Severe neonatal hypoglycaemia and intrapartum glycaemic control in pregnancies complicated by type 1, type 2 and gestational diabetes.

AIMS: To determine if in-target intrapartum glucose control is associated with neonatal hypoglycaemia in women with type 1, type 2 or gestational diabetes. METHODS: This was a retrospective cohort study of pregnant women with diabetes and their neonates. The primary exposure was in-target glucose control, defined as all capillary glucose values within the range 3.5-6.5 mmol/l during the intrapartum period. The primary outcome, neonatal hypoglycaemia, was defined as treatment with intravenous dextrose therapy. Multiple logistic regression was used to examine the association between maternal intrapartum glycaemic control and neonatal hypoglycaemia, adjusting for covariates. RESULTS: Intrapartum glucose testing was available for 157 (86.3%), 267 (76.3%) and 3256 (52.4%) women with type 1, type 2 and gestational diabetes, respectively. In the univariate analysis, in-target glycaemic control was significantly associated with neonatal hypoglycaemia in women with gestational diabetes, but not in women with type 1 or 2 diabetes. However, after adjustment for important neonatal factors (large for gestational age, preterm delivery and infant sex), intrapartum in-target glycaemic control was not significantly associated with neonatal hypoglycaemia in women regardless of diabetes type [adjusted odds ratios 0.4 (95% CI 0.1, 1.4), 0.7 (95% CI 0.3, 1.3) and 0.7 (95% CI 0.5, 1.0) for women with type 1, type 2 and gestational diabetes, respectively]. CONCLUSIONS: There was no significant association between in-target glycaemic control and neonatal hypoglycaemia after adjustment for neonatal factors. Given the high risk of maternal hypoglycaemia and the resources required, future trials should consider whether more relaxed intrapartum glycaemic targets may be safer and yield similar neonatal outcomes.

Maternal glycaemic control and risk of neonatal hypoglycaemia in Type 1 diabetes pregnancy: a secondary analysis of the CONCEPTT trial.

AIMS: To examine the relationship between maternal glycaemic control and risk of neonatal hypoglycaemia using conventional and continuous glucose monitoring metrics in the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT) participants. METHODS: A secondary analysis of CONCEPTT involving 225 pregnant women and their liveborn infants. Antenatal glycaemia was assessed at 12, 24 and 34 weeks gestation. Intrapartum glycaemia was assessed by continuous glucose monitoring measures 24 hours prior to delivery. The primary outcome was neonatal hypoglycaemia defined as glucose concentration < 2.6 mmol/l and requiring intravenous dextrose. RESULTS: Neonatal hypoglycaemia occurred in 57/225 (25.3%) infants, 21 (15%) term and 36 (40%) preterm neonates. During the second and third trimesters, mothers of infants with neonatal hypoglycaemia had higher HbA1c [48 ± 7 (6.6 ± 0.6) vs. 45 ± 7 (6.2 ± 0.6); P = 0.0009 and 50 ± 7 (6.7 ± 0.6) vs. 46 ± 7 (6.3 ± 0.6); P = 0.0001] and lower continuous glucose monitoring time-in-range (46% vs. 53%; P = 0.004 and 60% vs. 66%; P = 0.03). Neonates with hypoglycaemia had higher cord blood C-peptide concentrations [1416 (834, 2757) vs. 662 (417, 1086) pmol/l; P < 0.00001], birthweight > 97.7th centile (63% vs. 34%; P < 0.0001) and skinfold thickness (P ≤ 0.02). Intrapartum continuous glucose monitoring was available for 33 participants, with no differences between mothers of neonates with and without hypoglycaemia. CONCLUSIONS: Modest increments in continuous glucose monitoring time-in-target (5-7% increase) during the second and third trimesters are associated with reduced risk for neonatal hypoglycaemia. While more intrapartum continuous glucose monitoring data are needed, the higher birthweight and skinfold measures associated with neonatal hypoglycaemia suggest that risk is related to fetal hyperinsulinemia preceding the immediate intrapartum period.

The association between vascular complications during pregnancy in women with Type 1 diabetes and congenital malformations.

