Interventions for treating cholestasis in pregnancy.

BACKGROUND: Obstetric cholestasis has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been empiric. The first version of this review, published in 2001, and including nine randomised controlled trials involving 227 women, concluded that there was insufficient evidence to recommend any of the interventions alone or in combination. This is the first update. OBJECTIVES: To evaluate the effectiveness and safety of therapeutic and delivery interventions in women with cholestasis of pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 February 2013) and reference lists of identified studies. SELECTION CRITERIA: Randomised controlled trials that compared two intervention strategies for women with a clinical diagnosis of obstetric cholestasis. DATA COLLECTION AND ANALYSIS: The review authors independently assessed trials for eligibility and risk of bias. We independently extracted data and checked these for accuracy. MAIN RESULTS: We included 21 trials with a total of 1197 women. They were mostly at moderate to high risk of bias. They assessed 11 different interventions resulting in 15 different comparisons.Compared with placebo, ursodeoxycholic acid (UDCA) showed improvement in pruritus in five (228 women) out of seven trials. There were no significant differences in instances of fetal distress in the UDCA groups compared with placebo (average risk ratio (RR) 0.67; 95% confidence interval (CI) 0.22 to 2.02; five trials, 304 women; random-effects analysis: T² = 0.74; I² = 48%). There were significantly fewer total preterm births with UDCA (RR 0.46; 95% CI 0.28 to 0.73; two trials, 179 women). The difference for spontaneous preterm births was not significant (RR 0.99; 95% CI 0.41 to 2.36, two trials, 109 women).Two trials (48 women) reported lower (better) pruritus scores for S-adenosylmethionine (SAMe) compared with placebo, while two other trials of 34 women reported no significant differences between groups.UDCA was more effective in improving pruritus than either SAMe (four trials; 133 women) or cholestyramine (one trial; 84 women), as was combined UDCA+SAMe when compared with placebo (one trial; 16 women) and SAMe alone (two trials; 68 women). However, combined UDCA+SAMe was no more effective than UDCA alone in regard to pruritus improvement (one trial; 53 women) and two trials (80 women) reported data were insufficient to draw any conclusions from. In one trial comparing UDCA and dexamethasone (83 women), a significant improvement with UDCA was seen only in a subgroup of women with severe obstetric cholestasis (23 women).Danxiaoling significantly improved pruritus in comparison to Yiganling. No significant differences were seen in pruritus improvement with other interventions.Eight trials reported fetal or neonatal deaths, with two deaths reported overall (both in the placebo groups).Women receiving UDCA and cholestyramine experienced nausea, vomiting and diarrhoea. Guar gum caused mild abdominal distress, diarrhoea and flatulence during the first days of treatment. Women found charcoal suspension unpleasant to swallow. Dexamethasone caused nausea, dizziness and stomach pain in one woman.One trial (62 women) looked at the timing of delivery intervention. There were no stillbirths or neonatal deaths in 'early delivery' or the 'await spontaneous labour' group. There were no significant differences in the rates of caesarean section, meconium passage or admission to neonatal intensive care unit between the two groups. AUTHORS' CONCLUSIONS: Different approaches to assessing and reporting pruritus precluded pooling of trials comparing the effects of UDCA versus placebo on pruritus, but examination of individual trials suggests that UDCA significantly improves pruritus, albeit by a small amount. Fewer instances of fetal distress/asphyxial events were seen in the UDCA groups when compared with placebo but the difference was not statistically significant. Large trials of UDCA to determine fetal benefits or risks are needed.A single trial was too small to rule in or out a clinically important effect of early term delivery on caesarean section.There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction (YCHD), Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy.

Pilot study for a trial of ursodeoxycholic acid and/or early delivery for obstetric cholestasis.

BACKGROUND: Obstetric cholestasis (OC) is a serious problem in pregnancy. It affects about 4500 women per year in the UK. Affected women develop itching and occasionally jaundice. More importantly, the condition is associated with premature delivery, fetal distress and is believed to be an important cause of stillbirth. However, even now, there is no clear evidence as to whether the most popular treatment, a drug called ursodeoxycholic acid is beneficial to the baby, or even if it is safe in pregnancy. Nor do we know whether planned early delivery of the baby at 37-38 weeks, another popular treatment, does more good than harm. A randomised trial to evaluate both ursodeoxycholic acid and timed delivery is needed but will be complicated and expensive. We plan a preliminary study, Pilot study for a trial of ursodeoxycholic acid and/or early delivery for obstetric cholestasis (Acronym PITCH- Pregnancy Intervention Trial in Cholestasis) trial, to evaluate the feasibility of a larger trial. The trial is funded by the NHS Research for Patient Benefit (RfPB) Programme. METHODS: PITCH is a multi-centre, double blinded, randomised, controlled, factorial design trial. The trial is being run in six UK centres and women with obstetric cholestasis will be recruited for eighteen months. In this pilot trial we aim to collect data to finalize the design for the main trial. This will include measuring trial recruitment rate, including recruitment to each factorial comparison separately. We will also measure the spectrum of disease among recruits and non-recruits and compliance with the four possible treatment allocations. We will use these data to design the main trial. DISCUSSION: The ultimate aim of the main trial is to enable clinicians to manage this condition more effectively. If it transpires that ursodeoxycholic acid and early delivery are both safe and effective then steps will be taken to ensure that all women with OC who could benefit from them receives this treatment. Conversely, if one or both the treatments turn out to be ineffective or even harmful, they will be stopped and researchers will work at developing other modes of treatment.

