Atypical eclampsia in a normotensive patient with altered mental status and severely elevated transaminases: Case report and review.

Classically, pre-eclampsia and eclampsia are considered hypertensive disorders of pregnancy, and current diagnostic criteria include hypertension with proteinuria or other laboratory abnormalities or symptoms suggestive of end-organ damage. However, atypical presentations can occur in the absence of elevated blood pressures. We present the case of a pregnant patient who developed status epilepticus at 24 weeks and 4 days of gestation, followed by altered mental status and severely elevated transaminases. She had no elevated blood pressures during her prenatal care or hospital course. Following delivery, she experienced normalization of transaminase levels and a return to her baseline mental status. Pre-eclampsia and eclampsia can occur in the absence of elevated blood pressures, which highlights the limitations of using standard diagnostic criteria in normotensive patients with end-organ damage. In such cases, it is important to include pre-eclampsia and eclampsia in the differential diagnosis, as the diagnosis usually warrants preterm delivery to minimize maternal morbidity and mortality.

Hypertensive disorders of pregnancy and occurrence of ADHD, ASD, and epilepsy in the child: A meta-analysis.

AIM: To synthesize epidemiologic literature pertaining to the association between preeclampsia (PE), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. METHOD: A systematic search of PubMed and Embase was performed supplemented by hand-searching of reference lists of eligible studies. Two independent reviewers screened abstracts following a prepared protocol. Data extraction and quality appraisal using the Newcastle Ottawa Scale were performed by an independent reviewer. PRISMA guidelines were followed throughout. Random-effects meta-analyses were performed. Adjusted pooled Odds Ratios and their 95% confidence intervals were reported. RESULTS: Fifteen out of 121 identified studies were eligible for inclusion. Six reported adjusted estimates for ADHD, resulting in a pooled odds ratio of 1.29 (95% CI: 1.20, 1.38). Eight reported adjusted estimates for ASD, resulting in a pooled odds ratio of 1.27 (95% CI:1.22, 1.32). Three reported adjusted estimates for epilepsy, resulting in a pooled odds ratio of 1.35 (95% CI: 1.12, 1.63). INTERPRETATION: Intrauterine exposure to PE increased the risk of ADHD, ASD, and epilepsy, though it is unclear whether the true association is with pre-term birth. To our knowledge, this is the first meta-analysis to quantify the association between PE and epilepsy. The results of this meta-analysis can inform screening strategies among children born to preeclamptic mothers for early identification and treatment.

Metabolic factors associated with incident fracture among older adults with type 2 diabetes mellitus: a nested case-control study.

Older adults with type 2 diabetes mellitus have an increased risk of fracture despite a paradoxically higher average bone mineral density. This study identified additional markers of fracture risk in this at-risk population. Non-esterified fatty acids and the amino acids glutamine/glutamate and asparagine/aspartate were associated with incident fractures. PURPOSE: Type 2 diabetes mellitus (T2D) is associated with an increased risk of fracture despite a paradoxically higher bone mineral density. Additional markers of fracture risk are needed to identify at-risk individuals. METHOD: The MURDOCK study is an ongoing study, initiated in 2007, of residents in central North Carolina. At enrollment, participants completed health questionnaires and provided biospecimen samples. In this nested case-control analysis, incident fractures among adults with T2D, age ≥ 50 years, were identified by self-report and electronic medical record query. Fracture cases were matched 1:2 by age, gender, race/ethnicity, and BMI to those without incident fracture. Stored sera were analyzed for conventional metabolites and targeted metabolomics (amino acids and acylcarnitines). The association between incident fracture and metabolic profile was assessed using conditional logistic regression, controlled for multiple confounders including tobacco and alcohol use, medical comorbidities, and medications. RESULTS: 107 incident fractures were identified with 210 matched controls. Targeted metabolomics analysis included 2 amino acid factors, consisting of: 1) the branched chain amino acids, phenylalanine and tyrosine; and 2) glutamine/glutamate, asparagine/aspartate, arginine, and serine [E/QD/NRS]. After controlling for multiple risk factors, E/QD/NRS was significantly associated with incident fracture (OR 2.50, 95% CI: 1.36-4.63). Non-esterified fatty acids were associated with lower odds of fracture (OR 0.17, 95% CI: 0.03-0.87). There were no associations with fracture among other conventional metabolites, acylcarnitine factors, nor the other amino acid factors. CONCLUSION: Our results indicate novel biomarkers, and suggest potential mechanisms, of fracture risk among older adults with T2D.

Postpartum Glucose Tolerance Testing Among Patients With Gestational Diabetes During the Coronavirus Disease 2019 Pandemic.

