Pruritus (Cholestasis) of Pregnancy Case File

Pruritus (Cholestasis) of Pregnancy Case File

Eugene C. Toy, MD, Patti Jayne Ross, MD, Benton Baker III, MD, John C. Jennings, MD

CASE 14

A 24-year-old G1P0 woman at 28 weeks’ gestation complains o a 2-week duration o generalized pruritus. She denies rashes, exposures to insects, or allergies. Her medications include prenatal vitamins and iron supplementation. On examination, her blood pressure (BP) is 100/60 mm Hg, heart rate (HR) is 80 beats per minute (bpm), and weight is 140 lb. She is anicteric. The skin is without rashes. The etal heart tones are in the range o 140 bpm. The patient says the itching is intense and she cannot sleep at night.

» What is the most likely diagnosis?

» What is the best treatment or this condition?

» What is the best management o the pregnancy?

ANSWER TO CASE 14:

Pruritus (Cholestasis) of Pregnancy                                        

Summary: A 24-year-old G1P0 at 28 weeks’ gestation complains of a 2-week duration of generalized pruritus. She is anicteric and normotensive. The skin is without rashes. The fetal heart tones are in the range of 140 bpm.

• Most likely diagnosis: Intrahepatic cholestasis of pregnancy (ICP).
• Best treatment: Ursodeoxycholic acid (UDCA).
• Management of the pregnancy: Fetal testing such as a biophysical profile once a week with consideration of delivery at 37 to 38 weeks due to the increased risk of stillbirth associated with ICP.

ANALYSIS

Objectives

1. Know the differential diagnosis of pruritus in pregnancy.
2. Understand the clinical presentation of intrahepatic cholestasis of pregnancy.
3. Know that the first line of treatment of cholestasis of pregnancy is ursodeoxycholic acid.
4. Be aware of the increased risk of stillbirth with ICP, and the rationale for fetal testing.

Considerations

This 24-year-old woman, who is at 28 weeks’ gestational age, complains of generalized pruritus in the absence of a rash, which is consistent with ICP. The diffuse location of the itching and lack of rash makes a contact dermatitis unlikely. Another cause of pruritus unique to pregnancy is pruritic urticarial papules and plaques of pregnancy (PUPPP), which are erythematous papules and hives beginning in the abdominal area and often spreading to the buttocks. This is unlikely, as the patient does not have a rash. This patient’s clinical picture does not resemble herpes gestationis, a condition causing intense itching but associated with erythematous blisters on the abdomen and extremities. Thus, the most likely etiology in this case is intrahepatic cholestasis, a process in which bile salts are incompletely cleared by the liver, accumulate in the body, and are deposited in the dermis, causing pruritus. This disorder usually begins in the third trimester. There are no associated skin rashes, other than excoriations from patient scratching. The diagnosis is one of exclusion, but serum bile acid levels are usually elevated. Oral UDCA is the treatment of choice, which decreases total serum bile acid levels and help to relieve the itching. Fetal testing such as biophysical profile or nonstress test examinations are usually started, with the plan for early delivery such as between 37 and 38 weeks’ gestation due to the increased risk of stillbirth.

APPROACH TO:

Pruritus in Pregnancy                                                  

DEFINITIONS

INTRAHEPATIC CHOLESTASIS OF PREGNANCY (ICP): Intrahepatic cholestasis of unknown etiology in pregnancy whereby the patient usually complains of pruritus with or without jaundice and no skin rash.

PRURITIC URTICARIAL PAPULES AND PLAQUES OF PREGNANCY (PUPPP): A common skin condition of unknown etiology unique to pregnancy characterized by intense pruritus and erythematous papules on the abdomen and extremities.

HERPES GESTATIONIS: Rare skin condition only seen in pregnancy; it is characterized by intense itching and vesicles on the abdomen and extremities.

FETAL TESTING: Examinations such as biophysical profile, nonstress tests, and umbilical Doppler velocity testing to assess the health of the fetus (likelihood of fetal death, usually within 1 week).

