4. El método de van der Corput 33
4.4. El método de pares de exponentes
Sickle cell disease
Liver and biliary tract dysfunction are common complications of sickle cell anaemia. The disorders are related to haemolysis, anaemia and transfusion management, and the consequences of sickling and vaso-occlusion.
Chronic haemolysis and accelerated bilirubin turnover leads to a high incidence of pigment gallstones and biliary sludge. In addition to biliary colic, this predisposes to cholecystitis and pancreatitis. Complications of repeated blood transfusion include transmission of hepatitis B and C. Measurement of antibodies to these viruses should be performed antenatally.
Prophylactic transfusion for anaemia exacerbated by pregnancy is controversial, unless other complications co-exist, such as severe anaemia, pre- eclampsia, or increased frequency of painful crises. Iron overload occurs with frequent transfusion which can lead to haemochromatosis.
Painful vaso-occlusive crises affect the liver causing right upper quadrant pain, fever, jaundice, elevated AST/ALT and hepatic enlargement. Treatment is supportive.
Malaria
Haemolysis due to the malaria parasite frequently causes jaundice. Pregnant women are especially at-risk from malaria because the malarial parasite favours the placenta as a site of parasite accumulation. At least 24 million pregnancies are affected by malaria annually in Africa and malaria causes up to 15% of maternal anaemia and about 35% of preventable low birth-weight. The management of uncomplicated falciparum malaria comprises specific antimalarial drugs and supportive therapy. Hepatic failure is rare.
Iatrogenic (heart valves)
Mechanical trauma to red blood cells by prosthetic heart valves may cause haemolytic disease with anaemia, jaundice, and congestive cardiac failure. Treatment involves assessing valvular and cardiac function, as well as iron therapy to correct anaemia
INHERITED DISORDERS OF BILIRUBIN METABOLISM
Gilbert’s syndrome, Dubin-Johnson syndrome, and Rotor syndrome
This group of hyperbilirubinaemias are relatively benign causing life-long mild, asymptomatic jaundice. They are caused by deficiencies in bilirubin conjugation (Gilbert’s syndrome) and bile transporters (Dubin-Johnson and Rotor syndromes). Jaundice may be exacerbated in pregnancy and by the combined oral contraceptive pill. Treatment is usually unnecessary and fetal outcomes are good.
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DRUG-RELATED HEPATIC DYSFUNCTION Paracetamol
Paracetamol overdose is often fatal, secondary to fulminant hepatic failure, and is the commonest cause of acute liver failure in the UK. The toxic metabolite causes irreversible hepatotoxicity. Treatment with N-acetylcysteine is advised.
Alcohol
Alcohol-induced hepatic dysfunction is uncommon in pregnancy. BUDD-CHIARI SYNDROME (THROMBOPHILIAS)
In this rare syndrome, the venous outflow of the liver is obstructed with occlusion of the hepatic vein. Thrombophilias such as activated protein C deficiency due to Factor V Leiden mutation predispose to this condition in pregnancy. Acute hepatic venous occlusion presents with abdominal pain, vomiting, tender hepatomegally and ascites. Liver transplantation is the treatment of choice.
VIRAL HEPATITIS
Viral hepatitis is the commonest cause of jaundice in pregnancy.4The principal
viruses infecting the liver are shown in Table 4. Hepatitis A
Hepatitis A virus is a RNA virus spread predominantly by the faecal-oral route. Exposure is usually in childhood and the disease is usually mild, consisting of influenza-like symptoms. Cholestatic jaundice with pruritis, dark
Table 4 Serological antibodies and markers of acute viral hepatitis
Virus Antibodies Other markers
Hepatitis A IgM antihepatitis A virus
Hepatitis B IgM antihepatitis B core Hepatitis B virus DNA
antigen (HBc) clearance
Presence of hepatitis Be anti- gen (Hbe) indicates replication and active infection
Hepatitis C IgM antihepatitis C virus Hepatitis C RNA detection by PCR Hepatitis D IgM antihepatitis D Hepatitis D virus RNA
clearance
Hepatitis E IgM antihepatitis E Hepatitis E virus RNA clearance
Herpes viruses IgM antibodies Cultures, paired sera,
(simplex, zoster, and in situ hybridisation
cytomegalovirus, Epstein-Barr)
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urine and pale stools develops within a few days. Liver function tests reveal normal alkaline phosphatase and γ-GT, with elevated aspartate transaminase and alanine transaminase. Differentiation from other causes of jaundice presenting in pregnancy may be difficult and testing for hepatitis A IgM is required to exclude it. Management is supportive only and the disease is not more severe in pregnancy.
