4/2/06njm

**Q. Is cholestasis in pregnancy significant in American Indians and
Alaska Natives?**

A. Yes, cholestasis can be associated with infant mortality and maternal
discomfort. See details

Intrahepatic cholestasis of pregnancy (IHCP) is a disorder that develops
in the latter half of pregnancy characterized by pruritus without rash
and accompanied by elevated bile acids. A genetic etiology is suspected
because of the high incidence in certain ethnic groups. Araucana and
Aymara indigenous women in Chile and Bolivia have the highest known
incidence, followed by Scandinavian women. Our preliminary survey shows
a high prevalence (3.9 %) of IHCP in pregnant Alaska Native women.

An inherited mutation involving a polymorphism in certain bile
transporter genes, whose function is influenced by the metabolism of
estrogen or progesterone in pregnancy, has been postulated as the
possible genetic mechanism, but, to date, no specific gene has been
definitively implicated.

We recently encountered an unexpected stillbirth in a woman with IHCP
who had had reassuring fetal surveillance (reactive non-stress test) two
days prior to presenting with no fetal movements. This woman had had
severe pruritus but had experienced excellent relief of her symptoms
with ursodiol.

Let's look at fetal and maternal outcomes, delivery plans, and other
complications.

**Fetal outcome** --- In contrast to the favorable prognosis for
mothers, ICP carries significant risk for the fetus. The main
complications are fetal prematurity, meconium stained amniotic fluid,
and intrauterine demise. The incidence of prematurity varies greatly
among studies (6 to 60 percent), and may in part reflect the high rate
of multiple pregnancies in patients with ICP. In one series of 61 babies
born to women with ICP, the incidence of prematurity was 100 percent in
multiple pregnancies and 41 percent in singleton pregnancies; three
babies (5 percent) died. The incidence of fetal demise has been lower (1
to 3 percent) in other studies. The risk of prematurity also appears to
correlate inversely with gestational age at onset of pruritus.

Fetal demise rarely occurs before the last month of pregnancy. The cause
is unknown. There is no ideal method for fetal surveillance in ICP. Some
obstetricians recommend non stress tests or biophysical assessment.
However, no test reliably predicts the risk of fetal demise. Measurement
of the serum total bile acid concentration has also been suggested for
fetal assessment in ICP. In one study of 693 women with ICP, the
probability of fetal complications (defined as preterm delivery,
asphyxial events, meconium staining of amniotic fluid, placenta, and
membranes) was directly related to concentration of bile acid levels
even after controlling for other risk factors. Fetal complications were
not observed until bile acid levels were
![](media/image1.png){width="8.333333333333333e-2in"
height="9.236111111111112e-2in"}40 micromol/L. Further validation of
these results is needed to determine the accuracy of this cutoff value.
Furthermore, determination of bile acid concentrations may take several
days even in major laboratories, making it an impractical tool for
immediate risk stratification.

In addition, there has been an association between maternal cholestasis
and neonatal respiratory distress syndrome. (see Zecca et al below) The
authors describe 3 cases of neonatal respiratory distress syndrome (RDS)
in near-term infants, born from mothers with severe intrahepatic
cholestasis of pregnancy. Common pictures of the cases were: good
indices of lung maturity in the amniotic fluid; severe RDS requiring
mechanical ventilation; high serum bile acid (BA) levels in the early
days of life; no meconium aspiration; negative cultures; and absence of
indirect laboratory signs of infection

**Maternal outcome** --- The maternal prognosis in ICP is good. Pruritus
usually disappears in the first few days following delivery (and may
resolve before delivery in some cases), accompanied by normalization of
serum bile acid concentrations and other liver tests.

Affected women generally have no hepatic sequelae. For this reason, the
disease is sometimes referred to as \"benign\" intrahepatic cholestasis
of pregnancy. Progressive fibrosis is uncharacteristic, but was reported
in four sisters who had an atypical familial form of prolonged recurrent
intrahepatic cholestasis.

