Maternal cholestasis during pregnancy programs metabolic disease in offspring

Abstract

The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.

The Metabolic Profile of Intrahepatic Cholestasis of Pregnancy Is Associated With Impaired Glucose Tolerance, Dyslipidemia, and Increased Fetal Growth

“…Despite no difference in maternal BMI or fetal birth weight, a recent study looking at the metabolic characteristics of 16-year-old offspring of women whose pregnancy was complicated by ICP (without GDM) reported sex-specific differences in BMI, fat distribution, cholesterol, and insulin resistance (19). There is mounting evidence to suggest that GDM increases the risk of the offspring of developing diabetes, obesity, and metabolic syndrome in later life (44,45).…”

“…There is also now increasing evidence to suggest accelerated fetal growth in pregnancy complicated by ICP (17) with reports of infants who are large for gestational age at birth (4,14). Although unconfirmed, it is possible that this may contribute to the metabolic changes reported in the adolescent offspring of cholestatic pregnancies (19).…”

Prenatal sensitization of a postnatal trigger for metabolic disease

“…Furthermore, the cholic acid-exposed, Western diet-fed female mice had a more severe obesogenic and diabetic phenotype than females born to cholestatic mothers but then fed a normal diet. Gene expression profiles obtained from the liver and white adipose tissues of these mice also showed an increased inflammatory response (8).…”

“…Papacleovoulou et al (8) demonstrated that the accelerated weight gain associated with a Western diet was markedly exacerbated by exposure to cholic acid during gestation in female mice. Furthermore, the cholic acid-exposed, Western diet-fed female mice had a more severe obesogenic and diabetic phenotype than females born to cholestatic mothers but then fed a normal diet.…”

Original Research: Metabolic alterations from early life thyroxine replacement therapy in male Ames dwarf mice are transient

“…For instance, birth weight has been linked to adult onset of several diseases such as cardiovascular disease and diabetes. 13,14 Further, maternal diabetes, 15 or cholestasis, 16 during pregnancy increases the offspring's risk of developing metabolic disorders. These examples of early life programming can only indirectly be utilized as a predictive marker of aging (i.e.…”