmodified apolipoproteins A-I, A-II, C-I, C-II, and C-III was determined by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in plasma prospectively collected from 11 gravidas with uncomplicated pregnancies at 4-5 gestational time points per patient. Apolipoproteins were readily identifiable by spectral pattern. Apo C-III(2) and Apo C-III(1) (doubly and singly sialylated Apo C-III subtypes) increased with gestational age (r(2)0.8). Unmodified Apo A-II, Apo C-I, and Apo C-III(0) showed no correlation (r(2) = 0.01-0.1). Pro-Apo C-II did not increase significantly until third trimester (140 ± 13% of first trimester), but proteolytically cleaved, mature Apo C-II increased in late pregnancy (702 ± 130% of first trimester). Mature Apo C-II represented 6.7 ± 0.9% of total Apo C-II in early gestation and increased to 33 ± 4.5% in third trimester. A label-free, semiquantitative targeted proteomics approach was developed using LTQ-Orbitrap mass spectrometry to confirm the relative quantitative differences observed by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in Apo C-III and Apo C-II isoforms between first and third trimesters. Targeted apolipoprotein screening was applied to a cohort of term and preterm patients. Modified Apo A-II isoforms were significantly elevated in plasma from mothers who delivered prematurely relative to term controls (p = 0.02). These results support a role for targeted proteomics profiling approaches in monitoring healthy pregnancies and assessing risk of adverse obstetric outcomes.

Determine the Bishop score most predictive of induction of labor (IOL) success for different maternal weight groups.Retrospective cohort study. Prospectively collected database utilized to determine the optimum Bishop score within each prepregnancy body mass index (BMI) category of term, nulliparous patients undergoing IOL.For the total group (n = 696), Bishop score ≥ 5 was most predictive of success (75% versus 56%, p0.0001). Within each BMI category, Bishop score ≥ 5 remained most predictive: normal weight (79% versus 64%, p0.01); overweight (72% versus 58%, p = 0.03); and obese (73% versus 45%, p0.0001). Overall, nonobese patients had more success than obese patients (70% versus 59%, p0.01). The nonobese group had more success than the obese group when the Bishop score was3 (57% versus 39%, p0.05) but not when it was ≥ 3 (72% versus 65%, p = 0.1). Also, there was a higher fraction of patients with Bishop score3 in the obese group compared with the nonobese group (25% versus 14%, p0.001).The optimum Bishop score for predicting successful IOL in nulliparous patients was 5 regardless of BMI class. The higher IOL failure rate observed in obese women was associated with lower starting Bishop scores and was compounded by higher failure rates in obese women with Bishop scores3.

Preeclampsia is a hypertensive disorder unique to pregnancy. Although the pathogenesis of the disease begins with aberrant spiral artery invasion in the first trimester, clinical symptoms usually do not present until late in pregnancy. Apolipoprotein CII (ApoCII) and its negative regulator, apolipoprotein CIII (ApoCIII), have recently been described as atherogenesis biomarkers in models of cardiovascular disease. Given the similarities in pathology, etiology, and clinical presentation between cardiovascular disease and preeclampsia, we hypothesized that the ratio of ApoCIII to ApoCII in maternal first trimester plasma would predict preeclampsia later in pregnancy. To test this hypothesis, plasma was prospectively collected from 311 nulliparas at 8 to 12 weeks gestation. After delivery, patients were divided into cohorts based on preeclampsia diagnosis. Conditioning monocytes with preeclamptic plasma potentiated monocyte adhesion to endothelial cells in an in vitro model. The ratio of ApoCIII to ApoCII was significantly elevated in patients with severe preeclampsia relative to normotensive and gestational hypertensive individuals (P < .05) as determined by mass spectrometry and competitive enzyme-linked immunosorbent assay (ELISA) assays. These results support a predictive change in the ratio of ApoCIII to ApoCII in pregnancies complicated by severe preeclampsia.

Background: Gestational diabetes mellitus (GDM) complicates 5-6% of pregnancies, placing affected individuals at higher risk for pregnancy-related complications and persistent metabolic and cardiovascular

urine specimens from normal pregnant women and from chronic hypertension. In PE, urinary nephrin and podocalyxin concentrations were significantly higher than those in normal pregnancy and chronic hypertension (p 0.01), and their levels were highly correlated to each other, y 4.611x 327,491, r2 0.595. Nephrin and podocalyxin with urine protein concentrations were also highly correlated, y 257.354x 297.898, r2 0.746 for nephrin and y 31.115x 10.640, r2 0.390 for podocalyxin, respectively. ig-h3 was detected in the urine specimens from PE but undetectable in normal pregnancy and pregnancy complicated with chronic hypertension. In PE, urinary ig-h3 levels were also highly correlated to nephrin and podocalyxin concentrations, y 117.069x 260.337, r2 0.515 for nephrin and y 18.571x 41.694, r2 0.463 for podocalyxin. CONCLUSION: These results provide strong evidence that specific podocyte protein shedding is associated with glomerular barrier dysfunction in PE. Urinary ig-h3 excretion indicates that increased TGFactivity might be involved in the pathology of renal dysfunction in PE. Nephrin, podocalyxin, and ig-h3 could serve as surrogate biomarkers of glomerular barrier dysfunction in PE.