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Hyperemesis gravidarum, gastrointestinal and liver disease in pregnancy
Current Obstetrics & Gynaecology (2001) 11, 336 ^343
c 2001 Harcourt Publishers Ltd doi:10.1054/cuog.2001.0205 available online at http://www.idealibrary.com on
Hyperemesis gravidarum, gastrointestinal and liver disease in pregnancy A. P. Kenyon* and C. Nelson-Piercy{ *Research Fellow, Department of Obstetrics,10th Floor North Wing, St Thomas’ Hospital, Lambeth Palace Road, London, SE17EH,UK; {Consultant Obstetric Physician, Guy’s & St Thomas NHS Trust, Directorate O⁄ce, 9th Floor New Guy’s House, Guy’s Hospital, St Thomas’ Street, London, SE19RT, UK
KEYWORDS pregnancy, obstetric cholestasis, hyperemesis gravidarum, ulcerative colitis, crohn’s disease, coeliac disease, obstetric cholestasis, gallstones, liver function
Summary Women of childbearing age may be a¡ected by diseases of the gastrointestinal tract or liver; some have no e¡ect on obstetric outcome, some are improved in pregnancy and some deteriorate.Gastrointestinal or liver disease may be caused by pregnancy and resolve following delivery e.g. hyperemesis gravidarum, pre-eclampsia, acute fattyliver of pregnancy,HELLP syndrome and obstetric cholestasis, or maypresent for the ¢rsttime in pregnancy e.g. in£ammatory bowel disease, cholelithiasis and hepatitis.These examples and other common gastrointestinal and liver disorders will be discussed giving details of diagnosis, management and e¡ects on pregnancy outcome and also background information on normalliver physiology in pregnancy.
c 2001Harcourt Publishers Ltd
INTRODUCTION New onset liver disease is uncommon in pregnancy. Many of the signs of liver disease may be seen in normal pregnancy e.g. spider naevi and palmar erythema but have no pathological signi¢cance. Gastrointestinal symptoms are also common. Nausea, vomiting, re£ux oesophagitis and constipation are all considered normal and do not adversely a¡ect outcome but re£ect the normal pregnancy-induced changes in maternal physiology. All need to be distinguished from pathological conditions that may present with similar signs and symptoms.
TESTING LIVER FUNCTION Liver metabolism is increased in pregnancy and alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin and gamma glutamyl transferase (GGT) are at least 20% lower in normal pregnancies than the quoted reference ranges for non-pregnant individuals. Particular patterns of abnormality in liver function may be helpful in determining the site of damage within the liver, with important exceptions in pregnancy.Transaminases (AST and ALT) are elevated in hepatocellular damage, alkaline phosphatase and GGTare produced by cells lining the bile canaliculi and are elevated when liver damage occurs at this site.The placenta also produces alkaline phosphatase and di¡erential testing to distinguish Correspondenceto: APK.Tel: 020 79289292,Ext: 2247;fax: 020 76201227; E-mail: [email protected]
the liver isoenzyme may be required; the placental form is heat stable. Liver function rather than liver damage is re£ected by serum albumin and bilirubin which are reduced (reduced synthesis) and elevated (reduced excretion), respectively, in disease. Albumin falls by 20 ^ 40% in pregnancy not due to abnormal function but due to dilution as a result of the increased blood volume. An additional important functional role of the liver is in glucose homeostasis (hypoglycaemia in disease) and the synthesis of the clotting factors II,VII, IX and X.These clotting factors all require vitamin K which itself may not be absorbed if there is obstructed bile £ow i.e. cholestasis. The prothrombin time is dependent on many of these and, although insensitive, can be an early indicator of severe acute liver damage. It can be corrected with vitamin K if the pathology is cholestasis but not in severe hepatitis or chronic liver disease. Clotting factors II, IX and X are raised in normal pregnancies. Liver function tests may also be a¡ected by mode of delivery; ALT and AST rise after Caesarean section and by a smaller degree after vaginal delivery. The reasons for this are as yet unclear.
GASTROINTESTINAL AND LIVER DISEASE UNIQUE TO PREGNANCY Hyperemesis gravidarum Fifty per cent of pregnant women report vomiting and 70 ^ 80% nausea. Hyperemesis gravidarum (HG) is much less common, a¡ecting 1^2% of all pregnancies and is de¢ned as severe or protracted vomiting in early
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pregnancy su⁄cient to cause £uid, electrolyte and nutritional disturbance, weight loss and ketosis. The onset is around 6 ^ 8 weeks gestation but the diagnosis is one of exclusion and new symptoms appearing after the 12th week should not be attributed to HG. Urinary tract infection, pancreatitis, peptic ulceration, hyperthyroidism or Addison’s disease (rarely) should be excluded and a pelvic ultrasound to exclude molar pregnancy or con¢rm multiple pregnancy should be performed. Investigations may reveal hyponatraemia, hypokalaemia, low serum urea, ketonuria and a hypochloraemic alkalosis. The haematocrit is raised and the speci¢c gravity of urine increased. Fifty per cent of cases may be associated with abnormal liver function of which a moderate rise in transaminases (450 m mol/l but 5200 m mol/l) and bilirubin (not frank jaundice) are the most commonly seen. Elevated free T4 and a low TSH may also be seen and at early gestations but do not always indicate hyperthyroidism. Human chorionic gonadotrophin (HCG) is a weak thyrotropin (TSH) agonist and when the levels are the highest (10 ^12 weeks) there is a rise inT4 resulting in the suppression of TSH. Only a small proportion have clinical hyperthyroidism (and these probably secrete a variant of HCG with increased TSH activity). Where HCG concentrations are high for extended periods of time e.g. in twin and HG pregnancies, signi¢cant HCG-induced stimulation can occur decreasingTSH and increasing free hormone concentrations. The abnormal tests do not require treatment and improve spontaneously as the HCG levels fall in later pregnancy or as HG resolves. An association between HG and immunoglobulin (Ig) G positivity to Helicobacter Pylorii, particularly in cases where symptoms persist into the second trimester, has been reported. Women entering pregnancy with an untreated or partially treated eating disorder are also at increased risk of HG. Treatment in HG is directed at controlling the symptoms, rehydrating and correcting any biochemical abnormalities.
