Prevalence of gestational diabetes mellitus, maternal obesity and associated perinatal outcomes over 10 years in an Australian tertiary maternity provider.

BACKGROUND: The International Association of Diabetes in Pregnancy Study Groups (IADPSG) gestational diabetes mellitus (GDM) criteria have been heavily scrutinised with concerns that the consequent GDM prevalence increase has not been associated with improved perinatal outcomes. AIMS: At a tertiary hospital in Melbourne, Australia we aimed to evaluate prevalence trends for GDM, type 2 diabetes (T2DM), maternal obesity and large-for-gestational age (LGA) and assess changes in perinatal outcomes following IADPSG criteria uptake in 2015. METHODS: A retrospective cohort study of singleton births from 20 weeks' gestation was conducted between 1st January 2011 and 31st December 2020. Maternal characteristics and perinatal outcomes were extracted from medical records. RESULTS: 52,795 pregnancies were included. GDM prevalence increased 2.7 times from 8.9% in 2011 to 23.7% in 2020 and increased annually by 8.59% (95%CI 7.77, 9.42). The rate of T2DM increased annually by 11.69% (95%CI 7.72, 16.67). Obesity prevalence increased annually by 3.18% (95%CI 2.58, 3.78). Induction of labour (IOL) prevalence increased annually by 8.35% (95%CI 5.69, 11.06). LGA prevalence remained unchanged. Increasing maternal obesity was the major contributing factor for LGA prevalence. CONCLUSIONS: From 2011 to 2020 GDM, obesity and T2DM prevalence increased significantly, with associated increased IOL, without change in LGA rates. Prospective studies are required to explore interactions between GDM, obesity, LGA and obstetric interventions.

Sodium glucose co-transporter-2 inhibitor-induced diabetic ketoacidosis following tooth extraction: improving awareness among dental practitioners.

Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are a relatively new class of oral glucose lowering agents that improve glycaemic control and also provide significant cardiac and renal benefits. However, SGLT-2i use is associated with a small but significant increased risk of diabetic ketoacidosis (DKA) especially during periods of reduced oral intake such as following dental procedures, bowel preparation for colonoscopy, surgery and concurrent illness. In contrast with typical DKA, in many cases of SGLT2i-associated DKA, the blood glucose is normal or only slightly elevated, giving rise to the term euglycaemic DKA (euDKA). Patients with euDKA often present with non-specific symptoms. Moreover, their normal or only mildly elevated blood glucose levels might lead to delayed diagnosis and treatment and hence potentially life-threatening complications. Not only should patients taking an SGLT-2i be informed about the risk of euDKA, and be provided with SGLT-2i sick day management education, but clinicians should also be alert to this diagnosis.

Recombinant human thyroid-stimulating hormone (Thyrogen) in thyroid cancer follow up: experience at a single institution.

BACKGROUND: Recombinant human thyroid-stimulating hormone (Thyrogen; Genzyme Corporation, Cambridge, MA, USA) (rhTSH)-stimulated serum thyroglobulin (Tg) (stim-Tg) and (131)I whole-body scanning (WBS) have been reported to allow follow up of patients with thyroid cancer without the symptoms of thyroxine withdrawal and with equivalent diagnostic information to that obtained after thyroxine withdrawal. The aim of the study was to report results of rhTSH use at the Alfred Hospital, Melbourne, from 1999 to 2006 and in particular to examine the significance of detectable serum Tg after rhTSH in relation to thyroid cancer staging and to compare the sensitivity of rhTSH-stimulated serum Tg to whole-body (131)I scanning (WBS) in the detection of residual and recurrent thyroid cancer. METHODS: The study was a retrospective chart review. RESULTS: In 90 patients, rhTSH was used for 96 diagnostic episodes and 18 doses of rhTSH were used to facilitate treatment with (131)I. In stages I and II cancer (n = 42), of three patients with stim-Tg 1-2 microg/L, none had identifiable disease, and the three patients who had stim-Tg >2 microg/L did not experience recurrent disease during follow up. In contrast, in stages III and IV cancer (n = 43) 2 of 5 with stim-Tg 1-2 microg/L had identifiable disease and 7 of 10 with stim-Tg >2 microg/L had identifiable disease. In Tg-positive, WBS-negative disease, further imaging identified persistent/recurrent disease. CONCLUSION: rhTSH was effective and safe in the management of thyroid cancer follow up for diagnosis of persistent/recurrent cancer and to enable (131)I treatment. In no case did rhTSH-stimulated WBS identify the presence of disease not also identified by raised basal Tg or stim-Tg. Therefore, in low risk cancer WBS may be omitted.

