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Considerable progress has been made to explain the aetiology of intrahepatic cholestasis of pregnancy (ICP) and of the adverse pregnancy outcomes associated with high maternal total serum bile acids (TSBAs). The reported thresholds for non-fasting TSBA associated with the risk of stillbirth and spontaneous preterm birth can be used to identify pregnancies at risk of these adverse outcomes to decide on appropriate interventions and to give reassurance to women with lower concentrations of TSBA. Data also support the use of ursodeoxycholic acid to protect against the risk of spontaneous preterm birth. A previous history of ICP may be associated with higher rates of subsequent hepatobiliary disease: if there is a suspicion of underlying susceptibility, clinicians caring for women with ICP should screen for associated disorders or for genetic susceptibility and, where appropriate, refer for ongoing hepatology review. [ABSTRACT FROM AUTHOR]

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver-specific disorder affecting pregnant women, with an Australian incidence of 0.6% pa and recurring in 70% of those affected. ICP causes mild to severe pruritus, often resulting in considerable skin excoriations, profound sleep disturbances, and severe anxiety, and yet the aetiology and optimal treatment or management of this condition remains unknown. In this review, we consider the role of viruses in causing or exacerbating ICP and discuss viruses that have been most closely implicated in the disease, including the role of Hepatitis B and Hepatitis C viruses in ICP. [ABSTRACT FROM AUTHOR]

In this paper, we discuss the Bile Acid Comparison and Harmonisation project, a sub-study of the Trial of URsodeoxycholic acid vs RIFampicin in early-onset severe Intrahepatic Cholestasis of pregnancy, giving an overview of the current state of affairs for total bile acid measurements. [ABSTRACT FROM AUTHOR]

Catherine Leggett,1,* Ei Mon Phyo Lwin,2,* Usha Ritchie,1 Yunmei Song,2 Jacobus P Gerber,2 Sean Turner,1 William M Hague,3,4 Michael Stark,3,5 Richard Upton,2 Sanjay Garg2 1SA Pharmacy, Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; 2School of Pharmacy and Medical Sciences, Reid Building, City East Campus, University of South Australia, Adelaide, SA 5000, Australia; 3Robinson Research Institute, University of Adelaide, North Adelaide, SA 5006, Australia; 4Obstetric Medicine, Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; 5Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia*These authors contributed equally to this workCorrespondence: Sanjay GargCentre for Pharmaceutical Innovation and Development (CPID), School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, AustraliaTel +61 8 830 21575Fax +61 8 830 22389Email Sanjay.Garg@unisa.edu.auObjective: This study aimed to quantify the amount of perindopril and its active metabolite perindoprilat present in breast milk and corresponding maternal and infant plasma concentrations.Design: Prospective, longitudinal, observational.Setting: Tertiary specialist paediatric and obstetric hospital in Adelaide, South Australia.Population: Breastfeeding women actively treated with perindopril for hypertensive disorders postpartum.Methods: Eight breast milk samples and a single plasma sample were collected from each participant over a 24 hrs period, and plasma samples were taken from eligible breastfed infants. Breast milk and plasma concentrations of perindopril and perindoprilat were analysed using a validated Liquid Chromatography tandem-Mass Spectrometry (LC-MS/MS) method.Main Outcome Measures: Mean breast milk concentrations of perindopril and perindoprilat, Relative Infant Dose (RID) < 10%, and Theoretical Infant Dose (TID).Results: Ten women and three infants participated in the study. The mean concentration of perindopril in breast milk for each participant ranged from 0.003 to 1.2 ng/mL and perindoprilat 0.2– 36 ng/mL. RID for perindopril was 0.0005– 0.2% and perindoprilat 0.03– 4.6%. TID for perindopril was 0.00045– 0.18 μg/kg/day and perindoprilat 0.032– 5.4 μg/kg/day. Infant plasma levels for perindopril ranged from 0.44 to 1.12 ng/mL and perindoprilat undetectable – 10.14 ng/mL. Maternal reports described normal infant growth and development.Conclusion: Infant exposure to perindopril and perindoprilat through breast milk is low. However, some infants were found to have plasma perindoprilat concentrations consistent with pharmacodynamic effects. Perindopril may be used in mothers of healthy term infants, provided the infant is carefully monitored.Keywords: perindopril, perindoprilat, LC-MS/MS, human plasma, human milk, clinical lactation, infant drug exposure

