Smoking affects the oral glucose tolerance test profile and the relationship between glucose and HbA1c in gestational diabetes mellitus.

AIMS: Current smokers in the general population have a lower 2 h plasma glucose after an oral glucose tolerance test (OGTT) and a higher HbA1c than non-smokers, but the relationships between OGTT/HbA1c and smoking status have not been addressed in pregnancy. We analysed glycaemic measurements in women with gestational diabetes mellitus in relation to smoking status. METHODS: We performed a review of the prospectively collected database of the diabetes and pregnancy clinic. We included women with gestational diabetes mellitus and a singleton pregnancy who delivered between 1986 and 2006. Bivariate and multivariate analyses were used to evaluate patient characteristics in relation to smoking status. RESULTS: A total of 2361 women met the inclusion criteria: 556 (23.5%) were active smokers, 266 (11.3%) quit during pregnancy and 1539 (65.2%) were non-smokers. Most baseline characteristics were similar across groups. Diagnostic OGTT was performed at a gestational age of [median (25th, 75(th) centiles)] 29 weeks (26, 33). Women who smoked at the beginning of pregnancy had a higher 1-h plasma glucose than non-smokers [11.8 (11, 12.7), 11.6 (11, 12.6) and 11.5 (10.8, 12.5) mmol/l, for active smokers, those who quit during pregnancy and non-smokers, respectively, P < 0.001] and a lower 3-h plasma glucose [7.3 (5.9, 8.4), 7.6 (6.4, 8.7) and 8.0 (6.8, 9.0) mmol/l, respectively, P < 0.001]. HbA1c was higher in women who smoked at the beginning of pregnancy. Multiple regression analysis confirmed the independent association of smoking status with HbA1c and OGTT plasma glucose. CONCLUSIONS: In women with gestational diabetes mellitus who smoke at the beginning of pregnancy, the shape of the OGTT is consistent with accelerated glucose absorption, and HbA1c is higher than expected for glycaemic values.

Poorer perinatal outcome in male newborns of women with pregestational diabetes mellitus.

AIMS: To assess perinatal outcome in women with pregestational diabetes mellitus according to the sex of the fetus. METHODS: A retrospective review of all singleton pregnancies of women with pregestational diabetes progressing to a gestational age of 22 weeks or more who attended the diabetes and pregnancy clinic from 1981 to 2006 (n=455). We compared maternal characteristics and perinatal outcomes (perinatal mortality, major congenital malformations, small and large for gestational age newborns, preterm birth and a composite of the former) according to the sex of the fetus. A logistic regression analysis was performed using the composite perinatal outcome as the dependent variable and all maternal variables and sex of fetus as potential predictors. RESULTS: Maternal characteristics did not differ in mothers of male and female newborns. In the whole cohort, the composite perinatal outcome was significantly higher in male fetuses; adjusted OR 1.61 (95% CI 1.04-2.50). CONCLUSIONS: In women with pregestational diabetes, perinatal outcome was poorer in male newborns despite similar maternal characteristics.

Insulin requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction.

AIMS/HYPOTHESIS: The aim of the study was to analyse the insulin requirements of women with type 1 diabetes mellitus throughout pregnancy. METHODS: We have examined the weekly mean blood glucose (mmol/l), insulin requirements (U kg(-1) day(-1)) and total insulin requirements (U/day) in 65 women with type 1 diabetes mellitus and tight metabolic control since before pregnancy (HbA(1c) < or =6.0%). RESULTS: Both insulin requirement and total insulin requirement displayed a peak in week 9, a nadir in week 16 and a second peak in week 37. For the change in insulin requirement (4.08% per week) and in total insulin requirement (5.19% per week), the sharpest slope was observed from week 16 to week 37. However, two changes of direction took place in the first 11 weeks and eight out of nine episodes of severe hypoglycaemia requiring treatment with glucagon or i.v. glucose took place in the first 16 weeks. CONCLUSIONS/INTERPRETATION: Pregnant women with type 1 diabetes mellitus and tight metabolic control since before pregnancy displayed changes in insulin requirement and total insulin requirement with successive changes of direction. The sharpest slope was observed between 16 and 37 weeks, but insulin requirements were more unstable in the first 16 weeks. This information could help patients and physicians to react to changes in glycaemic pattern in a prompt and adequate way.