AIMS: To assess the association between vascular complications of diabetes and the risk of congenital malformations in pregnant women with Type 1 diabetes. METHODS: We conducted an observational retrospective cohort study in women with Type 1 diabetes who received care consecutively from three tertiary care diabetes-in-pregnancy clinics in Calgary, Alberta, Canada. Multivariable logistic regression was used to assess the association between vascular complications (retinopathy, nephropathy and pre-existing hypertension) and congenital malformations in offspring of women with Type 1 diabetes. RESULTS: Of 232 women with Type 1 diabetes, 49 (21%) had at least one vascular complication and there were 52 babies with congenital malformations. Maternal age (31.8 ± 5.0 vs. 29.4 ± 4.7 years, P < 0.01), diabetes duration (20.9 ± 6.7 vs. 11.2 ± 7.4 years, P < 0.01) and pre-eclampsia rate (12.5% vs. 1.3%, P < 0.01) were higher in mothers with vascular complications than in those without. Multivariable analyses showed that vascular complications were not associated with an increased risk of congenital malformations (odds ratio 1.16, 95% confidence interval 0.46 to 2.88). CONCLUSIONS: Vascular complications are common, occurring in one-fifth of pregnant women with Type 1 diabetes, and in this study do not appear to be associated with an increased risk of congenital malformations in children.

Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies.

BACKGROUND: Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in WFS1, a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care. CASE: We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations in WFS1 were identified, supporting a diagnosis of classical WS. CONCLUSIONS: The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserve ß-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies for ß-cell preservation for individuals with type 1 and 2 diabetes.

Intrapartum glycaemic control and neonatal hypoglycaemia in pregnancies complicated by diabetes: a systematic review.

AIMS: To examine whether, in neonates of mothers with Type 1, Type 2 and gestational diabetes, in-target intrapartum glycaemic control was associated with a lower risk of neonatal hypoglycaemia compared with out-of-target glycaemic control. METHODS: We searched PubMed and EMBASE for all available publications, regardless of year, based on a published protocol (PROSPERO CRD42016052439). Studies were excluded if they did not report original data or were animal studies. Data were extracted from published reports in duplicate using a prespecified data extraction form. The main outcome of interest was the association between in-target intrapartum glycaemic control and neonatal hypoglycaemia. RESULTS: We screened 2846 records for potential study inclusion; 23 studies, including approximately 2835 women with diabetes, were included in the systematic review. Only two of those studies specifically examined in-target vs out-of-target intrapartum glycaemic control. Of the studies included, six showed a relationship between intrapartum glucose and neonatal hypoglycaemia, five others showed a relationship in at least one of the analyses performed and 12 did not find a significant relationship. Only one study was identified as having a low risk of bias. CONCLUSIONS: There is a paucity of high-quality data supporting the association of glucose during labour and delivery with neonatal hypoglycaemia in pregnancies complicated by diabetes. Further studies are required to examine the impact of tight glycaemic targets in labour.

Population-Level Outcomes with a 2-Step Approach for Gestational Diabetes Screening and Diagnosis.

OBJECTIVES: To examine outcomes associated with alternative glucose thresholds in a 2-step approach for screening and diagnosing gestational diabetes mellitus (GDM). METHODS: We studied 178,527 pregnancies between 2008 and 2012 in Alberta, Canada. They were categorized retrospectively as normal 50 g screen (n=144,191); normal 75 g oral glucose tolerance test (OGTT) (n=21,248); abnormal at glucose thresholds suggested by the International Association of Diabetes and Pregnancy Group (IADPSG) (HAPO 1.75, n=4308); abnormal at glucose thresholds associated with an odds ratio of 2.0 for adverse events in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. This latter group, which would have been treated for GDM based on customary care, was further divided into those with 1 (HAPO 2-1 n=5528) or 2 or more abnormal glucose values (HAPO 2-2 n=3252). Main outcomes were large for gestational age (LGA), induced labour and Cesarean-section rates. RESULTS: LGA rates were 8.2%, 10.5%, 14.2%, 11.8% and 16.5% among normal 50 g, normal 75 g OGTT, HAPO 1.75, HAPO 2-1, and HAPO 2-2 groups, respectively. Labour induction and caesarean-section rates were 29.6% and 36.2% in the IADPSG, 38.2% and 36.8% in the HAPO 2-1 group, and 42.3% and 41.1% in the HAPO 2-2 groups, respectively. Excessive maternal weight (≥91 kg) was associated with a higher risk for all adverse outcomes. CONCLUSIONS: The 2-step approach effectively identifies pregnancies at low risk for adverse outcomes. Labelling influences induction practice. Any glucose intolerance increases risk for adverse outcomes, and pregnancies with highest (2 or higher) abnormal glucose values remain at greatest risk. Further research is needed to determine whether glycemic thresholds for GDM diagnosis should incorporate information about maternal weight.