CLINICAL APPROACH

Intrahepatic Cholestasis of Pregnancy

Pruritus in pregnancy may be caused by many disorders, of which one of the most common is intrahepatic cholestasis of pregnancy (ICP), a condition that usually begins in the third trimester. It begins as mild pruritus without lesions, usually at night, and gradually increases in severity. The itching is usually more severe on the extremities than on the trunk, with predilection for the palms and soles. It may recur in subsequent pregnancies and with the ingestion of oral contraceptives, suggesting a hormone-related pathogenesis. The disease is common in some ethnic populations such as Swedes and Chileans, suggesting a genetic basis for the disease process. Approximately 15% are associated with adenosine triphosphate binding cassette gene, which transports phospholipids across hepatocyte membranes. Thus, a family history of ICP may suggest this defect.

Increased levels of circulating bile acids can help to confirm the diagnosis, but ICP is a clinical diagnosis. Elevated liver function tests can be seen and there are no hepatic sequelae in the mother. ICP is associated with significant adverse risk for the fetus, such as spontaneous preterm birth, meconium stained amniotic fluid and stillbirth. The risk of fetal demise and adverse fetal outcomes increases with higher bile acid concentrations and increasing gestational age. There is also an increased incidence of gallstones associated with the pruritus of pregnancy. The first line of treatment for ICP is a synthetic bile acid, ursodeoxycholic acid (UDCA). It reduces circulating bile acid in mother and baby. It improves pruritus in mother and reduces the risk of preterm labor, nonreassuring fetal status and respiratory depression in the baby. Other treatments for ICP include antihistamines, cornstarch baths, and cholestyramine (a bile salt binder). There is not complete agreement about the management of the pregnancy, but many practitioners will utilize weekly fetal testing such as biophysical profile, and delivery at 37 weeks to try to prevent stillbirth. Cholestasis of pregnancy must be distinguished from viral hepatitis and other causes of pruritus or liver disease. Women with a history of ICP may have a recurrence of cholestasis and pruritus with the use of oral contraceptives or other estrogen containing medications; alternative contraception should be recommended.

Herpes gestationis, which has no relationship to herpes simplex virus, is a pruritic bullous disease of the skin. It usually begins in the second trimester of pregnancy and the reported incidence is less than 1 in 1000 pregnancies. The etiology is thought to be autoimmune related. The presence of IgG autoantibody directed at the basement membrane has been demonstrated and may result in activation of the classic complement pathway by autoantibodies directed against the basement membrane zone. The clinical features are characterized by intense pruritus followed by extensive patches of cutaneous erythema and subsequent formation of small vesicles and tense bullae. The limbs are affected more often than the trunk. Definitive diagnosis is made by immunofluorescent examination of biopsy specimens. There have been reports of an increased incidence of fetal growth retardation and stillbirth. Transient neonatal herpes gestationis has also been reported at birth. Treatment has primarily been the use of oral corticosteroids.

The lesions of PUPPP usually begin on the abdomen and spread to the thighs and sometimes the buttocks and arms. The lesions, as their name describes, consist of erythematous urticarial plaques and small papules surrounded by a narrow, pale halo. The incidence of PUPPP is <1% of pregnant women. Immunofluorescent studies are negative for both immunoglobulin G (IgG) and complement levels. Histologic findings consist of normal epidermis accompanied by a superficial perivascular infiltrate of lymphocytes and histiocytes associated with edema of the papillary dermis. There are no studies to suggest an adverse effect on fetal and maternal outcome. Therapy includes topical steroids and antihistamines.

Acute Fatty Liver of Pregnancy

Acute fatty liver of pregnancy (AFLP) is a rare, serious condition involving microvesicular steatosis of the liver thought to be due to mitochondrial dysfunction in the oxidation of fatty acids, which leads to its accumulation in liver cells. Affected women often are heterozygous for long chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency. This presents as right upper quadrant pain, malaise, nausea and vomiting, acute renal failure, hypoglycemia, coagulopathy, and acute and fulminant liver failure. Hyperbilirubinemia and jaundice are common. Delivery of the infant is the only definitive treatment and should be performed immediately due to the high maternal and fetal mortality with this condition.

TESTS TO MONITOR FETAL HEALTH

When conditions affect fetal well being, and increase the risk of stillbirth (such as hypertension or fetal growth restriction), a test for fetal health is often employed. These are usually started at 32 to 34 weeks’ gestation, but may be started as early as viability. Table 14– 1 lists various fetal tests.