In women with gestational diabetes mellitus factors influencing growth have a larger effect on placental weight than on birth weight.

BACKGROUND AND AIMS: Excessive fetal and placental growth are very common in diabetic pregnancy. We aimed to analyze in women with gestational diabetes mellitus (GDM) the association with birth weight (BW), placental weight (PW) and placental-to-birth weight (PWBW) ratio of acknowledged BW predictors. MATERIAL AND METHODS: We performed a retrospective analysis of a prospective cohort database from a tertiary hospital. Inclusion criteria were singleton pregnancy, diagnosis of GDM, delivery between 1982 and 2011 and gestational age at birth ≥23 weeks. Multiple regression analysis was performed using as dependent variables BW, PW and PWBW ratio and as independent ones maternal characteristics at baseline, metabolic characteristics (GDM diagnosis, treatment, control), pregnancy-induced hypertension, gestational age at delivery and fetal sex. Two sensitivity analyses were performed. RESULTS: We evaluated 2547 women, PW being available in 85.3%. BW was 3260g (2976, 3575), PW 620g (540, 720) and PWBW ratio 19.27 (17.20, 21.47). Among the 24 analyzed variables, there was an important overlap among those associated with BW, PW and PWBW ratio. For most characteristics associated with both BW and PW, the magnitude of the association was greater for the latter, both when promoting growth (i.e. prepregnancy body mass index, 3h plasma glucose at diagnosis) and when restricting it (insulin treatment). CONCLUSION: We conclude that in women with GDM and singleton pregnancies, variables associated with BW, PW and PWBW ratio overlap. The latter is the result of disproportionate associations with BW and PW, usually larger with PW.

Gestational diabetes mellitus in women with multiple pregnancies: is the metabolic abnormality milder?

OBJECTIVE: We aimed to compare maternal characteristics and dysglycemia after delivery in women with gestational diabetes mellitus (GDM) according to pregnancy being multiple (MP) or singleton (SP). The hypothesis was that women with GDM and MP would have a milder glycemic abnormality before and after pregnancy than those with SP. METHODS: We performed a cohort study of 2908 women giving birth between 1986 and 2009. Logistic regression was performed to discriminate between MP and SP after anamnestic pre-pregnancy characteristics. Kaplan-Meier and Cox regression analyses were performed to assess if MP was independently associated with both impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and diabetes after delivery. RESULTS: Family history of diabetes was the only independent anamnestic pre-pregnancy characteristic discriminating MP versus SP, OR 2.04 (95% CI 1.12, 3.70, p 0.019). The median time to progress to IFG/IGT was 7.52 years in SP (95% CI 6.92, 8.13) and 7.41 in MP (95% CI 3.84, 10.98), ns and the progression to DM did not differ. In addition, MP was not associated to IFG/IGT or to DM in the Cox regression analysis. CONCLUSIONS: In this cohort of women with GDM, those with MP did not demonstrate a lesser degree of dysglycemia after controlling for other pregnancy characteristics and pregnancy-independent factors.

Insulin antibody response to a short course of human insulin therapy in women with gestational diabetes.

OBJECTIVE: To assess the insulin antibody (IA) response to human insulin (HI) therapy in women with gestational diabetes. RESEARCH DESIGN AND METHODS: IAs were measured by a competitive radiobinding assay in 50 women with gestational diabetes before and during treatment with HI and after delivery. At delivery, 15 maternal-cord blood sample pairs were analyzed for IA. As a reference, we searched for IA in 25 new-onset type I diabetic patients, before and at 3, 6, and 12 months after insulin therapy. RESULTS: Insulin autoantibodies (IAAs) were detected in 1 of 50 women with gestational diabetes and 4 of 16 type I diabetic patients (P < 0.05). At the end of pregnancy after 9.3 +/- 6.8 weeks on insulin therapy, 22 of 50 (44%) women with gestational diabetes became IA+ and 4 additional women were found to be positive 2 months postpartum. After 3 months on insulin, type I diabetic patients showed a higher rate of IA positivity (92%, P < 0.001). IA titers at the end of pregnancy were associated with the cumulative insulin dose (r = 0.29, P < 0.05). Postpartum, IA disappeared slowly in most IA+ women, but two women still showed IA 2 years after delivery Titers in cord blood were strongly related to those in maternal blood (r = 0.74, P < 0.01). The rate of adverse fetal outcome did not differ in IA and IA- mothers (27 vs. 40%, NS). CONCLUSIONS: HI is immunogenic, and a short course of HI therapy induces IA in approximately 50% of women with gestational diabetes and 92% of type I diabetic patients. In women with gestational diabetes, insulin dose is slightly associated with IA titers. These IAs apparently cross the placenta. Fetal outcome does not differ according to the maternal IA status, and IAs disappear gradually after delivery but may remain positive for 2 years after delivery.