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taken either as bendectin (debendox: a drug combining doxylamine, dicyclomine and pyridoxine) one tablet b.d.+10 mg extra pyridoxine daily, or as pyridoxine alone, 50 ^100 mg daily. Home administration of subcutaneous metoclopramide may also be helpful. Treatment with antibiotics and a proton pump inhibitor or H2 receptor antagonist (to eradicate H. Pylorii) has been shown in one study to be of bene¢t in controlling nausea and vomiting in HG.
Steroids in hyperemesis gravidarum Corticosteroids, possibly acting via an e¡ect on the chemoreceptor trigger zone or because they correct a relative adrenal insu⁄ciency in early pregnancy have been used to treat HG with promising results. The suggested adrenal insu⁄ciency, although an interesting theory low cortisol levels have not been demonstrated in HG and corticosteroid doses used to treat HG are much higher than those needed to acheive replacement. A placebocontrolled trial has suggested a possible bene¢t of corticosteroids in HG. Women were treated with either 40 mg prednisolone daily in two divided doses, progressing to hydrocortisone100 mg i.v. diluted in normal saline twice daily after three days in refractory cases or given placebo tablets or injection. Treatment was continued for 1 week. Another placebo-controlled study used 48 mg methylprednisolone orally for 3 days followed by a 10 -day tapering of the dose. Additional study regimes described are 48 mg methylprednisolone daily for 3 days and tapered for 12 days in those who responded and stopped in those who did not. All studies treated only women for whom all other treatments had failed and found that steroids led to an improvement in symptoms. Steroids are only recommended for refractory cases and other options in those who fail to respond include termination of the pregnancy or total parenteral nutrition (TPN). TPN has signi¢cant side e¡ects such as lengthy hospital stay, venous thrombosis, cellulitis, line sepsis, bacterial endocardiitis and pneumonia and should be used only with specialist involvement.
Symptom control Antiemetics that may be used are: . . . . . .
Cyclizine 50 mg p.o./i.m./i.v. t.d.s Promethazine 25 mg p.o. Nocte Metoclopramide 10 mg p.o./i.m./i.v. t.d.s Stemetil 5 mg p.o. tds.12.5 mg i.m./i.v. t.d.s Domperidone 10 mg p.o. q.d.s or 30 ^ 60 mg p.r. t.d.s Chlorpromazine 10 ^25 mg p.o. 25 mg i.m. t.d.s
All are safe in the ¢rst trimester.Other treatments for nausea and vomiting in pregnancy include acupuncture or acupressure (above the wrist on the palmer aspect, position ‘PC6’) ginger (powdered ginger root 250 mg q.d.s) and pyridoxine (vitamin B6). Pyridoxine may be
Rehydration Fluid (and sodium) replacement in HG should be with normal saline or Hartmann’s solution with potassium in addition as required. Low sodium values (particularly if rapid in onset) of less than 120 mmol/l may cause agitation, confusion, ¢ts, myoclonus, asterixis and coma when levels fall below 110 ^115 mmol/l. Persistent vomiting results in malnutrition and leads to vitamin B1 (thiamine) de¢ciency that can cause peripheral neuropathy (especially of the legs), ataxia and optic atrophy. In addition, these individuals can develop Wernicke’s encephalopathy. Classically this condition results in confusion, opthalmoplegia (nystagmus) and ataxia and if untreated carries a
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17% mortality. The end stage of the disease, Korsako¡’s psychosis, is irreversible in up to 50% and characterized by confusion, memory loss and confabulation. The diagnosis can be con¢rmed on ¢nding an elevated erythrocyte transketolase activity and elevated blood pyruvate but this may only be of retrospective diagnostic value. Treatment to prevent Wernicke’s encephalopathy is with thiamine100 mg i.v. diluted in100 ml normal saline infused over 0.5 to1h or 25^50 mg thiamine hydrochloride orally t.d.s. Thiamine replacement should continue until a normal diet is resumed. Wernicke’s encephalopathy can be precipitated by the use of dextrose-containing £uids, particularly if given prior to the replacement of thiamine (thiamine plays an important role in the enzymatic steps involved in glucose metabolism) and these should therefore be avoided. Central pontine myelinolysis (massive progressive demyelination within the central nervous system) can also occur, either as a result of the malnutrition or as a result of too rapid a correction in serum sodium. This causes confusion, cranial nerve palsies (especially of the IVth, Vth and VIth cranial nerves), disturbances of vasomotor control and hypotension. All women admitted with HG should have early appropriate £uid replacement and supplementation with thiamine. Perinatal outcome may be a¡ected in severe HG: growth restriction and intrauterine death. Those with HG (regardless of hospitalization) give birth to a higher proportion of female infants.