Table 14–1 • SELECTED TESTS OF FETAL WELL BEING
Test	Description	Results	Rationale
Nonstress test (NST)	Fetal heart rate and uterine contraction monitor or 20 minutes	Two accelerations in 20 minutes is considered reactive or reassuring (significant decelerations may be nonreassuring)	A well-oxygenated fetus will have the capacity to develop accelerations; however, a nonreactive NST may be a sleep cycle and further testing such as with BPP is the usual next step
Contraction stress test	Fetal heart rate and uterine contraction monitor with the inducement of uterine contractions such as with oxytocin	Two accelerations in 20 minutes, with the absence of late decelerations with considered reassuring	A reactive NST is reassuring, but a fetus without late decelerations “under stress” is even more reassuring. However, there can be false positive CST results. Also in preterm gestations, CST can be problematic since it may cause a preterm delivery
Biophysical profile (BPP)	Five components each scored with 0 or 2 points: • NST • Fetal breathing • Fetal tone • Fetal movement • Amniotic fluid volume*	Scores o 8/10 with normal amniotic fluid, or 10/10 are considered reassuring. Scores of 6/10 is equivocal, and 4/10 or lower is considered nonreassuring (high risk of fetal death)	Acute placental insufficiency affects the NST, breathing, tone, and movement; chronic uteroplacental insufficiency affects the amniotic fluid volume. Together, there is a more complete picture of fetal status
Modified biophysical profile	Taking only part of the BPP components, usually the NST and amniotic fluid volume	A reactive NST without decelerations with normal amniotic fluid volume is considered reassuring	A reassuring modified BPP has been shown to be as predictive as the full BPP
Umbilical Doppler velocity	Assessment of umbilical artery blood low	Velocity of low during systole and diastole	Reverse end diastolic low is ominous and usually means fetal death in 24-48 hours; absent end diastolic flow also worrisome

*Normal amniotic fuid volume is either the summation o our quadrant vertical measures (amniotic f uid index >5 cm or deepest vertical pocket o at least 2 cm × 2 cm).

COMPREHENSION QUESTIONS

14.1 A 31-year-old G2P1001 woman at 28 weeks’ gestation presents with generalized pruritus. She has no rashes on her body and is diagnosed as having probable intrahepatic cholestasis of pregnancy. Which of the following is most accurate?

A. Hepatic transaminase levels are usually in the 2000 U/ L range.

B. Is associated with hypertension.

C. May be associated with an increased perinatal morbidity.

D. Often is associated with thrombocytopenia.

14.2 A 30-year-old G1P0 woman presents for her routine prenatal care appointment at 36 weeks’ gestation with pruritic skin rash over her abdomen. She is diagnosed as having pruritic urticarial papules and plaques of pregnancy (PUPPP). Which of the following best describes the pregnancy outcome with her diagnosis?

A. Somewhat increased perinatal morbidity and mortality

B. Increased preterm delivery rate

C. Increased preeclampsia

D. No effect on pregnancy

14.3 A 33-year-old G1P0 woman at 39 weeks’ gestation is in labor. She has been diagnosed with herpes gestationis with the characteristic pruritus and vesicular lesions on the abdomen. Which of the following precautions is best advised for this patient?

A. Cesarean delivery is indicated.

B. Neonatal lesions may be noted and will resolve.

C. Vaginal delivery is permissible if the lesions are not in the introitus region and provided that oral acyclovir is given to the baby.

D. Tocolysis and oral steroid use is advisable until the lesions are healed.

14.4 A 24-year-old G2P1001 woman is at 34 weeks’ gestation and noted to be icteric. She also has nausea and vomiting and malaise. A diagnosis of acute fatty liver of pregnancy is made, and the obstetrician recommends immediate delivery. Which of the following is most consistent with acute fatty liver of pregnancy?

A. Elevated serum bile acid levels

B. Hypoglycemia requiring multiple D50 injections

C. Proteinuria of 500 mg over 24 hours

D. Oligohydramnios noted on ultrasound

14.5 A 34-year-old G2P1 woman at 36 weeks’ gestation with a diagnosis of ICP is undergoing fetal testing. If the BPP shows the following, what is your next step?