Postpartum thyroiditis in women with hypothyroidism antedating pregnancy?

In women with hypothyroidism, levothyroxine (LT) requirements after delivery are assumed to return to prepregnancy values. The occasional observation of discordances prompted this study. Forty-one women (31 receiving LT replacement therapy and 10 receiving suppressive therapy for thyroid carcinoma) were followed during the first year after delivery. A control group of 31 nonpregnant women with hypothyroidism (n = 21) or thyroid carcinoma (n = 10) were also followed during a similar period. Twenty-three patients of 41 (56.1%) had discordant requirements at follow-up after delivery vs. 3 of 31 in the control group (9.7%; P < 0.001). The patterns of discordance in the postdelivery group were hyperthyroidism in 12, increase in LT dose in 5, hyper- and hypothyroidism in 5, and recurrence of Graves' disease in 1 women. Those in the control group were increase in LT dose, hyperthyroidism, and hypo- and hyperthyroidism. The rate of patients with discordant prepregnancy-postpartum LT doses was higher in the noncarcinoma subgroup (67.7% vs. 20.0%; P < 0.01), whereas in the control group, both subgroups displayed a similar rate of discordance (9.5% vs. 10%; P = NS). In conclusion, this study documents that women with hypothyroidism antedating pregnancy display changes in LT requirements in the first year after delivery that suggest postpartum thyroiditis.

Melatonin concentration before and during testosterone replacement in primary hypogonadic men.

OBJECTIVE: To study circadian levels of melatonin in primary hypogonadic adult men before and after testosterone treatment. DESIGN AND METHODS: Circadian serum melatonin profiles were studied in six men with primary hypogonadism before and during testosterone substitution and compared with an age-matched control group (n = 6). RESULTS: Hypogonadal patients had higher plasma melatonin concentrations than the control group during day time (34.2 +/- 8.8 compared with 5.4 +/- 0.5 ng/l, means +/- SD; P < 0.005) and night-time (74.8 +/- 34.5 compared with 30.8 +/- 3.2 ng/l). A 3 months course of testosterone replacement treatment in the hypogonadal group was followed by a diminution of the amplified melatonin circadian rhythm, with lower mean values both during the day (34.2.8 +/- 8 compared with 12.7 +/- 2.45 ng/l, P < 0.001) and at night (74.8 +/- 34.5 compared with 41.5 +/- 13.5 ng/l, P < 0.01), and a decrease in the total area under the curve (958 +/- 318 compared with 475.5 +/- 222.9, P = 0.046). There was a significant negative correlation between melatonin (r = -0.69) and testosterone concentrations. CONCLUSIONS: These data indicate that diminished testosterone in male primary hypogonadism is associated with enhanced plasma levels of melatonin, and that testosterone substitution treatment induces a deamplification of the circadian rhythm of melatonin values in humans.

Is selective screening for gestational diabetes mellitus worthwhile everywhere?

We assessed if selective screening for gestational diabetes mellitus (GDM) as recommended by the Fourth Workshop on GDM is worthwhile in our centre. Detection is performed using universal screening in three pregnancy periods using the tests recommended by the first three Workshops. We have analysed the prevalence of low-risk characteristics for GDM in the 917 women delivering in the centre in 1992 and in the whole cohort of 1635 women with GDM delivering between 1986 and 1998. The rate of women with all low risk characteristics was 7.0% among the general pregnant population and 1.3% in the cohort of women with GDM (p<0.001). We conclude that in our population, selective screening of GDM is reliable in identifying women at low risk of GDM, but since only a negligible subset of the pregnant population would not need to be screened, adherence to these guidelines would make the screening policy unnecessarily complicated.

Does preconceptional counselling in diabetic women influence perinatal outcome?

