Elisabeth Wikstrom Shemer

Intrahepatic Cholestasis of Pregnancy and Associated Hepatobiliary Disease : A Population-Based Cohort Study

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. We aimed to estimate the risk of developing hepatobiliary disease in women with ICP and the odds of developing ICP in women with prevalent hepatobiliary disease. We analyzed data of women with births between 1973 and 2009 and registered in the Swedish Medical Birth Register. By linkage with the Swedish Patient Register, we identified 11,388 women with ICP who were matched to 113,893 women without this diagnosis. Diagnoses of preexisting or later hepatobiliary disease were obtained from the Patient Register. Main outcome measures were hazard ratios (HRs) for later hepatobiliary disease in women with ICP and odds ratios (ORs) for developing ICP in preexisting hepatobiliary disease. Risk estimates were calculated through Cox and logistic regression analyses. Women with ICP were more often diagnosed with later hepatobiliary disease (HR 2.62; 95% confidence interval [CI] 2.47‐2.77; increment at 1% per year), hepatitis C or chronic hepatitis (HR 4.16; 3.14‐5.51 and 5.96; 3.43‐10.33, respectively), fibrosis/cirrhosis (HR 5.11; 3.29‐7.96), gallstone disease or cholangitis (HR 2.72; 2.55‐2.91, and 4.22; 3.13‐5.69, respectively) as compared to women without ICP (P < 0.001 for all HRs). Later ICP was more common in women with prepregnancy hepatitis C (OR 5.76; 1.30‐25.44; P = 0.021), chronic hepatitis (OR 8.66; 1.05‐71.48; P = 0.045), and gallstone disease (OR 3.29; 2.02‐5.36; P < 0.0001). Conclusion: Women with ICP have substantially increased risk for later hepatobiliary disease. Beyond gallstone‐related morbidity we found a strong positive association between ICP and hepatitis C both before and after ICP diagnosis. Thus, we advocate testing for hepatitis C in women with ICP, in particular, since this potentially life‐threatening infection can be treated successfully in the majority of patients. (Hepatology 2013;58:1385–1391)

Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: A population-based cohort study

BACKGROUND & AIMS Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. It is associated with hepatobiliary diseases that might predispose to cancer and also with gestational diabetes and preeclampsia. In this study, we examined associations between ICP and cancer, and immune-mediated and cardiovascular diseases. METHODS By linking the Swedish Medical Birth Register and the Swedish Patient Register, we identified 11,388 women with ICP and 113,893 matched women without ICP who gave birth between 1973 and 2009. Diagnoses of cancer and immune-mediated and cardiovascular diseases both before and after delivery were obtained from the Patient Register. The main outcome measures were hazard ratios (HRs), calculated through Cox regression, for the indicated diseases after delivery. RESULTS ICP was not associated with later overall cancer (HR 1.07, 95% confidence interval [CI] 0.94-1.21), but it was associated with later liver and biliary tree cancer (HR 3.61, 95% CI 1.68-7.77, and 2.62, 95% CI 1.26-5.46, respectively). ICP was also associated with later immune-mediated diseases (HR 1.28, 95% CI 1.19-1.38), and specifically diabetes mellitus (HR 1.47, 95% CI 1.26-1.72), thyroid disease (HR 1.30, 95% CI 1.14-1.47), psoriasis (HR 1.27, 95% CI 1.07-1.51), inflammatory polyarthropathies (HR 1.32, 95% CI 1.11-1.58) and Crohns disease (HR 1.55, 95% CI 1.14-2.10), but not ulcerative colitis (HR 1.21, 95% CI 0.93-1.58). Women with ICP also had a small increased risk of later cardiovascular disease (HR 1.12, 95% CI 1.06-1.19). CONCLUSIONS Women with ICP have increased risk of later hepatobiliary cancer and immune-mediated and cardiovascular diseases.

Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy.

OBJECTIVE To describe the use of combined ursodeoxycholic acid (UDCA) and rifampicin treatment in intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN A questionnaire survey of 27 women with 28 affected pregnancies identified via the UK and International Obstetric Medicine forum. The clinical case notes of women with ICP treated with combined UDCA and rifampicin therapy were reviewed, and data regarding maternal and perinatal outcomes extracted. RESULTS Serum bile acids remained high whilst taking UDCA as monotherapy. In 14 pregnancies (54%) serum bile acids decreased following the introduction of rifampicin. In 10 pregnancies (38%), there was a 50% reduction in serum bile acids. There were no adverse effects reported with either drug. CONCLUSIONS This is the first report of the use of rifampicin in ICP. The data suggest that combined treatment with UDCA and rifampicin is an effective way of treating women with severe ICP who do not respond to treatment with UDCA alone.

Decreased 1,25-dihydroxy vitamin D levels in women with intrahepatic cholestasis of pregnancy

Objective. The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) involves impaired bile acid and estrogen/progesterone metabolism and excretion based on genetic and environmental factors. The role of vitamin D is undefined. Design. Observational study. Setting. Department of Obstetrics and Gynecology, Danderyd Hospital, Stockholm, Sweden. Population. Swedish. Method. We measured serum 1,25‐dihydroxy vitamin D3 (1,25‐D3) and parathormone in 22 women with ICP at presentation, in comparison with 11 healthy women at delivery. Results. ICP women had significantly (p = 0.0041) lower levels of 1,25‐D3 in serum (76.4 ± 23.1 vs. 112.0 ± 40 ng/L, mean ± SD), unrelated to serum bile acids. 1,25‐D3 levels were inversely correlated (p < 0.05) to meconium staining of amniotic fluid. Parathormone levels did not differ between ICP and healthy women. Conclusion. Lower 1,25‐D3 levels in ICP are inversely correlated by meconium staining, a major indicator of fetal distress. Our finding may have pathogenetic and clinical implications since vitamin D regulates steroid metabolism and 1,25‐D3 deficiency may impair fetal outcome.