Objective: Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency?Design: Secondary outcomes of the FRUIT-RCT.Setting: Multicentre, international.Population: The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestational-age infant and an inheritable thrombophilia.Methods: After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22-24, 28-30 and 34-36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22-24 weeks) was examined using a chi-square test.Main Outcome Measures: Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries.Results: No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms.Conclusion: The addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity.Tweetable Abstract: LMWH does not influence fetal growth or uterine or umbilical flow velocities. [ABSTRACT FROM AUTHOR]

Objective: In women with gestational diabetes mellitus, who were randomized to metformin or insulin treatment, pregnancy outcomes were similar (Metformin in Gestational diabetes [MiG] trial). Metformin crosses the placenta, so it is important to assess potential effects on growth of the children.Research Design and Methods: In Auckland, New Zealand, and Adelaide, Australia, women who had participated in the MiG trial were reviewed when their children were 2 years old. Body composition was measured in 154 and 164 children whose mothers had been randomized to metformin and insulin, respectively. Children were assessed with anthropometry, bioimpedance, and dual energy X-ray absorptiometry (DEXA), using standard methods.Results: The children were similar for baseline maternal characteristics and pregnancy outcomes. In the metformin group, compared with the insulin group, children had larger mid-upper arm circumferences (17.2 ± 1.5 vs. 16.7 ± 1.5 cm; P = 0.002) and subscapular (6.3 ± 1.9 vs. 6.0 ± 1.7 mm; P = 0.02) and biceps skinfolds (6.03 ± 1.9 vs. 5.6 ± 1.7 mm; P = 0.04). Total fat mass and percentage body fat assessed by bioimpedance (n = 221) and DEXA (n = 114) were not different.Conclusions: Children exposed to metformin had larger measures of subcutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone. Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive. If so, this would have significant implications for the current pandemic of diabetes. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association of timing of commencing glucose management with glycemia, glycemic variability, and pregnancy outcomes among women with early gestational diabetes mellitus (GDM)., Research Design and Methods: In this substudy among participants of a trial of immediate vs. delayed treatment of early GDM diagnosed by 2013 World Health Organization criteria, all women treated immediately and those with delayed diagnosis at 24-28 weeks' gestation (treated as if late GDM) were instructed to monitor capillary blood glucose (BG) four times a day (fasting and 2-h postprandial) until delivery. Optimal glycemia was defined as ≥95% of BG measurements between 70 and 140 mg/dL (3.9-7.8 mmol/L)., Results: Overall, 107,716 BG values were obtained from 329 of 549 (59.9%) women (mean age 32.3 ± 4.9 years, BMI 32.0 ± 8.0 kg/m2, 35% European, gestation at GDM diagnosis 15.2 ± 2.4 weeks). Women treated early (n = 213) showed lower mean glucose (MG) and mean fasting glucose (MFG) compared with those treated late (n = 116) (MG: 5.7 ± 0.4 vs. 5.9 ± 0.5, P < 0.001; MFG: 5.2 ± 0.3 vs. 5.3 ± 0.4, P = 0.004), with greater optimal glycemia (74.6% vs. 59.5%, P = 0.006) and similar glycemic variability. MG was similar from 30 weeks' gestation. Overall, optimal glycemia was achieved in 69% of women and associated with lower birth weight, fewer large-for-gestational-age infants (14.4% vs. 26.7%, P = 0.01), more small-for-gestational-age infants (15.3% vs. 5.9%, P = 0.02), and lower gestational weight gain (4.9 ± 6.4 vs. 7.6 ± 6.2 kg, P = 0.001). Suboptimal glycemia was associated with non-European ethnicity, prior GDM, 1-h glucose at booking oral glucose tolerance test, and insulin use., Conclusions: Both early and delayed treatment of early GDM resulted in similar glycemia toward the end of pregnancy. Early treatment was associated with improved glycemia overall., (© 2024 by the American Diabetes Association.)

