Perinatal Outcomes in Early and Late Gestational Diabetes Mellitus After Treatment From 24-28 Weeks' Gestation: A TOBOGM Secondary Analysis.

OBJECTIVE: In most gestational diabetes mellitus (GDM) studies, cohorts have included women combined into study populations without regard to whether hyperglycemia was present earlier in pregnancy. In this study we sought to compare perinatal outcomes between groups: women with early GDM (EGDM group: diagnosis before 20 weeks but no treatment until 24-28 weeks if GDM still present), with late GDM (LGDM group: present only at 24-28 weeks), and with normoglycemia at 24-28 weeks (control subjects). RESEARCH DESIGN AND METHODS: This is a secondary analysis of a randomized controlled treatment trial where we studied, among women with risk factors, early (<20 weeks' gestation) GDM defined according to World Health Organization 2013 criteria. Those receiving early treatment for GDM treatment were excluded. GDM was treated if present at 24-28 weeks. The primary outcome was a composite of birth before 37 weeks' gestation, birth weight ≥4,500 g, birth trauma, neonatal respiratory distress, phototherapy, stillbirth/neonatal death, and shoulder dystocia. Comparisons included adjustment for age, ethnicity, BMI, site, smoking, primigravity, and education. RESULTS: Women with EGDM (n = 254) and LGDM (n = 467) had shorter pregnancy duration than control subjects (n = 2,339). BMI was lowest with LGDM. The composite was increased with EGDM (odds ratio [OR] 1.59, 95% CI 1.18-2.12)) but not LGDM (OR 1.19, 95% CI 0.94-1.50). Induction of labor was higher in both GDM groups. In comparisons with control subjects there were higher birth centile, higher preterm birth rate, and higher rate of neonatal jaundice for the EGDM group (but not the LGDM group). The greatest need for insulin and/or metformin was with EGDM. CONCLUSIONS: Adverse perinatal outcomes were increased with EGDM despite treatment from 24-28 weeks' gestation, suggesting the need to initiate treatment early, and more aggressively, to reduce the effects of exposure to the more severe maternal hyperglycemia from early pregnancy.

Treatment of Gestational Diabetes Mellitus Diagnosed Early in Pregnancy.

BACKGROUND: Whether treatment of gestational diabetes before 20 weeks' gestation improves maternal and infant health is unclear. METHODS: We randomly assigned, in a 1:1 ratio, women between 4 weeks' and 19 weeks 6 days' gestation who had a risk factor for hyperglycemia and a diagnosis of gestational diabetes (World Health Organization 2013 criteria) to receive immediate treatment for gestational diabetes or deferred or no treatment, depending on the results of a repeat oral glucose-tolerance test [OGTT] at 24 to 28 weeks' gestation (control). The trial included three primary outcomes: a composite of adverse neonatal outcomes (birth at <37 weeks' gestation, birth trauma, birth weight of ≥4500 g, respiratory distress, phototherapy, stillbirth or neonatal death, or shoulder dystocia), pregnancy-related hypertension (preeclampsia, eclampsia, or gestational hypertension), and neonatal lean body mass. RESULTS: A total of 802 women underwent randomization; 406 were assigned to the immediate-treatment group and 396 to the control group; follow-up data were available for 793 women (98.9%). An initial OGTT was performed at a mean (±SD) gestation of 15.6±2.5 weeks. An adverse neonatal outcome event occurred in 94 of 378 women (24.9%) in the immediate-treatment group and in 113 of 370 women (30.5%) in the control group (adjusted risk difference, -5.6 percentage points; 95% confidence interval [CI], -10.1 to -1.2). Pregnancy-related hypertension occurred in 40 of 378 women (10.6%) in the immediate-treatment group and in 37 of 372 women (9.9%) in the control group (adjusted risk difference, 0.7 percentage points; 95% CI, -1.6 to 2.9). The mean neonatal lean body mass was 2.86 kg in the immediate-treatment group and 2.91 kg in the control group (adjusted mean difference, -0.04 kg; 95% CI, -0.09 to 0.02). No between-group differences were observed with respect to serious adverse events associated with screening and treatment. CONCLUSIONS: Immediate treatment of gestational diabetes before 20 weeks' gestation led to a modestly lower incidence of a composite of adverse neonatal outcomes than no immediate treatment; no material differences were observed for pregnancy-related hypertension or neonatal lean body mass. (Funded by the National Health and Medical Research Council and others; TOBOGM Australian New Zealand Clinical Trials Registry number, ACTRN12616000924459.).