• NST is reactive without decelerations.
• Fetal breathing is present.
• Fetal movement is present.
• Fetal tone is present.
• Amniotic fluid index is 4 cm.

A. Contraction stress testing

B. Induce labor

C. Repeat BPP in 1 week

D. Umbilical Doppler velocity testing

ANSWERS

14.1 C. Intrahepatic cholestasis in pregnancy may be associated with increased perinatal morbidity, especially when accompanied by jaundice. It is rare for liver enzymes to be elevated or for there to be any hepatic sequelae in the mother; however, every patient who is suspected of having cholestasis of pregnancy should have their liver enzymes checked to avoid fetal morbidity and mortality. Hepatic enzyme levels are normally < 3 U/ L; women with intrahepatic cholestasis may have slightly elevated levels but almost never in the thousands. On presentation, no rash typically accompanies the pruritus. Thrombocytopenia is not involved in this disorder; however, it is involved in a life-threatening condition of pregnancy known as HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.

14.2 D. PUPPP is not thought to be associated with adverse pregnancy outcomes. The diagnosis is made presumptively based on clinical presentation, with the rash almost always starting on or near the abdominal striae of the abdomen. They are usually small red “bumps” that are intensely pruritic. The treatment is symptomatic. Interestingly, this condition usually occurs with the first pregnancy and usually does not recur, with the most common onset at 35 to 36 weeks’ gestation.

14.3 B. Neonatal lesions are sometimes seen with herpes gestationis caused by the IgG antibodies crossing the placenta, and these lesions will resolve. Herpes gestationis is not the same as herpes simplex virus. The latter would necessitate cesarean delivery to avoid infection to the baby.

14.4 B. Hypoglycemia is relatively unique to acute fatty liver of pregnancy. Because of the liver insufficiency, glycogen storage is compromised leading to low serum glucose levels, which often require multiple doses of dextrose. Proteinuria is more consistent with preeclampsia, oligohydramnios is nonspecific, and bile acids are more consistent with ICP.

14.5. B. The biophysical profile in this case is 8/10 but with low amniotic fluid volume (oligohydramnios). The oligohydramnios is concerning and is associated with a 20 to 40× increase in fetal death as compared to normal amniotic fluid. Thus, the best management in this setting is induction of labor. Contraction stress testing or umbilical Doppler flow testing would not add much, or be reassuring. Repeat BPP in 1 week would be appropriate if the BPP were reassuring.

    CLINICAL PEARLS    

» The most common cause o generalized pruritus in pregnancy in the absence o skin lesions is cholestasis o pregnancy. » Cholestatic jaundice in pregnancy may be associated with increased adverse pregnancy outcomes. » The lesions o PUPPP usually begin on the abdomen and spread to the thighs and sometimes the buttocks and arms. » ICP is associated with adverse fetal outcomes, which PUPPP is not. » Acute fatty liver o pregnancy is a rare but serious condition that can lead to fulminant liver failure. Immediate delivery is warranted. » Fetal testing or well being include NST, CST, BPP, and umbilical Doppler velocity assessment, and are used in circumstances o increased risk o stillbirth.

REFERENCES

Bacq Y, Sentilhes L, Reyes HB, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology. 2012;143:1492. 

Castro LC, Ognyemi D. Common medical and surgical conditions complicating pregnancy. In: Hacker NF, Gambone JC, Hobel CJ, eds. Essentials of Obstetrics and Gynecology. 5th ed. Philadelphia, PA: Saunders; 2009:191-218. 

Cunningham F, Leveno K, Bloom S, Spong CY, Dashe J. Williams Obstetrics 24/ E. McGraw-Hill Professional; 2014. 

Geenes V, Chappell LC, Seed PT, et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology. 2014;59:1482. 

Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol. 2006;26:527. 

Rajasri AG, Srestha R, Mitchell J. Acute fatty liver of pregnancy (AFLP)—an overview. J Obstet Gynecol. 2007;27(3):237-240. 

Williamson F, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014;124(1):120-133.

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