Triiodothyronine regulation of multiple rat hepatic genes: requirement for ongoing protein synthesis.

We have examined the role of rapidly turning over proteins in the T3 regulation of multiple rat hepatic genes. T3 induction of the rapidly responsive mRNA-S14 was markedly inhibited by cycloheximide (1 mg/100 g BW) or emetine (3 mg/100 g) injected ip 30 min before T3 (mRNA-S14 concentration was only 35% of that in T3-treated controls 8.5 h after administration of either protein synthesis inhibitor, P less than 0.01). Cycloheximide exhibited a similar effect on each of five other more slowly responsive T3 regulated genes. When cycloheximide was given 10 h after T3, the expected T3-induced rise of mRNA-S7 activity was completely prevented, and for mRNA-S4 activity the anticipated rise was blunted to 40% of T3-treated control (P less than 0.05). Cycloheximide caused sharp declines in the activity of two other mRNAs, S6 and S8, which because of shorter lag times of response to T3, had already risen when the drug was given. Values for both these mRNAs returned to the baseline hypothyroid level within 6 h of injection of the drug and remained low for a further 8 h (P less than 0.05). The expected deinduction of mRNA-S10 by T3 was also markedly modified. T3 lowered this mRNA to 11% of the hypothyroid control after 8 h, whereas cycloheximide given 30 min before the hormone blunted this fall to only 72% of control (P less than 0.01). Thus there appeared to be a 70% reduction in the rate of T3 induced fall of mRNA-S10. We did not find that cycloheximide caused a generalized decrease in poly (A)+ RNA mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Triiodothyronine rapidly reverses inhibition of S14 gene transcription by glucagon.

The rapid response of hepatic mRNA-S14 to T3 has made this sequence an important model for studying the mechanism of hormonal induction of gene expression. In previous studies we showed, in the intact rat, that glucagon administration during the peak of the mRNA S14 diurnal rhythm causes a monoexponential fall in the level of mRNA-S14, and that T3 reverses this effect. We have now defined more precisely the mechanism governing this interaction. Measurement of in vitro nuclear transcriptional rates shows that T3 can reverse the glucagon-induced reduction of mRNA-S14 transcription. Reversal can be demonstrated within 5 min after the iv injection of T3. Further, the reversal appears to be related to the occupation of specific nuclear receptors, as inferred from the calculated nuclear occupancy and the effects of various iodothyronine analogs of T3. These results suggest that the effects of T3 are mediated by varying rates of production of the nuclear precursor and not by its stabilization, as previously proposed. Ancillary evidence supporting this conclusion came from the demonstration that the apparent t1/2 of the 4.5-kilobase precursor was not prolonged by T3.

Effects of thyroid hormone on sex hormone-binding globulin gene expression in human cells.

