Management of Jaundice in Pregnancy 2010

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thought to involve procoagulant and proinf lammatory states that

create glomerular endotheliosis, increased vascular permeability,

and a systemic inflammatory response that results in end organ

damage and hypoperfusion.

Abnormal laboratory values include a 10- to 20-fold elevation

in aminotransferases, elevations in alkaline phosphatase levels

that exceed those normally observed in pregnancy, and bilirubin

elevations of less than 5 mg/dL. Liver histology generally showshepatic sinusoidal deposition of fibrin along with periportal

hemorrhage, liver cell necrosis, and in severe cases, infarction; these

changes are likely due to vasoconstriction of hepatic vasculature10.

Microvesicular fatty infiltration has also been observed in some

cases of preeclampsia, suggesting a possible overlap with acute

fatty liver of pregnancy 11. Maternal mortality from preeclampsia/

eclampsia is rare in developed countries, but may approach 15%-

20% in developed countries 8. Likewise, the fetal mortality rate is

rare, occurring in 1%-2% of births. The only effective treatment for

preeclampsia is delivery of the fetus and placenta. Pharmacological

agents used in preeclampsia include antihypertensives such as

calcium channel blockers and low-dose aspirin. Magnesium sulfate

may be administered if eclampsia develops.

HEMOLYSIS, ELEVATED LIVER TESTS AND LOW

PLATELETS (HELLP)

HELLP syndrome is a multisystemic disorder of pregnancy

involving hemolysis, elevated liver tests, and low platelets. About

70% of cases occur antenatally, during the last trimester of

pregnancy 12. The pathogenesis of HELLP is thought to involve

Table 2 : Safety of drugs used in pregnancy-associated liver diseases

Drug FDA pregnancy category Comments

Antiemetics Promethazine C Possible respiratory depression if drug is administered near time of delivery

Metoclopramide B Available evidence suggests safe use during pregnancy

Ondansetron B Additional studies are needed to determine safety to the fetus, particularly during the rst

trimester

Prochlorperazine C There are isolated reports of congenital anomalies; however, some included exposures to other

drugs. Jaundice, extrapyramidal signs, hyper-/hyporeexes have been noted in newborns

Antihypertensives

ACE inhibitors

C/D First trimester exposure to ACE inhibitors may cause major congenital malformations Second

and third trimester use of an ACE inhibitor is associated with oligohydramnios and anuria,

hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate

Beta blockers C/D Fetal bradycardia, hypotension, risk of intrauterine growth retardation

Calcium channel blockers C Teratogenic and embryotoxic effects have been demonstrated in small animals. There are no

adequate and well-controlled studies in pregnant women

Anticoagulation Aspirin C (1st/2nd trimesters)

D (3rd trimester)

Adverse effects in the fetus include intrauterine growth retardation, salicylate intoxication,

bleeding abnormalities, and neonatal acidosis. Use of aspirin close to delivery may cause

premature closure of the ductus arteriosus. Data have shown low-dose aspirin (60-150 mg/ day)

may be safe in pregnancy

Enoxaparin B No adequate and well-controlled studies using enoxaparin. Postmarketing reports include

congenital abnormalities and also fetal death

Heparin C Does not cross the placenta

Intrahepatic cholestasis

Ursodeoxycholic acid

B Relatively low risk

S-adenosyl-L-methionine Not evaluated by FDA Relatively low risk

Cholestyramine C Cholestyramine is not absorbed systemically, but may interfere with vitamin absorption

While maternal morbidity is well documented, the effects of HG on

the fetus are less clear. Some data suggest no differences between

fetuses born to mothers with HG and non-HG mothers 6. In one

large cohort study, infants of HG mothers were found to have

lower birth weights and higher rates of being small for gestational

age 7. Treatment of HG is primarily supportive. Patients should

avoid triggers that aggravate nausea, and eat small, frequent, low-

fat meals. Intravenous fluids, thiamine and folate supplementation,and antiemetic therapy may be administered. Promethazine is a

first-line agent, but other medications such as metoclopramide,

ondansetron, and steroids have also been used.