Cholestasis recurs during subsequent pregnancies in 60 to 70 percent.
Recurrent episodes are variable in severity. Affected women may also be
at increased risk for the development of gallstones.

The administration of oral contraceptives to women with a history of ICP
rarely results in recurrent cholestasis. Thus, oral contraception with a
low dosage of estrogen can be initiated after normalization of liver
function tests. However, women should be informed of a possible risk of
pruritus. We also routinely check liver function tests after three or
six months

**Complications of cholestasis** --- In addition to alleviating
symptoms, treatment should also focus on preventing complications of
cholestasis. If cholestasis is severe, fat soluble vitamin deficiency
can occur, and may be worsened by administration of anion exchange
resins (such as
[cholestyramine](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/56558&drug=true)).
However, steatorrhea is modest and nutritional requirements are
generally easily met. An occasional exception is hypoprothrombinemia
induced by [vitamin
K](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/200299&drug=true)
deficiency; this possibility should be treated before delivery to
prevent hemorrhage.

.

**Delivery** --- The best approach is early delivery, the timing of
which should be guided by the patients symptoms (mostly pruritus), the
gestational age, and whether the cervix is favorable. In most patients
delivery should be accomplished by 38 weeks. However, when cholestasis
is severe (such as when patients are jaundiced), delivery should be
considered at 36 weeks gestation if lung maturity is achieved or as soon
thereafter as fetal lung maturity is established.

**Background**

**A.)** **Maternal cholestasis and neonatal respiratory distress
syndrome**

The authors describe 3 cases of neonatal respiratory distress syndrome
(RDS) in near-term infants, born from mothers with severe intrahepatic
cholestasis of pregnancy. Common pictures of the cases were: good
indices of lung maturity in the amniotic fluid; severe RDS requiring
mechanical ventilation; high serum bile acid (BA) levels in the early
days of life; no meconium aspiration; negative cultures; and absence of
indirect laboratory signs of infection. After the first case, we
hypothesized that abnormally high BA levels could have reversed the
action of phospholipase A2 in the lungs, causing a degradation of
phosphatidylcholines to lysophosphatidylcholines and the consequent lack
of surfactant activity, leading to the severe respiratory distress.

Consequently, in cases 2 and 3, we gave intratracheal surfactant to the
infants, which, although administered around the first 24 hours of life,
showed to be helpful. Our experience suggests that a high level of
attention in the management of newborn infants (even near-term infants)
born from women with intrahepatic cholestasis of pregnancy is necessary
to detect as soon as possible signs and symptoms of this \"unexpected\"
RDS, which can assume a very severe clinical picture. In such instances,
we recommend that the diagnosis of BA pneumonia be kept in mind and that
exogenous surfactant be given as soon as possible, even in the presence
of indices of normal lung maturity in the amniotic fluid. Finding high
levels of BA and lysophosphatidylcholines in the bronchoalveolar lavage
of affected infants would aid in support of the diagnosis.

Zecca E,  et al Bile acid pneumonia: a \"new\" form of neonatal
respiratory distress syndrome? Pediatrics. 2004 Jul;114(1):269-72

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15231944>

**B.) Intrahepatic cholestasis of pregnancy, UpToDate**

**INTRODUCTION** --- Intrahepatic cholestasis of pregnancy (ICP) occurs
in the second and third trimester, and is characterized by pruritus and
an elevation in serum bile acid concentrations. The incidence of ICP
varies widely among studies (0.2 to 4 percent). Geographic variations in
the rates of the disease may reflect differences in susceptibility
between ethnic groups. The incidence of ICP is increased in Bolivia, and
is highest among the Araucanos Indians in Chile. For unknown reasons the
disease is seen more commonly in the colder months in Chile and
Scandinavia.

The major clinical features of intrahepatic cholestasis of pregnancy
will be reviewed here. A general approach to the pregnant women who
develops liver disease is presented elsewhere.

