Factors predicting clinical outcomes from 494 vitrified oocyte donation cycles at a UK-regulated egg bank.

RESEARCH QUESTION: Do donor age, AMH, AFC, BMI and reproductive history predict response to ovarian stimulation? Do donor and recipient clinical markers and embryology parameters predict recipient pregnancy and live birth? DESIGN: Retrospective cohort study of 494 altruistic oocyte donors aged 18-35 years; 340 were matched to 559 recipients. Predictors of donor total oocyte yield and total mature oocyte yield were identified. Total and mature oocyte number were compared according to stratified donor AMH and age. Donor, recipient and embryology parameters predictive of recipient primary outcomes (clinical pregnancy and live birth) were identified. RESULTS: Donor age and AMH predicted total oocyte yield (P = 0.030 and P < 0.001)) and total mature oocyte yield (P = 0.011 and P < 0.001). Donors aged 30-35 years with AMH 15-29.9 pmol/l had lower total oocyte yield (P = 0.004) and mature oocyte yield (P < 0.001) than donors aged 18-24 years. Up to an AMH threshold of 39.9 pmol/l, increasing AMH levels predicted higher total oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.001; 15-29.9 pmol/l versus 30-39.9 pmol/l, P < 0.001; 30-39.9pmol/l versus ≥ 40 pmol/l, P = 1.0) and mature oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.005; 15-29.9 pmol/l versus 30-39.9 pmol/l, P = 0.006; 30-39.9 pmol/l versus ≥40 pmol/l, P = 1.0). In recipients, the rate of transferrable embryos per oocytes received, fertilized and number of embryo transfers needed to achieve the primary outcome were predictors of cumulative clinical pregnancy (P = 0.011, P = 0.017 and P < 0.001) and live birth (P = 0.008, P = 0.012 and P < 0.001) rates. Recipient BMI (P = 0.024) and previous miscarriages (P = 0.045) were predictors of cumulative live birth rate. Donor age 18-22 years was associated with a lower incidence of recipient clinical pregnancy (P = 0.004) and live birth (P = 0.001) after the first embryo transfer versus donor age 23-29 years. CONCLUSIONS: Donor age and AMH are independent predictors of oocyte yield. Raised recipient BMI and history of miscarriages reduce cumulative live birth rates, which may be increased by selecting donors aged 23-29 years, instead of younger donors.

Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated maternal circulating bile acid levels and associated dyslipidemia. ICP leads to accumulation of bile acids in the fetal compartment, and the elevated bile acid concentrations are associated with an increased risk of adverse fetal outcomes. The farnesoid X receptor agonist obeticholic acid (OCA) is efficient in the treatment of cholestatic conditions such as primary biliary cholangitis. We hypothesized that OCA administration during hypercholanemic pregnancy will improve maternal and fetal bile acid and lipid profiles. Female C57BL/6J mice were fed either a normal chow diet, a 0.5% cholic acid (CA)-supplemented diet, a 0.03% OCA-supplemented diet, or a 0.5% CA + 0.03% OCA-supplemented diet for 1 wk before mating and throughout pregnancy until euthanization on day 18. The effects of CA and OCA feeding on maternal and fetal morphometry, bile acid and lipid levels, and cecal microbiota were investigated. OCA administration during gestation did not alter the maternal or fetal body weight or organ morphometry. OCA treatment during hypercholanemic pregnancy reduced bile acid levels in the fetal compartment. However, fetal dyslipidemia was not reversed, and OCA did not impact maternal bile acid levels or dyslipidemia. In conclusion, OCA administration during gestation had no apparent detrimental impact on maternal or fetal morphometry and improved fetal hypercholanemia. Because high serum bile acid concentrations in ICP are associated with increased rates of adverse fetal outcomes, further investigations into the potential use of OCA during cholestatic gestation are warranted.NEW & NOTEWORTHY We used a mouse model of gestational hypercholanemia to investigate the use of obeticholic acid (OCA), a potent FXR agonist, as a treatment for the hypercholanemia of intrahepatic cholestasis of pregnancy (ICP). The results demonstrate that OCA can improve the fetal bile acid profile. This is relevant not only to women with ICP but also for women who become pregnant while receiving OCA treatment for other conditions such as primary biliary cholangitis and nonalcoholic steatohepatitis.

Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy.

Perturbations in the intrauterine environment can result in lifelong consequences for metabolic health during postnatal life. Intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease in adulthood, likely due to a combination of the effects of increased bile acids, maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Whereas ursodeoxycholic acid (UDCA) is a commonly used treatment for ICP, no studies have yet addressed whether it can also prevent the metabolic effects of ICP in the offspring and fetoplacental unit. We therefore analyzed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we showed that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. We therefore conclude that UDCA can be used as an intervention in pregnancy to reduce features of metabolic disease in the offspring of hypercholanemic mothers.

Paternal cholestasis exacerbates obesity-associated hypertension in male offspring but is prevented by paternal ursodeoxycholic acid treatment.

BACKGROUND: Obesity is a heterogeneous phenotype and risk associations to non-communicable diseases such as cardiovascular disease and type 2 diabetes are influenced by several factors. The paternal metabolic status at the time of conception influences offspring susceptibility to developing obesity and adiposity-associated cardiometabolic disease. Cholestatic liver diseases are characterized by raised circulating serum bile acid levels and dyslipidemia, and are commonly treated with ursodeoxycholic acid (UDCA). We hypothesized that paternal cholestasis alters offspring susceptibility to developing obesity and adiposity-associated cardiometabolic disease and that this may be modified by paternal UDCA treatment. METHODS: Cholestasis was induced in male C57BL/6 mice with a 0.5% cholic acid (CA)-supplemented diet for 10 weeks prior to mating with normal chow (NC)-fed females. Offspring of cholestatic and NC-fed fathers were fed either a NC diet or challenged with an obesogenic 'western diet' (WD) from 12 weeks of age. Offspring body weight and cardiometabolic function were assessed, and the impact of treatment of paternal cholestasis with UDCA was evaluated. RESULTS: Male offspring (18 weeks old) of cholestatic fathers challenged with WD had raised fasting insulin, hepatic triglyceride content and serum cholesterol levels compared to diet-matched controls. At 25-29 weeks of age, WD-fed male offspring of cholestatic fathers had higher systolic and diastolic blood pressure than controls and this was prevented by paternal UDCA treatment. In contrast, WD-challenged female offspring of cholestatic fathers showed improved glucose tolerance compared to controls. CONCLUSIONS: We demonstrated in our model of paternal cholestasis that offspring susceptibility to adiposity-associated cardiometabolic disease is affected in a sex-specific manner and paternal UDCA treatment had a protective effect against hypertension in the obese male offspring. The most prevalent human cholestatic conditions are primary sclerosing cholangitis and primary biliary cholangitis. These findings are of clinical relevance to children of men with these conditions.

Pregnancy and bile acid disorders.

During pregnancy, extensive adaptations in maternal metabolic and immunological physiology occur. Consequently, preexisting disease may be exacerbated or attenuated, and new disease susceptibility may be unmasked. Cholestatic diseases, characterized by a supraphysiological raise in bile acid levels, require careful monitoring during pregnancy. This review describes the latest advances in the knowledge of intrahepatic cholestasis of pregnancy (ICP), the most common bile acid disorder specific to pregnancy, with a focus on the disease etiology and potential mechanisms of ICP-associated adverse pregnancy outcomes, including fetal demise. The course of preexisting cholestatic conditions in pregnancy is considered, including primary sclerosing cholangitis, primary biliary cholangitis, biliary atresia, and Alagille syndrome. The currently accepted treatments for cholestasis in pregnancy and promising new therapeutics for the condition are described.