Hepatitis B
Hepatitis B (HBV) affects more than 350 million people world-wide and is transmitted in blood and serum mainly by sexual intercourse, blood transfusion and intravenous drug use. Acute infection can be relatively asymptomatic and without jaundice. However, 1–10% of healthy adults and over 90% of infected babies may fail to clear the virus and become chronic carriers of the virus.4Cirrhosis, liver failure, or hepatocellular carcinoma will
develop in approximately 15–40% of infected patients. In the West, the incidence of chronic carrier status is 0.5–5% of the population.23
The relevance to maternal–fetal medicine is the high risk of vertical transmission, the predisposition of the infected neonate to become a chronic carrier, and the potential for eradication by immunisation. In the UK, it is recommended that the antenatal population should be screened for HBV so that immunisation can be instituted for the offspring of carriers.31,32National
guidelines advise that: (i) all women have information on, and access to, HBV screening as part of their antenatal care; and (ii) all babies born to mothers with HBV infection receive immunisation at or as soon after birth.
There is no contra-indication to vaginal delivery. Breast-feeding of infants of chronic HBV carriers causes no additional risk for the transmission of the hepatitis B virus.
Hepatitis C
Infection with hepatitis C (HCV) occurs world-wide, with a prevalence of antibody to HCV (anti-HCV) in serum in most industrialised countries of 1–2%. Hepatitis C is a blood-borne viral infection that was discovered in the context of blood transfusion. Most Western countries screen donated blood for hepatitis C. Injection-drug abuse accounts for most new infections in the US. HCV may also be transmitted from about 5% of infected mothers to their infant.
Most patients with acute infection are symptom-free and only a small proportion become jaundiced. HCV infection becomes chronic in about 85% of individuals as demonstrated by the persistence of HCV RNA in serum. Virtually all patients with chronic HCV infection develop histological features of chronic hepatitis and around 20% of patients develop cirrhosis in the first or second decade of HCV infection. Unlike with hepatitis B there is no means of immunising a neonate against the vertical transmission of hepatitis C. Hepatitis D
Hepatitis D is an incomplete RNA virus that requires hepatitis B surface antigen to transmit its genome from cell to cell. It only occurs in patients that are positive for hepatitis B surface antigen and is mainly confined to intravenous drug users in the UK.
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Hepatitis E
Hepatitis E causes epidemic, enteric infection in the non-industrialised world and is extremely rare in the UK. The illness is similar to hepatitis A, but, in 15% of pregnant women, fulminant liver failure is reported.
AUTOIMMUNE DISEASE: CHRONIC ACTIVE HEPATITIS
Chronic active hepatitis in women of reproductive age may have autoimmune features with smooth muscle antibodies, nuclear factor (ANF) and auto- antibodies to specific proteins. Some are due to Wilson’s disease, viral hepatitis, and drugs including methyldopa. Untreated chronic active hepatitis is associated with amenorrhoea and infertility. Flare-up of chronic active hepatitis has been reported during pregnancy. Drugs used to treat chronic active hepatitis (e.g. prednisolone and azathioprine) may be used during pregnancy without ill effect on the fetus. Pregnant women with chronic active hepatitis have a higher incidence of still-births and low birth-weight infants.
INHERITED LIVER DISEASES
Primary biliary cirrhosis
Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterised by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serological hallmark of PBC is the presence of antibodies to mitochondria. Treatment is symptomatic and vitamin K supplements should be given.
Wilson’s disease (hepatolenticular degeneration)
Wilson’s disease is rare, autosomal recessive condition characterised by the deposition of copper in the brain, liver, cornea and other organs. Clinical features include liver cirrhosis, liver failure, neurological dysfunction and intellectual deterioration. Pregnant patients with Wilson’s disease should remain on anti-copper therapy with zinc during pregnancy.