Obstetric cholestasis Obstetric cholestasis (OC) is a liver disorder unique to pregnancy. It classically presents with pruritus often involving the palms of the hands and the soles of the feet in the third trimester of pregnancy but has been described in earlier trimesters. On testing liver function transaminases, particularly ALT, are elevated. Less commonly GGT, bilirubin and alkaline phospatase (in excess of the normal pregnancy rise) may be raised. Total bile acids are also elevated and are a sensitive marker for the condition. Women may additionally report dark urine, pale stools, right upper quadrant pain, malaise or an intolerance of fatty foods. The diagnosis is only con¢rmed by excluding other causes of abnormal liver function e.g. hepatitis, biliary obstruction or primary biliary cirrhosis. The condition is more common in multiple pregnancies and women of South American, Scandinavian and Indian descent, and in those with a family history. The pathophysiology of the condition is uncertain, but a genetically inherited susceptibility to oestrogen is likely. Fisk et al analysed all OC case series reported in the English literature from 1966 to 1986 and recorded an overall perinatal mortality rate of 70/1000 and stillbirth rate of 30/1000. Higher incidences of meconium staining (27%) and intrapartum fetal distress (18%) were also noted. By adopting a policy of active management includ-
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ing fetal antenatal monitoring and elective early delivery by 38 weeks, it has been suggested that the perinatal mortality rate can be reduced (18/1000 ^35/1000). However, reported rates of other complications remain high: meconium-stained liquor 16 ^58%, premature delivery 16 ^ 60%, fetal distress 2^33% and postpartum haemorrhage (PPH) 20 ^22% . To date, there is no accurate method of identifying those fetuses at risk of stillbirth but most centres advocate a policy of active management: fetal surveillance and early elective delivery by 38 weeks. A suggested mechanism for the observed risk of PPH is malabsorption of vitamin K and oral supplementation (10 mg water-soluble vitamin K daily) may help to reduce this risk. The pruritus and liver function normalize on delivery (3 days^ 6 weeks) and the recurrence rate in subsequent pregnancies is high (at least 90%).There are no long-term sequelae but a possible association with gallstones has been suggested. There is no correlation between absolute values of liver function or bile acid values and obstetric outcome and liver failure does not occur. Treatment is aimed at controlling pruritus. Initially piriton (4 mg p.o.t.d.s.) and topical emollients can be helpful. Ursodeoxycholic acid (450 mg b.d. Max 1g b.d.) improves liver function and pruritus in some but has not been shown to improve outcome. Reduction in symptom severity has also been reported with dexamethasone (12 mg orally daily for 7 days), S adenosyl methionine and cholestyramine. For the latter two, there are con£icting reports in the literature regarding their bene¢t and cholestyramine may worsen malabsorption of vitamin K. They are no longer widely used.
Research directions . Women heterozygous for defects in the genes coding for proteins involved in bile acid transport from the hepatocyte into the bile canaliculus have been identi¢ed in women with OC and a raised GGT.
Acute fatty liver of pregnancy and HELLP syndrome There is overlap between acute fatty liver of pregnancy (AFLP), HELLP syndrome and liver abnormalities of pre-eclampsia (PET). They are probably a spectrum of diseases with a common aetiology.
HELLP Pre-eclampsia is a multisystem disorder arising as a result of vascular endothelial damage. Abnormalities of liver function may be seen in 20 ^50% of those with PET and are often clinically silent and noted on biochemical screening. However 5^20% of those with PET will develop the more serious complication of haemolysis,
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elevated liver enzymes and low platelets (HELLP) which may be clinically apparent with epigastric pain (65%), nausea and vomiting (35%) and right upper quadrant pain. Hypertension may be seen as with PET but proteinuria may be absent.On testing, liver function transaminases (ALT and AST) are elevated. Bilirubin may also be elevated due to decreased excretion and increased haemolysis which additionally elevates serum lactate dehydrogenase (red blood cell isoenzyme). Platelets are consumed and levels fall. Further endothelial injury releases additional procoagulant substances into the circulation and disseminated intravascular coagulopathy with further consumption of clotting factors and platelets may develop (20%). Fetal growth restriction, placental abruption (16%) and fetal distress are all associated features. Maternal risks are the same as for PET. Rarely, subcapsular liver haematomas, massive hepatic necrosis and liver rupture may occur. Acute renal failure (7%), metabolic acidosis and pulmonary oedema may also be seen. Initial management is resuscitation, correction of coagulopathy, control of blood pressure followed by delivery. Most cases improve after delivery. Some may deteriorate in the ¢rst 48 h and 30% can present postpartum. As with PET meticulous attention to £uid balance is required.The risk of recurrence of HELLP syndrome in subsequent pregnancies is small (4%), however, there is a 25% risk of PETand if there is pre-existing hypertension this rises to 75%.
Acute fattyliver of pregnancy This is a rare (1 in 9000 ^1 in 13 000) but potentially fatal complication of pregnancy for both mother (10 ^20% mortality) and baby (20 ^30% mortality). Untreated, it may cause hepatic failure and encephalopathy. An association with maternal obesity, multiple pregnancy and male fetuses (3 :1) has been observed. It may be more common in ¢rst pregnancies although this association is not as marked as for PET. It usually occurs in the third trimester but has been reported in the second trimester and early postpartum period. It presents with nausea, vomiting, anorexia and malaise. Abdominal pain is a common feature. The disease may initially appear similar to PET but hypertension and proteinuria are usually mild, and hyperuricaemia excessive. Liver function tests (transaminases) are markedly abnormal with values higher than those seen in HELLP and jaundice may be present. White blood cell count may be elevated in excess of the normal pregnancy rise (4156109/l). Hypoglycaemia may be noted. In advanced cases hepatic failure with DIC and renal failure may ensue. The diagnosis can only be con¢rmed on ¢nding microvesicular fatty in¢ltration (steatosis) at liver biopsy but this is rarely performed in those with clotting defects and a clinical diagnosis is su⁄cient. Transient diabetes insipidus has been described in association with AFLP and should be suspected if exces-
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sive thirst or polyuria are noted. Delivery is the only treatment. There is no bene¢t in conservative management. Resuscitation including correction of any coagulopathy and hypoglycaemia should be undertaken prior to delivery and a multidisciplinary team (obstetrician, anaesthetist, and paediatrician) should be involved. The fetus is also at risk and should be carefully monitored. Recovery after delivery may be rapid with no long-term sequelae, but those developing fulminant hepatic failure prior to delivery may require liver transplantation, and haemorrhagic complications secondary to coagulopathy are common. Prompt diagnosis and delivery are essential. The recurrence rate in subsequent pregnancies is not thought to be high (10 ^20%). Subsequent pregnancies should be monitored with serial liver function tests.