Hyperglycaemia in early pregnancy: the Treatment of Booking Gestational diabetes Mellitus (TOBOGM) study. A randomised controlled trial.

BACKGROUND: Gestational diabetes mellitus (GDM) causes adverse pregnancy outcomes that can be averted by treatment from 24-28 weeks' gestation. Assessing and treating women for overt diabetes in pregnancy (ODIP) at the first antenatal clinic booking is now recommended in international guidelines. As a consequence, women with milder hyperglycaemia are being diagnosed and treated for early GDM, but randomised controlled trial (RCTs) assessing the benefits and harms of such treatment have not been undertaken. The Treatment Of Booking Gestational diabetes Mellitus (TOBOGM) study is a multi-centre RCT examining whether diagnosing and treating GDM diagnosed at booking improves pregnancy outcomes. Methods and analysis: 4000 adult pregnant women (< 20 weeks' gestation) at risk of ODIP will be recruited from 12 hospital antenatal booking clinics and referred for an oral glucose tolerance test (OGTT). 800 women with hyperglycaemia (ie, booking GDM) according to the 2014 Australasian Diabetes-in-Pregnancy Society criteria for pregnant women at 24-28 weeks' gestation will be randomised to immediate treatment for GDM (intervention) or to no treatment (control), pending the results of a second OGTT at 24-28 weeks' gestation. Antenatal and GDM care will otherwise follow local guidelines. Randomisation will be stratified by site and OGTT glycaemic risk strata. The primary pregnancy outcome is a composite of respiratory distress, phototherapy, birth trauma, birth before 37 weeks' gestation, stillbirth or death, shoulder dystocia, and birthweight ≥ 4.5 kg. The primary neonatal outcome is neonatal lean body mass. The primary maternal outcome is pre-eclampsia. Ethics approval: South Western Sydney Local Health District Research and Ethics Office (reference, 15/LPOOL/551). Dissemination of results: Peer-reviewed publications, scientific meetings, collaboration with research groups undertaking comparable studies, discussions with guideline groups and policy makers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000924459.

Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial.

OBJECTIVE: Vitamin D deficiency in pregnancy is associated with an increased risk of gestational diabetes mellitus (GDM) and neonatal vitamin D deficiency. We conducted a double-blind, randomized controlled trial of low-dose (LD) versus high-dose (HD) vitamin D supplementation to investigate the effects of vitamin D supplementation on glucose metabolism during pregnancy. RESEARCH DESIGN AND METHODS: Women with plasma 25-hydroxyvitamin D (25OHD) levels <32 ng/mL before 20 weeks' gestation were randomized to oral vitamin D3 at 5,000 IU daily (HD) (n = 89) or the recommended pregnancy dose of 400 IU daily (LD) (n = 90) until delivery. The primary end point was maternal glucose levels on oral glucose tolerance test (OGTT) at 26-28 weeks' gestation. Secondary end points included neonatal 25OHD, obstetric and other neonatal outcomes, and maternal homeostasis model assessment of insulin resistance. Analysis was by intention to treat. RESULTS: There was no difference in maternal glucose levels on OGTT. Twelve LD women (13%) developed GDM versus seven (8%) HD women (P = 0.25). Neonatal cord 25OHD was higher in HD offspring (46 ± 11 vs. 29 ± 12 ng/mL, P < 0.001), and deficiency was more common in LD offspring (24 vs. 10%, P = 0.06). Post hoc analysis in LD women showed an inverse relationship between pretreatment 25OHD and both fasting and 2-h blood glucose level on OGTT (both P < 0.001). Baseline 25OHD remained an independent predictor after multiple regression analysis. CONCLUSIONS: HD vitamin D supplementation commencing at a mean of 14 weeks' gestation does not improve glucose levels in pregnancy. However, in women with baseline levels <32 ng/mL, 5,000 IU per day was well tolerated and highly effective at preventing neonatal vitamin D deficiency.

Beliefs, barriers, social support, and environmental influences related to diabetes risk behaviours among women with a history of gestational diabetes.