Risks of emergency cesarean section and fetal asphyxia after induction of labor in intrahepatic cholestasis of pregnancy: a hospital-based retrospective cohort study.

OBJECTIVES Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy liver-specific disease. Induction of labor in gestational weeks 37-39 is commonly performed with the perspective to avoid the complication of stillbirth. We aimed to study whether this practice increases the risks of emergency cesarean section (CS) and fetal asphyxia. STUDY DESIGN We assessed the risk of emergency CS and fetal asphyxia in ICP among women with spontaneous and induced onset of labor in comparison to women without ICP. We performed a hospital based retrospective cohort study with 25,870 singleton pregnancies, 333 with ICP (1.3%), of which 231 gave birth in weeks 37-39. Obstetric outcome was assessed through linkage of the Swedish Medical Birth Registry and a local obstetrical database based on the patients medical files. MAIN OUTCOME MEASURE Risk for emergency CS; fetal asphyxia and postpartum hemorrhage. RESULTS The risk of emergency CS in ICP with spontaneous onset of labor (12.5%) did not differ from non ICP women with spontaneous onset of labor (9.3%; aOR, 1.33; 95% CI 0.60-2.96). When labor was induced, risk of emergency CS was significantly lower among women with ICP than among without ICP (aOR, 0.47; 95% CI 0.26-0.86). Exclusion of women with preeclampsia, gestational hypertension or diabetes mellitus did not alter the result. The risk for fetal asphyxia was not significantly associated with ICP status. CONCLUSION Induction of labor in women with ICP gestational weeks 37-39 did not increase the risks of emergency CS or fetal asphyxia.

Evaluation of stationary colposcope and the Gynocular, by the Swede score systematic colposcopic system in VIA positive women: a crossover randomized trial.

Objective This study aimed to evaluate cervical lesions by the Swede coloscopy system, histologic finding, liquid-based cytology, and human papillomavirus (HPV) in women who resulted positive for visual inspection of the cervix with acetic acid (VIA) by using a pocket-sized battery-driven colposcope, the Gynocular (Gynius AB, Sweden). Methods This study was a crossover, randomized clinical trial at the colposcopy clinic of Bangabandhu Sheikh Mujib Medical University in Dhaka, Bangladesh, with 540 VIA-positive women. Swede scores were obtained by the Gynocular and stationary colposcope, as well as samples for liquid-based cytology, HPV, and cervical biopsies. The Swede scores were compared against the histologic diagnosis and used as criterion standard. The percentage agreement and the κ statistic for the Gynocular and standard colposcope were also calculated. Results The Gynocular and stationary colposcope showed high agreement in Swede scores with a κ statistic of 0.998, P value of less than 0.0001, and no difference in detecting cervical lesions in biopsy. Biopsy detected cervical intraepithelial neoplasia (CIN) 2+ (CIN2, CIN3, and invasive cancer) in 38 (7%) of the women, whereas liquid-based cytology detected CIN2+ in 13 (2.5%) of the women. Forty-four (8.6%) women who were tested resulted positive for HPV; 20 (3.9%) women had HPV-16, 2 (0.4%) had HPV-18, and 22 (4.3%) had other high-risk HPV. Conclusions Our study showed that few VIA-positive women had CIN2+ lesions or HPV infection. Colposcopy by Swede score identified significantly more CIN2+ lesions than liquid-based cytology and could offer a more accurate screening and selection for immediate treatment of cervical lesions in low-resource settings.

Evaluation of the accuracy in detecting cervical lesions by nurses versus doctors using a stationary colposcope and Gynocular in a low-resource setting

Objectives Evaluation of the performance of VIA (visual inspection with acetic acid) trained nurses to learn colposcopy and the Swede score method to detect cervical lesions by using stationary colposcope or a portable, hand-held colposcope; the Gynocular, as compared to doctors. Design A crossover randomised clinical trial. Setting The Colposcopy Clinic of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Participants 932 women attending the clinic as either screening naïve for VIA screening (404) or women referred as VIA positive (528) from other VIA screening centres in the Dhaka region. Intervention VIA trained nurses were trained on-site in colposcopy and in the Swede score systematic colposcopy method. The Swede score grade cervical acetowhiteness, margins plus surface. vessel pattern, lesion size and iodine staining. The women were randomised to start the examination by either a stationary colposcope or the Gynocular. Swede scores were first obtained by a nurse and the same patient was equally evaluated by a doctor. Primary and secondary outcome measures Agreement between nurses and doctors in Swede scores was evaluated using the weighted κ statistic for the Gynocular and standard colposcope. The ability to predict CIN 2+ (CIN 2, CIN 3 and invasive cervical cancer) using Swede scores was evaluated using receiver-operating characteristic curves. Results The Swede scores obtained by nurses and doctors using the Gynocular and stationary colposcope showed high agreement with a κ statistic of 0.858 and 0.859, respectively, and no difference in detecting cervical lesions in biopsy. Biopsy detected CIN 2+ in 39 (4.2%) women. Conclusions Our study showed that VIA nurses can perform colposcopy. There was no significant differences compared to doctors in detecting cervical lesions by stationary colposcope or the Gynocular using the Swede score system. Swede scores obtained by nurses using the Gynocular could offer an accurate cervical diagnostic approach in low resource settings. Trial registration number ISRCTN53264564.