Preexisting or coincident liver disease Hepatitis Acute viral hepatitis is the most common cause of jaundice in pregnancy worldwide and may be caused by the hepatitis viruses A, B, C, D, E and G, or by cytomegalovirus (CMV), Epstein Barr virus (EBV) or herpes simplex virus (HSV). Many infections are asymptomatic. Only a third of patients with acute hepatitis A virus infection (HAV) are jaundiced and primary infections with hepatitis C virus (HCV) and hepatitis B virus (HBV) may be asymptomatic except in IVdrug abusers when 30% with a primary infection with HBV are jaundiced.The course is una¡ected by pregnancy except in those with hepatitis E virus (HEV) or disseminated HSV, when mortality for mother and baby are increased. Common symptoms of the acute illness are myalgia, right upper quadrant pain, nausea, vomiting, fatigue and malaise. All may occur prior to the onset of jaundice (preicteric phase).The ALT is raised (may be100 times normal) and alkaline phosphatase and GGTare frequently normal. A few patients may develop cholestasis during the acute phase. This is most common with HAV and can be prolonged. Only HCV, HBV and hepatitis D virus (HDV) result in chronic hepatitis which is a histological diagnosis (¢brosis, cirrhosis) that may only be discovered during the investigation of abnormal liver function (many have a chronically elevated ALT) or because of complications. The course of chronic hepatitis is una¡ected by pregnancy. Liver biopsy is often required in the management of chronic liver disease but should be avoided in pregnancy.
Hepatitis A Transmission is by the orofaecal route and by sexual contact and and may be possible (rarely) after contact with infected blood products. Diagnosis is done by testing for antihepatitis A IgM. Typically, HAV causes a minor illness
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in childhood and the acute illness is often self-limiting. HAVdoes not cause a chronic carrier state and perinatal transmission is extremely rare.
Hepatitis B Transmission is by sexual contact and contact with infected blood products, though orofaecal transmission may be possible. Standard testing is for the surface antigen (HBsAg), other tests determine whether the virus is active or replicating. Testing can detect core antigen (HBc) (found only in liver cells), its blood-borne derivative the e antigen (HBeAg) and later in the disease course their antibodies (antiHBcIgM, antiHBcIgG, antiHBeIgG and antibody to HBsAg (antiHBsIgG)). IgM anti-HBc suggests that an immune response is being mounted within hepatocytes i.e. acute HBV infection. Antigen replacement with antibody can cease at any stage leaving persistent antigenaemia. If the antigen is still detectable after 6 months the individual is said to be a carrier of hepatitis B antigen. Persistant e antigen is associated with a high infectivity and an increased risk of chronic liver disease and eventual hepatocellular carcinoma. The acute illness is usually self-limiting. Those with chronic disease but normal biochemistry and appearance of the liver on ultrasound require no intervention.Those where these features are not normal require liver biopsy. Interferon or lamivudine (DNA replication inhibitor) are e¡ective in treating the disease. Perinatal infection is common especially for those mothers with persisitent e antigenaemia (or lack e antibody). The transmission, however, is thought to occur at delivery and not across the placenta. Neonates should be given Hepatitis B immunoglobulin and hepatitis B vaccine at birth. If immunized, babies may safely be breast-fed. Hepatitis D virus is dependent on co-infection with Hepatitis B virus for replication. Immunoprophylaxis for HBV is e¡ective against HDV.
Hepatitis C Transmission is by contact with infected blood products. Sexual contact may rarely account for some cases but orofaecal transmission is not thought to occur. Following the introduction of screening pregnant women for HBV (and vaccination of their o¡spring), HCV is emerging as a more signi¢cant form of liver disease and can be detected in 0 ^ 4.3% of pregnant women. This ¢gure varies across geographic regions. Testing is by enzyme-linked immunosorbent assay, measuring binding of an antigen with antiHCV antibodies in the patient’s serum. Acute HCV infection, however cannot be reliably diagnosed in this way because tests may not become positive for up to three months. In chronic HCV, detection of antibodies is
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not su⁄cient and persisting viral RNA can be detected in the serum by PCR. Those with detectable virus or those with abnormal liver function test require a liver biopsy to assess the stage of disease. Since the introduction of HCV screening of blood products vertical transmission is now a major route of transmission and is the most common cause of infection in children. Transmission via infected drug-abusing individuals is, however, still an important cause. The rate of mother-to-infant transmission is about 5% where the mother is not co-infected with HIV when the risk of transmission is 3^5 times higher. Transmission rates may also be higher if the maternal viral load (as measured by HCV-RNA) is high. Passive transfer means that HCV material can be detected in fetal blood for up to 18 months. Testing of the fetus should therefore be done after this time. Breast-feeding and vaginal delivery do not in£uence the rate of transmission. It is important to arrange follow-up of both the woman and her o¡spring if HCV is diagnosed during pregnancy, for there is strong evidence to suggest that early treatment with interferon alpha and tribavarin reduces the risk of chronic infection (80% to 50% with treatment). Disease progression is slow, with a median of 30 years between infection and cirrhosis. Age 40 or over at the time of infection, high alcohol consumption and male sex are all associated with an increased risk of progressive liver disease. In patients with chronic HCV, serum transaminases may return to normal during pregnancy. An association between HCV and OC has been reported and screening for HCV should be undertaken in anyone with OC, particularly if the OC is early in onset. No immunoprophylaxis for HCV is available.
Hepatitis E HEV is rare in the United Kingdom (UK). The importance of this condition is the apparent predilection of the virus for pregnant women, in whom infection can be fatal. It is particularly dangerous if contracted in the third trimester and may result in hepatic encephalopathy and liver failure. Outside pregnancy the primary infection is mild and self-limiting. It is transmitted via the orofaecal route. There is no chronic carrier state and perinatal transmission does not occur. HGV is related to HCV and has only recently been identi¢ed.