Haemochromatosis
Haemochromatosis is an autosomal recessive condition, affecting around 1 in 300 Caucasians. Iron is absorbed in excess and deposited in various organs including the liver leading to eventual fibrosis and functional organ failure. Cirrhosis is a late feature in untreated individuals. Venesection relieves iron overload, prolongs life and may reverse tissue damage.
CIRRHOSIS
Pregnancy in advanced cirrhosis is rare and fetal loss is high.4 Maternal
prognosis depends on the degree of hepatic dysfunction. Bleeding from oesophageal varices is the most significant complication, and most likely in the first trimester. Vitamin supplementation is essential.
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POST-HEPATIC CAUSES OF LIVER DYSFUNCTION Cholelithiasis
Gallstones and pancreatitis are two non-obstetric causes of abdominal pain and abnormal liver function tests. Typically, liver function tests will show an obstructive picture. Gallbladder surgery in pregnancy is second only to that for acute appendicitis. Endoscopic cholecystectomy can successfully be performed in the first and second trimesters, but is technically more difficult in late pregnancy.
Cholangiocarcinoma
Cholangiocarcinomas can be either intra- or extrahepatic: extrahepatic tumours give rise to post-hepatic jaundice. The prognosis for these tumours is poor. Cholangitis
Acute cholangitis is due to bacterial infection in the biliary tree and is always secondary to bile duct abnormalities (e.g. bile duct stones, biliary strictures, neoplasms). The symptoms are fever, upper abdominal pain and jaundice. Gram-negative septicaemia may develop. Treatment is with intravenous antibiotics and fluids.
Inflammatory bowel disease
Crohn’s disease and ulcerative colitis affect 3–7 per 100,000 and 6–10 per 100,000 of the population in Western countries, respectively. A considerable proportion of patients with inflammatory bowel disease have abnormal liver function tests. Pregnancy neither relieves nor exacerbates inflammatory bowel disease.
Key points for clinical practice
• Liver dysfunction arises in up to 3% of pregnancies. • Patients with pre-eclampsia should be screened for HELLP
syndrome with liver function tests and platelet count.
• For patients with hepatic involvement, a multidisciplinary team is required, with intensive care facilities and ready availability of blood products.
• Acute fatty liver of pregnancy presents in the third trimester with malaise of gradual onset followed by jaundice. Early recognition and delivery with supportive care usually results in good maternal and fetal outcome.
• Obstetric cholestasis presents in the second half of pregnancy with progressive pruritus which may be followed by jaundice. Most fetal deaths occur after 36 weeks of gestation; therefore, early delivery when fetal lungs are mature should be considered. • Viral hepatitis is the commonest cause of jaundice in pregnancy.
Antenatal screening for hepatitis B (HBV) is recommended to enable immunisation of all babies born to mothers with HBV.
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References
1. Ch’ng CL, Morgan M, Hainsworth I, Kingham J. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut2002; 51: 876–880.
2. Department of Health. Why Mothers Die. Report on Confidential Enquiries into Maternal
Deaths in the United Kingdom 1997–99. London: Stationary Office; 2002.
3. Lammert F, Marschall H, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol2000; 33:1012–1021. 4. Fagan EA. Diseases of the liver, biliary system and pancreas. In: Creasy RK, Resnik RP.
(eds) Maternal–Fetal Medicine. Principles and Practice. Philadelphia, PA: WB Saunders, 1986; 1040–1061.
5. Chesley LC. Cardiovascular changes in pregnancy. Obstet Gynecol Annu1975; 4: 71–97. 6. Britton RC. Pregnancy and esophageal varices. Am J Surg1982; 143: 421–425.
7. van Thiel D. Effects of pregnancy and sex hormones on the liver. Semin Liver Dis1987; 7: 1–66.
8. Rahman TM, Wendon J. Severe hepatic dysfunction in pregnancy. Q J Med2002; 95: 343–357.
9. Abraham KA, Connolly G, Farrell J, Walshe JJ. The HELLP syndrome, a prospective study. Ren Fail2001; 23: 705–713.
10. Tyni T, Ekholm E, Pihko H. Pregnancy complications are frequent in long-chain 3- hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Obstet Gynecol1998; 178: 603–608.
11. Isler CM, Rinehart BK, Terrone DA, Martin RW, Magann EF, Martin Jr JN. Maternal mortality associated with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol1999; 181: 924–928.