PREECLAMPSIA/ECLAMPSIA

Preeclampsia defined by the triad of hypertension, edema, and

proteinuria. It affects about 5%-10% of all pregnant women

and usually occurs late in the second trimester or in the third

trimester. In preeclampsia, hypertension is defined as having a

systolic pressure greater than 140 mmHg and a diastolic pressure

greater than 90 mmHg on at least two occasions that are at least 4

to 6 h apart in a previously normotensive patient, and proteinuria is

defined as equal to or greater than 300 mg of protein in a 24 h urinecollection or 1+ protein or greater on urine dipstick testing of two

random urine samples collected at least 4 to 6 h apart 8. Eclampsia

involves all features of preeclampsia and includes neurologic

symptoms such as headaches, visual disturbances, and seizures

or coma. Risk factors for preeclampsia and eclampsia include

nulliparity, extremes of maternal age, insulin resistance, obesity,

and infection 8, 9. The pathophysiology of preeclampsia/ eclampsia is


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alterations in platelet activation, increases in proinflammatory

cytokines, and segmental vasospasm with vascular endothelial

damage. An association with a defect in long-chain 3-hydroxyacyl-

coenzyme A dehydrogenase (LCHAD) has also been described,

suggesting a possible overlap of HELLP syndrome and acute fatty

liver of pregnancy.

Most patients present with right upper quadrant abdominal pain,nausea, vomiting, malaise, and edema with significant weight gain.

Less commonly associated conditions include renal failure (with

increased uric acid), diabetes insipidus, and antiphospholipid

syndrome. Other late findings of HELLP include disseminated

intravascular coagulopathy (DIC), pulmonary edema, placental

abruption, and retinal detachment. Laboratory findings include

hemolysis with increased bilirubin levels (usually less than 5 mg/

dL) and lactate dehydrogenase (LDH) levels greater than 600 IU/L,

moderately elevated aspartate aminotransferase (AST) and ALT

levels (200 IU/L to 700 IU/L), and thrombocytopenia (less than 100

000/mL). In early stages, prothrombin time and activated partial

thromboplastin time are normal, but in later phases, DIC may be

present with increased levels of fibrin degradation products and

D-dimer, and thrombin- antithrombin complexes.

Histology of Hemolysis, elevated liver enzymes, low platelet

count syndromePathogenesis involve intravascular fibrin deposition and sinusoidal

obstruction that can lead to hepatic hemorrhage and infarction.

Histologically, one may see focal hepatocyte necrosis, periportal

hemorrhage, and fibrin deposits. The reported maternal mortality

from HELLP is 1%, and the perinatal mortality rate ranges from

7%-22% and may be due to premature detachment of placenta,

intrauterine asphyxia, and prematurity 4. Other complications of

HELLP syndrome include acute renal failure, adult respiratory

distress syndrome, pulmonary edema, stroke, liver failure, and

hepatic infarction. The only definitive treatment for HELLP

syndrome is delivery. If the pregnant woman is greater than 34

wk gestation, immediate induction is recommended. If gestational

age is between 24 wk and 34 wk, corticosteroids are administered

to accelerate fetal lung maturity in preparation for delivery 48

h later. After delivery, close monitoring of the mother should

continue, as data have shown worsening thrombocytopenia and

increasing LDH levels up to 48 h postpartum 13. However, most

laboratory values (transaminases, bilirubin, LDH) normalize in

48 h. For patients with ongoing or newly developing postpartum

symptoms of HELLP, modalities such as antithrombotic agents,

plasmapheresis, and dialysis may be employed.

ACUTE FATTY LIVER OF PREGNANCY

Acute fatty liver of pregnancy (AFLP) is a rare but serious maternal

illness that occurs in the third trimester of pregnancy. With an

incidence of 1 in 10 000 to 1 in 15 000 pregnancies, it has a

maternal mortality rate of 18% and a fetal mortality rate of 23%10,14. AFLP is more commonly seen in nulliparous women and

with multiple gestation. The pathophysiology of AFLP involvesdefects in mitochondrial fatty acid beta-oxidation. Under normal

circumstances, an individual that is heterozygous for enzymatic

mutations in fatty acid oxidation will not have abnormal fatty

oxidation. However, when a heterozygous woman has a fetus that

is homozygous for such mutations, fetal fatty acids accumulate

and return to the mothers circulation. The extra load of long-

chain fatty acids and subsequent triglyceride accumulation lead to

hepatic fat deposition and impaired hepatic function in the mother.