Herpes simplex virus Primary infection with HSV type 2 (sexually transmitted compared with type 1 that is usually acquired in childhood) can cause fulminant hepatic failure in a pregnant woman and is associated with a high mortality. The disease is often disseminated and pneumonitis or encephalitis may co-exist. Diagnosis is made on liver biopsy (focal haemorrhagic necrosis, intranuclear inclusion bodies)
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and treatment should be with intravenous antiviral therapy.
Other causes of viral hepatitis Acute hepatitis is common in infections with EBV and rare with CMV. Jaundice is uncommon. EBV is transmitted by close oral contact and may be acquired asymptomatically. If symptoms occur they are usually those of a sore throat and generalized lymphadenopathy (glandular fever/infectious mononucleosis).The average age of infection is 20 years. Perinatal transmission does not occur. 50% to 60% of women of childbearing age in the UK will have antibodies to CMV indicating past infection. In primary CMV infection, the virus is present in the circulation and is shed from the cervix, crosses the placenta and is found in the urine. IgG and IgM against CMV can be detected in the maternal serum. IgM may remain positive for several months. Signs and symptoms include a sore throat, generalized lymphadenopthy or splenomegally and may occur in association with a mild febrile illness.The average age of infection is 30 years.Overt disease occurs in only a few patients and the immunocompromised are particularly at risk. Primary infection in the pregnant woman at any gestation may a¡ect the fetus (30 ^ 40%) causing congenital abnormalities and growth restriction. Problems are rare after reactivation or reinfection with a di¡erent strain. Five to 7% will be symptomatic at birth (of which 20% die) with e.g. jaundice, hepatosplenomegally, rash, chorioretinitis, intracranial calci¢cation, encephalitis or microcephally and 10 ^15% may have abnormalities later e.g. psychomotor delay, sensorineural hearing loss.
Cholelithiasis Cholesterol and triglycerides accumulate in the liver during normal pregnancy, perhaps to sustain the fetus during periods of starvation. Serum cholesterol levels rise by 25^50% and serum triglycerides by150% from the fourth month of pregnancy to their peak at term. This, in association with the enlarged gallbladder and supersaturation of bile with cholesterol, contributes to the increased gallstone formation seen in pregnant women. During routine obstetric ultrasound 2^ 4% of women are found to have asymptomatic gallstones. Symptomatic disease occurs in only 0.5^1%. Features are much the same as outside pregnancy and include right upper quadrant pain and nausea and vomiting.Those with acute cholecystitis may also have tenderness and pyrexia. Investigations should include an ultrasound of the gallbladder (distension or thickening of the wall or a £uid collection), white cell count (may be raised), liver function tests and a serum amylase. Pancreatitis must be excluded although mild elevations of serum amylase are seen with acute cholecystitis. Management is the same as in the non-pregnant
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patient and is medical initially (intravenous £uids, analgesia,+antibiotics) with those who have persisting symptoms or complicated gallstone disease (i.e. cholangitis/ cholecystitis, acute pancreatitis) being referred for early ERCP or surgery. Laparoscopic surgery is safe in pregnancy. It has been suggested that it should be performed with fetal monitoring and supraumbilical open cannulation for insu¥ation.The woman should be adequately hydrated preoperatively.
Coeliac disease Coeliac disease is a permanent gluten-sensitive enteropathy possibly of immunological, autoimmune origin resulting in in£ammation of the small bowel. It a¡ects 1: 300 of the general population. Many present in adulthood with malaise, nausea, vomiting, abdominal pain, bloating or diarrhoea. Diagnosis is now made easier due to the availability of testing for endomysial autoantibodies. However, biopsy of the small bowel mucosa remains the de¢nitive diagnostic test. A gluten-free diet is an effective treatment and if strict can lead to complete remission. Prolonged breast-feeding during the period at which gluten rich foods would normally be introduced, reduces the risk. Large amounts of gluten in the diet increases the risk.The condition frequently leads to malabsorption of many nutrients such as iron, folic acid, calcium and fat-soluble vitamins. The disease itself is una¡ected by pregnancy but women with CD should pay careful attention to diet and receive adequate supplementation with iron and folate.
In£ammatory bowel disease: ulcerative colitis and Crohn’s disease Crohn’s Disease Crohn’s Disease (CD) is a progressive, granulomatous, in£ammatory disorder of the intestine, most commonly the terminal ileum. Short a¡ected segments of bowel are often separated by normal bowel i.e. skip lesions. Its prevalence is 40 ^ 80 per 100 000 and it commonly presents in the teens and early twenties with cramping abdominal pain and diarrhoea. There may be associated anaemia and weight loss (50%), fresh blood or melaena per rectum (40%), ¢stulae or perianal sepsis (15^20%). Intermittent intestinal obstruction or strictures may occur.Occasionally uveitis, arthritis, skin rashes (erythema nodosum and pyoderma) or renal stones may occur. Diagnosis is made on the basis of the clinical picture, radiological ¢ndings (‘rose thorn’, ‘skip lesions’, cobblestone, ¢brosis or ‘string sign’ on barium enema) or biopsy (laparotomy or endoscopy). Some cases remit spontaneously. Long-term management for recurrent disease includes attention to diet and vitamin supplementation (folic acid, vitamin B12, iron, Vitamins A, D, E, K,
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potassium, zinc and calcium). Steroids in low doses orally may reduce recurrence rates and may suppress acute intestinal symptoms (i.v. or orally, depending on disease severity) in those with ileal or colonic disease. Mesalazine (an antiin£ammatory agent: 5 amino salicylic acid (5ASA), or azathioprin (cytotoxic immunosuppressant) are also of use in ileal and colonic disease but an elemental diet is usually only helpful in ileal disease and sulphasalazine (an antibiotic compound, sulphapyridine and an antiin£ammatory agent, 5ASA, in combination) in colonic disease. Sulphasalazine is associated with side e¡ects (marrow supresssion, haemolysis, skin rashes, gastrointestinal symptoms) and 5ASA alternatives (which lack the sulphapyridine) such as mesalazine are often better tolerated and are available in slow release, targeted release and enema formulations. Anal disease and ¢stulae may be treated with metronidazole. Surgery is reserved for emergencies (obstruction), those failing to settle with conservative management or to treat abscesses and ¢stulae.