Objective: To compare the prevalence and clinical characteristics of early gestational diabetes (eGDM) and associated birth outcomes amongst women of different ethnic groups., Research Design and Methods: This is a secondary analysis of an international, multicentre randomized controlled trial of treating eGDM among pregnant women with GDM risk factors enrolled <20 weeks' gestation. The diagnosis of GDM was made using WHO-2013 criteria. While Europids required at least one risk factor for recruitment, for others, ethnicity itself was a risk factor., Results: Among women of Europid (n=1,567), South Asian (SA: n=971), East and South-East Asian (ESEA: n=498), Middle Eastern (ME: n=242) and Māori and Pasifika (MP: n=174) ethnicities; MP (26.4%) had the highest eGDM crude prevalence compared with Europid (20.3%), SA (24.7%), ESEA (22.3%) and ME (21.1%) (p<0.001). Compared with Europid, the highest eGDM adjusted odds ratio (aOR) was seen in SA (2.43 [95%CI 1.9-3.11]) and ESEA (aOR 2.28 [95%CI 1.68-3.08]); in late GDM, SA had the highest prevalence (20.4%: aOR 2.16 [95%CI 1.61-2.9]). Glucose patterns varied between ethnic groups and ESEA were predominantly diagnosed with eGDM through post-glucose load values, while all other ethnic groups were mainly diagnosed on fasting glucose values. There were no differences in the eGDM composite primary outcome or neonatal and pregnancy-related hypertension outcomes between the ethnic groups., Conclusions: In women with risk factors, eGDM was most prevalent in SA and ESEA women, particularly identified by the post-glucose load samples. These findings suggest an early OGTT should particularly be performed in women from these ethnic groups., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To compare pregnancy outcomes among women with a normal oral glucose tolerance test (OGTT) before 20 weeks' gestation (early) and at 24-28 weeks' gestation (late) (no gestational diabetes mellitus, or No-GDM), those with early GDM randomized to observation with a subsequent normal OGTT (GDM-Regression), and those with GDM on both occasions (GDM-Maintained)., Research Design and Methods: Women at <20 weeks' gestation with GDM risk factors who were recruited for a randomized controlled early GDM treatment trial were included. Women with treated early GDM and late GDM (according to the World Health Organization's 2013 criteria) were excluded from this analysis. Logistic regression compared pregnancy outcomes., Results: GDM-Regression (n = 121) group risk factor profiles and OGTT results generally fell between the No-GDM (n = 2,218) and GDM-Maintained (n = 254) groups, with adjusted incidences of pregnancy complications similar between the GDM-Regression and No-GDM groups., Conclusions: Women with early GDM but normal OGTT at 24-28 weeks' gestation had pregnancy outcomes that were similar to those of individuals without GDM. Identifying early GDM likely to regress would allow treatment to be avoided., (© 2024 by the American Diabetes Association.)

Objective: We evaluated associations between early-pregnancy oral glucose tolerance test (OGTT) glucose and complications in the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) cohort to inform prognostic OGTT thresholds., Research Design and Methods: Individuals with risk factors for hyperglycemia were recruited for an international, multicenter, randomized controlled gestational diabetes mellitus (GDM) (World Health Organization 2013 criteria) treatment trial. A 2-h 75-g OGTT was performed at <20 weeks' gestation. Individuals with early treated hyperglycemia in pregnancy were excluded from the primary analysis. Early OGTT glucose concentrations were analyzed continuously and in glycemic categories (normal, low band, and high band)., Results: Overall, 3,645 individuals had an OGTT at (mean ± SD) 15.6 ± 2.5 weeks. For each 1-SD increase in fasting, 1-h, and 2-h glucose values, there were continuous positive associations with late GDM: adjusted odds ratio (aOR) 2.04 (95% CI 1.82-2.27), 3.05 (2.72-3.43), and 2.21 (1.99-2.45), respectively. There were continuous positive associations between 1-h and 2-h glucose and the perinatal composite (birth <37 + 0 weeks, birth trauma, birth weight ≥4,500 g, respiratory distress, phototherapy requirement, stillbirth/neonatal death, and shoulder dystocia), with aOR 1.15 (95% CI 1.04-1.26) and 1.14 (1.04-1.25), respectively, and with large-for-gestational-age offspring, with aOR 1.18 (1.06-1.31) and 1.26 (1.01-1.25), respectively. Significant associations were also observed between 1-h glucose and cesarean section and between fasting and 2-h glucose and neonatal hypoglycemia. In categorical analysis, only the high-band 1-h glucose (≥10.6 mmol/L [191 mg/dL]) predicted the perinatal composite., Conclusions: There is a continuous positive association between early-pregnancy OGTT glucose and complications. In individuals with hyperglycemia risk factors, only the high-glycemic-band 1-h glucose corresponded to increased risk of major perinatal complications., (© 2024 by the American Diabetes Association.)

