A Kenyon

Obstetric cholestasis, outcome with active management: a series of 70 cases

Objective To determine the nature and outcome of obstetric cholestasis in a United Kingdom population.

Longitudinal Profiles of 15 Serum Bile Acids in Patients With Intrahepatic Cholestasis of Pregnancy

OBJECTIVES:Increased maternal serum bile acids are implicated in intrahepatic cholestasis of pregnancy. Individual bile acid profiles and their relationship with disease progression, however, remain unknown. The purpose of this prospective study was to determine the temporal changes in bile acids in normal pregnancy and in pregnancies complicated with intrahepatic cholestasis of pregnancy and pruritus gravidarum.METHODS:A validated method for the evaluation of 15 bile acids (conjugated and unconjugated) in a single serum sample was developed using high-performance liquid chromatography/mass spectrometry (HPLC-MS) with an electrospray interface. Bile acid concentrations were assessed in samples (16 weeks of gestation to 4 weeks postpartum) from women with, or who later developed, intrahepatic cholestasis of pregnancy (n=63) and were compared with those from normal pregnant women (n=26) and from women with pruritus gravidarum (n=43).RESULTS:Intrahepatic cholestasis of pregnancy was associated with a predominant increase in cholic acid conjugated with taurine and glycine, from 24 weeks of pregnancy. Ursodeoxycholic acid (UDCA) treatment (≥21 days, n=15) significantly reduced serum taurocholic and taurodeoxycholic acid concentrations (P<0.01). Bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum.CONCLUSIONS:The bile acid profiles and effects of treatment by UDCA implicate a role for taurine-conjugated bile acids in the syndrome of intracranial pressure. With regard to individual bile acid profiles, pruritus gravidarum is a disorder quite distinct from intrahepatic cholestasis of pregnancy.

Plasma lipid profiles of women with intrahepatic cholestasis of pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy is associated with dyslipidemia, but the gestational lipid profile in relation to clinical diagnosis of the disease is unknown. The aim of this study was to undertake a detailed analysis of plasma lipids in women presenting with intrahepatic cholestasis of pregnancy and pruritus gravidarum. METHODS: Plasma lipid concentrations were assessed in nonfasting blood samples from 63 women with intrahepatic cholestasis of pregnancy (n = 54, recruited at the time of diagnosis, and n = 9, who later developed the disease), 43 women with pruritus gravidarum, and 26 healthy pregnant controls during pregnancy and at 4–6 weeks postpartum. RESULTS: Intrahepatic cholestasis of pregnancy was associated with an abnormal lipid profile. Low-density lipoprotein (LDL) cholesterol, apolipoprotein B-100, and total cholesterol concentrations were significantly raised during pregnancy in women with intrahepatic cholestasis of pregnancy compared with pruritus gravidarum and controls, and LDL-cholesterol was raised before clinical diagnosis. High-density lipoprotein cholesterol was lower in women with intrahepatic cholestasis of pregnancy compared with the pruritus gravidarum group. Ursodeoxycholic acid did not alter plasma lipid concentrations. CONCLUSION: Intrahepatic cholestasis is associated with dyslipidemia, which may contribute to the pathogenesis of the disease. The elevation of LDL cholesterol and reduction of high-density lipoprotein cholesterol before clinical diagnosis may prove to be a useful biomarker for the early identification of intrahepatic cholestasis of pregnancy and differentiation from pruritus gravidarum. LEVEL OF EVIDENCE: II-2

Glutathione S‐transferase and liver function in intrahepatic cholestasis of pregnancy and pruritus gravidarum

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy‐specific liver disease associated with poor maternal and fetal outcome. The diagnosis is based on pruritus with abnormal liver function in the absence of other pathological conditions. However, pruritus in pregnancy is common, and it may be the only presenting feature in ICP. No reliable test currently exists that can discriminate between those women destined to develop ICP and those with the benign condition of pruritus gravidarum (PG). The purpose of this prospective study was to investigate longitudinally the serum concentration of glutathione S‐transferase alpha (GSTA, a specific marker of hepatocellular integrity) and to compare this with the temporal profile of conventional liver function markers in women with ICP (n = 63), PG (n = 43), and normal pregnant controls (n = 26). Blood was sampled on at least 3 separate occasions between 16 weeks of gestation and 4 weeks postpartum. Serum concentrations of GSTA increased with gestation in ICP, being significantly higher from 24 (±2) weeks compared with controls (400% difference; 95% CI, 240%–734%; P < .001). GSTA was also higher in ICP versus PG (433% difference; 95% CI, 228%‐790%; P < .001) throughout the gestational period studied. Significant differences in the ICP compared with control and PG groups were also found for total bile acids, alanine aminotransferase, aspartate aminotransferase, γ‐glutamyl transpeptidase and alkaline phosphatase. In conclusion, the measurement of GSTA provides a test of liver dysfunction that distinguishes women with ICP from those with PG. Additionally, on the basis of this study, reference ranges for biochemical markers of liver function require reevaluation in pregnancy. (HEPATOLOGY 2004;40:1406–1414.)