Ulcerative Colitis Ulcerative Colitis (UC) is a chronic in£ammatory disease primarily of the colonic mucosa and usually presents with frequent, loose, small-volume motions with mucus and blood in those aged 20 ^ 40 years. It may present after a single short episode of diarrhoea, years of general ill health with continuous or intermittent diarrhoea or a severe acute episode of bloody diarrhoea, fever, abdominal distension (toxic megacolon) that may be fatal. A mild attack may involve ¢ve motions a day, a moderate attack 10 and a severe attack in excess of 10 times a day. Stool microscopy and culture are important to exclude an infection as the cause of symptoms. It is usual to see rectal disease that spreads continuously but for a variable distance proximally up the large bowel (Unlike CD where there are skip lesions). Diagnosis is based on clinical ¢ndings, radiology (‘hosepipe’ bowel, ulcers, pseudopolyps on barium enema), endoscopy ¢ndings (granular mucosa, pus, blood) and biopsy. Complications include anaemia, weight loss, protein loss, hypoalbuminaemia (and oedema), electrolyte loss, carcinoma of the colon (10% after 10 years; this is not a risk if disease is con¢ned to the rectum), toxic megacolon and subsequent perforation, skin rashes, arthropathy, liver disease, iritis and venous thrombosis. Acute attacks require treatment with steroids. Mild attacks of distal disease may respond to steroid or 5ASA enemas. More extensive disease requires oral 5ASA preparations (sulphasalazine 1g b.d, mesalazine 400 mg t.d.s) or prednisolone (30 ^ 40 mg daily). Severe attacks will require intravenous hydrocortisone (100 mg t.d.s.). Use of 5ASA preparations during times of remission may reduce relapse rates. Patients with toxic megacolon, extensive
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unremitting disease or long-standing disease (and risk of cancer) may bene¢t from surgery, either panproctocolectomy and ileostomy or subtotal colectomy and later terminal ileal pouch formation.
In£ammatory bowel disease in pregnancy Fertility is normal in UC but impaired in CD. Sulphasalazine may cause a reversable reduction in male fertility. In£ammatory bowel disease (IBD) is largely una¡ected by pregnancy.Well-controlled disease prior to pregnancy is likely to remain so.One-third of those in whom disease was active at the time of conception improve but the remainder will have ongoing symptoms throughout pregnancy despite medical treatment. Active disease at the time of conception is associated with an increased risk of miscarriage. IBD is associated with an increased risk of preterm birth and the risk is further increased if there is active disease at any time during the pregnancy. It has been suggested that IBD may £are in the postpartum period due to falling steroid levels.This is probably more common in CD than UC. Azathioprine, steroids and 5ASA-type drugs including sulphasalzine are safe. The prompt treatment of exacerbations is as important in pregnancy as it is outside pregnancy. Careful monitoring for anaemia and high-dose prophylactic folic acid (5 mg daily), especially in those with ileal disease or on sulphasalzine, should be recommended. Active perianal CD at the time of delivery is an indication for Caesarean section but those with no perianal disease, or those with inactive disease, do not require CS unless scarring has resulted in an inelastic perineum. Those with stomas, previous colectomies, ileoanal anastomoses are not known to be at increased risk of complications apart from surgical complications possible at the time of CS. Those women on steroids at a dose 7.5 mg or more for 2 weeks or more require prophylactic steroids during labour (100 mg hydrocortisone 100 mg i.v. or i.m.t.d.s). Breast-feeding is not usually recommended in those on azathioprine.
CONCLUSION Most women with gastrointestinal or liver disease have successful pregnancies. Those women a¡ected by pregnancy- speci¢c gastrointestinal and liver diseases require their early detection and appropriate management. PRACTICE POINTS
Hyperemesis gravidarum . Aims: Accurate diagnosis of HG, improvement of symptoms and correction of dehydration and
HYPEREMESIS GRAVIDARUM,GASTROINTESTINAL AND LIVER DISEASE IN PREGNANCY
malnutrition. Prevention of thiamine de¢ciency and Wernicke’s encephalopathy. . Management: Stop iron supplements; rehydrate with normal saline or Hartmann’s solution adding potassium chloride as required. Avoid dextrosecontaining £uid. Supplement with thiamine. Prescribe regular antiemetic. Emotional support. . Investigations: Weigh on admission and repeat weekly. Daily pulse, lying and standing blood pressure and urinalysis. Urea and electrolyte, liver function, calcium, blood glucose and thyroid function tests. Full blood count, midstream urine for microscopy and culture. Pelvic ultrasound.
Obstetric cholestasis . Aims: To screen all women with pruritus in pregnancy for OC. To exclude any other liver abnormality. To observe those women with OC closely because of the risk of stillbirth. . Management: Explain risks of OC: Stillbirth, fetal distress, meconium-stained liquor, preterm labour and postpartum haemorrhage.O¡er treatment for pruritus (emollients, piriton, ursodeoxycholic acid). O¡er vitamin K if labour is anticipated. (534 weeks is suggested). O¡er delivery at 37^38 weeks gestation. . Investigations: Liver function tests, total serum bile acid measurement, ultrasound of the liver and biliary tree. Screen for hepatitis A, B, and C, Epstein Barr virus. Cytomegalovirus, primary biliary cirrhosis (antimitochondrial antibodies) chronic active hepatitis (antismooth-muscle antibodies).