Aim: To evaluate the incidence and predictors of postpartum dysglycaemia among high-risk women who develop early gestational diabetes (eGDM) prior to 20 weeks' gestation., Methods: This is a sub-study of the Treatment of Booking Gestational Diabetes (TOBOGM) Study, a randomised controlled trial of early or deferred treatment for women with risk factors for gestational diabetes diagnosed with eGDM, using current WHO criteria. Overt diabetes in pregnancy was excluded. A repeat oral glucose tolerance test (oGTT) was recommended at 6-12 weeks postpartum., Results: Of 793 participants, 352 (44.4%) underwent a postpartum oGTT. Baseline characteristics of participants with and without an oGTT were similar. Ninety-two (26.1%) had postpartum dysglycaemia: 11 (3.1%) diabetes, 31 (8.8%) impaired fasting glucose (IFG), 39 (11.1%) impaired glucose tolerance (IGT), and 11 (3.1%) combined IFG/IGT. Participants with postpartum dysglycaemia were more likely to have had past GDM, lower body mass index, more gestational weight gain, and higher 1 and 2-hour glucose concentrations on the early pregnancy oGTT. On logistic regression, higher 1 and 2-hour glucose concentration, previous GDM and greater gestational weight gain were independently associated with postpartum dysglycaemia., Conclusion: There is a high incidence of postpartum dysglycaemia among high-risk women with eGDM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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' gestation but no treatment until 24-28 weeks' gestation if GDM still present), with late GDM (LGDM group: present only at 24-28 weeks' gestation), and with normoglycemia at 24-28 weeks' gestation (control participants)., 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' gestation. 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 participants (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 participants 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., (© 2024 by the American Diabetes Association.)

