Cervilenz assessment of cervical length compared to fetal fibronectin in the prediction of preterm delivery in women with threatened preterm labor.

OBJECTIVE: To determine whether cervical length (CL) measured by the Cervilenz™ measuring device is an effective screening tool for the prediction of preterm delivery (PTD) compared to fetal fibronectin (fFN). METHODS: We evaluated fFN and CL among women who enrolled into a randomized control trial (RCT) comparing management algorithms for threatened preterm labor between 24 and 34 weeks' gestation. In all subjects, fFN was collected, with CL determined in blinded fashion. The sensitivity, specificity, and positive and negative predictive values (NPV) for fFN or Cervilenz in prediction of PTD within 7 days or prior to 37 weeks were determined. RESULTS: Fifty-two subjects were evaluated. CL <30 mm correlated with PTD <7 days (r = 0.31, p = 0.04) and fFN positivity (r = 0.43, p = 0.006). CL <30 mm and fFN had excellent NPV for PTD <7 days (97.1 vs. 97.3%), and the area under the receiver operator characteristic curves were similar for prediction of PTD <7 days (76.6 vs. 75.2%, p = 0.71) or <37 weeks (56.7 vs. 55.2%, p = 0.71). CONCLUSIONS: Measurement of CL with Cervilenz appears to be equivalent to fFN in screening symptomatic women for PTD within 7 days or prior to 37 weeks. Given cost and turnaround time with fFN testing, Cervilenz represents a promising new tool for real time, clinically useful results in the management of women with threatened preterm labor.

Detailed physiological characterization of the development of type 2 diabetes in Hispanic women with prior gestational diabetes mellitus.

OBJECTIVE: To identify physiological and clinical variables associated with development of type 2 diabetes up to 12 years after pregnancies complicated by gestational diabetes. RESEARCH DESIGN AND METHODS: Seventy-two islet cell antibody-negative nondiabetic Hispanic women had oral (oGTT) and intravenous (ivGTT) glucose tolerance tests, glucose clamps, and body composition assessed between 15 and 30 months after pregnancies complicated by gestational diabetes mellitus (GDM). They returned for oGTTs at 15-month intervals until they dropped out, developed diabetes, or reached 12 years postpartum. Cox regression analysis was used to identify baseline predictors and changes during follow-up that were associated with development of type 2 diabetes. RESULTS: At baseline, relatively low insulin sensitivity, insulin response, and ß-cell compensation for insulin resistance were independently associated with development of diabetes. During follow-up, weight and fat gain and rates of decline in ß-cell compensation were significantly associated with diabetes, while additional pregnancy and use of progestin-only contraception were marginally associated with diabetes risk. CONCLUSIONS: In Hispanic women, GDM represents detection of a chronic disease process characterized by falling ß-cell compensation for chronic insulin resistance. Women who are farthest along at diagnosis and/or deteriorating most rapidly are most likely to develop type 2 diabetes within 12 years after the index pregnancy. Weight gain, additional pregnancy, and progestin-only contraception are potential modifiable factors that increase diabetes risk.

Declining beta-cell compensation for insulin resistance in Hispanic women with recent gestational diabetes mellitus: association with changes in weight, adiponectin, and C-reactive protein.

OBJECTIVE: To identify factors associated with declining beta-cell compensation for insulin resistance. RESEARCH DESIGN AND METHODS: In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining beta-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on beta-cell compensation decline. RESULTS: A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance. CONCLUSIONS: These results identify weight gain as the strongest factor associated with declining beta-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance.

How do we reduce the number of cases of missed postpartum diabetes in women with recent gestational diabetes mellitus?