PRACTICE POINTS
AFLP . Aims: To identify AFLP in those with anorexia, nausea, vomiting or abdominal pain. To resuscitate mother and deliver fetus. . Management: Fetal monitoring. Correct hypoglycaemia with I.V. 50% glucose. Correct any coagulopathy with fresh frozen plasma or platelet transfusion as required. Deliver fetus. Caution with £uid replacement: Large volumes of dilute urine (diabetes insipidus) should be replaced, maintainence £uid should be limited because of risk of £uid overload and pulmonary oedema . Investigations: Blood pressure, urinalysis, full blood count, clotting screen, blood glucose, liver and renal function tests, uric acid, hourly urine output measurement, serum and urine osmolality (if urine output is excessive).
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RESEARCH DIRECTIONS . An association between HELLP and AFLP and asymptomatic maternal heterozygosity for a defect in mitrochondrial fatty acid oxidation (long c 3hydroxyacyl CoA dehydrogenase (LCHAD) de¢ciency) has been proposed. . Mortality is high for homozygous children (metabolic derangement, liver disease, cardiomyopathy or neuropathy in the ¢rst 2 years of life) and may present as sudden infant death in the neonatal period. Observation of the fetuses for this disorder may be indicated in children born to mothers a¡ected by AFLP or HELLP. . What is unclear is what contribution an a¡ected fetus plays in the maternal development of these conditions. Maternal disease may be more severe in those carrying a¡ected babies.
FURTHER READING Girling J C, Dow E, Smith J H (1997) Liver function tests in pre-eclampsia: importance of comparison with a reference range derived for normal pregnancy. Br J Obstet Gynaecol 104, 246^250. David A L, Kotecha M, Girling J C (2000) Factors in£uencing postnatal liver function tests. Br J Obstet Gynaecol 107,1421^1426. Nelson-Piercy C, Fayers P, de Swiet M (2001) Randomised, doubleblind, placebo-controlled trial of corticosteroids for the treatment of hyperemesis gravidarum. Br J Obstet Gynaecol 108, 9^15. Raine Fleming N, Kilby M (1997) Obstetric Cholestasis. Fetal Maternal Med Rev 9,1^17. Ryder S D, Beckingham I J (1901b) ABC of diseases of liver, pancreas, and biliary system ö Acute hepatitis. Br Med J 322,151^153. Ryder S D, Beckingham I J (1901a) ABC of diseases of liver, pancreas, and biliary system ö Chronic viral hepatitis. Br Med J 322, 219^221.
c 2001 Harcourt Publishers Ltd doi:10.1054/cuog.2001.0205 available online at http://www.idealibrary.com on
Hyperemesis gravidarum, gastrointestinal and liver disease in pregnancy A. P. Kenyon* and C. Nelson-Piercy{ *Research Fellow, Department of Obstetrics,10th Floor North Wing, St Thomas’ Hospital, Lambeth Palace Road, London, SE17EH,UK; {Consultant Obstetric Physician, Guy’s & St Thomas NHS Trust, Directorate O⁄ce, 9th Floor New Guy’s House, Guy’s Hospital, St Thomas’ Street, London, SE19RT, UK
KEYWORDS pregnancy, obstetric cholestasis, hyperemesis gravidarum, ulcerative colitis, crohn’s disease, coeliac disease, obstetric cholestasis, gallstones, liver function
Summary Women of childbearing age may be a¡ected by diseases of the gastrointestinal tract or liver; some have no e¡ect on obstetric outcome, some are improved in pregnancy and some deteriorate.Gastrointestinal or liver disease may be caused by pregnancy and resolve following delivery e.g. hyperemesis gravidarum, pre-eclampsia, acute fattyliver of pregnancy,HELLP syndrome and obstetric cholestasis, or maypresent for the ¢rsttime in pregnancy e.g. in£ammatory bowel disease, cholelithiasis and hepatitis.These examples and other common gastrointestinal and liver disorders will be discussed giving details of diagnosis, management and e¡ects on pregnancy outcome and also background information on normalliver physiology in pregnancy.
c 2001Harcourt Publishers Ltd
INTRODUCTION New onset liver disease is uncommon in pregnancy. Many of the signs of liver disease may be seen in normal pregnancy e.g. spider naevi and palmar erythema but have no pathological signi¢cance. Gastrointestinal symptoms are also common. Nausea, vomiting, re£ux oesophagitis and constipation are all considered normal and do not adversely a¡ect outcome but re£ect the normal pregnancy-induced changes in maternal physiology. All need to be distinguished from pathological conditions that may present with similar signs and symptoms.
TESTING LIVER FUNCTION Liver metabolism is increased in pregnancy and alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin and gamma glutamyl transferase (GGT) are at least 20% lower in normal pregnancies than the quoted reference ranges for non-pregnant individuals. Particular patterns of abnormality in liver function may be helpful in determining the site of damage within the liver, with important exceptions in pregnancy.Transaminases (AST and ALT) are elevated in hepatocellular damage, alkaline phosphatase and GGTare produced by cells lining the bile canaliculi and are elevated when liver damage occurs at this site.The placenta also produces alkaline phosphatase and di¡erential testing to distinguish Correspondenceto: APK.Tel: 020 79289292,Ext: 2247;fax: 020 76201227; E-mail: [email protected]
the liver isoenzyme may be required; the placental form is heat stable. Liver function rather than liver damage is re£ected by serum albumin and bilirubin which are reduced (reduced synthesis) and elevated (reduced excretion), respectively, in disease. Albumin falls by 20 ^ 40% in pregnancy not due to abnormal function but due to dilution as a result of the increased blood volume. An additional important functional role of the liver is in glucose homeostasis (hypoglycaemia in disease) and the synthesis of the clotting factors II,VII, IX and X.These clotting factors all require vitamin K which itself may not be absorbed if there is obstructed bile £ow i.e. cholestasis. The prothrombin time is dependent on many of these and, although insensitive, can be an early indicator of severe acute liver damage. It can be corrected with vitamin K if the pathology is cholestasis but not in severe hepatitis or chronic liver disease. Clotting factors II, IX and X are raised in normal pregnancies. Liver function tests may also be a¡ected by mode of delivery; ALT and AST rise after Caesarean section and by a smaller degree after vaginal delivery. The reasons for this are as yet unclear.