**PATHOGENESIS** --- The cause of ICP is unknown. However, the
preponderance of evidence suggests that genetic and hormonal factors are
important.

**Genetics** --- Genetic factors could explain familial cases and the
higher incidence in some ethnic groups. Recurrent familial ICP has been
described suggesting a heritable defect. Heterozygous mutations in the
MDR3 gene (encoding for a canalicular phospholipid translocator involved
in the biliary secretion of phospholipids) has been found in a large
consanguineous family in whom six women had at least one episode of ICP.
Also supporting genetic factors are the high rate of recurrence of ICP
in subsequent pregnancies and the susceptibility of affected women to
[progesterone](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/212059&drug=true).

Specific modes of inheritance or HLA associations have not been
identified. It is not known if there is any relation between ICP and
familial forms of benign or progressive intrahepatic cholestasis. In the
latter disorders, defects have been identified in the multidrug
resistance (MDR) gene and a gene encoding a P-type ATPase.

**Estrogens and progesterone** --- Estrogens are known to cause
cholestasis in both experimental and clinical conditions, and a role in
ICP is likely. ICP occurs mainly during the third trimester, when serum
concentrations of estrogen reach their peak. ICP is also more common in
twin pregnancies, which are associated with higher levels of circulating
estrogens than singleton pregnancies
\[[8](http://www.uptodateonline.com/utd/content/abstract.do?topicKey=hep_dis/10385&refNum=8)\].
It is not known if genetically determined abnormalities in estrogen
metabolism effect on bile transport mechanisms are a risk factor for
ICP.

ICP also may be associated with alterations in
[progesterone](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/212059&drug=true)
metabolism and the administration of progesterone may be a risk factor
for ICP. The formation of large amounts of sulfated progesterone
metabolites, possibly related to greater 5-alpha and 3-alpha reduction,
may result in saturation of the hepatic transport system(s) utilized for
biliary excretion of these compounds in some genetically predisposed
women. In one study of 50 women with ICP from France, 32 (64 percent)
had been treated with oral natural progesterone to prevent premature
delivery. It is recommended that progesterone treatment be avoided in
pregnant women with a previous history of ICP and immediately withdrawn
when cholestasis occurs during pregnancy.

**CLINICAL MANIFESTATIONS** --- The onset of ICP is typically heralded
by the development of pruritus, which may be intolerable. It is often
generalized but predominates on the palms and the soles of the feet, and
is worse at night. Pruritus may precede laboratory abnormalities.
Abdominal pain is uncommon. Encephalopathy or other stigmata of liver
failure are unusual and their presence should initiate a search for
other causes of liver disease.

Physical examination is nonspecific, but may show excoriations due to
scratching. Jaundice occurs in 10 to 20 percent, typically within four
weeks of the onset of itching. The presence of jaundice without pruritus
is rare and should prompt investigation of other causes.

**Laboratory data** --- Serum total bile acid concentrations increase in
ICP, and may be the first or only laboratory abnormality. Serum cholic
acid increases more than chenodeoxycholic acid, resulting in a marked
elevation of the cholic/chenodeoxycholic acid ratio compared to pregnant
women without ICP. The ratio of glycine/taurine conjugates is decreased.

Other laboratory findings reflecting cholestasis also may be present.
These include elevations in the serum concentrations of alkaline
phosphatase (up to four times normal), 5\' nucleotidase, and total and
direct bilirubin concentrations. Total bilirubin levels rarely exceed 6
mg/dL. Surprisingly, the serum concentrations of gamma glutamyl
transpeptidase (GGTP) are normal or modestly elevated, which is unusual
in most other forms of cholestatic liver disease in which GGTP levels
parallel other cholestatic markers.

