Intrahepatic Cholestasis of Pregnancy and Neonatal Deliveries

A 29-year-old gravida −2 para 0 woman with dichorionic diamniotic twin gestation presented at 34 weeks’ gestation with a 5-day history of generalized pruritus that included her palms and soles. She has a past medical history of asthma and polycystic ovarian syndrome that was previously treated with metformin. Her pregnancy was notable for iron deficiency anemia. She had normal liver enzymes and total bile acid (TBA) level of 15.2 umol/L (nonpregnant normal level <10 umol/L). She was diagnosed with intrahepatic cholestasis of pregnancy (ICP) based on clinical and laboratory criteria. She was started on ursodiol 300 mg twice daily and diphenhydramine. Betamethasone was administered with a plan for induction. She subsequently presented at 35 weeks’ gestation in labor with premature rupture of membranes.The maternal patient had an uncomplicated spontaneous twin vaginal delivery.The maternal postpartum course was complicated by a postpartum hemorrhage from uterine atony, which was successfully treated with uterotonics. Following delivery, the obstetrical team discontinued ursodiol, and she was discharged on postpartum day 2.The twins were delivered at 35 weeks’ gestation without complications. Girl twin 1 had an Apgar score of 9 at 1 and 5 minutes of age and had a birthweight of 1820 g (10%). Girl twin 2 also had an Apgar score of 9 at 1 and 5 minutes of age and had a birthweight of 1930 g (15%). Both neonates were admitted to the neonatal intensive care unit and had unremarkable courses.A 33-year-old gravida 1 para 0 Honduran woman was admitted at 39 weeks’ gestation for induction of labor. Her prenatal history was unremarkable until 37 weeks’ gestation when she developed itching over her legs, forearms, and back. She was prescribed ursodiol 300 mg twice daily and Benadryl. Laboratory testing revealed normal liver function tests and normal TBA levels. One week later, her pruritus progressed and repeat bile acids increased to 7.8 umol/L on ursodiol and she was diagnosed with ICP. Two days later, she was admitted for induction for a category 2 tracing with variable decelerations.The labor induction progressed to a spontaneous vaginal delivery. The maternal postpartum period was uncomplicated.A vigorous full male was delivered via normal spontaneous vaginal delivery weighing 3470 g (70th percentile). The Apgar score was 7 and 9 at 1 and 5 minutes of age, respectively. He was initially tachycardic to 210 beats per minute. The infant was admitted to the neonatal intensive care unit and treated for chorioamnionitis with ampicillin and gentamicin; these were discontinued at 48 hours when the blood culture result was negative. The tachycardia resolved and the electrocardiogram was normal. The infant was discharged at 3 days of age without complications.ICP is a common finding among pregnant people with an incidence of 0.3%–2% and varies widely within ethnic groups.1,2 Northern Europeans, Latin Americans, South Asians, and indigenous Chileans have a higher incidence ranging up to 27%.1–3 ICP is the most common cause of liver dysfunction during pregnancy with a multifactorial etiology involving hormonal, genetic, and environmental factors.4Clinically, pruritus and an elevated serum TBA level are diagnostic.1,4 Pruritus typically starts in the second or third trimester, begins on the hands and feet, and occurs 3–4 weeks before the occurrence of abnormal TBA levels and development of transaminitis.3,4 Pruritus is typically worse at night and can progress to intense scratching resulting in dermatitis.2,3 Jaundice is a presenting finding in only 10%–15% of patients and, similar to pruritus, occurs before the elevated laboratory results.2,3 A clinical diagnosis of ICP can be made in pregnant persons with an unexplained pruritus without a rash without laboratory abnormalities.3 Other symptoms are uncommon, but affected pregnant persons can manifest with pale stools, dark urine, abdominal pain, and fatigue.2,4 Nonfasting levels of bile acids higher than 10 umol/L is the typical diagnostic cutoff threshold for laboratory diagnosis of ICP, although this threshold is based on limited data.3,5,6The exact pathophysiology of cholestasis has not been discerned. During pregnancy, a cholestatic effect on the liver occurs, which is attributed to the hormonal influences of both progesterone and estrogen resulting in altered hepatic transport protein expression and homeostasis.2,7 Additionally, genetic susceptibility for ICP is increased in patients with variations in the hepatic function genes involved in other liver disease, including intrahepatic familial cholestasis, cholelithiasis, and other hepatobiliary diseases; altered autosomal recessive genes found in this disorder include ABCB4, ABCB11, Farnesoid X receptor (FXR), and ATP8B1.8 The genes NR1H4/FXR, ABCC2, and NR1I2/pregnane X receptor have also been diagnosed as altered in ICP.8 Advanced age in the pregnant person, multiparity, multiple gestation, in vitro fertilization, vitamin D deficiency, and other nutritional deficiencies including selenium are environmental causes contributing to ICP.9Bile acids are composed of