We aimed to assess the impact of a preconceptional clinic (PC) on the perinatal outcome (PO) of diabetic pregnancies attended in our centre. We studied 185 pregnancies attended in the 1986-1996 period (152 in women with insulin dependent diabetes mellitus (IDDM) and 33 with non insulin-dependent diabetes mellitus (NIDDM)) and we analysed the perinatal outcome for both mother and fetus. Sixty-six women (36.1%) had enrolled in the PC, 41.4% for IDDM and 9.1% for NIDDM pregnancies, p < 0.01. First pregnancy HbA1c (in SD around the mean) was 3.98 +/- 3.00 in non-attenders (NA) vs 2.57 +/- 2.41 in attenders (A), p < 0.01. The final HbA1c was in the normal range in both groups. D-R class according to White classification was 33.0% for NA vs 54.5% for A, p < 0.01. There were no differences in the rates of abortion and major malformations (8.8% NA vs 3.6% A, ns). Both groups differed in the rate of cesarean sections (54.9% NA vs 71.0% A, p < 0.05) and in the rate of small for gestational age infants (SGA) (8.7% NA vs 1.8% A, p < 0.05). There were no differences between groups in maternal or neonatal outcomes. In this group of diabetic women with a moderate although less than optimal metabolic control at the beginning of pregnancy, the impact of PC on PO is less evident than described.

Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis.

CONTEXT: Glycemic disturbance is usually less severe in pregnant women with type 2 than in those with type 1 diabetes mellitus (DM). Nevertheless, a worse perinatal outcome in women with type 2 DM has been reported in some studies. OBJECTIVE: Our objective was to review maternal and fetal outcomes in pregnant women with type 2 vs. type 1 DM. STUDY SELECTION: We conducted a systematic review of papers providing original data on pregnancy outcomes in both type 2 and type 1 DM (Medline search of the period January 1, 1987, to June 30, 2008). Two independent investigators considered papers for eligibility, and a third one solved discrepancies. DATA EXTRACTION: Metaanalysis tools were used to compare four main outcomes (major congenital malformations, stillbirth, and neonatal and perinatal mortality) and 15 secondary ones (five maternal, 10 fetal). Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were used to assess quality. DATA SYNTHESIS: Thirty-three studies qualified for inclusion of 3743 citations retrieved. Women with type 2 DM had lower glycated hemoglobin (HbA1c) at booking and throughout pregnancy but a higher risk of perinatal mortality [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.15-1.96] without significant differences in the rates of major congenital malformations, stillbirth, and neonatal mortality. As to secondary outcomes, women with type 2 DM had less diabetic ketoacidosis (OR 0.09, 95% CI 0.02-0.34) and cesarean section (OR 0.80, 95% CI 0.59-0.94) without differences in other outcomes. CONCLUSIONS: Despite a milder glycemic disturbance, women with type 2 DM had no better perinatal outcomes than those with type 1, indicating that type 2 DM in pregnancy is a serious condition.

Thirty years of human pineal research: do we know its clinical relevance?

A role for melatonin in humans is becoming evident in an increasing number of clinical situations. Marked variations in the magnitude of the nocturnal melatonin peak are observed throughout the human lifespan. The highest levels occur in children and then fall during puberty and further during adulthood. A negative correlation between circulating melatonin and sex steroids has been observed in a number of instances, and appears to be independent of concomitant gonadotrophins. No clear melatonin pattern has been observed in pituitary tumors, but in large lesions that involve the hypothalamus, a reduced nocturnal rise has been reported. Reported effects of exogenously administered melatonin are variable, probably reflecting differences in dose and timing; a slight stimulation of prolactin, as well as a partial inhibition of gonadotrophins, has been reported, which explains its utility as an oral contraceptive, associated with a progestogen. A potential clinical use of melatonin as an oncostatic drug still awaits confirmation, although experimental data firmly support this possibility. The indole has also been used to hasten entrainment of subjects travelling across various time zones, and has been found to be specially useful in eastward travel. Finally, changes in the normal melatonin circadian pattern have been reported in psychiatric diseases and in sudden infant death syndrome.

In pregnancies with gestational diabetes mellitus and intensive therapy, perinatal outcome is worse in small-for-gestational-age newborns.

