Guideline for screening and diagnosing gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is on the rise, especially with the increase in obesity in childbearing women as well as the rising prevalence of diabetes mellitus type 2. The Maltese gestational women are of no exception especially with an established link to intra-uterine nutritional environment adverse effects as well as to genetic factors. There is no set international screening strategy for GDM and so diagnosis differs between countries. The most common diagnostic test for GDM is by performing a 75g oral glucose tolerance test (oGTT). Most countries and organizations including the World Health Organization have adopted the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria for diagnosing GDM. Performing a 75g OGTT on all women at risk of GDM is expensive as well as unpleasant for the women. A combination of risk criteria including pre-pregnancy body mass index with random plasma glucose and/or fasting plasma glucose based on Maltese and Mediterranean population studies have shown to be a useful screening tool. This tool would help identify women likely to have an abnormal or normal oGTT without the need to perform an oGTT. A screening GDM protocol is essential to pick up and manage at an early stage those that are at risk to develop GDM without the need to have an oGTT performed in every pregnant woman. This would result in better perinatal and maternal outcomes.peer-reviewe

Obstetrics and gynaecology

A review of publications relating to significant advances in the specialty of Obstetrics and Gynaecology over the past four years will be discussed: topics reviewed will have an important impact on reducing maternal/fetal morbidity and mortality and should improve on woman's health care.peer-reviewe

Lowest threshold values for the 75g oral glucose tolerance test in pregnancy

Introduction: A previous study has suggested that with increasing oGTT thresholds there was a statistically increasing risk of maternal and foetal morbidity in the form of hypertensive disorders complicating pregnancy and macrosomia. The present study aims to identify whether this gradient risk is extant with lower blood glucose levels. Methodology: A total of 1289 75-gm oGTTs were performed during pregnancy. These were divided according to their fasting and 2-hour values into categories: A. Fasting values =5.6 mmol/l (n=292); and 2-hour values =9.6 mmol/l (n=208). The incidence of hypertensive disease during pregnancy, the macrosomia rate, and the mean birth weight were assessed in each group. Results: The data confirm that a significant rise in the incidence of hypertensive disease occurs at a fasting vlood glucose value of >=5.6 mmol/l, while the macrosomia rate rises after >=4.6 mmol/l. The mean birth weight increased progressively with increasing fasting blood glucose thresholds. There is furthermore a progressive rise in the incidence of hypertension noted with significance being reached at a 2-hour blood glucose value greater than 9.6 mmol/l. However no such relationship appears to be present for the incidence of macrosomia; and there was no significant differences in mean birth weights with increasing 2-hour post-load glucose values. Conclusions: The study suggests that fasting blood glucose values may be a better indicator of maternal and foetal adverse risk outcomes with increased adverse foetal outcomes being indicated at levels >=4.6 mmol/l. The 2-hour post-75g oGTT values appear to be useful as adverse risk indicators only at levels >-9.6 mmol/l.peer-reviewe

Primary hyperparathyroidism in pregnancy : case report and review

A twenty-six year old secundagravida booked her pregnancy at 14 weeks gestation. It was noted in the past obstetric history that the woman had lost her first child at 41 weeks gestation, delivering a stillborn baby weighing 4.2kg. At 34 weeks into the second pregnancy mild polyhydramnios was noted and the patient was admitted. During her hospitalisation the patient complained of having passed a small renal stone. Two serum calcium levels were found to be significantly elevated 3.36mmol/l and 3.2mmol/l. Serum parathormone was found to be significantly elevated - 247pg/ml (Normal levels: 12.0 - 72.0pg/ml) and an ultrasound scan of the neck confirmed the presence of a parathyroid adenoma. A parathyroidectomy was performed and the postoperative period was uneventful. The rest of the pregnancy was uneventful and at 38 weeks gestation a healthy child was delivered vaginally. In view of this woman’s past history and the events occurring during the second pregnancy it may be useful to consider obtaining serum levels of calcium in cases of idiopathic stillbirth.peer-reviewe

The role of untimed blood glucose in screening for gestational diabetes mellitus in a high prevalent diabetic population

Global prevalence increase of diabetes type 2 and gestational diabetes (GDM) has led to increased awareness and screening of pregnant women for GDM. Ideally screening for GDM should be done by an oral glucose tolerance test (oGTT), which is laborious and time consuming. A randomized glucose test incorporated with anthropomorphic characteristics may be an appropriate cost-effective combined clinical and biochemical screening protocol for clinical practice as well as cutting down on oGTTs. A retrospective observational study was performed on a randomized sample of pregnant women who required an OGTT during their pregnancy. Biochemical and anthropomorphic data along with obstetric outcomes were statistically analyzed. Backward stepwise logistic regression and receiver operating characteristics curves were used to obtain a suitable predictor for GDM without an oGTT and formulate a screening protocol. Significant GDM predictive variables were fasting blood glucose () and random blood glucose (). Different RBG and FBG cutoff points with anthropomorphic characteristics were compared to carbohydrate metabolic status to diagnose GDM without oGTT, leading to a screening protocol. A screening protocol incorporating IADPSG diagnostic criteria, BMI, and different RBG and FBG criteria would help predict GDM among high-risk populations earlier and reduce the need for oGTT test.peer-reviewe

Identification of an HNF1B p.Arg527Gln mutation in a Maltese patient with atypical early onset diabetes and diabetic nephropathy