A deficiency in longchain 3-hydroxyacyl-CoA dehydrogenase

(LCHAD) is thought to be associated with the development of

AFLP. LCHAD is a component of an enzyme complex known

as the mitochondrial trifunctional protein (MTP), and it is

believed that the G1528C and E474Q mutations of the MTP are

responsible for causing LCHAD deficiency that subsequently leads

to AFLP 15. Patients with AFLP typically present with a 1 to 2 wk

history of nausea, vomiting, abdominal pain, and fatigue. Jaundice

occurs frequently, and some women experience moderate to

severe hypoglycemia, hepatic encephalopathy, and coagulopathy.

Approximately 50% of these patients will also have signs of

preeclampsia, although hypertension is generally not severe 16.

Laboratory findings include elevations in aminotransferase levels,

which may range from being mildly elevated to approaching 1000

IU/L.

Since AFLP can lead to significant maternal and fetal morbidity

and mortality, prompt diagnosis must be made. The most definitive

test is liver biopsy. Histopathologic findings reveal swollen, palehepatocytes in the central zones with microvesicular fatty

infiltration that can be identified on frozen section with oil red O

staining. Electron microscopy may also show megamitochondria

and paracrystalline mitochondrial inclusions. Although liver

biopsy may be helpful, it is often not done due to the presence

of coagulopathy. Therefore, the diagnosis of AFLP is usually made

on clinical and laboratory findings.

Histology of acute fatty liver of pregnancy


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As with most pregnancy-associated liver diseases, the treatment

of AFLP involves delivery of the fetus. In rare cases, patients

will progress to fulminant hepatic failure with need for liver

transplantation17. careful attention should also be paid to the infant

given the increased risk of cardiomyopathy, neuropathy, myopathy,

nonketotic hypoglycemia, hepatic failure, and death associated

with fatty acid oxidation defects in newborns.

INTRAHEPATIC CHOLESTASIS OF PREGNANCY

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric

cholestasis, is a rare pregnancyspecific liver condition that occurs

in the late second or third trimester and has a prevalence of about

1/1000 to 1/10 000. It is significantly more common in South

Asia, South America (especially Chile), and Scandinavian countries.

ICP is also more common in women of advanced maternal age,

multiparous women, and in women with a personal history of

cholestasis with oral contraceptive use 18. The prognosis for

women with ICP is usually good, but it is associated with increased

fetal morbidity and mortality, particularly from chronic placental

insufficiency, preterm labor, fetal distress, and intrauterine death19. The etiology of ICP is likely multifactorial and variations.

Mutations in the phospholipid translocator known as the ATP-

cassette transporter B4 (ABCB4) or multidrug resistant protein-3

(MDR3) are associated with the development of ICP 20. Changes

induced by these genetic mutations lead to increased sensitivity

to estrogen, which impairs the sulfation and transportation of bile

acids. Estrogens are thought to act on hepatocytes by decreasing

membrane permeability and bile acid uptake by the liver. The

maternal-tofetal transfer of bile acids across the placenta becomes

impaired, leading to potentially toxic bile acid levels in the fetus21. The elevation in bile acid levels is also thought possibly to

affect myometrial contractility and to cause vasoconstriction of

chorionic veins in the placenta, which may contribute to preterm

deliveries and fetal distress seen in ICP 22, 23.

The classic symptom is pruritus that usually begins in the second

or third trimester. It usually occurs in the palms and soles and may

progress to the rest of the body, and the pruritus is often worse

at night. Pruritus may be severe but is usually relieved within 48

h after delivery of the fetus. Jaundice occurs in approximately

10%-25% of patients and may appear within the first four weeks

of the onset of pruritus 24. Cholelithiasis and cholecystitis have

been observed to occur with greater frequency in women with

ICP 25. Abnormal laboratory findings include elevated total bile

acid levels up to 10- to 25-fold, with an increase in cholic acid

and a decrease in chenodeoxycholic acid leading to a marked

elevation in the cholic/ chenodeoxycholic acid ratio. The glycine/taurine ratio is also reduced. AST and ALT levels rarely exceed

two times the upper limits of normal, but may approach 10- to

20-fold elevations in rare cases. Bilirubin levels may be elevated,

but are usually less than 6 mg/dL. Serum alkaline phosphatase

levels may also be elevated, but this is usually less helpful to follow

given typical alkaline phosphatase elevations seen in pregnancy.

Liver biopsy is usually not required to make the diagnosis of ICP.

The treatment of choice for ICP is ursodeoxycholic acid (UDCA),

which helps to relieve pruritus and improve liver test abnormalities.