We have used a human hepatoblastoma cell line to establish a model system for thyroid hormone (T3) action in human cells. HepG2 cells were grown for 3 days in Dulbecco's Modified Eagle's Medium containing fetal calf serum and were maintained in serum-free medium for experimental manipulations. [125I]T3 incubated with cells was bound by newly secreted protein and degraded. After 24-h exposure to HepG2 cells in Dulbecco's Modified Eagle's Medium, only 35-40% of the radioactivity was recovered as authentic T3. Degradation of hormone was neither time nor concentration dependent, and occurred to a greater degree in the absence of cells, suggesting an interaction between the hormone and the plastic culture dish. After 4 days, in the absence of fetal calf serum and considering hormone binding and degradation, the concentration of free T3 available to cells was approximately 15% of that added initially. Sex hormone-binding globulin (SHBG) was secreted by HepG2 cells in the absence of T3 and was specifically stimulated by the addition of T3. After 4 days, maximum stimulation occurred with added T3 concentrations of 10(-8) M or greater, and half-maximal stimulation of SHBG secretion was observed at about 3 x 10(-11) M free T3. No significant changes in total secreted protein or cellular DNA content were observed under similar conditions. Northern analysis of RNA extracted from HepG2 cells revealed a SHBG mRNA of 2 kilobases, which was stimulated in a dose-responsive manner by T3. No stimulation of corticosteroid-binding globulin mRNA was seen. Stimulation of the SHBG gene in HepG2 cells may be a useful model for investigation of T3 action in human cells.

Interaction of furosemide with serum thyroxine-binding sites: in vivo and in vitro studies and comparison with other inhibitors.

The diuretic furosemide inhibits serum protein binding of T4 in equilibrium dialysis, dextran-charcoal, and competitive ligand binding separation systems and displaces [125I]T4 from isolated preparations of T4-binding globulin (TBG), prealbumin, and albumin. Equilibrium dialysis studies of undiluted normal serum showed that about 10 micrograms/ml furosemide increased the free T4 and free T3 fractions. Displacement occurred at lower drug concentrations in sera with subnormal albumin and TBG levels. Binding of [14C]furosemide to TBG was inhibited by unlabeled T4, suggesting that furosemide and T4 share a common binding site. A single oral dose of 500 mg furosemide given to five patients maintained on peritoneal dialysis increased the percentage of charcoal uptake of [125I]T4 (using serum diluted 1:10) from 4.1 +/- 1.0 (+/- SE) to 10.8 +/- 4.3 (P less than 0.01) after 2 h, while decreasing total T3 from 75 +/- 5 to 56 +/- 13 ng/dl (P less than 0.01) and total T4 from 6.7 +/- 0.9 to 4.8 +/- 0.8 micrograms/dl (P less than 0.01) after 5 h. Various ligands inhibited [125I]T4 binding to serum proteins in the following relative molar relationship: T4, 1; furosemide, 1.5 X 10(3); fenclofenac, 2 X 10(4); mefenamic acid. 2.5 X 10(4); diphenylhydantoin, 4 X 10[4); ethacrynic acid, 10(5); heparin 5 X 10(5); 2-hydroxybenzoylglycine, 10(6); and sodium salicylate, 1.5 X 10(6). These studies demonstrate that furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T4 and T3 levels. The drug is much more potent on a molar basis than other drug inhibitors of T4 binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T4 or T3. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T4- and T3-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness. The significance of this drug in reports of impaired hormone and drug binding in renal failure requires further assessment.

Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness.