Objective: To identify factors associated with neonatal respiratory distress (NRD) in early Gestational diabetes mellitus (eGDM)., Design: Nested case-control analysis of the TOBOGM trial., Setting: Seventeen hospitals: Australia, Sweden, Austria and India., Population: Pregnant women, <20 weeks' gestation, singleton, GDM risk factors., Methods: Women with GDM risk factors completed an oral glucose tolerance test (OGTT) before 20 weeks: those with eGDM (WHO-2013 criteria) were randomised to immediate or deferred GDM treatment. Logistic regression compared pregnancies with/without NRD, and in pregnancies with NRD, those with/without high-dependency nursery admission for ≤24 h with those admitted for >24 h. Comparisons were adjusted for age, pre-pregnancy body mass index, ethnicity, smoking, primigravity, education and site. Adjusted odds ratios (95% CI) are reported., Main Outcome Measures: NRD definition: ≥4 h of respiratory support (supplemental oxygen or supported ventilation) postpartum. Respiratory distress syndrome (RDS): Supported ventilation and ≥24 h nursery stay., Results: Ninety-nine (12.5%) of 793 infants had NRD; incidence halved (0.50, 0.31-0.79) if GDM treatment was started early. NRD was associated with Caesarean section (2.31, 1.42-3.76), large for gestational age (LGA) (1.83, 1.09-3.08) and shorter gestation (0.95, 0.93-0.97 per day longer). Among NRD infants, >24 h nursery-stay was associated with higher OGTT 1-h glucose (1.38, 1.08-1.76 per mmol/L). Fifteen (2.0%) infants had RDS., Conclusions: Identifying and treating eGDM reduces NRD risk. NRD is more likely with Caesarean section, LGA and shorter gestation. Further studies are needed to understand the mechanisms behind this eGDM complication and any long-term effects., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: A recently undertaken multicenter randomized controlled trial (RCT) " Treatment Of BOoking Gestational diabetes Mellitus" (TOBOGM: 2017-2022) found that the diagnosis and treatment of pregnant women with early gestational diabetes mellitus (GDM) improved pregnancy outcomes. Based on data from the trial, this study aimed to assess the cost-effectiveness of diagnosis and treatment of early GDM (from <20 weeks') among women with risk factors for hyperglycemia in pregnancy compared with usual care (no treatment until 24-28 weeks') from a healthcare perspective., Methods: Participants' healthcare resource utilization data were collected from their self-reported questionnaires and hospital records, and valued using the unit costs obtained from standard Australian national sources. Costs were reported in US dollars ($) using the purchasing power parity (PPP) estimates to facilitate comparison of costs across countries. Intention-to-treat (ITT) principle was followed. Missing cost data were replaced using multiple imputations. Bootstrapping method was used to estimate the uncertainty around mean cost difference and cost-effectiveness results. Bootstrapped cost-effect pairs were used to plot the cost-effectiveness (CE) plane and cost-effectiveness acceptability curve (CEAC)., Findings: Diagnosis and treatment of early GDM was more effective and tended to be less costly, i.e., dominant (cost-saving) [-5.6% composite adverse pregnancy outcome (95% CI: -10.1%, -1.2%), -$1373 (95% CI: -$3,749, $642)] compared with usual care. Our findings were confirmed by both the CE plane (88% of the bootstrapped cost-effect pairs fall in the south-west quadrant), and CEAC (the probability of the intervention being cost-effective ranged from 84% at a willingness-to-pay (WTP) threshold value of $10,000-99% at a WTP threshold value of $100,000 per composite adverse pregnancy outcome prevented). Sub-group analyses demonstrated that diagnosis and treatment of early GDM among women in the higher glycemic range (fasting blood glucose 95-109 mg/dl [5.3-6.0 mmol/L], 1-h blood glucose ≥191 mg/dl [10.6 mmol/L] and/or 2-h blood glucose 162-199 mg/dl [9.0-11.0 mmol/L]) was more effective and less costly (dominant) [ - 7.8% composite adverse pregnancy outcome (95% CI: -14.6%, -0.9%), -$2795 (95% CI: -$6,638, -$533)]; the intervention was more effective and tended to be less costly [ - 8.9% composite adverse pregnancy outcome (95% CI: -15.1%, -2.6%), -$5548 (95% CI: -$16,740, $1547)] among women diagnosed before 14 weeks' gestation as well., Interpretation: Our findings highlight the potential health and economic benefits from the diagnosis and treatment of early GDM among women with risk factors for hyperglycemia in pregnancy and supports its implementation. Long-term follow-up studies are recommended as a key future area of research to assess the potential long-term health benefits and economic consequences of the intervention., Funding: National Health and Medical Research Council (grants 1104231 and 2009326), Region O¨rebro Research Committee (grants Dnr OLL-970566 and OLL-942177), Medical Scientific Fund of the Mayor of Vienna (project 15,205 and project 23,026), South Western Sydney Local Health District Academic Unit (grant 2016), and Western Sydney University Ainsworth Trust Grant (2019)., Competing Interests: WHH reports participation on Merck Sharp & Dohme Board and Rivus Pharmaceuticals Board. DS reports Presidency of the Australasian Diabetes in Pregnancy Society. All otherauthor(s) have no potential conflict of interests to report., (© 2024 The Author(s).)