It is unclear how UDCA works, but it is felt that UDCA conjugates

help target and insert key transporter proteins, such as MRP2

(ABCC2) or bile salt export pumps (ABCB11) into the canalicular

membranes 26. Other medications, such as cholestyramine and

S-adenosyl-L-methionine, have been associated with improving

pruritus and normalizing biochemical profiles, but studies havefound UCDA to be superior over cholestyramine and S-adenosyl-

L-methionine 27, 28. Dexamethasone has also been used, but has

shown to be much less effective in reducing bile acids and bilirubin

and ineffective in relieving pruritus 29. Antihistamines are frequently

used to alleviate pruritus, and vitamin K and other fat-soluble

vitamin supplementation should also be administered if fat

malabsorption is suspected.

COMMON LIVER DISEASES AND PREGNANCY

Viral Hepatitis

Viral hepatitis is the most common form of liver disease

worldwide and it frequently affects women of childbearing age,either as an acute infection or as a chronic disease. Hepatitis A

does not appear to alter the normal course of pregnancy nor

does pregnancy appear to influence the natural history of hepatitis

A. Acute and chronic viral hepatitis of other types however may

have implications for maternal well-being as well as the outcome

of gestation.

HEPATITIS E

Hepatitis E virus infection occurs in non-industrialized nations,

usually as an epidemic disease during the monsoon season in

central and south Asia and India; it is rare in the West. Acute

hepatitis E during the third trimester of pregnancy is a cause of

fulminant hepatic failure and has a mortality rate of up to 20%30. Maternal Hepatitis E virus infection also has been associated

with intrauterine fetal death 31, 32. The risks of intrauterine death

and abortion in any trimester are greater in pregnant women

with hepatitis E than they are in their uninfected counterparts.

Maternal-fetal transmission of hepatitis E resulting in symptomatic

neonatal hepatitis has occurred 33; no known therapy will prevent

vertical transmission of this virus.

HEPATITIS B

As a rule maternal hepatitis B virus infection does not influence

the course of pregnancy nor does pregnancy alter the natural

history of maternal hepatitis B. Most women of childbearing agewith chronic hepatitis B are healthy virus carriers with a very low

risk of developing complications of their disease during gestation.

The importance of hepatitis B during pregnancy is related to its

role in the perpetuation of chronic infection through vertical

transmission: Maternal-fetal transmission of hepatitis B virus is

responsible for most cases of chronic hepatitis B worldwide

especially in Southeast Asia and Africa 34. Mothers with a reactive

serum test for hepatitis B e antigen (HBeAg) have more circulating


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virus and higher rates of perinatal transmission than do mothers

without detectable serum HBeAg and a reactive serum test for

anti-HBeAg 35although the latter individuals are still a source

of neonatal infection 36. Without treatment 90% of infants born

to HBeAg positive mothers and 10% of infant born to HBeAg-

negative mothers develop hepatitis B virus infection. The infants

of mothers with a reactive serum test for hepatitis B surface

antigen should receive hepatits B immunoglobulin at birth and alsohepatitis B vaccine during the first day of life and at ages 1 and 6

months 37. Women with chronic hepatitis B are not treated with

interferon during pregnancy. Therapy with the nucleoside analog,

lamivudine is probably safe in pregnant patients and has been

reported to reduce the incidence of neonatal vaccination failure 38.

Data concerning the toxicity and efficacy in this setting of adefovir

dipivoxil a newer nucleotide analog of adenosine monophosphate

and of entecavir a guanosine nucleoside analog are insufficient to

allow any conculsion.

HEPATITIS C

HCV infection in pregnancy has a presentation that is similar to

that of HCV infection in non-pregnant patients.HCV-infectedwomen do not need to be advised against pregnancy, but

they should be counseled on the risks of mother-to-infant

transmission of HCV. The risk for vertical transmission of

HCV is about 5%-10%. The risk of perinatal transmission of HCV

is associated with the presence of HCV RNA in maternal blood at

the time of birth and coinfection with human immunodeficiency

virus (HIV) 39. HIV coinfection in pregnant women increases

the risk of perinatal HCV transmission by 2-fold, and in more

than 25% of cases, both HCV and HIV are transmitted together.