The reversed feto-maternal bile acid gradient in intrahepatic cholestasis of pregnancy is corrected by ursodeoxycholic acid.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.

Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial.

OBJECTIVES: To test whether ursodeoxycholic acid reduces pruritus in women with intrahepatic cholestasis of pregnancy, whether early term delivery does not increase the incidence of caesarean section, and the feasibility of recruiting women with intrahepatic cholestasis of pregnancy to trials of these interventions. DESIGN: First phase of a semifactorial randomised controlled trial. SETTING: Nine consultant led maternity units, United Kingdom. PARTICIPANTS: 125 women with intrahepatic cholestasis of pregnancy (pruritus and raised levels of serum bile acids) or pruritus and raised alanine transaminase levels (>100 IU/L) recruited after 24 weeks' gestation and followed until delivery. 56 women were randomised to ursodeoxycholic acid, 55 to placebo, 30 to early term delivery, and 32 to expectant management. INTERVENTIONS: Ursodeoxycholic acid 500 mg twice daily or placebo increased as necessary for symptomatic or biochemical improvement until delivery; early term delivery (induction or delivery started between 37+0 and 37+6) or expectant management (spontaneous labour awaited until 40 weeks' gestation or caesarean section undertaken by normal obstetric guidelines, usually after 39 weeks' gestation). MAIN OUTCOME MEASURES: The primary outcome for ursodeoxycholic acid was maternal itch (arithmetic mean of measures (100 mm visual analogue scale) of worst itch in past 24 hours) and for the timing of delivery was caesarean section. Secondary outcomes were other maternal and perinatal outcomes and recruitment rates. RESULTS: Ursodeoxycholic acid reduced itching by -16 mm (95% confidence interval -27 mm to -6 mm), less than the 30 mm difference prespecified by clinicians and women as clinically meaningful. 32% (14/44) of women randomised to ursodeoxycholic acid experienced a reduction in worst itching by at least 30 mm compared with 16% (6/37) randomised to placebo. The difference of 16% (95% confidence interval -3 to 34); this would represent a number needed to treat of 6, but it failed to reach significance. Early term delivery did not increase caesarean sections (7/30 (23%) in the early term delivery group versus 11/32 (33%) in the expectant management group (relative risk 0.70, 95% confidence interval 0.31 to 1.57). No serious harms were noted in either trial. 22% (73/325) of eligible women participated in the drug trial and 19% (39/209) in the timing of delivery trial; both groups had a similar spectrum of disease severity to non-participants. CONCLUSIONS: Ursodeoxycholic acid significantly reduces pruritus, but the size of the benefit may be too small for most doctors to recommend it, or for most women to want to take it. Women are, however, likely to differ in whether they consider the benefit to be worthwhile. Planned early term delivery seems not to increase incidence of caesarean section, although a small increase cannot be excluded. A trial to test whether ursodeoxycholic acid reduces adverse perinatal outcomes would have to be large, but is feasible. A trial to test the effect of early term delivery on adverse fetal outcomes would have to be significantly larger and may not be feasible. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37730443.

How accurate is symptomatic and clinical evaluation of prolapse prior to surgical repair?

The aim of this study is to assess the accuracy of pre-operative evaluation of pelvic organ prolapse. The design is a prospective observational audit set at the gynaecology department, Teaching Hospital, UK. The population is composed of patients undergoing surgery for prolapse. One hundred and four patients admitted for prolapse surgeries were enrolled in the audit. Patients' notes were initially reviewed for adequacy of prolapse assessment in the clinic. Patients were then interviewed by the researchers and assessed using a validated Prolapse Quality of Life (P-QOL) questionnaire. The presence of unrecorded symptoms was noted. Prolapse examination in theatre under anaesthesia was compared to the findings in the clinic and the operation performed compared to the proposed operation. The outcome measures were as follows: (1) number of patients who had accurate prolapse symptom assessment before surgery when comparing clinical records with entries on P-QOL questionnaires; (2) number of patients having symptoms related to their pelvic organ prolapse that were not accurately assessed pre-operatively; and (3) the differences, if any, between pre-operative and intra-operative examination of prolapse. Sixteen patients in our cohort (15%) had adequate assessment of their prolapse pre-operatively. Symptoms that were not adequately assessed in descending order were the impact of prolapse on quality of life (76%), sexual function (75%), bowel function (27%) and lower urinary tract symptoms (12.5%). Thirty one patients (30%) had sexual dysfunction, 24 (23%) had bowel symptoms and 23 patients (22%) had urinary symptoms that were not recorded before surgery. Prolapse physical examination was adequate in 59% of the cases. Examinations in theatre were different from clinic findings in 38 cases (37%); 16 cases (42%) had a greater or lesser degree of prolapse than that described in the notes; and 11 cases (29%) had prolapse in a different compartment in the vagina. A combination of both (i.e. different degree of prolapse and prolapse in a different vaginal compartment) was found in another 11 cases (29%). The operation performed was different from the one proposed in the clinic in 21% of the cases (n=22). Clinical evaluation and examination of patients with vaginal prolapse is often inadequate. Prolapse physical examination in a clinic setting could be different from findings under anaesthesia. This can affect the operation to repair the prolapse. Patients should be counselled about this when listed for surgery.