In a prospective study of critically ill hypothyroxinemic we assessed the relationship between serum TSH and T4 during the return of serum T4 to normal during recovery. In this longitudinal study of 60 patients with a variety of critical illnesses, including burns, septicemia, and acute renal failure, serum T4 fell to less than 2.7 micrograms/dl (35 nmol/liter) in 24 patients, of whom 14 survived with return of T4 to normal. A rise in total T4 of more than 1.9 microgram/dl (25 nmol/liter) within 96 h occurred 13 times in 10 patients, while 4 patients had slower increases in T4. All 13 episodes of rapid T4 rise [1.7 +/- 0.8 (+/- SD) to 5.6 +/- 2.1 micrograms/dl] were associated with a marked increase in serum TSH (1.1 +/- 0.8 to 7.0 +/- 5.2 mU/liter), and TSH was transiently above normal during 8 episodes of T4 recovery. In the 6 episodes with sampling less than 6 h apart, the TSH rise consistently preceded the T4 rise. In the 4 patients who received dopamine, TSH and T4 remained low until cessation of therapy. During the TSH rise, only minor changes, which could not account for the increase in total T4, occurred in T4-binding globulin (12.9 +/- 3.3 to 14.8 +/- 3.3 mg/liter), prealbumin (208 +/- 73 to 234 +/- 82 mg/liter), and albumin (28.3 +/- 2.9 to 31.9 +/- 2.9 g/liter). Mean free T4 increased (0.60 +/- 0.34 to 1.45 +/- 0.56 ng/dl), as did total T3 (16 +/- 14 to 76 +/- 44 ng/dl), during the phase of TSH rise, suggesting that the increase in TSH was not simply a consequence of diminished negative feedback due to increased plasma binding. The very close and consistent temporal relationship between TSH and T4 during the recovery phase suggests that TSH may have an essential role in the return of T4 to normal during recovery from critical nonthyroidal illness.

Selective versus universal screening for gestational diabetes mellitus: an evaluation of predictive risk factors.

OBJECTIVE: To assess whether selective screening for gestational diabetes mellitus (GDM) on the basis of risk-factor assessment is a practicable alternative to universal screening. DESIGN: Case-control study. SETTING: A 212-bed regional specialist hospital in Melbourne, providing services in obstetrics and gynaecology, paediatrics, geriatrics and rehabilitation. SUBJECTS: 6,032 women who gave birth at the hospital, May 1996 to August 1997 and November 1997 to August 1998; all were screened for GDM, and 313 were diagnosed with the condition. MAIN OUTCOME MEASURES: Odds ratios (ORs) for risk factors (age, obesity, family history of diabetes mellitus and high-risk racial heritage) in women with GDM compared to those without GDM; proportion of women with GDM whose diagnosis would have been missed by selective screening. RESULTS: ORs were 1.9 for age > or = 25 years (95% CI, 1.3-2.7), 2.3 for body mass index > or = 27kg/m2 (95% CI, 1.6-3.3), 2.5 for high-risk racial heritage (95% CI, 2.0-3.2), and 7.1 for family history of diabetes mellitus (95% CI, 5.6-8.9). Other proposed criteria (previous GDM and glycosuria) added no further diagnostic power. Selective screening using the above four criteria would have missed two of 313 cases (0.6%) and could have saved screening up to 1,025 women without GDM (17% of all women). CONCLUSIONS: Selective screening for GDM based on prior risk assessment can reduce the need for testing, with negligible loss of diagnostic efficiency.

Practical management of diabetic ketoacidosis and hyperosmolar coma.

In diabetic ketoacidosis (DKA) and particularly in hyperosmolar coma, rapid normalisation of the measured extracellular fluid abnormalities cannot be equated with optimal management. In both disorders there are complex imbalances between extra- and intracellular compartments that are best corrected in a series of rational steps, based on an understanding of pathophysiology. Fluid administration in DKA can generally be divided into three successive phases: (i) a short period of rapid isotonic saline infusion, (ii) slower infusion of isotonic saline with potassium chloride, and (iii) glucose-potassium infusion until oral food intake is well established. In severe cases, there is a definite place for judicious use of isotonic sodium bicarbonate in small amounts. While insulin infusion is desirable, intramuscular insulin remains a satisfactory alternative. Biochemical monitoring is mandatory and management must be reviewed and modified every three to four hours on the basis of the clinical and biochemical response. In the management of hyperosmolar coma, insulin and fluid therapy are more conservative, with the aim of achieving complete rehydration and normoglycaemia only after 36 to 72 hours. Pulmonary complications and the effects of tissue ischaemia, as well as thromboembolic events, remain important causes of death in both disorders. The frequent recurrences of DKA that occur in a group of psychiatrically-unstable young patients remain an unsolved problem.

Furosemide, fenclofenac, diclofenac, mefenamic acid and meclofenamic acid inhibit specific T3 binding in isolated rat hepatic nuclei.