Fetal fibronectin as a predictor of spontaneous preterm labour in asymptomatic women with a cervical cerclage

Objective  To assess the accuracy of fetal fibronectin (fFN) testing for prediction of preterm labour in asymptomatic high‐risk women with a cervical cerclage.

Dexamethasone in the treatment of obstetric cholestasis : A case series

Summary Twelve women with obstetric cholestasis were given dexamethasone after failure to respond to ursodeoxycholic acid. Clinical improvement was achieved in eight cases, without complete resolution of symptoms. Biochemical response was achieved in seven cases. All but two cases had good correlation between clinical and biochemical response. Women of Asian and South American origin were more likely to respond to dexamethasone than Caucasians. There were no reported maternal or fetal side-effects. However, the subsequent consequences of dexamethasone treatment for the mother and fetus have not been thoroughly evaluated. Therefore, even in Asian and South American women, larger studies of dexamethasone are required before this treatment can be recommended as a universally safe and effective treatment for obstetric cholestasis.

Metformin (alone or with insulin) was as effective as insulin for preventing perinatal complications in gestational diabetes

Source Citation Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358:2003-15. 18463376

Nondiabetic maternal hyperglycemia was associated with adverse pregnancy outcomes

Question Is nondiabetic maternal hyperglycemia diabetes associated with adverse pregnancy outcomes? Methods Design Cohort study (Hyperglycemia and Adverse Pregnancy Outcome [HAPO] study) with follow-up to delivery. Setting 15 centers in the US, Canada, Barbados, UK, the Netherlands, Israel, Thailand, Hong Kong, Singapore, and Australia. Patients 25505 women 18 years of age (mean age 29 y) who were pregnant with a singleton fetus of known gestational age and had an oral glucose tolerance test at 24 to 32 weeks of gestation. Exclusion criteria included previous glucose testing in the current pregnancy, diagnosis of diabetes before or during the current pregnancy, conception by fertility treatment, and infection with HIV or hepatitis B or C virus. Women were excluded after enrollment if they had a 2-hour plasma glucose level diagnostic of diabetes (>11.1 mmol/L [200 mg/dL]), fasting plasma glucose level >5.8 mmol/L (105 mg/dL), or other glucose results in an unsafe range (in which case, caregivers were provided with the results) (2.9% of women); had glucose testing or delivery outside the study (5.5%); or were missing key outcome data (0.1%). 23316 women were included in the analysis. Risk factors Fasting, 1-hour, and 2-hour plasma glucose levels (blinded). Outcomes Birthweight >90th percentile for gestational age, cord-blood serum C-peptide level >90th percentile, primary cesarean section, and clinical neonatal hypoglycemia. Main results Risk for each adverse outcome increased with increasing maternal glucose levels (Table). Frequencies in the lowest and highest categories, respectively, of fasting blood glucose were 5.3% and 26% for birthweight >90th percentile, 3.7% and 32% for cord-blood serum C-peptide level >90th percentile, 13% and 28% for primary cesarean section, and 2.1% and 4.6% for clinical neonatal hypoglycemia. Conclusion Maternal hyperglycemia that is less severe than that which is diagnostic of diabetes was associated with adverse pregnancy outcomes in a continuous manner with no obvious thresholds. Association between maternal glucose levels at mean 28 weeks of gestation and adverse pregnancy outcomes* Outcomes Odds ratio (95% CI) per 1 SD increase in glucose level Fasting plasma glucose 1-hour plasma glucose 2-hour plasma glucose Birthweight >90th percentile 1.38 (1.32 to 1.44) 1.46 (1.39 to 1.53) 1.38 (1.32 to 1.44) Cord-blood serum C-peptide >90th percentile 1.55 (1.47 to 1.64) 1.46 (1.38 to 1.54) 1.37 (1.30 to 1.44) Primary cesarean section 1.11 (1.06 to 1.15) 1.10 (1.06 to 1.15) 1.08 (1.03 to 1.12) Clinical neonatal hypoglycemia 1.08 (0.98 to 1.19) 1.13 (1.03 to 1.26) 1.10 (1.00 to 1.12) *SD = standard deviation. Odds ratios adjusted for multiple other risk factors. 