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy liver disease, characterised by pruritus and increased total serum bile acids (TSBA), Australian incidence 0.6-0.7%. ICP is diagnosed by non-fasting TSBA ≥19 μmol/L in a pregnant woman with pruritus without rash without a known pre-existing liver disorder. Peak TSBA ≥40 and ≥100 μmol/L identify severe and very severe disease respectively, associated with spontaneous preterm birth when severe, and with stillbirth, when very severe. Benefit-vs-risk for iatrogenic preterm birth in ICP remains uncertain. Ursodeoxycholic acid remains the best pharmacotherapy preterm, improving perinatal outcome and reducing pruritus, although it has not been shown to reduce stillbirth., (© 2023 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Both obesity and sleep disorders are common among women during pregnancy. Although prior research has identified a relationship between obesity and sleep disorders, those findings are from women later in pregnancy., Objective: To explore the relationships between self-reported sleep duration, insufficient sleep and snoring with body mass index (BMI) among multiethnic women at risk of gestational diabetes mellitus (GDM)in early pregnancy., Methods: Cross-sectional study of baseline data from women at risk of GDM enrolled in the Treatment of BOoking Gestational diabetes Mellitus (TOBOGM) multicentre trial across 12 Australian/Austrian sites. Participants completed a questionnaire before 20 weeks' gestation to evaluate sleep. BMI <25 kg/m 2 served as the reference group in multivariable logistic regression., Results: Among the 2865 women included, the prevalence of overweight and obesity classes I-III was 28%, 19%, 11% and 12%, respectively. There was no relationship between sleep duration and BMI. The risk of insufficient sleep >5 days/month was higher in class II and class III obesity (1.38 (1.03-1.85) and 1.34 (1.01-1.80), respectively), and the risk of snoring increased as BMI increased (1.59 (1.25-2.02), 2.68 (2.07-3.48), 4.35 (3.21-5.88) to 4.96 (3.65-6.74), respectively))., Conclusions: Obesity is associated with insufficient sleep among pregnant women at risk of GDM. Snoring is more prevalent with increasing BMI., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

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.)., (Copyright © 2023 Massachusetts Medical Society.)

Addition of placental histopathology studies to obstetric trials is likely to be cost-effective and may reveal structural changes suggestive of functional dysfunction to explain the success or failure of a clinical intervention. We share our recent experience in adding placental pathological examination to two clinical trials, retrospectively in one and at the outset in the other, so that other clinical trial investigators may benefit from it. The practical issues can be summarised as being regulatory and ethical, operational and reporting. Prospective inclusion of placental pathological examination as part of a clinical trial protocol is easier than retrospective, and is facilitated by fully-costed funding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Narcolepsy, a condition adversely affecting psychological, social, and cognitive function, is more prevalent in females of childbearing age than the general population. Modafinil and armodafinil are central nervous system stimulants approved for treatment of narcolepsy. Infant exposure to these agents through human milk has not been investigated. Poor quality medication safety information during lactation is associated with early cessation of breastfeeding and suboptimal healthcare for the breastfeeding family., Main Issue: In this case study, we measured the concentration of armodafinil (the most active form of modafinil) in human milk and infant plasma to quantify infant exposure., Management: The participant was a 30-year-old primipara with narcolepsy, taking modafinil (300 mg morning, 100 mg noon) while breastfeeding her 6-week-old infant despite the paucity of safety information. Armodafinil concentrations were measured in eight serial human milk samples collected over a 26-hr period and in single maternal and infant plasma samples using ultra performance liquid chromatography - tandem mass spectrometry. The average concentration of armodafinil in human milk was 1.96 mg/L; the relative infant dose was 4.85%; the theoretical infant dose was 0.294 mg/kg/day. Maternal and infant plasma concentrations of armodafinil were 12.02 mg/L and 0.19 mg/L, respectively. The participant continued to exclusively breastfeed the infant, who had normal growth and development., Conclusion: Based on these findings, relatively small amounts of armodafinil pass into human milk, with consequent limited infant exposure. Consideration can be given to the use of modafinil or armodafinil during breastfeeding, provided the infant is monitored. Further studies are needed to confirm these findings.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility., (© 2022. The Author(s).)