Serum aminotransferases are also elevated, and may reach values greater
than 1000 U/L, making distinction from viral hepatitis important. The
prothrombin time is usually normal. When present, prolonged prothrombin
times reflect [vitamin
K](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/200299&drug=true)
deficiency due to cholestasis or to the use of bile acid sequestrants
(such as
[cholestyramine](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/56558&drug=true))
rather than liver dysfunction.

**DIAGNOSIS** --- Most women are diagnosed after 30 weeks of gestation.
The diagnosis of ICP is based upon the presence of pruritus associated
with elevated levels of serum bile acids and/or aminotransferases, and
the absence of diseases that may produce similar symptoms. The cardinal
feature of ICP (ie, pruritus) helps distinguish it from other types of
liver disease that can share similar laboratory features (such as early
HELLP syndrome or preeclampsia). Ultrasound examination reveals no
biliary duct dilation, and the hepatic parenchyma appears normal.

Liver biopsy is rarely necessary for the diagnosis. When performed,
histopathology is characterized by cholestasis without inflammation.
Bile plugs in hepatocytes and canaliculi predominate in zone 3. The
portal tracts are unaffected.

**TREATMENT** --- Treatment for ICP focuses on reducing symptoms and
preventing maternal and fetal complications. Several drugs have been
studied, and most focus on relieving symptoms. [Ursodeoxycholic
acid](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/275906&drug=true)
(UDCA) has emerged as the most promising treatment.

**Ursodeoxycholic acid** --- [Ursodeoxycholic
acid](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/275906&drug=true)
(UDCA) increases bile flow and has been used to relieve pruritus and
improve liver biochemical tests in cholestatic liver diseases such as
primary biliary cirrhosis. Initial pilot studies in ICP followed by
controlled trials demonstrated that UDCA improved pruritus and liver
tests, and had no adverse effects in the mothers or babies.

The largest trial included 84 symptomatic patients who were randomly
assigned to UDCA (8 to 10 mg/kg body weight daily) or
[cholestyramine](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/56558&drug=true)
(8 g daily) for 14 days. The onset of pruritus was approximately 31 to
32 weeks of gestation while treatment was started at approximately 34
weeks of gestation. Pruritus was reduced significantly more effectively
in the UDCA group. Furthermore, babies were delivered significantly
closer to term in the UDCA group while serum aminotransferases and
endogenous bile acid levels improved significantly more in the UDCA
group. There were no adverse effects attributed to UDCA while 12
patients randomized to cholestyramine reported treatment-related adverse
effects (mainly nausea). Similar benefits were described in an earlier,
smaller controlled trial.

Another report provided further detail on the perinatal and long-term
outcomes associated with treatment with UDCA. During a 12-year
observation period, 32 patients had received UDCA (15 mg/kg per day) for
at least three weeks before delivery. Patients were compared with 16
historic controls who did not receive UDCA. UDCA treatment was
associated with improvement in pruritus, serum bilirubin,
aminotransferase and bile salt levels, higher birth weight, and a
greater proportion of deliveries at term. Twenty-six children whose
mothers received UDCA were reexamined after 1 to 12 years of follow-up
all of whom were healthy.

A concern with UDCA therapy is that bile acids can cross the placenta,
which might lead to fetal toxicity. However, one study found that
treatment restored the serum bile acid composition to more closely
resemble that seen in healthy, pregnant controls, while in another
report, meconium bile acid concentrations were not affected by maternal
UDCA administration. Furthermore, UDCA appears to restore the transport
capabilities of the placenta, which are altered in patients with ICP and
to normalize the serum bile acid pattern in babies. Accumulation in the
amniotic fluid and cord blood appears to be very low even when high
doses of UDCA (1.5 to 2.0 g/day) have been given. Furthermore, maternal
and fetal ouctomes appear to be improved with UDCA.

Given the absence of toxicity, we suggest the use of UDCA in ICP,
particularly in patients with severe cholestasis. The optimal dose has
yet to be determined; we usually prescribe 500 mg twice a day.