Validation of administrative and clinical case definitions for gestational diabetes mellitus against laboratory results.

AIM: To examine the validity of International Classification of Disease, version 10 (ICD-10) codes for gestational diabetes mellitus in administrative databases (outpatient and inpatient), and in a clinical perinatal database (Alberta Perinatal Health Program), using laboratory data as the 'gold standard'. METHODS: Women aged 12-54 years with in-hospital, singleton deliveries between 1 October 2008 and 31 March 2010 in Alberta, Canada were included in the study. A gestational diabetes diagnosis was defined in the laboratory data as ≥2 abnormal values on a 75-g oral glucose tolerance test or a 50-g glucose screen ≥10.3 mmol/l. RESULTS: Of 58 338 pregnancies, 2085 (3.6%) met gestational diabetes criteria based on laboratory data. The gestational diabetes rates in outpatient only, inpatient only, outpatient or inpatient combined, and Alberta Perinatal Health Program databases were 5.2% (3051), 4.8% (2791), 5.8% (3367) and 4.8% (2825), respectively. Although the outpatient or inpatient combined data achieved the highest sensitivity (92%) and specificity (97%), it was associated with a positive predictive value of only 57%. The majority of the false-positives (78%), however, had one abnormal value on oral glucose tolerance test, corresponding to a diagnosis of impaired glucose tolerance in pregnancy. CONCLUSIONS: The ICD-10 codes for gestational diabetes in administrative databases, especially when outpatient and inpatient databases are combined, can be used to reliably estimate the burden of the disease at the population level. Because impaired glucose tolerance in pregnancy and gestational diabetes may be managed similarly in clinical practice, impaired glucose tolerance in pregnancy is often coded as gestational diabetes.

The Biochemical Profile of Familial Hypocalciuric Hypercalcemia and Primary Hyperparathyroidism during Pregnancy and Lactation: Two Case Reports and Review of the Literature.

Background. Primary hyperparathyroidism (PHPT) and Familial Hypocalciuric Hypercalcemia (FHH) result in different maternal and fetal complications in pregnancy. Calcium to creatinine clearance ratio (CCCR) is commonly used to help distinguish these two conditions. Physiological changes in calcium handling during pregnancy and lactation can alter CCCR, making it a less useful tool to distinguish PHPT from FHH. Cases. A 25-year-old female presented with hypercalcemia and an inappropriately normal PTH. Her CCCR was 0.79% before pregnancy and rose to 1.99% in her second trimester. The proband's mother and neonate had asymptomatic hypercalcemia. Genetic analysis revealed a CaSR mutation consistent with FHH. A 19-year-old female presented with a history of nephrolithiasis who underwent emergent caesarean section at 29 weeks of gestation for severe preeclampsia. At delivery, she was diagnosed with hypercalcemia with an inappropriately normal PTH and a CCCR of 2.67%, which fell to 0.88% during lactation. Parathyroidectomy cured her hypercalcemia. Pathology confirmed a parathyroid adenoma. Conclusion. These cases illustrate the influence of pregnancy and lactation on renal calcium indices, such as the CCCR. To avoid diagnostic error of women with hypercalcemia during pregnancy and lactation, calcium biochemistry of first-degree relatives and genetic testing of select patients are recommended.

Impact of gestational diabetes mellitus and high maternal weight on the development of diabetes, hypertension and cardiovascular disease: a population-level analysis.