Prolonged rupture of membranes (greater than 6 h) has also

been associated with an increased risk of perinatal HCV

transmission; thus, it is advised that the second stage of labor be

kept short in HCV-infected pregnant women40

.Data on the effectsof the mode of delivery on HCV transmission are conflicting;

therefore, there are no recommendations regarding the

method of delivery that should be used in HCV-infected pregnant

women. Although HCV is detectable in breast milk, there is little

documented evidence of transmission of HCV via breastfeeding.

However, the Centers for Disease Control and Prevention (CDC)

recommend that HCV-infected women with cracked or bleeding

nipples should abstain from breastfeeding 41.

Combination antiviral therapy with pegylated interferon

and ribavirin is generally recommended for HCV-infected

patients. Ribavirin has a category X designation by the

FDA. Interferon has a designation as category C, as it has

been shown to have abortifacient effects in animal models.Therefore, combination antiviral therapy is not recommended

for HCV-infected pregnant women. There are a few reports of

women becoming pregnant while on interferon monotherapy for

HCV, and in these cases, healthy babies were delivered and were

found to have normal growth and development at follow up 42-44.

CHRONIC LIVER DISEASE & PORTAL

HYPERTENSION

Fertility is decreased in women with significant hepatic

dysfunction due to hypothalamic-pituitary dysfunction. However,

cirrhosis is not a contraindication, as pregnancy may be tolerated if

cirrhosis is well-compensated and without features of portal

hypertension45

. Portal hypertension leads to increased maternalcomplications, including variceal hemorrhage , hepatic failure,

encephalopathy, jaundice, malnutrition , and splenic artery

aneurysm 46. Bleeding from esophageal varices has been reported

in 20%-25% of pregnant women with cirrhosis 47. All pregnant

women with cirrhosis should be screened for varices starting in

the second trimester and started on beta-blockers if indicated.

The treatment of variceal bleeding consists of both endoscopic

and pharmacologic treatment. However, vasopressin has been

shown to cause placental ischemia, necrosis, andamputation of

fetal digits and is contraindicated in pregnancy; there is a paucity

of information about the use of octreotide in pregnancy 48. Finally,

though there are no good studies evaluating the impact of vaginal

delivery of the risk of variceal bleeding, it is recommendedthat patients have cesarean section to avoid increased straining 49.

WILSON DISEASE

Wilson disease in women of childbearing age is associated with

amenorrhea and infertility. Treatment of affected individuals to

remove excess copper may result in resumption of ovulatory

cycles and subsequent pregnancy. Pregnant patients must remain

on medication to treat Wilson disease because discontinuation

of therapy can cause sudden copper release hemolysis, acute liver

failure and death 50. D-penicillamine is potentially teratogenic in

humans 51but has beeen used safely during pregnancy at doses

necessary for copper chelation 52. Similarly trientine is teratogenic

in animals but appears to be saafe in humans as treatment forcopper overload. Zinc is not teratogenic and some experts favor

its use during pregnancy as therapy for Wilson disease for this

reason 53.

AUTOIMMUNE LIVER DISEASE

Autoimmune diseases of all types including autoimmune hepatitis

are more common in women then in men. In women, classic

(type 1) autoimmune hepatitis typically presents around the

expected time of menarche but is associated with amenorrhea.

Immunosuppressive therapy is highly effective in controlling the

disease in most patients; treated women who subsequently conceive

a child should continue taking immunosuppressive medications

during pregnancy. The doses of azathioprine prescribed as part of

standard treatment regimens are belived not to be teratogenic.

Occasionally autoimmune liver disease will worsen during the

postpartum period when the physiologic immunosuppression

of pregnancy resolves. For this reason affected patients should

have frequent measurements of serum aminotransferase levels

for approximately 6 months after delivery.


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REFERENCES

1 Fairweather DV. Nausea and vomiting in pregnancy. Am J Obstet Gyne-col 1968; 102: 135-175

2 Kallen B. Hyperemesis during pregnancy and delivery outcome: aregistry study. Eur J Obstet Gynecol Reprod Biol 1987; 26: 291-302

3 Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nau-sea and vomiting during pregnancy. Br J Gen Pract 1993; 43: 245-248

4 Hepburn IS , Schade RR . Pregnancy -associated liver disorders. DigDis Sci 2008; 53: 2334-2358

5 Conchillo JM, Pijnenborg JM, Peeters P, Stockbrugger RW, FeveryJ, Koek GH. Liver enzyme elevation induced by hyperemesis gravi-darum : aetiology , diagnosis and treatment. Neth J Med 2002; 60:374-378