Background The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1β mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy. HNF1β-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of HNF1β mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported. Case presentation An obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband’s phenotype. A rare missense mutation at a highly conserved site in exon 8 of HNF1β was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in-silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course. Conclusion This report highlights several atypical features in a proband with atypical diabetes associated with an HNF1β missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes.peer-reviewe

Insights from whole exome sequencing in a Maltese cohort with gestational diabetes

BACKGROUND: Gestational diabetes (GDM) can be driven by mutations or rare variants in various genes associated with monogenic or atypical forms of diabetes. The reported frequency of monogenic defects of beta cell function in GDM varies extensively, in part due to differences in ethnicity, patient ascertainment criteria and techniques used for genetic analysis. The objective was to evaluate the frequency and molecular spectrum of mutations in a curated list of genes associated with monogenic/atypical diabetes in non-obese women of Maltese ethnicity with GDM.METHOD: 30 non-obese Maltese women who met the International Association of the Diabetes and Pregnancy Study Group (IADPSG) criteria for diagnosis of GDM and with a first-degree relative with non-autoimmune diabetes were included in this study. Whole exome capture and high throughput sequencing was carried out. Rare sequence variants were filtered, annotated and prioritized according to the American College for Medical Genetics guidelines. For selected missense variants we explored effects on protein stability and structure through homology predictions or PDB structures using in-silico tools.RESULTS: In total, we identified three pathogenic mutations and twelve variants of uncertain significance (VUS). The disease-causing mutations comprise a nonsense mutation in GCK, an insertion-frameshift at a mutational hotspot in HNF1A and a missense substitution in ABCC8. Critically, the ABCC8 mutation leads to significant changes in interatomic interactions and to expansion of protein cavity volume, with resulting destabilising effects. Damaging VUS in PDX1, KLF11, DYRK1B, TRMT10A, AKT2, BLK, GLIS3 and NKX6-1 were detected, having either conflicting pathogenicity interpretationsor insufficient evidence for pathogenicity from in-vitro studies. Novel NEUROG3 and CEL VUS were also detected. Stereochemical analysis reveals that the missense variants described in NEUROG3, DYRK1B, TRMT10AandAKT2 have destabilising effects. Genotype-phenotype correlations for all detected variants are described, including associations with anthropometric traits, OGTT, HOMA-IR, treatment and post-pregnancy follow-up data where available. We show that GDM cases who were carriers of either pathogenic mutations or damaging VUS had a younger age of GDM diagnosis than females where no variant of interest was identified. (29 vs 32 years, P = 0.039).CONCLUSION: This study provides the first insight into an underlying monogenic aetiology in non-obese women with GDM from a high-prevalence island population. It suggests that monogenic variants constitute an underestimated cause of diabetes detected in pregnancy, and that careful evaluation of GDM probands to identify monogenic disease subtypes is indicated.peer-reviewe

Primary hyperparathyroidism in pregnancy - case report and review Case report

Abstract A twenty-six year old secundagravida booked her pregnancy at 14 weeks gestation. It was noted in the past obstetric history that the woman had lost her first child at 41 weeks gestation, delivering a stillborn baby weighing 4.2kg. At 34 weeks into the second pregnancy mild polyhydramnios was noted and the patient was admitted. During her hospitalisation the patient complained of having passed a small renal stone. Two serum calcium levels were found to be significantly elevated 3.36mmol/l and 3.2mmol/l. Serum parathormone was found to be significantly elevated -247pg/ml (Normal levels: 12.0 -72.0pg/ml) and an ultrasound scan of the neck confirmed the presence of a parathyroid adenoma. A parathyroidectomy was performed and the postoperative period was uneventful. The rest of the pregnancy was uneventful and at 38 weeks gestation a healthy child was delivered vaginally. In view of this woman's past history and the events occurring during the second pregnancy it may be useful to consider obtaining serum levels of calcium in cases of idiopathic stillbirth

Biological and biochemical characteristics of a Mediterranean population with Gestational Diabetes Mellitus

The interplay of various nutrients provided to the developing foetus determines the growth potential of the conceptus. This study assessed the inter-relationship between these nutrients in a Mediterranean population including 1062 pregnant, previously non-diabetic women. These underwent an oral glucose tolerance test (oGTT) and were accordingly classified into gestational hyperglycaemic and normoglycaemic groups. Fasting insulin, HbA1c, and lipid profiles were further assessed, and the anthropomorphic characteristics of the mother and child at birth were measured. Lipid profiles were compared between the two groups and related to the biological characteristics of the mother and child at birth. Gestational hyperglycaemia was significantly associated with elevated triglycerides (P<0.0001) and decreased low density lipoprotein cholesterol (LDL-C) (P=0.02). There were no significant changes in total cholesterol and high density lipoprotein cholesterol (HDL-C) levels. Maternal BMI correlated positively with the various glycaemic indices (P<0.0001) and triglycerides (P<0.0001), but inversely with cholesterol (P<0.0001), HDL-C (P<0.0001) and LDL-C (P<0.0001). The infant birth weight correlated positively with maternal body weight (P<0.0001), LDL-C (P<0.0001) and the glycaemic indices (P<0.0001), but negatively with cholesterol (P<0.0001), triglycerides (P<0.0001), HDL-C (P<0.0001) and FBG (P<0.0001). This study confirms that the maternal body mass index (BMI), insulin resistance, and LDL-C levels positively contribute towards foetal growth, whereas a negative correlation was noted with cholesterol, triglycerides, and HDL-C