Introduction The impact of the coronavirus disease (COVID-19) COVID-19 pandemic on the care of pregnant patients with gestational diabetes (GDM) is largely unreported. The objective of this study was to compare the completion of postpartum oral glucose tolerance testing (GTT) prior to and during the COVID-19 pandemic among patients with GDM. Methods This was a retrospective review of patients diagnosed with GDM between April 2019 and March 2021. Medical records of patients diagnosed with GDM prior to and during the pandemic were compared. The primary outcome was the difference in the completion of postpartum GTT prior to and during the COVID-19 pandemic. Completion was defined as testing between four weeks to six months postpartum. Secondary objectives were: 1) to compare maternal and neonatal outcomes prior to and during the pandemic among patients with GDM, and 2) to compare pregnancy characteristics and outcomes by compliance with postpartum GTT. Results There were 185 patients included in the study, of whom 83 (44.9%) delivered prior to the pandemic and 102 (55.1%) delivered during the pandemic. There was no difference in completion of postpartum diabetes testing prior, compared to during the pandemic (27.7% vs 33.3%, p=0.47). Postpartum diagnosis of pre-diabetes and type two diabetes mellitus (T2DM) did not differ between groups (p=0.36 and p=1.00, respectively). Patients who completed postpartum testing were less likely to have preeclampsia with severe features compared to patients who did not (OR 0.08, 95% CI 0.01-0.96, p=0.02). Conclusion Completion of postpartum testing for T2DM remained poor prior to and during the COVID-19 pandemic. These findings underscore the need for the adoption of more accessible methods of postpartum testing for T2DM among patients with GDM.

An Ethical Argument for Health Insurance Coverage of Paternal Prenatal Genetic Testing.

Despite evidence-based recommendations from the American College of Obstetricians and Gynecologists and the American College of Medical Genetics to offer prenatal genetic carrier screening for reproductive partners, partner carrier screening or genetic testing is inconsistently covered by pregnant patients' health insurance plans. Health policies that exclude reproductive partners from insurance coverage for prenatal carrier screening or genetic testing contradict multiple ethical principles and can even contribute to adverse maternal-child health outcomes. Incomplete or missing information regarding partner carrier status can lead to costly, invasive, and potentially risky interventions for the pregnant patient that can be avoided by a simple and less expensive blood test in the reproductive partner. Lack of information regarding carrier status also harms the neonate by obviating an opportunity for early detection and treatment of potential medical complications. Insurance policies that exclude coverage for paternal genetic testing perpetuate the disproportionate burdens of pregnancy care and risk shouldered by pregnant people. To rectify these ethical dilemmas, partner carrier screening and genetic testing should be considered and covered as routine components of obstetric health care that are covered by health insurance.

Racial and ethnic disparity in characteristics and outcomes of women with placenta accreta spectrum: a comparative study.

Placenta accreta spectrum (PAS) refers to the spectrum of diagnoses involving abnormally and morbidly adherent trophoblastic tissue to the gravid uterus. These disorders are associated with significant maternal morbidity and mortality. While race/ethnicity is known to impact pregnancy outcomes, racial disparities have not been previously examined in women with PAS. The objective of current study was to compare patient characteristics and perioperative outcomes of women with PAS who underwent cesarean delivery across race/ethnicity. This is a comparative study that retrospectively queried the National Inpatient Sample, a hospital-based inpatient database in the USA. The study cohort was women diagnosed with PAS who underwent cesarean delivery from 10/2015 to 12/2018. The exposure group was race/ethnicity. Main outcomes were (i) patient/pregnancy characteristics and (ii) surgical morbidity for cesarean delivery, assessed in multivariable analysis. A total of 10,535 women comprised the study cohort (White n = 5,230 [49.6%], Black n = 2,045 [19.4%], Hispanic n = 2,540 [24.1%], and Asian n = 720 [6.8%]). Patient demographics, pregnancy characteristics, and hospital factors for the non-White groups significantly differed compared to the White group. Older age, obesity, diabetes, placenta previa, percreta, non-elective surgery, lower median household income, and Medicaid particularly represented the non-White groups. When perioperative outcomes were compared, non-White women were more likely to have any measured complications, hemorrhage/transfusion, and shock/coagulopathy compared to White women. Various sensitivity analyses redemonstrated the main cohort results. In conclusion, this study suggests that there were significant disparities in patient characteristics and outcomes of women with PAS across race/ethnicity.

Diabetes is associated with a lower minimum moment of inertia among older women: An analysis of 3D reconstructions of clinical CT scans.