OBJECTIVE: This study analyzed the relationship between birth weight and perinatal outcome among women with gestational diabetes mellitus. STUDY DESIGN: The relationship between perinatal outcome and birth weight was analyzed for 821 pregnancies of women with gestational diabetes mellitus attended in a tertiary hospital and receiving intensive metabolic therapy (normocaloric diet, self-monitoring of blood glucose level and individually tailored insulin regimen when needed). The Mantel-Haenszel test was used to adjust for preterm delivery. RESULTS: Seven percent of neonates were small for gestational age, 85% were appropriate for gestational age, and 8% were large for gestational age. After adjustment for preterm delivery the rates of adverse fetal outcome, low 1-minute Apgar score, and hypoglycemia were greater among small for gestational age neonates than among appropriate and large for gestational age infants (odds ratios 3.08, 2.51, and 3.17, respectively). CONCLUSION: Among women with gestational diabetes mellitus who are receiving intensive therapy, perinatal outcome is worse for small for gestational age neonates than for appropriate and large for gestational age neonates.

Gestational diabetes mellitus: metabolic control during labour.

The purpose of this study was to assess, in women with gestational diabetes mellitus (GDM): 1) metabolic control during labour using a standardised protocol; 2) the influence of therapy during pregnancy in intrapartum metabolic control and insulin requirements; and 3) the impact of maternal glycaemia during labour on neonatal hypoglycaemia. An observational study of 85 women with GDM (54 insulin-treated) was performed. Intrapartum metabolic management included i.v. glucose and insulin infusions, urinary ketone measurement and hourly capillary blood glucose (CBG) monitoring. Mean CBG from arrival to delivery was 4.7 +/- 1.1 mmol/l with 83% of mean CBG values within the target range (2.8-6.9 mmol/l). Mean CBG and insulin requirements were unrelated to therapy during pregnancy, but hypoglycaemia (CBG<2.8 mmol/l) was more frequent in women receiving insulin during pregnancy (40.7 vs 19.4 %, p<0.01). In several logistic regression models, CBG during labour was predictive of neonatal hypoglycaemia. We conclude that in women with GDM, the use of a standardised intrapartum management protocol is associated to fair metabolic control, that insulin requirements during labour are unrelated to therapy during pregnancy and that high CBG during labour increases the risk of neonatal hypoglycaemia.

In human gestational diabetes mellitus congenital malformations are related to pre-pregnancy body mass index and to severity of diabetes.

AIMS/HYPOTHESIS: This study analysed the relationship between congenital malformations (CM) and severity of gestational diabetes mellitus. METHODS: A cohort of 2060 infants of mothers with gestational diabetes was studied. Universal screening and 3(rd) Workshop-Conference criteria were used to diagnose gestational diabetes. The severity of diabetes was assessed on the basis of previous hyperglycaemia, blood glucose values in diagnostic OGTT, area under the glucose curve, gestational age and HbA(1)c at diagnosis, insulin requirements during pregnancy, and OGTT after delivery. Potentially confounding variables (age, pre-pregnancy BMI, smoking) were considered. The relationship of potential predictors with CM was analysed with several multivariate logistic regression analyses. RESULTS: The rate of CM was 6% for minor and 3.8% for major malformations (1.4% heart, 0.8% renal/urinary, 0.7% skeletal, 0.3% hypospadias, 0.2% central nervous system, 0.2% cleft lip/palate, 0.1% digestive tract, 0.3% other). In the final models, forward logistic regression analysis identified pre-pregnancy BMI as the predictor of CM (area under receiver operating characteristic curve 0.616); in the backward analysis additional predictors were 1-h blood glucose in diagnostic OGTT and gestational age at diagnosis (area under receiver operating characteristic curve 0.646). Both BMI and severity of gestational diabetes were predictors of heart and minor CM, whereas BMI predicted renal/urinary CM and severity of diabetes predicted skeletal CM. CONCLUSIONS/INTERPRETATION: In these infants of mothers with gestational diabetes, severity of diabetes and pre-pregnancy BMI were predictors of CM, in accordance with the well-documented pathogenic role of BMI (in the general population) and hyperglycaemia (in diabetic pregnancy). BMI was the main predictor of more prevalent CM.

Dopaminergic resistance in a case of invasive macroprolactinoma.

Invasive prolactinoma is a relatively infrequent variety of macroprolactinoma characterized by a fast and aggressive growth, with infiltration to adjacent structures, and whose management is frequently difficult. We present the case of a fatal invasive macroprolactinoma in whom resistance to different dopaminergic drugs developed.

High reproducibility of K for assessment of first phase insulin secretion in healthy subjects

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