OBJECTIVE: Up to 30% of women with recent gestational diabetes mellitus (GDM) remain glucose intolerant after delivery. However, the rate of postpartum oral glucose tolerance tests (ppOGTTs) is low. Our aim in this study was to develop a model for risk assessment to target women with high risk for postpartum diabetes. RESEARCH DESIGN AND METHODS: In 605 Caucasian women with GDM, antenatal obstetrical and glucose data and the glucose data of the ppOGTTs performed 13 weeks (median) after delivery were prospectively collected. RESULTS: A total of 132 (21.8%) women had an abnormal ppOGTT (2.8% impaired fasting glucose, 13.6% impaired glucose tolerance, and 5.5% diabetes). Independent risk factors were BMI >or=30 kg/m(2) (prevalence of abnormal ppOGTT 36.0 vs. 17.3%), gestational age at diagnosis <24 weeks (32.4 vs. 18.0%), 1-h antenatal value >200 mg/dl (11.1 mmol/l) (35.2 vs. 14.8%), and insulin therapy (30.3 vs. 14.5%). The prevalence of an abnormal ppOGTT was assessed according to the number of risk factors: 0, 9.2% (14 of 153); 1, 13.4% (25 of 186); 2, 28.5% (43 of 151); 3, 45.6% (26 of 57); and 4, 68.4% (13 of 19). Subjects were divided according to a significant increase of prevalence and risk for a ppOGTT: low risk (59.9% of subjects), <2 risk factors, 11.6%, odds ratio 1.3; intermediate risk, 2 risk factors, 28.5%, 4.0; and high risk, >2 risk factors, 51.3%, 10.5. The intermediate/high-risk group included 86.6% of those with diabetes and 67% of all those with abnormal ppOGTTs. CONCLUSIONS: Women with >or=2 risk factors have a high risk for an abnormal ppOGTT, and 86% of postpartum diabetes is diagnosed within this group. Targeting women for ppOGTTs based on a risk assessment using available antenatal risk factors might reduce the number of missed cases of postpartum diabetes.

Blinded comparison of cervical portio length measurements by digital examination vs Cervilenz.

OBJECTIVE: Cervical length (CL) examinations may identify patients in preterm labor or those who may benefit from prophylactic therapy. We sought to compare the accuracy of clinician digital CL examinations with objective measurements using the Cervilenz device in women presenting with symptoms of preterm labor. STUDY DESIGN: Forty-two patients with singleton gestation from 24 to 34 weeks' gestation and cervical dilation less than 3 cm underwent speculum examination and Cervilenz measurement. A second examiner, blinded to results, digitally measured CL. Pearson's correlation coefficient, Student t tests and McNemar's tests were used to compare digital and Cervilenz measures. RESULTS: Digital CL was significantly less than Cervilenz (2.88 vs 3.40 cm; P < .001), and in 36% of subjects, this difference exceeded 1 cm. The discrepancy in CL estimates persisted whether women were multiparous or had soft cervices or a history of preterm delivery. CONCLUSION: Digital assessment underestimates CL, whereas the Cervilenz device permits a visualized and objective CL measure in patients with preterm labor.

Maternal lipids as strong determinants of fetal environment and growth in pregnancies with gestational diabetes mellitus.

OBJECTIVE: To determine the contribution of maternal glucose and lipids to intrauterine metabolic environment and fetal growth in pregnancies with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: In 150 pregnancies, serum triglycerides (TGs), cholesterol, free fatty acids (FFAs), glycerol, insulin, and glucose were determined in maternal serum and cord blood during the 3rd trimester. Maternal glucose values came from oral glucose tolerance testing and glucose profiles. Measurements of fetal abdominal circumference (AC) were performed simultaneously with maternal blood sampling and birth weight, and BMI and neonatal fat mass were obtained following delivery. RESULTS: Maternal TGs and FFAs correlated with fetal AC size (at 28 weeks: triglycerides, P = 0.001; FFAs, P = 0.02), and at delivery they correlated with all neonatal anthropometric measures (FFA: birth weight, P = 0.002; BMI, P = 0.001; fat mass, P = 0.01). After adjustment for confounding variables, maternal FFAs and TGs at delivery remained the only parameters independently related to newborns large for gestational age (LGA) (P = 0.008 and P = 0.04, respectively). Maternal FFA levels were higher in mothers with LGA newborns than in those with appropriate for gestational age (AGA) newborns (362.8 +/- 101.7 vs. 252.4 +/- 10.1, P = 0.002). Maternal levels of TGs, FFAs, and glycerol at delivery correlated with those in cord blood (P = 0.003, P = 0.004, and P = 0.005, respectively). Fetal triglyceride and cholesterol levels were negatively correlated with newborn birth weight (P = 0.001), BMI (P = 0.004), and fat mass (P = 0.001). TGs were significantly higher in small for gestational age (SGA) newborns compared with AGA or LGA newborns, while insulin-to-glucose ratio and FFAs were the highest in LGA newborns. CONCLUSIONS: In well-controlled GDM pregnancies, maternal lipids are strong predictors for fetal lipids and fetal growth. Infants with abnormal growth seem to be exposed to a distinct intrauterine environment compared with those with appropriate growth.