6 Tsang IS, Katz VL, Wells SD. Maternal and fetal outcomes in hypereme-sis gravidarum. Int J Gynaecol Obstet 1996; 55: 231-235

7 Bailit JL. Hyperemesis gravidarium: Epidemiologic ndings from a largecohort. Am J Obstet Gynecol 2005; 193: 811-814

8 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005; 365:785-799

9 Thadhani R, Solomon CG. Preeclampsia--a glimpse into the future? NEngl J Med 2008; 359: 858-860

10 Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med 1996; 335:569-576

11 Dani R, Mendes GS, Medeiros Jde L, Peret FJ, Nunes A. Study of theliver changes occurring in preeclampsia and their possible pathoge-netic connection with acute fatty liver of pregnancy. Am J Gastroenterol1996; 91: 292-294

12 Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA.Maternal morbidity and mortality in 442 pregnancies with hemoly-sis, elevated liver enzymes, and low platelets (HELLP syndrome). Am JObstet Gynecol 1993; 169: 1000-1006

13 Martin JN Jr , Blake PG , Perry KG Jr , McCaul JF , Hess LW, MartinRW. The natural history of HELLP syndrome: patterns of disease pro-gression and regression. Am J Obstet Gynecol 1991; 164: 1500-1509;discussion 1509-1513

14 Castro MA, Fassett MJ, Reynolds TB, Shaw KJ, Goodwin TM. Revers-ible peripartum l iver failure: a new perspective on the diagnosis, treat-

ment, and cause of acute fatty liver of pregnancy, based on 28 con-secutive cases. Am J Obstet Gynecol 1999; 181: 389-395

15 Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesisand clinical implications. World J Gastroenterol 2006; 12: 7397-7404

16 Bacq Y. Acute fatty liver of pregnancy. Semin Perinatol 1998; 22: 134-140

17 Ockner SA, Brunt EM, Cohn SM, Krul ES, Hanto DW, Peters MG. Fulmi-nant hepatic failure caused by acute fatty liver of pregnancy treatedby orthotopic liver transplantation. Hepatology 1990; 11: 59-64

18 Reyes H. Review: intrahepatic cholestasis . A puzzling disorder ofpregnancy. J Gastroenterol Hepatol 1 9 9 7 ; 1 2 : 211-216

19 Tan LK . Obstetric cholestasis : current opinions and manage-ment. Ann Acad Med Singapore 2003; 32: 294-298

20 Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M. Hetero-zygous non-sense mutation of the MDR3 gene in familial intrahepaticcholestasis of pregnancy. Lancet 1999; 353: 210-211

21 Rodrigues CM, Marin JJ, Brites D. Bile acid patterns in meconiumare in uenced by cholestasis of pregnancy and not altered by ursode-oxycholic acid treatment. Gut 1999; 45: 446-452

22 Sepulveda WH , Gonzalez C , Cruz MA , Rudolph MI. Vasoconstric-tive effect of bile acids on isolated human placental chorionic veins.Eur J Obstet Gynecol Reprod Biol 1991; 42: 211-215

23 Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL , Glasi-novic JC . Bile acids increase response and expression of humanmyometrial oxytocin receptor. Am J Obstet Gynecol 2003; 189: 577-

582

24 Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems. World J Gastroenterol2008; 14: 5781-5788

25 Ropponen A, Sund R, Riikonen S, Ylikorkala O, Aittomaki K. Intrahepaticcholestasis of pregnancy as an indicator of liver and biliary diseases: apopulation-based study. Hepatology 2006; 43: 723-728

26 Beuers U. Drug insight: Mechanisms and sites of action of ursode-

oxycholic acid in cholestasis . Nat Clin Pract Gastroenterol Hepa-tol 2006; 3: 318-328

27 Kondrackiene J, Beuers U, Kupcinskas L. Efcacy and safety of ur-sodeoxycholic acid versus cholestyramine in intrahepatic cholestasisof pregnancy. Gastroenterology 2005; 129: 894-901

28 Roncaglia N, Locatelli A, Arreghini A, Assi F, Cameroni I, Pezzullo JC,Ghidini A. A randomised controlled trial of ursodeoxycholic acid andS-adenosyl-l-methionine in the treatment of gestational cholestasis.BJOG 2004; 111: 17-21

29 Glantz A , Marschall HU , Lammert F , Mattsson LA . Intrahepaticcholestasis of pregnancy : a randomized controlled trial compar-ing dexamethasone and ursodeo-xycholic acid. Hepatology 2005; 42:1399-1405