ISSUE ADDRESSED: Women with previous gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes; this risk is higher in non-Caucasian women. This study explored the beliefs, attitudes, social support, environmental influences and other factors related to diabetes risk behaviours among Arabic, Cantonese/Mandarin, and English speaking women with recent GDM. METHODS: Women living in the Sydney metropolitan area (Australia) who had GDM 6-36 months previously were included. In-depth semi-structured telephone interviews on women's experiences and perceptions of GDM and the lifestyle risk factors for developing type 2 diabetes were conducted in the language participants spoke at home (n=20 Arabic, 20 Cantonese/Mandarin, 17 English). Data were analysed for underlying themes using NVivo software. RESULTS: Mental distress, role perceptions, social support and cultural expectations were major issues related to women's struggles to find the right balance between the large proportion of household and child care responsibilities and leading a healthy lifestyle. CONCLUSION: Women's ability to follow a healthy lifestyle is embedded in their psychological wellbeing and the social and cultural context of their lives. The study highlights the need for a holistic approach that ensures personal support and access to services as well as lifestyle specific programs.

Prostaglandin F2alpha suppresses rat steroidogenic acute regulatory protein expression via induction of Yin Yang 1 protein and recruitment of histone deacetylase 1 protein.

Prostaglandin F2alpha (PGF2alpha) plays a pivotal role in ovarian luteolysis by inhibiting the expression of steroidogenic acute regulatory (StAR) protein, leading to a decrease in intracellular cholesterol transport and luteal steroid production. Previously we have demonstrated that the transcription factor Yin Yang 1 (YY1) bound to three regions in the StAR promoter in vitro and repressed promoter activity. This study further defined the YY1-mediated PGF2alpha effect on the inhibition of StAR protein expression through YY1 interaction with a single region in the StAR promoter in vivo. PGF2alpha consistently suppressed StAR mRNA and protein expression in cultured luteal cells in a dose-dependent manner. PGF2alpha also enhanced YY1 protein expression and binding to its cis-element in a time-dependent pattern that preceded the decline in StAR protein levels. The StAR promoter region bound by YY1 was also associated with histone deacetylase 1 (HDAC1). PGF2alpha treatment promoted HDAC1 binding to and suppressed the histone H3 acetylation in this region. On the contrary, YY1 knockdown decreased HDAC1 binding, increased histone H3 acetylation, enhanced StAR protein expression, and negated PGF2alpha effect on StAR protein expression. Luciferase assays showed that YY1 overexpression inhibited StAR promoter activity and the addition of a HDAC inhibitor, trichostatin A, abrogated the effect of YY1. Trichostatin A-treated luteal cells displayed increased StAR protein expression. These data indicate that PGF2alpha enhances a direct YY1/StAR promoter interaction and the recruitment of HDAC1 to the promoter, thereby preventing transcriptional activation of the StAR gene.

The clinical utility of alternative, less invasive sampling techniques in the assessment of oral hydrocortisone therapy in children and adolescents with hypopituitarism.

OBJECTIVE: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol). DESIGN: Cross-sectional study in a paediatric teaching hospital. METHODS: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings. RESULTS: In ACTH-deficient patients taking oral HC, the bloodspot-plasma correlation (p=0.90) was stronger than the salivary-plasma correlation (p=0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma-bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%). CONCLUSION: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.

Repression of the steroidogenic acute regulatory gene by the multifunctional transcription factor Yin Yang 1.

The transport of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory (StAR) protein is a critical step in steroidogenesis. The current study was designed to examine whether the multifunctional transcription factor Yin Yang 1 (YY1) was able to repress activation of the StAR gene. YY1 bound to three putative YY1-binding sites in the rat StAR promoter. Cotransfection of the StAR promoter linked to a luciferase reporter gene and YY1 in the presence or absence of sterol regulatory element binding protein-1a (SREBP-1a) resulted in transcriptional repression. YY1 was found to colocalize in the nucleus with SREPB-1a. YY1 inhibited SREBP-1a/nuclear factor Y (NF-Y) enhancement of StAR activation and YY1 decreased SREBP-1a binding to a sterol regulatory element in the presence or absence of NF-Y. YY1 also decreased NF-Y binding to a nonconsensus NF-Y-binding motif in the StAR promoter. These studies provide novel information on the mechanisms of YY1-mediated repression of the StAR gene.