Hip fractures are a significant burden on the aging population, often resulting in reduced mobility, loss of independence, and elevated risk of mortality. While fracture risk is generally inversely related to bone mineral density (BMD), people with diabetes suffer a higher fracture rate despite having a higher BMD. To better understand the connection between diabetes and fracture risk, we developed a method to measure the minimum moment of inertia (mMOI; a geometric factor associated with fracture risk) from clinical CT scans of the pelvis. Since hip fractures are more prevalent in women, we focused on females in this study. We hypothesized that females with diabetes would have a lower mMOI along the femoral neck than those without diabetes, indicative of a higher fracture risk. Three-dimensional models of each hip were created from clinical CT scans of 40 older women (27 with diabetes: 10 fracture/17 non-fractured; 13 without diabetes: non-fractured controls). The mMOI of each hip (n = 80) was reported as the average from three trials. People with diabetes had an 18% lower mMOI as compared to those without diabetes after adjusting for age and BMI (p = 0.02). No differences in the mMOIs between the fractured and contralateral hips in the diabetic group were observed (p = 0.78). Similarly, no differences were observed between the fractured and non-fractured hips of people with diabetes (p = 0.29) when accounting for age and BMI. This suggests structural differences in the hips of individuals with diabetes (measured by the mMOI) may be associated with their elevated fracture risk.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

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.

Perinatal death by bile acid levels in intrahepatic cholestasis of pregnancy: a systematic review.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is characterized by the elevation of total bile acids (TBAs). The primary concern in women with ICP is the increased risk of stillbirth. ICP is generally considered as "mild" when TBA levels range from 10 to 39 µmol/L and "severe" with levels greater than 40 µmol/L, although levels of TBA ≥100 µmol/L have been also considered as a further threshold of severity. OBJECTIVE: To quantify the association between different severities of ICP (TBA 10-39, 40-99, and ≥100 µmol/L) and perinatal death. DATA SOURCES: Medline, Embase, Scopus, Web of Sciences, and ClinicalTrial.gov were searched from the inception of each database to February 2019. METHODS OF STUDY SELECTION: Randomized, cohort, case-control, or case series studies reporting maternal and perinatal outcomes on women with ICP by the three prespecified TBA levels (10-39, 40-99, and ≥100 µmol/L) were included. We excluded multiple gestations and trials which included an intervention. The analysis was performed with Pearson chi-square and Fisher's exact test as appropriate. Continuous outcomes were compared using metaregression with inverse variance weighting using reported sample sizes and standard deviations. Pairwise comparisons used a Bonferroni correction to control for multiple testing. TABULATION, INTEGRATION, AND RESULTS: Six articles including 1280 singleton pregnancies affected by ICP were included in the systematic review. Out of the 1280 singleton pregnancies affected by ICP included, 118 had ICP with TBA ≥100 µmol/L. Perinatal death was more common in women with TBA ≥100 µmol/L (0.4% for TBA 10-39 µmol/L versus 0.3% for TBA 40-99 µmol/L versus 6.8% for TBA ≥ 100 µmol/L, p < .0001). Of the 8 perinatal deaths in the TBA ≥100 µmol/L group, 3 occurred ≥34 weeks. TBA ≥100 µmol/L increased the risk of spontaneous preterm birth (PTB) (5.4% versus 8.6% versus 18.2% respectively, p < .0001) and iatrogenic PTB (10.8% versus 21.6% versus 35.8% respectively, p<.0001) as well as meconium-stained amniotic fluid (9.0% versus 18.4% versus 31.6% respectively, p < .0001). CONCLUSIONS: Maternal TBA ≥100 µmol/L is associated with a 6.8% incidence of perinatal death, most of which (5.9% overall) are stillbirths, while TBA <100 µmol/L are associated with an incidence of perinatal death of 0.3%. It may be reasonable to consider late preterm delivery (at about 35-36 weeks) in women with TBA ≥100 µmol/L.

Society for Maternal-Fetal Medicine Consult Series #53: Intrahepatic cholestasis of pregnancy: Replaces Consult #13, April 2011.