**Other drugs** --- Several other treatments for ICP may be beneficial
in individual patients:

-   [Hydroxyzine](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/127710&drug=true)
    (25 to 50 mg/day) may improve pruritus, although antihistamines can
    aggravate respiratory difficulties in preterm babies.

```{=html}
<!-- -->
```
-   [Cholestyramine](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/56558&drug=true)
    (8 to 16 g/day) decreases ileal absorption of bile salts, thereby
    increasing their fecal excretion. Treatment should be initiated with
    a small dose and gradually increased. However, its effect on
    pruritus is limited in our experience, and it can increase
    steatorrhea, and exacerbate [vitamin
    K](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/200299&drug=true)
    deficiency. As noted above, it was less effective than UDCA in a
    controlled trial.

```{=html}
<!-- -->
```
-   The efficacy of the glutathione precursor S-adenosyl-methionine
    (SAMe) is controversial. Early studies which found that SAMe
    reversed estrogen-induced models of cholestasis in rats prompted
    studies in humans. In an initial uncontrolled series, 18 women with
    ICP were given a 20-day course of SAMe (800 mg per day
    intravenously). Treatment was associated with clinical and
    biochemical improvement. However subsequent studies, including a
    small controlled trial of 18 patients, have not reproduced these
    results. A controlled trial comparing SAMe with UDCA found that both
    equally reduced pruritus, but that UDCA was significantly more
    effective at improving the concentration of serum bile acids and
    other liver biochemical tests. We do not use SAMe for treating ICP.

Other modalities have produced disappointing results. A short course of
oral
[dexamethasone](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/74688&drug=true)
improved pruritus and decreased serum levels of bile acids in one
report, but was associated with clinical deterioration in another. Other
treatments, including
[charcoal](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/51487&drug=true),
ultraviolet light, topical emollients, and
[phenobarbital](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/198093&drug=true)
have been used, but few patients have been treated with uncertain
efficacy.

<http://www.uptodateonline.com/utd/content/topic.do?topicKey=hep_dis/10385&type=A&selectedTitle=1~7>

**References: Other cholestasis of pregnancy related articles**
(chronologic order)

Howard PJ, Murphy GM Bile acid stress in the mother and baby unit. Eur J
Gastroenterol Hepatol. 2003 Mar;15(3):317-21.

Mazzella G, et al Ursodeoxycholic acid administration in patients with
cholestasis of pregnancy:

effects on primary bile acids in babies and mothers. Hepatology. 2001
Mar;33(3):504-8.

Rodrigues CM, et al Bile acid patterns in meconium are influenced by
cholestasis of pregnancy and not altered by ursodeoxycholic acid
treatment. Gut. 1999 Sep;45(3):446-52

Heinonen S, Kirkinen P Pregnancy outcome with intrahepatic cholestasis.
Obstet Gynecol. 1999 Aug;94(2):189-93

Clark TJ, Dwarakanath L, Weaver JB. Pruritus in pregnancy and obstetric
cholestasis.

Hosp Med. 1999 Apr;60(4):254-60.

Alsulyman OM et al Intrahepatic cholestasis of pregnancy: perinatal
outcome associated with

expectant management. Am J Obstet Gynecol. 1996 Oct;175(4 Pt 1):957-60

Rioseco AJ, et al Intrahepatic cholestasis of pregnancy: a retrospective
case-control study of

perinatal outcome. Am J Obstet Gynecol. 1994 Mar;170(3):890-5.

Fisk NM, Storey GN. Fetal outcome in obstetric cholestasis. Br J Obstet
Gynaecol. 1988 Nov;95(11):1137-43.

Johnston WG, Baskett TF. Obstetric cholestasis. A 14 year review. Am J
Obstet Gynecol. 1979 Feb 1;133(3):299-301.

Laatikainen TJ. Fetal bile acid levels in pregnancies complicated by
maternal intrahepatic

cholestasis. Am J Obstet Gynecol. 1975 Aug 1;122(7):852-6.