Previous studies with phenytoin (DPH) show that this inhibitor of thyroid hormone binding to plasma proteins also interacts with specific nuclear T3 binding sites. In order to further define the nuclear effects of drugs that inhibit plasma protein binding of thyroid hormones, we assessed furosemide and a number of non-steroidal antiinflammatory drugs using isolated rat liver nuclei. The effects were compared with those of DPH, ipodate and amiodarone. The T3 binding site in isolated nuclei (Ka 1.2 X 10(9)M-1) showed relative affinity triac approximately equal to T3 greater than T4. Drugs were studied over the concentration range 10(-3)-10(-7)M, approximating the known therapeutic total plasma concentrations, in competition with 125I-T3 0.1 nM, expressing inhibition as the percent decrement from maximum specific binding of 125I-T3 in drug vehicle (assay buffer or thanol 1-10%). Specific T3 binding was inhibited by furosemide to 78.8 +/- 3.5% at 2 mM, by fenclofenac to 37.6 +/- 2.8% at 1 mM, by meclofenamic acid to 70.2 +/- 2.4% at 0.1 mM, by mefenamic acid to 60.6 +/- 4.6% at 0.05 mM (each p less than 0.02) and by diclofenac to 87.4 +/- 5.6% at 0.2 mM (p less than 0.05). In comparison, DPH inhibited T3 binding to only 88.1 +/- 0.6% at 0.3 mM, as did calcium ipodate (68 +/- 3.5% at 1 mM, p less than 0.02). Amiodarone (0.3 mM), sodium salicylate (1 mM) and phenylbutazone (0.1 mM) were inactive. In order to achieve a level of nuclear receptor occupancy that approaches in vivo occupancy, the concentration 125I-T3 was increased over the range 0.1-0.5 nM.2+t

Deaths associated with diabetic ketoacidosis and hyperosmolar coma. 1973-1988.

We assessed the possibility of improvements in the management of the potentially fatal acute hyperglycaemic complications of diabetes by a review of all deaths in patients who presented to the Alfred Hospital, Melbourne, with diabetic ketoacidosis or hyperosmolar coma during the 16 years, 1973-1988. All late deaths of patients during hospitalization were included in the mortality data. In the 610 episodes of diabetic ketoacidosis (pH, 7.30 or lower) or hyperosmolar coma (osmolality, 350 mOsmol/kg or greater), only one death occurred as a result of the acute metabolic disturbance--in a patient who had suffered a cardiac arrest before admission to hospital. The over-all mortality rate was 6.2% (38 deaths). The mortality rate was 4.9% (26 deaths) for 528 episodes of diabetic ketoacidosis and 14.6% (12 deaths) for 82 episodes of hyperosmolar coma. Patients with diabetic ketoacidosis who died were older than were those who survived (64 +/- 13 years compared with 40 +/- 21 years, respectively; P less than 0.001). Mortality in patients with hyperosmolar coma did not relate to age, initial blood-glucose level or osmolality. Twelve deaths resulted from bacterial pneumonia and two deaths resulted from aspiration pneumonia. Other major causes of death were mesenteric and iliac thromboses (six cases), myocardial infarction (eight cases) and cerebral haemorrhage (two cases). Of the 26 deaths that were associated with diabetic ketoacidosis, only two deaths--as a result of aspiration pneumonia and bowel infarction, respectively--were assessed as potentially avoidable after the patient's admission to hospital. Eight of the 12 hyperosmolar-coma-associated deaths occurred in newly recognized diabetic patients in whom there were avoidable delays in diagnosis. We conclude that further improvements in outcome will be difficult to achieve, but that efforts should be directed towards the earlier diagnosis of diabetes and the earlier recognition and treatment of associated acute pulmonary and vascular complications.

Iopanoic acid is of minimal benefit in the treatment of severe hyperthyroidism: conclusions from a case study.