Intrahepatic cholestasis of pregnancy is a hepatic disorder characterized by pruritus and an elevation in serum bile acid levels. Although intrahepatic cholestasis of pregnancy poses little risk for women, this condition carries a significant risk for the fetus, including complications such as preterm delivery, meconium-stained amniotic fluid, and stillbirth. The purpose of this Consult is to review the current literature on intrahepatic cholestasis of pregnancy and provide recommendations based on the available evidence. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we recommend measurement of serum bile acid and liver transaminase levels in patients with suspected intrahepatic cholestasis of pregnancy (GRADE 1B); (2) we recommend that ursodeoxycholic acid be used as the first-line agent for the treatment of maternal symptoms of intrahepatic cholestasis of pregnancy (GRADE 1A); (3) we suggest that patients with a diagnosis of intrahepatic cholestasis of pregnancy begin antenatal fetal surveillance at a gestational age when delivery would be performed in response to abnormal fetal testing results or at the time of diagnosis if the diagnosis is made later in gestation (GRADE 2C); (4) we recommend that patients with total bile acid levels of ≥100 µmol/L be offered delivery at 36 0/7 weeks of gestation, given that the risk of stillbirth increases substantially around this gestational age (GRADE 1B); (5) we recommend delivery between 36 0/7 and 39 0/7 weeks of gestation for patients with intrahepatic cholestasis of pregnancy and total bile acid levels of <100 µmol/L (GRADE 1C); (6) we recommend administration of antenatal corticosteroids for fetal lung maturity for patients delivering before 37 0/7 weeks of gestation if not previously administered (GRADE 1A); (7) we recommend against preterm delivery at <37 weeks of gestation in patients with a clinical diagnosis of intrahepatic cholestasis of pregnancy without laboratory confirmation of elevated bile acid levels (GRADE 1B).

Neonatal hypoglycemia after initiation of late preterm antenatal corticosteroids.

OBJECTIVE: To compare the frequency and severity of neonatal hypoglycemia in pregnancies treated with and without late preterm antenatal corticosteroids. STUDY DESIGN: We conducted a retrospective cohort study of late preterm deliveries at LAC + USC (2015-2018). Neonatal outcomes were compared between pregnancies treated with and without corticosteroids. RESULTS: 93 pregnancies (39.9%) received corticosteroids and 140 (60.1%) did not. Neonates born to women given corticosteroids were more likely to be hypoglycemic (47.3 vs. 29.3%, ORadj 2.25, padj = 0.01). The mean initial glucose (45.6 mg/dL vs. 51.9 mg/dL, p = 0.01) and glucose nadir (39.1 mg/dL vs. 45.4 mg/dL, p < 0.001) were significantly lower if the neonates received corticosteroids. Neonates admitted to the NICU solely for hypoglycemia were more likely to be born to women treated with corticosteroids (ORadj 4.71, padj = 0.01). CONCLUSION: Administration of late preterm corticosteroids was associated with an increased incidence and severity of neonatal hypoglycemia.

Multidrug Therapy for Refractory Immune Thrombocytopenia in Pregnancy.

BACKGROUND: Severe immune thrombocytopenia complicating pregnancy may require treatment beyond first-line medications (intravenous immunoglobulins or corticosteroids), but there is a paucity of literature on the use of such second-line agents in pregnancy. CASE: The patient is a 29-year-old woman with early-onset severe immune thrombocytopenia at 13 weeks of gestation. Maternal platelet counts reached a nadir of less than 5×10/L. The thrombocytopenia persisted despite first-line medications. Romiplostim, rituximab, and azathioprine were added to the therapeutic regimen. Platelet counts eventually stabilized at greater than 150×10/L before delivery. After delivery at term, the neonate had transient B-cell suppression, which was presumed to be secondary to rituximab, but was otherwise doing well and meeting all milestones at 7 months of age. CONCLUSION: The addition of second-line agents was associated with sustained elevation in maternal platelet counts and may have obviated the need for splenectomy.

Acetylcholinesterase Inhibitors Are Associated with Reduced Fracture Risk among Older Veterans with Dementia.

Acetylcholinesterase inhibitors (AChEIs) have been noted to increase bone density and quality in mice. Human studies are limited but suggest an association with improved bone healing after hip fracture. We examined the relationship between AChEI use and fracture risk in a national cohort of 360,015 male veterans aged 65 to 99 years with dementia but without prior fracture using Veterans Affairs (VA) hospital, Medicare, and pharmacy records from 2000 to 2010. Diagnosis of dementia, any clinical fracture (excluding facial and digital), comorbidities, and medications were identified using ICD-9 and drug class codes. Cox proportional hazard models considering AChEI use as a time-varying covariate and adjusting for fall and fracture risk factors compared the time-to-fracture in AChEI users versus non-AChEI users. Potential confounders included demographics (age, race, body mass index), comorbidities associated with fracture or falls (diabetes, lung disease, stroke, Parkinson's, seizures, etc.) and medications associated with fracture or falls (bisphosphonates, glucocorticoids, androgen deprivation therapy [ADT], proton pump inhibitors [PPIs], selective serotonin receptor inhibitors [SSRIs], etc.). Competing mortality risk was considered using the methods of Fine and Gray. To account for persistent effects on bone density or quality that might confer protection after stopping the medication, we completed a secondary analysis using the medication possession ratio (MPR) as a continuous variable in logistic regression models and also compared MPR increments of 10% to minimal/no use (MPR 0 to <0.10). Among older veterans with diagnosis of dementia, 20.1% suffered a fracture over an average of 4.6 years of follow-up. Overall, 42.3% of the cohort were prescribed AChEIs during the study period. The hazard of any fracture among AChEI users compared with those on other/no dementia medications was significantly lower in fully adjusted models (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.75-0.88). After considering competing mortality risk, fracture risk remained 18% lower in veterans using AChEIs (HR = 0.82; 95% CI 0.76-0.89). © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Glycemic Control and Insulin Treatment Alter Fracture Risk in Older Men With Type 2 Diabetes Mellitus.