Objectives: One approach to assessing reference material (RM) commutability and agreement with clinical samples (CS) is to use ordinary least squares or Deming regression with prediction intervals. This approach assumes constant variance that may not be fulfilled by the measurement procedures. Flexible regression frameworks which relax this assumption, such as quantile regression or generalized additive models for location, scale, and shape (GAMLSS), have recently been implemented, which can model the changing variance with measurand concentration., Methods: We simulated four imprecision profiles, ranging from simple constant variance to complex mixtures of constant and proportional variance, and examined the effects on commutability assessment outcomes with above four regression frameworks and varying the number of CS, data transformations and RM location relative to CS concentration. Regression framework performance was determined by the proportion of false rejections of commutability from prediction intervals or centiles across relative RM concentrations and was compared with the expected nominal probability coverage., Results: In simple variance profiles (constant or proportional variance), Deming regression, without or with logarithmic transformation respectively, is the most efficient approach. In mixed variance profiles, GAMLSS with smoothing techniques are more appropriate, with consideration given to increasing the number of CS and the relative location of RM. In the case where analytical coefficients of variation profiles are U-shaped, even the more flexible regression frameworks may not be entirely suitable., Conclusions: In commutability assessments, variance profiles of measurement procedures and location of RM in respect to clinical sample concentration significantly influence the false rejection rate of commutability., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Multicentre international trials relying on diagnoses derived from biochemical results may overlook the importance of assay standardisation from the participating laboratories. Here we describe a study protocol aimed at harmonising results from total bile acid determinations within the context of an international randomised controlled Trial of two treatments, URsodeoxycholic acid and RIFampicin, for women with severe early onset Intrahepatic Cholestasis of pregnancy (TURRIFIC), referred to as the Bile Acid Comparison and Harmonisation (BACH) study, with the aims of reducing inter-laboratory heterogeneity in total bile acid assays., Methods: We have simulated laboratory data to determine the feasibility of total bile acid recalibration using a reference set of patient samples with a consensus value approach and subsequently used regression-based techniques to transform the data., Results: From these simulations, we have demonstrated that mathematical recalibration of total bile acid results is plausible, with a high probability of successfully harmonising results across participating laboratories., Conclusions: Standardisation of bile acid results facilitates the commutability of laboratory results and collation for statistical analysis. It may provide the momentum for broader application of the described techniques in the setting of large-scale multinational clinical trials dependent on results from non-standardised assays., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes., Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495., Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016)., Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment., Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research., Competing Interests: Declaration of interests CO and H-UM are consultants for Mirum Pharmaceuticals. CW is a consultant for Mirum Pharmaceuticals and GlaxoSmithKline. KK is an unpaid consultant for Myriad Pharmaceuticals. WMH reports non-financial support from the Falk Foundation, during the conduct of the study, and is co-author of the Cochrane review on pharmacological interventions for treating intrahepatic cholestasis of pregnancy.(14) RMT reports grants from Tommy's and the Lauren Page Trust during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Exposure to gestational diabetes mellitus (GDM) in utero is associated with a range of adverse cognitive and neurological outcomes. Previously, we reported altered neuroplastic responses to continuous theta burst stimulation (cTBS) in GDM-exposed adolescents. Recent research suggests that the relative excitability of complex oligosynaptic circuits (late I-wave circuits) can predict these responses. We aimed to determine if altered I-wave recruitment was associated with neuroplastic responses in adolescents born to women with GDM. A total of 20 GDM-exposed adolescents and 10 controls (aged 13.1 ± 1.0 years) participated. cTBS was used to induce neuroplasticity. I-wave recruitment was assessed by comparing motor-evoked potential latencies using different TMS coil directions. Recruitment of late I-waves was associated with stronger LTD-like neuroplastic responses to cTBS ( p = < 0.001, R 2 = 0.36). There were no differences between groups in mean neuroplasticity ( p = 0.37), I-wave recruitment ( p = 0.87), or the association between these variables ( p = 0.41). The relationship between I-wave recruitment and the response to cTBS previously observed in adults is also present in adolescents and does not appear to be altered significantly by in utero GDM exposure. Exposure to GDM does not appear to significantly impair LTD-like synaptic plasticity or interneuron recruitment.

Background: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach., Methods: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool., Discussion: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial., Trial Identifiers: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

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)., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth., Methods: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134., Findings: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I 2 =59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001)., Interpretation: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery., Funding: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)