Iopanoic acid (1 g/d) was used together with propylthiouracil (1200 mg/d) in the treatment of a patient with very severe hyperthyroidism and associated cardiac failure. Although serum total T3 decreased by 75% within 48 h and reached normal after 72 h, free T3 levels did not fall to normal. Total and free T4 remained markedly elevated and features of hyperthyroidism persisted. Estimations of theoretical in vivo occupancy of nuclear thyroid hormone receptors, based on serum free T4 and free T3, suggest that the marked decrease in total T3 would not result in a corresponding decrease in thyroid hormone action. Hence, estimates of potential benefit from oral cholecystographic contrast agents, based only on measurements of total T3, may be unduly optimistic. When temporary agranulocytosis developed in this patient, the prior use of iopanoic acid, by markedly reducing thyroidal iodine uptake, restricted the therapeutic options. Caution should, therefore, be exercised in the use of iodine-containing contrast media as adjunctive antithyroid agents.

Interaction between fructose and glucose on the regulation of the nuclear precursor for mRNA-S14.

We have examined the mechanism of the carbohydrate induction of rat hepatic mRNA-S14 to the intragastric administration of sucrose and its constituent hexoses, fructose and glucose. A maximal sucrose response (26-fold) was obtained with 2 ml of 60% sucrose/100 g of body weight, yet equimolar concentrations of fructose and glucose were not able to reproduce the response. Fructose yielded less than one-third the response observed with sucrose, whereas glucose administration was ineffective. On the other hand, the simultaneous administration of both hexoses restored the full response observed with sucrose. The synergism between fructose and glucose was not due to the administration of extra calories or enhanced insulin release but was correlated with altered carbohydrate metabolism as reflected by the hepatic pyruvate content (0.058 +/- 0.003 mumol/g fasting, 0.067 +/- 0.009 glucose treated, 0.218 +/- 0.030 fructose treated, 0.292 +/- 0.015 sucrose treated). The time course of induction of mRNA-S14 nuclear precursor in response to fructose, glucose, or sucrose correlated with the mature mRNA-S14 values. In addition, enhanced transcriptional activity of the S14 gene was observed after sucrose feeding (from 25 +/- 8 ppm baseline to 108 +/- 40 ppm at 4 h) and fructose feeding (40 +/- 21 ppm at 4 h). These studies demonstrate that the carbohydrate regulation of mRNA-S14 is due to a synergistic interaction between fructose and glucose reflected in the hepatic pyruvate content and leading to the induction of the nuclear precursor with an associated increase in transcriptional activity of the S14 gene.

Effect of oral frusemide on diagnostic indices of thyroid function.

We studied the acute effect of standard therapeutic doses of oral frusemide on indices of thyroid function in 34 hospital in-patients with congestive cardiac failure. A transient decrease in total T4, elevation in the T3 resin uptake and consequent increase in the free T4 index (FT4I) were seen 2-5 h after ingestion of frusemide at a chronic morning dosage of 80, 120 or 250 mg. The FT4I pre-vs post-frusemide values after 250 mg of drug were 109 +/- 12 vs 129 +/- 18 (P less than 0.05) after 120 mg 92 +/- 14 vs 119 +/- 12 (P less than 0.01), and after 80 mg 102 +/- 6 vs 112 +/- 4 (P less than 0.01) (mean +/- SEM). Similar increases in apparent free T4 measured by an analogue tracer assay (free T4 RIA sol, Henning, Berlin) were seen after frusemide. In a time course study, the major change in the T3 uptake 120 min after frusemide ingestion correlated with the change in serum frusemide concentration. When frusemide was added to serum in vitro its influence was greatest in methods that involved least dilution of serum. In two of the patients difficulty in clinical assessment of thyroid status was compounded by the effect of oral frusemide on FT4I. We conclude that oral frusemide may influence biochemical assessments of thyroid function in patients with congestive cardiac failure. It is necessary to consider the time interval between ingestion of high doses of oral frusemide and blood sampling in evaluating such results.