AIMS: To examine the association between gestational diabetes mellitus (GDM) and high maternal weight and the risk of development of chronic disease. METHODS: Women with singleton deliveries between April 1999 and March 2010 in Alberta, Canada, were categorized according to pre-pregnancy weight (overweight ≥ 91 kg) and GDM status. Obstetric and neonatal outcomes, as well as the long-term incidence of maternal diabetes, hypertension and cardiovascular disease were examined. RESULTS: Of 240 083 women, 213 765 (89%) had no GDM and were not overweight (reference group), 17 587 (7.3%) were overweight only, 7332 (3%) had GDM only and 1399 (0.6%) had GDM and were overweight. Significant differences in Caesarean section rates, induction rates and birthweight were observed across the four groups. During a median follow-up of 5.3 years, diabetes incidence was 36% in the GDM and overweight, 18.8% in the GDM only, 4.8% in the overweight only and 1.1% in the reference group. With respect to hypertension and cardiovascular disease, the GDM and overweight group had the highest rates (26.8% and 3.1%, respectively) and the reference group had the lowest rates (5.8% and 1.0%, respectively). However, rates were similar in the GDM only (14.9% and 1.9%, respectively) and overweight only groups (14.9% and 1.5%, respectively). CONCLUSIONS: Not surprisingly, the presence of both high maternal weight and GDM compounds the risk of developing diabetes. However, the association between overweight alone and GDM alone and hypertension and cardiovascular disease appears similar suggesting a need for effective interventions to manage both these conditions to improve the health of these patients.

Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal.

BACKGROUND: The idea that exposure to hyperglycaemia in utero is an important factor in the development of obesity and diabetes in the offspring has become entrenched as popular belief. AIM: To appraise the literature supporting this hypothesis in the light of recent studies that have clarified the main drivers of obesity in children and adolescents. METHODS: A review of published evidence from animal studies, human observational studies, systematic reviews and experimental trials that address the impact of diabetes (Types 1 and 2, genetic or gestational) on the future risk of obesity and/or glucose intolerance in the offspring. RESULTS: Some animal studies support a relationship between exposure to hyperglycaemia in utero and future development of obesity and diabetes, but the results are inconsistent. Most of the human studies claiming to show a relationship have not taken into account important known confounders, such as maternal and paternal BMI. Evidence supporting a dose-response relationship between maternal hyperglycaemia exposure and obesity and diabetes in the offspring is weak, and there is no convincing evidence that treating gestational diabetes reduces the later risk of offspring obesity or glucose intolerance. CONCLUSIONS: Exposure to hyperglycaemia in utero has minimal direct effect on the later risk of obesity and Type 2 diabetes. The increased risk of obesity in the offspring of women with Type 2 or gestational diabetes can be explained by confounding factors, such as parental obesity.

The natural history of the pituitary incidentaloma.

BACKGROUND: The wide availability of computed tomography and magnetic resonance imaging has resulted in the discovery of unsuspected endocrinologically silent pituitary masses (incidentalomas). Because the natural history of this entity is not known, the approach to the pituitary incidentaloma has not been established. OBJECTIVE: To determine the natural history of untreated pituitary incidentaloma, recognizing that this includes lesions of various causes. METHODS: Thirty-one adults with incidentalomas were prospectively followed up conservatively for a mean of 6.4 years (range, 3 to 11 years). Clinical and biochemical assessment, computed tomography or magnetic resonance imaging of the pituitary, and visual field testing by Goldmann perimetry at baseline, 6 months, and yearly thereafter were the outcomes assessed. RESULTS: Only patients with pituitary incidentalomas greater than 10 mm in greatest diameter developed tumor enlargement or complications. Three patients developed asymptomatic tumor enlargement. In four patients, masses decreased in size. Only two patients developed complications. One required subsequent surgery. The only permanent impairment was panhypopituitarism following surgery in this patient. CONCLUSIONS: Patients with pituitary incidentalomas of unknown causes usually follow a benign course for at least 6 years after discovery. Neurosurgical intervention is not initially required in the management of is not initially required in the management of pituitary incidentalomas, particularly those less than 10 mm, as long as clinical observation can be continued.