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.

Pharmacological interventions for treating intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013. OBJECTIVES: To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy. DATA COLLECTION AND ANALYSIS: The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy. AUTHORS' CONCLUSIONS: When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).

Neurodevelopmental outcome at 2†years in offspring of women randomised to metformin or insulin treatment for gestational diabetes.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a common complication of pregnancy and is increasingly being treated with metformin that crosses the placenta rather than insulin, which does not. This study seeks to examine the neurodevelopment of offspring of women treated with metformin or insulin for GDM. DESIGN: We performed a prospective follow-up study of children whose mothers had been randomly assigned at 20-33 weeks gestation to treatment with metformin or insulin for GDM. Of the 211 children followed up at 2 years, 128 were from Auckland, New Zealand (64 metformin vs 64 insulin), and 83 from Adelaide, Australia (39 metformin vs 49 insulin). Neurodevelopment was examined with the Bayley Scales of Infant Development V.2 mental development index (MDI) and psychomotor development index (PDI). Clinical and demographic background characteristics were obtained at enrolment, birth and follow-up. RESULTS: No significant differences were found between treatment groups in clinical or demographic characteristics. The MDI and PDI composite scores were tested with general linear models. No significant differences were found between metformin and insulin, respectively, in New Zealand (MDI, M=83.6 vs 86.9 and PDI, M=83.4 vs M=85.2) or Australia (MDI, M=102.5 vs M=98.4 and PDI, M=105.6 vs M=99.9) and no interactions observed. The differences in neurodevelopmental outcomes between the Auckland and Adelaide cohorts were explained by parental ethnicity, infant birth weight >4000 g, neonatal hypoglycaemia, maternal glycaemia and smoking in the household. CONCLUSIONS: This study provides additional data supporting the safety of metformin in the treatment of GDM. TRIAL REGISTRATION NUMBER: ACTRN 12605000311651.

The IDEAL study: investigation of dietary advice and lifestyle for women with borderline gestational diabetes: a randomised controlled trial - study protocol.

BACKGROUND: The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) showed that treatment of pregnant women with mild gestational diabetes mellitus is beneficial for both women and their infants. It is still uncertain whether there are benefits of similar treatment for women with borderline gestational diabetes.This trial aims to assess whether dietary and lifestyle advice and treatment given to pregnant women who screen for borderline gestational diabetes reduces neonatal complications and maternal morbidities. DESIGN: Multicentre, randomised controlled trial. INCLUSION CRITERIA: Women between 240 and 346 weeks gestation with a singleton pregnancy, a positive oral glucose challenge test (venous plasma glucose ≥7.8 mmol/L) and a normal oral 75 gram glucose tolerance test (fasting venous plasma glucose <5.5 mmol/L and a 2 hour glucose <7.8 mmol/L) with written, informed consent.Trial entry and randomisation: Women with an abnormal oral glucose tolerance test (fasting venous plasma glucose ≥5.5 mmol/L or 2 hour glucose ≥7.8 mmol/L) will not be eligible and will be offered treatment for gestational diabetes, consistent with recommendations based on results of the ACHOIS trial. Eligible women will be randomised into either the 'Routine Care Group' or the 'Intervention Group'.Study groups: Women in the 'Routine Care Group' will receive routine obstetric care reflecting current clinical practice in Australian hospitals. Women in the 'Intervention Group' will receive obstetric care, which will include dietary and lifestyle advice, monitoring of blood glucose and further medical treatment for hyperglycaemia as appropriate.Primary study outcome: Incidence of large for gestational age infants. SAMPLE SIZE: A sample size of 682 women will be sufficient to show a 50% reduction in the risk of large for gestational age infants (alpha 0.05 two-tailed, 80% power, 4% loss to follow up) from 14% to 7% with dietary and lifestyle advice and treatment. DISCUSSION: A conclusive trial outcome will provide reliable evidence of relevance for the care of women with borderline glucose intolerance in pregnancy and their infants. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12607000174482.

Genetic susceptibility to viral exposure may increase the risk of cerebral palsy.

AIM: Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples. RESULTS: At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50-0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05-1.83). For infants born 32-36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34-80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21-14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13-0.76). CONCLUSION: Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection.

Diabetes insipidus in pregnancy.

Diabetes insipidus is an uncommon condition with various aetiologies. Recent research has uncovered new mechanisms underlying the syndrome. Careful attention to management is essential in pregnant women to avoid serious complications. Diabetes insipidus in pregnancy may be due to relative reduction in secretion of AVP from the posterior pituitary (cranial DI), increase in breakdown of AVP by placental cystine aminopeptidase with vasopressinase activity, or resistance of the rental tubules to AVP (nephrogenic DI).