1 SD for fasting plasma glucose =0.4 mmol/L (6.9 mg/dL); 1 SD for 1-h plasma glucose =1.7 mmol/L (31 mg/dL); 1 SD for 2-h plasma glucose =1.3 mmol/L (24 mg/dL). Commentary The 2003 UK National Institute for Health and Clinical Excellence (NICE) guideline for routine prenatal care stated that current evidence does not support routine screening for gestational diabetes. The basis of this statement was the uncertainty of glucose thresholds associated with morbidity and the lack of evidence of interventions to improve outcome. The randomized Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) subsequently showed that women with mild gestational diabetes (7.8 and <11.1 mmol/L 2 h after a 75-g glucose load) benefited from diagnosis and treatment, with a 67% reduction in serious perinatal complications (1). As a result of ACHOIS, the revised NICE guideline now recommends that women with risk factors be screened for diabetes using a 2-hour 75-g oral glucose tolerance test at 24 to 28 weeks of gestation (2). The resource implications of initiating this screening strategy and managing women thus diagnosed are great and will vary with different prenatal populations. Conversely, if screening is limited to women with risk factors, almost 40% of cases may be missed (3). Balancing the costs of screening everyone with the risk for missed cases when only high-risk women are screened has been the subject of debate. The HAPO study showed that complications arising from carbohydrate intolerance in pregnancy occur in a continuum, with no obvious threshold at which risks escalate. In 1999, the World Health Organization (WHO) widened its definition of gestational diabetes to include any woman meeting the criteria for impaired glucose tolerance or diabetes during pregnancy. The HAPO and ACHOIS studies considered women who would have been below the threshold for gestational diabetes using the former WHO definition, but would now be above the threshold. The ACHOIS authors justified this approach by arguing the need to include women with mild diabetes for whom clinical management was previously uncertain (1). Having gone some way to answer this question, we still need to determine what level of glucose should be considered normal. Although ACHOIS showed benefit with treatment, the absolute risk reduction was small: 34 women with gestational diabetes need to be treated to prevent 1 serious infant outcome (1). This benefit must be balanced against a higher risk for induced labor, more infants admitted to the special care baby unit, and no reduction in cesarean deliveries. These results have important health resource implications. The HAPO study reported cesarean section rates proportional to blood glucose levels. What is not clear is how to reduce caesarean sections in gestational diabetes. The MiG trial showed that metformin (plus insulin as needed) is as effective as insulin and, as has been shown for glibenclamide (2), may be more cost-effective than insulin for treating gestational diabetes. The reduction in weight gain with metformin may be of additional benefit in the long-term health of these women. It is reassuring that alternatives to daily injections are available and will likely be welcomed by pregnant women. The consequence of these studies will probably be that more women are screened and treated for gestational diabetes. ACHOIS provides reassurance that a diagnosis of gestational diabetes and its management are not associated with psychological morbidity (1). Although the HAPO and MiG studies contribute to our understanding of the diagnosis and management of gestational diabetes, changes in screening practices will still depend on local populations.

Cord liver function and bile acids in actively managed obstetric cholestasis (OC) are not abnormal

Obstetric cholestasis (OC) is associated with increased fetal morbidity and mortality. Active management (delivery by 38 weeks) may reduce this. Poor fetal outcome may be linked to high concentrations of bile acids in the maternal or fetal circulation. This study compared maternal and fetal liver function in a group of actively managed women with OC. Matched cord and maternal (day of delivery) serum was obtained from women with: (i) OC [n = 43, 16 ursodeoxycholic acid (UDCA)], (ii) pruritus gravidarum (PG, n = 28) and (iii) healthy controls (n = 9). Women with OC were delivered by 38 weeks; there were no stillbirths. Bile acids, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutathione S-transferase alpha 1-1 (GSTA1-1) were measured. Maternal liver function parameters were raised in OC and not reduced significantly by UDCA treatment (P = 0.748, 95% CI= 0.934–1.099). In OC, cord serum liver function values were no different to controls and PG. Cord serum ALT, AST and GSTA1-1 in OC were lower than the maternal serum. Cord serum bile acid concentrations (µm) in the OC group were 16.97 ± 1.13 and in maternal blood 18.57 ± 3.20 compared to 12.89 ± 1.00 and 7.24 ± 1.2 in PG and 15.99 ± 1.95 and 6.76 ± 0.96 in controls, respectively.