Effect of pioglitazone on progression of subclinical atherosclerosis in non-diabetic premenopausal Hispanic women with prior gestational diabetes.

The Pioglitazone in the Prevention of Diabetes (PIPOD) study was a single arm 3-year open-label pioglitazone treatment to determine the effects of pioglitazone in women with prior gestational diabetes mellitus (GDM) who had completed the troglitazone in the Prevention of Diabetes (TRIPOD) study. Here we report the results on progression of subclinical atherosclerosis, measured by carotid intima-media thickness (CIMT) in non-diabetic women. Data were analyzed to compare CIMT progression rates during pioglitazone treatment to rates that had been observed during either placebo or troglitazone treatment in the TRIPOD study. Sixty-one women met the entry criteria with mean age of 40 years. In the 30 women who came to PIPOD from the placebo arm of TRIPOD, the CIMT rate was 69% lower during pioglitazone treatment than it had been during placebo (0.0031 vs. 0.0100mm/yr, p=0.006). In the 31 women who came to PIPOD from the troglitazone arm of TRIPOD, CIMT rate was 38% lower during pioglitazone than it had been during troglitazone, a difference that was not statistically significant (0.0037 vs. 0.0060mm/year; p=0.26). Adjustment for differences in baseline characteristics and potential on-trial confounders did not alter the conclusion but did increase the CIMT rates differences slightly. We conclude that treatment with pioglitazone slowed CIMT progression in women who had been on placebo in the TRIPOD study and maintained a relatively low rate of progression in women who had been on troglitazone. Pioglitazone slows progression of subclinical atherosclerosis in young Hispanic women at increased risk for type 2 diabetes.

Evidence of interaction between PPARG2 and HNF4A contributing to variation in insulin sensitivity in Mexican Americans.

OBJECTIVE: We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes-related quantitative traits in Mexican-American families of a proband with previous gestational diabetes. RESEARCH DESIGN AND METHODS: The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests. RESULTS: Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes-related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (S(I)) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher S(I) compared with individuals with at least one G allele. S(I) did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for S(I) was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher S(I) compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401). CONCLUSIONS: Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes.

After pregnancy complicated by diabetes: postpartum care and education.

The postpartum period in women with pregestational or gestational diabetes allows the physician and mother to switch from intensive medical and obstetric management into a proactive and preventive mode, and to jointly develop a reproductive health plan. The woman's individual needs regarding contraception and breastfeeding, an appropriate diet to achieve healthy weight goals, the medical management of diabetes, daily exercise, and future pregnancy planning must be considered. Essential is the active participation of the woman, who, through education, gains an understanding of the far-reaching effects her active participation will have on her subsequent health, her newborn child's health, and possibly that of her future children.

A longitudinal study of lipids and blood pressure in relation to method of contraception in Latino women with prior gestational diabetes mellitus.

OBJECTIVE: To investigate the effect of nonhormonal contraception (NHC), combination oral contraception (COC), and depo-medroxyprogesterone acetate (DMPA) on lipids and blood pressure in women with recent gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: An observational cohort of 972 nondiabetic, normotensive, postpartum Latino women who elected NHC (n = 448), COC (n = 430), or DMPA (n = 94) were followed for at least one subsequent metabolic evaluation on the same contraception. Baseline and follow-up measures included glucose tolerance testing, fasting serum LDL and HDL cholesterol, triglycerides, and systolic (SBP) and diastolic (DBP) blood pressure. Patterns of changes in lipids and blood pressure were evaluated by comparing slopes over follow-up time using random coefficient linear mixed-effects models. RESULTS: Median follow-up times were 20, 12, and 11 months in the NHC, COC, and DMPA groups. The DMPA users gained significantly more weight (4.3 +/- 6.9 kg/year) compared with NHC and COC users (1.2 +/- 4.7 and 0.7 +/- 6.0 kg/year, respectively; P < 0.0001). Patterns of change in LDL cholesterol, triglycerides, and DBP were not significantly different among groups. HDL cholesterol change differed only between COC and NHC groups (adjusted slopes: 1.0 vs. -1.6 mg x dl(-1) x year(-1), respectively; P < 0.0001). SBP change differed only between COC and DMPA groups (adjusted slopes: 1.3 vs. -1.7 mmHg/year, respectively; P = 0.01). CONCLUSIONS: These results, derived predominantly from the initial 1-2 years of treatment in Hispanic women, demonstrate that DMPA was associated with greater weight gain than NHCs or COCs. Other differences in blood pressure and lipid effects were very small. These findings should be taken into account when advising women with recent GDM about their contraceptive choices.