30 Khuroo MS, Teli MR, Skidmore S, et al: Incindence and severity of viralhepatitis in pregnancy. Am J Med 70:252, 1981.

31 Khurro MS, Kamili S, Jameel S: Vertical transmission of hepatitis E virus.Lancet 345:1025, 1995

32 Nanda SK, Ansari IH, Acharya SK, et at: Protracted viremia during acutesporadic hepatitis E virus infection. Gastroenterology 108:225, 1995

33 Rab MA, Bile MK, Mubarik MM, et al: Water-borne hepatitis E virusepidemic in Islamabad, Pakistan: A common source outbreak traced tothe malfunction of a modern water treatment plat. Am J Trop Med Hyg57:151, 1997

34 Lok AS: Natural history and control of perinatally acquired hwpatitis Bvirus infection. Dig Dis 10:46, 1992

35 Beasley RP, Trepo C, Stevens CE, et al : The e antigen and vertical trans-mission of hepatitis B surface antigen. Am J Epidemiol 105:94, 1977

36 Beath SV, Boxall EH, Watson RM, et al: Fulminant hepatitis B in infantsborn to anti-HBe hepatitis B carrier mothers. BMJ 304:1169, 1992.

37 American Academy of Pediatrics Committee on Infectious Diseases:Universal hepatitis B immunization. Pediatrics 89:795, 1992.

38 ven Zonneveld M, van Nunen AB, Niesters HG : Lamivudine treatmentduring pregnancy to prevent perinatal transmission of hepatittis B virusinfection. J viral Hepat 10:294, 2003

39 Conte D , Fraquelli M , Prati D , Colucci A , Minola E.Prevalenceand clinical course of chronic hepatitis C virus(HCV) infection andrate of HCV vertical transmission in a cohort of 15,250 pregnantwomen. Hepatology 2000; 31: 751-755

40 Mast EE , Hwang LY , Seto DS , Nolte FS , Nainan OV , Wurtzel H,Alter MJ. Risk factors for perinatal transmission of hepatitis C virus(HCV ) and the natural history of HCV infection acquired in in-fancy. J Infect Dis 2005; 192: 1880-1889

41 Hepatitis B and C Infections Centers for Disease Control and Pre-vention website. Available at: http://www.cdc. gov/breastfeeding/dis-ease/hepatitis.htm. Accessed on September 10, 2008

42 Hiratsuka M , Minakami H , Koshizuka S , Sato I. Administrationof interferon -alpha during pregnancy : effects on fetus. J Perinat Med2000; 28: 372-376

43 Trotter JF, Zygmunt AJ. Conception and pregnancy during interferon-alpha therapy for chronic hepatitis C . J Clin Gastroenterol 2001; 32:76-78

44 Ruggiero G, Andreana A, Zampino R. Normal pregnancy under inad-vertent alpha-interferon therapy for chronic hepatitis C. J Hepatol1996; 24: 646


7/7


476

45 Yip DM, Baker AL . Liver diseases in pregnancy . Clin Perinatol 1985;12: 683-694

46 Cheng YS. Pregnancy in liver cirrhosis and /or portal hypertension.Am J Obstet Gynecol 1977; 128: 812-822 101

47 Hay JE. Liver disease in pregnancy. Hepatology 2008; 47: 1067-1076

48 Russell MA, Craigo SD. Cirrhosis and portal hypertension in pregnancy.Semin Perinatol 1998; 22: 156-165

49 Britton RC. Pregnancy and esophageal varices. Am J Surg 1982; 143:421-425

50 Shimono N, Ishihashi H, Ikematsu H, Kudo J, et al: Fulminant hepatic fail-ure during perinatal period in a pregnant woman with Wilsons disease.Gastroenterol Jpn 26:69, 1991

51 Solomon L, Abrams G, Dinner M, et al: Neonatal abnormalities associ-ated with D-penicillamine treatment during pregnancy. N Engl J Med269:54, 1977

52 Scheinberg IH, Sternlieb I: Pregnancy in penicillamine-treated patientswith Wilsons disease. N Engl J Med 293:1300, 1975

53 Breqer GJ, Johnson VD, Dick RD, et al: Treatment of Wilsons disease withzinc. XVII: Treatment during pregnancy. Hepatology 31:364, 2000

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Management of Jaundice in Pregnancy 2010