a 24-carbon steroid nucleus resulting from metabolic cholesterol metabolism and are hydrophobic.2,10 They are therefore conjugated to glycine or taurine and become water soluble.2 In cholestasis, bile is retained within hepatocytes and accumulates in the blood, resulting in elevated serum bile acids, primarily cholic and chenodeoxycholic acids.2 Usually, the ratio of chenodeoxycholic acid to cholic acid is higher in nonpregnant healthy women, but in ICP it is reversed and is typically a 3:1 ratio.2,10 Additionally, fetal bile acids are produced from 12 weeks of gestation and are normally cleared by the placenta.2 In ICP, bile acid levels are elevated in the pregnant person and induce a reverse gradient, causing bile acids to cross the placenta to the fetus with subsequent fetal risks of toxicity, particularly to the fetal myocardium.11 Moreover, preterm delivery in pregnant patients with ICP has been attributed to the direct vasoconstrictive vascular effect of taurocholic acid on the placenta and the increased expression and sensitivity of the oxytocin receptor to cholic acid.2,9In a large meta-analysis, Ovadia et al correlated the risk of perinatal adverse outcomes directly with TBA levels and found that fetal complications increase by 1%–2% for each micromole per liter of elevated TBA.5 Of note, pregnant persons with bile acid levels both less than 40 umol/L and in the range of 40–99 umol/L did not have a higher rate of stillbirth compared with that of the general population and between groups.5,12 However, TBA higher than 40 umol/L has been associated with increased fetal myocardial complications and mortality.5 Patients with TBA higher than 100 umol/L had a 10-fold increase in intrauterine fetal demise.5,10,12 Among all patients with ICP, there is a higher rate of iatrogenic preterm birth attributed, which may decrease the stillbirth rate among this stratification.5,12The pathophysiological mechanism of intrauterine fetal demise with elevated TBA levels has been explained by the toxicity of bile acids affecting the myocardium and resulting in fetal arrythmias.13 The fetal myocardial function in ICP has been studied with multiple cardiac measures, including the myocardial performance index, E/A wave ratio, and PR intervals.13 Overall, pregnant patients with severe ICP had a higher fetal myocardial performance index and a longer PR interval indicating cardiac dysfunction.13 However, a direct causative association of myocardial dysfunction to stillbirth is still lacking.13 Although not universal, fetal cardiac monitoring may be of benefit in ICP.1,6,14In addition to preterm birth and cardiac effects, additional neonatal complications in ICP include meconium-stained amniotic fluid and respiratory distress syndrome, which correlate with higher TBA levels in the pregnant person.1,5 Although preterm delivery is mostly iatrogenic, the risk of meconium passage is a direct effect of bile acids on gut motility.1,2,5 Similarly, bile acids have a direct toxic effect on the respiratory epithelium and altered surfactant production in animal models.2,10 Small for gestational age has not been consistently associated with cholestasis.1,5Ursodeoxycholic acid (ie, ursodiol) is the most common treatment for ICP.1,2 It is a tertiary bile acid, endogenously synthesized in the intestine by bacterial metabolism, and is both an anticholelithic because it decreases cholesterol synthesis, absorption, and hepatic secretion and a choleretic because it increases bile flow.2 Although no known pharmaceutical management, including ursodiol, is proven effective to prevent fetal demise or preterm delivery, it does reduce symptoms and TBA levels in the pregnant person.15Antepartum serum bile acid monitoring can be considered, particularly for patients with progressive symptoms, as the peak total bile salt level may influence delivery timing. Fetal monitoring has not been shown to prevent stillbirth; however, the Society of Maternal Fetal Medicine recommends that antenatal fetal surveillance with ICP begin at a gestational age when delivery can be considered if the fetal testing is abnormal.1Delivery of the placenta is typically curative of cholestasis and the only treatment to avoid the risk of fetal demise.1,5,6 The recommended timing of delivery is therefore dependent on bile acid levels, and usually a preterm delivery is not advised for bile acids under 40 umol/L1,3,5,6 (Table 1).Generally, ICP has been managed successfully with ursodiol, routine surveillance, and in moderate-to-severe cases with late preterm delivery. However, continued studies are required to elucidate optimal antenatal screening to prevent associated fetal myocardial dysfunction, fetal demise, preterm delivery, and associated neonatal complications.American Board of Pediatrics Neonatal–Perinatal Content SpecificationUnderstand maternal medical disorders and medications affecting the fetus and newborn infantRecognize prenatal fetal interventionsUnderstand the particulars of preterm birthin regards to intrahepatic cholestasisKnown biochemistry and metabolism issues regarding bilirubinUnderstand the particulars of cardiac arrythmias in regards to intrahepatic cholestasis