Long-acting injectable progestin contraception and risk of type 2 diabetes in Latino women with prior gestational diabetes mellitus.

OBJECTIVE: To investigate the impact of a long-acting injectable progestin, depo-medroxyprogesterone acetate (DMPA), compared with combination oral contraceptives (COCs) on the risk of diabetes in Latino women with prior gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: An observational cohort study of 526 Hispanic women with prior GDM who were not diabetic in their postpartum visit during January 1987 to October 1997 and who elected DMPA (n = 96) or COCs (n = 430) as initial contraception were followed for a maximum of 9.2 years with a median follow-up of approximately 12 months. Oral glucose tolerance tests were performed and choice of contraception method was recorded at each visit as part of routine clinical care. RESULTS: Annual diabetes incidence rates were 19% in the DMPA group and 12% in the COC group, with an unadjusted hazard ratio (HR) of 1.58 (95% CI 1.00-2.50; P = 0.05) for DMPA compared with COCs. Adjustment for baseline imbalances reduced the HR to 1.18 (0.67-2.28; P = 0.57). Additional adjustment for weight gain during follow-up, which was on average 1.8 kg higher in the DMPA group (P < 0.0001), reduced the HR to 1.07. DMPA interacted with baseline serum triglyceride levels and, separately, with breast-feeding to increase the diabetes risk. CONCLUSIONS: DMPA use was associated with an increased risk of diabetes that appeared to be explained by three factors: 1) use in women with increased baseline diabetes risk, 2) weight gain during use, and 3) use with high baseline triglycerides and/or during breast-feeding.

Coordinate changes in plasma glucose and pancreatic beta-cell function in Latino women at high risk for type 2 diabetes.

The purpose of this study was to examine longitudinally the relationship among glucose levels, pancreatic beta-cell function, and insulin resistance in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and intravenous glucose tolerance tests (IVGTTs) were performed at 15-month intervals for up to 5 years or until fasting plasma glucose exceeded 140 mg/dl in Hispanic women with recent gestational diabetes. Data were analyzed 1) to compare changes in insulin sensitivity, beta-cell function, and glucose levels between women who had diabetes at one or more visits and women who remained diabetes free and 2) to determine longitudinal patterns of change in glucose levels and acute beta-cell compensation for insulin resistance. Seventy-one women provided data from a total of 280 paired OGTTs and IVGTTs during a median follow-up of 46 months. Compared with the 47 women who remained free of diabetes, the 24 who either had diabetes (n = 9) or developed it during follow-up (n = 15) had higher baseline glucose levels and lower acute beta-cell compensation for insulin resistance. Baseline insulin sensitivity was low in both groups and did not change significantly during follow-up. Fasting and 2-h glucose levels increased more rapidly in the diabetic group despite a decline in acute beta-cell compensation that was significantly slower than the decline in women who did not develop diabetes. This paradox was explained by an accelerated rise in glucose levels for any decline in beta-cell compensation when beta-cell compensation reached approximately 10% of normal, a level that was reached in the women who had or developed diabetes but not in the women who remained diabetes free. These findings define a pathogenesis for type 2 diabetes in one high-risk group that is characterized by a relatively long-term decline in acute beta-cell compensation for chronic insulin resistance that is attended by slowly rising glucose levels. Only relatively late in this process do glucose levels rise rapidly and into the diabetic range.

Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes.