Diabetes mellitus among older men has been associated with increased bone mineral density but paradoxically increased fracture risk. Given the interactions among medication treatment, glycemic control, and diabetes-associated comorbidities, the relative effects of each factor remains unclear. This retrospective study includes 652,901 male veterans aged ≥65 years with diabetes and baseline hemoglobin A1c (HbA1c) value. All subjects received primary care in the Veterans Health Administration (VHA) from 2000 to 2010. Administrative data included ICD9 diagnoses and pharmacy records and was linked to Medicare fee-for-service data. Hazard ratios (HR) for any clinical fracture and hip fracture were calculated using competing risk hazards models, adjusted for fracture risk factors including age, race/ethnicity, body mass index (BMI), alcohol and tobacco use, rheumatoid arthritis, corticosteroid use, as well as diabetes-related comorbidities including cardiovascular disease, chronic kidney disease, and peripheral neuropathy. HbA1c <6.5% was associated with a higher risk of any clinical fracture (HR = 1.08, 95% confidence interval [CI] 1.06-1.11) compared with the reference HbA1c of 7.5% to 8.5%. Fracture risk was not increased among those with A1c ≥8.5%, nor among those with A1c 6.5% to 7.5%. Use of insulin was independently associated with greater risk of fracture (HR = 1.10, 95% CI 1.07-1.12). There was a significant interaction between insulin use and HbA1c level, (p < 0.001), such that those using insulin with HbA1c <6.5% had HR = 1.23 and those with HbA1c 6.5% to 7.5% had HR = 1.15. Metformin use was associated with decreased fracture risk (HR = 0.88, 95% CI 0.87-0.90). We conclude that among older men with diabetes, those with HbA1c lower than 6.5% are at increased risk for any clinical and hip fracture. Insulin use is associated with higher fracture risk, especially among those with tight glycemic control. Our findings demonstrate the importance of the treatment regimen and avoiding hypoglycemia for fracture prevention in older men with diabetes. © 2019 American Society for Bone and Mineral Research.

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.

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]; I2=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.

Clinical Fractures Among Older Men With Diabetes Are Mediated by Diabetic Complications.

Introduction: Type 2 diabetes mellitus among older women has been associated with increased bone mineral density, but paradoxically with increased fracture risk. Findings among older men have varied, and potential mechanisms have not been fully elucidated. Methods: A retrospective study of male veterans 65 to 99 years of age who received primary care in the Veterans Health Administration from 2000 to 2010, using administrative data from all 146 Veterans Health Administration medical centers linked to Centers for Medicare and Medicaid Services Medicare fee-for-service data. Potential mediating factors of the diabetes-associated risk were evaluated using negative binomial regression models with the outcomes of any clinical fracture and hip fracture. Results: Of 2,798,309 Veterans included in the cohort, 900,402 (32.3%) had a diagnosis of diabetes. After adjusting for age, race, ethnicity, body mass index, alcohol and tobacco use, rheumatoid arthritis, and corticosteroid use, the risk of any clinical fracture associated with diabetes was 1.22 (95% confidence interval, 1.21 to 1.23) and that of hip fracture was 1.21 (95% confidence interval, 1.19 to 1.23). Significant mediating factors included peripheral neuropathy, cardiovascular disease, and congestive heart failure, with 45.5% of the diabetes-associated fracture risk explained by these diagnoses. Conclusions: Older male Veterans with diabetes have a 22% increased risk of incident clinical fracture compared with those without. A significant portion of this risk is explained by diabetes-related comorbidities, specifically peripheral neuropathy and congestive heart failure. Identification of these mediating factors suggests possible mechanisms, as well as potential interventions.