12. Saphier CJ, Repke JT. Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: a review of diagnosis and management. Semin Perinatol1998; 22: 118–133. 13. Walker JJ. Pre-eclampsia. Lancet2000; 356: 1260–1265.
14. Chan AD, Gerscovich EO. Imaging of subcapsular hepatic and renal hematomas in pregnancy complicated by pre-eclampsia and the HELLP syndrome. J Clin Ultrasound 1999; 27: 35–40.
15. Anon. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet2002; 359: 1877–1890.
16. Isler CM, Barrilleaux PS, Magann EF, Bass JD, Martin Jr JN. A prospective, randomized trial comparing the efficacy of dexamethasone and betamethasone for the treatment of antepartum HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol2001; 184: 1332–1337.
17. Girling JC, Dow E, Smith JH. Liver function tests in pre-eclampsia: importance of comparison with a reference range derived for normal pregnancy. Br J Obstet Gynaecol 1997; 104: 246–250.
18. Walker JJ. Current thoughts on the pathophysiology of pre-eclampsia/eclampsia. In: Studd J. (ed) Progress in Obstetrics and Gynaecology, vol. 13. Edinburgh: Churchill Livingstone, 1998; 177–190.
19. Ockner SA, Brunt EM, Cohn SM, Krul ES, Hanto DW, Peters MG. Fulminant hepatic failure caused by acute fatty liver of pregnancy treated by orthoptic liver
transplantation. Hepatology1990; 11: 59–64.
20. Castro MA, Fassett MJ, Reynolds TB, Shaw KJ, Goodwin TM. Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol1999; 181: 389–395. 21. Strauss AW, Bennett MJ, Rinaldo Pet al. Inherited long-chain 3-hydroxyacyl-CoA
dehydrogenase deficiency and a fetal-maternal interaction cause maternal liver disease and other pregnancy complications. Semin Perinatol1999; 23: 100–112.
22. Ibdah JA, Bennett MJ, Rinaldo Pet al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med1999; 340: 1723–1731.
23. Fagan EA. Disorders of liver, biliary system and pancreas. In: de Swiet M. (ed) Medical
Disorders in Obstetric Practice. London: Blackwell Science, 1995; 321–379.
24. Larrey D, Rueff B, Feldmann G, Degott C, Danan G, Benhamou JP. Recurrent jaundice caused by recurrent hyperemesis gravidarum. Gut1984; 25: 1414–1415.
69
Management of abnormal liver function in pregnancy
25.Nelson-Piercy C, Fayers P, de Swiet M. Randomised, double-blind, placebo-controlled trial of corticosteroids for the treatment of hyperemesis gravidarum. Br J Obstet Gynaecol 2001; 108: 9–15.
26. Milkiewicz P, Elias E, Williamson C, Weaver J. Obstetric cholestasis. BMJ2002; 324: 123–124.
27. Mazzella G, Rizzo N, Azzaroli F et al. Ursodeoxycholic acid administration in patients with cholestasis of pregnancy: effects on primary bile acids in babies and mothers. Hepatology2001; 33: 504–508.
28. Reyes H, Sjovall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med2000; 32: 94–106.
29. Rioseco AJ, Ivankovic MB, Manzur Aet al. Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome. Am J Obstet Gynecol1994; 170: 890–895.
30. Loo CC, Tan JY. Decreasing the plasma triglyceride level in hypertriglyceridemia- induced pancreatitis in pregnancy: a case report. Am J Obstet Gynecol2002; 187: 241–242. 31. NHS Executive. Screening of Pregnant Women for Hepatitis B and Immunisation of Babies At
Risk. London: Department of Health (HSC 1998/127), 1998.
32. Department of Health and Royal College of Midwives. Hepatitis B – Testing in Pregnancy. London: Department of Health/Royal College of Midwives, 2000.
Caesarean section rates have risen in many countries.1,2There is concern that
the result will be a rise in complications without benefit to either mother or baby.3 Three main issues need to be addressed in answering the question
posed in the title: (i) justification for reducing a Caesarean section rate; (ii) acceptability to women of reducing a Caesarean section rate; and (iii) safe implementation of reducing a Caesarean section rate.