The Pioglitazone In Prevention Of Diabetes (PIPOD) study was conducted to evaluate beta-cell function, insulin resistance, and the incidence of diabetes during treatment with pioglitazone in Hispanic women with prior gestational diabetes who had completed participation in the Troglitazone In Prevention Of Diabetes (TRIPOD) study. Women who completed the TRIPOD study were offered participation in the PIPOD study for a planned 3 years of drug treatment and 6 months of postdrug washout. Oral glucose tolerance tests were performed annually on pioglitazone and at the end of the postdrug washout. Intravenous glucose tolerance tests (IVGTTs) for assessment of insulin sensitivity and beta-cell function were conducted at baseline, after 1 year on pioglitazone, and at the end of the postdrug washout. Of 95 women who were not diabetic at the end of the TRIPOD study, 89 enrolled in the PIPOD study, 86 completed at least one follow-up visit, and 65 completed all study visits, including the postdrug tests. Comparison of changes in beta-cell compensation for insulin resistance across the TRIPOD and PIPOD studies revealed that pioglitazone stopped the decline in beta-cell function that occurred during placebo treatment in the TRIPOD study and maintained the stability of beta-cell function that had occurred during troglitazone treatment in the TRIPOD study. The risk of diabetes, which occurred at an average rate of 4.6% per year, was lowest in women with the largest reduction in total IVGTT insulin area after 1 year of treatment. The similarity of findings between the PIPOD and TRIPOD studies support a class effect of thiazolidinedione drugs to enhance insulin sensitivity, reduce insulin secretory demands, and preserve pancreatic beta-cell function, all in association with a relatively low rate of type 2 diabetes, in Hispanic women with prior gestational diabetes.

Insulin resistance and preeclampsia in gestational diabetes mellitus.

OBJECTIVE: To compare the degree of insulin resistance in women with gestational diabetes mellitus (GDM) who do and do not develop preeclampsia. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of initially normotensive women with GDM who underwent oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and glucose clamp studies in the early third trimester (n = 150) and 15 months postpartum (n = 89). After delivery, the women were categorized as nonpreeclamptic or preeclamptic (systolic blood pressure [SBP] > or = 140 mmHg, diastolic blood pressure [DBP] > or = 90 mmHg, and at least >1+ proteinuria or >300 mg/24 h). Metabolic parameters between the groups were compared by chi2 or Fisher's exact tests and ANOVA with P < 0.05 as significant. RESULTS: A total of 29 women (19%) developed preeclampsia, which was mild in 21 and severe in 8 women. At entry, there were no differences in age, weight indexes, and glycemic measures between the nonpreeclamptic and preeclamptic groups. Those with preeclampsia were significantly taller (61.5 +/- 2.4 vs. 60.1 +/- 2.3 in, P = 0.003), were more often nulliparous (38 vs. 16%, P = 0.01), and had higher entry SBP (112 +/- 10 vs. 103 +/- 6.9 mmHg, P < 0.0001) and DBP (64 +/- 9 vs. 59 +/- 5 mmHg, P = 0.002). No significant differences between the groups were found in any measures of the OGTT glucose levels, insulin sensitivity index, glucose effectiveness, acute response to glucose, or disposition index, nor were there any differences found in the euglycemic clamp measures of basal or steady-state levels of glucose, insulin, free fatty acid, hepatic glucose output, peripheral glucose clearance, C-peptide, or glucagon. At 15 months postpartum, blood pressure levels remained significantly higher in the preeclamptic group (n = 19) compared with the nonpreeclamptic group (n = 70). No differences in any glycemic or insulin resistance measures were found. CONCLUSIONS: Women with GDM were uniformly insulin resistant. Those who developed preeclampsia, when compared with those who remained nonpreeclamptic, were not more insulin resistant in either the third trimester or 15 months postpartum. However, women who developed preeclampsia had blood pressure levels that were significantly higher, although still in the normal range, than those of women who remained nonpreeclamptic.

Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes.

We tested the effects of treatment with a thiazolidinedione drug on rates of progression of carotid intima-media thickness (CIMT) and some putative determinants of CIMT in young women at high risk for type 2 diabetes. A total of 266 nondiabetic, Hispanic women with recent gestational diabetes were randomized to placebo or troglitazone. CIMT measurements were made at baseline, annually, and at study end, together with measurements of obesity, serum lipids, and glucose and insulin levels during oral glucose tolerance tests. Insulin sensitivity (minimal model analysis) was measured at baseline and 3 months later. Data were analyzed to compare CIMT progression rates between treatment groups and investigate potential determinants of differences in CIMT progression. One hundred ninety-two women had a CIMT measurement at baseline and at least one follow-up visit. The mean rate of CIMT change was 31% lower in women assigned to troglitazone (P = 0.048). This intergroup difference was not explained by baseline or on-trial differences in obesity, lipids, glucose, or insulin. The reduction in CIMT progression developed gradually, occurred only in women who had an increase in insulin sensitivity, and was unrelated to the presence of the metabolic syndrome at baseline. Troglitazone reduced the progression of subclinical atherosclerosis via a mechanism that involved unmeasured mediators of atherosclerosis, either in the circulation or directly in the arterial wall.