GASTROINTESTINAL AND LIVER DISEASE UNIQUE TO PREGNANCY Hyperemesis gravidarum Fifty per cent of pregnant women report vomiting and 70 ^ 80% nausea. Hyperemesis gravidarum (HG) is much less common, a¡ecting 1^2% of all pregnancies and is de¢ned as severe or protracted vomiting in early
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pregnancy su⁄cient to cause £uid, electrolyte and nutritional disturbance, weight loss and ketosis. The onset is around 6 ^ 8 weeks gestation but the diagnosis is one of exclusion and new symptoms appearing after the 12th week should not be attributed to HG. Urinary tract infection, pancreatitis, peptic ulceration, hyperthyroidism or Addison’s disease (rarely) should be excluded and a pelvic ultrasound to exclude molar pregnancy or con¢rm multiple pregnancy should be performed. Investigations may reveal hyponatraemia, hypokalaemia, low serum urea, ketonuria and a hypochloraemic alkalosis. The haematocrit is raised and the speci¢c gravity of urine increased. Fifty per cent of cases may be associated with abnormal liver function of which a moderate rise in transaminases (450 m mol/l but 5200 m mol/l) and bilirubin (not frank jaundice) are the most commonly seen. Elevated free T4 and a low TSH may also be seen and at early gestations but do not always indicate hyperthyroidism. Human chorionic gonadotrophin (HCG) is a weak thyrotropin (TSH) agonist and when the levels are the highest (10 ^12 weeks) there is a rise inT4 resulting in the suppression of TSH. Only a small proportion have clinical hyperthyroidism (and these probably secrete a variant of HCG with increased TSH activity). Where HCG concentrations are high for extended periods of time e.g. in twin and HG pregnancies, signi¢cant HCG-induced stimulation can occur decreasingTSH and increasing free hormone concentrations. The abnormal tests do not require treatment and improve spontaneously as the HCG levels fall in later pregnancy or as HG resolves. An association between HG and immunoglobulin (Ig) G positivity to Helicobacter Pylorii, particularly in cases where symptoms persist into the second trimester, has been reported. Women entering pregnancy with an untreated or partially treated eating disorder are also at increased risk of HG. Treatment in HG is directed at controlling the symptoms, rehydrating and correcting any biochemical abnormalities.
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taken either as bendectin (debendox: a drug combining doxylamine, dicyclomine and pyridoxine) one tablet b.d.+10 mg extra pyridoxine daily, or as pyridoxine alone, 50 ^100 mg daily. Home administration of subcutaneous metoclopramide may also be helpful. Treatment with antibiotics and a proton pump inhibitor or H2 receptor antagonist (to eradicate H. Pylorii) has been shown in one study to be of bene¢t in controlling nausea and vomiting in HG.
Steroids in hyperemesis gravidarum Corticosteroids, possibly acting via an e¡ect on the chemoreceptor trigger zone or because they correct a relative adrenal insu⁄ciency in early pregnancy have been used to treat HG with promising results. The suggested adrenal insu⁄ciency, although an interesting theory low cortisol levels have not been demonstrated in HG and corticosteroid doses used to treat HG are much higher than those needed to acheive replacement. A placebocontrolled trial has suggested a possible bene¢t of corticosteroids in HG. Women were treated with either 40 mg prednisolone daily in two divided doses, progressing to hydrocortisone100 mg i.v. diluted in normal saline twice daily after three days in refractory cases or given placebo tablets or injection. Treatment was continued for 1 week. Another placebo-controlled study used 48 mg methylprednisolone orally for 3 days followed by a 10 -day tapering of the dose. Additional study regimes described are 48 mg methylprednisolone daily for 3 days and tapered for 12 days in those who responded and stopped in those who did not. All studies treated only women for whom all other treatments had failed and found that steroids led to an improvement in symptoms. Steroids are only recommended for refractory cases and other options in those who fail to respond include termination of the pregnancy or total parenteral nutrition (TPN). TPN has signi¢cant side e¡ects such as lengthy hospital stay, venous thrombosis, cellulitis, line sepsis, bacterial endocardiitis and pneumonia and should be used only with specialist involvement.
Symptom control Antiemetics that may be used are: . . . . . .
Cyclizine 50 mg p.o./i.m./i.v. t.d.s Promethazine 25 mg p.o. Nocte Metoclopramide 10 mg p.o./i.m./i.v. t.d.s Stemetil 5 mg p.o. tds.12.5 mg i.m./i.v. t.d.s Domperidone 10 mg p.o. q.d.s or 30 ^ 60 mg p.r. t.d.s Chlorpromazine 10 ^25 mg p.o. 25 mg i.m. t.d.s
All are safe in the ¢rst trimester.Other treatments for nausea and vomiting in pregnancy include acupuncture or acupressure (above the wrist on the palmer aspect, position ‘PC6’) ginger (powdered ginger root 250 mg q.d.s) and pyridoxine (vitamin B6). Pyridoxine may be
Rehydration Fluid (and sodium) replacement in HG should be with normal saline or Hartmann’s solution with potassium in addition as required. Low sodium values (particularly if rapid in onset) of less than 120 mmol/l may cause agitation, confusion, ¢ts, myoclonus, asterixis and coma when levels fall below 110 ^115 mmol/l. Persistent vomiting results in malnutrition and leads to vitamin B1 (thiamine) de¢ciency that can cause peripheral neuropathy (especially of the legs), ataxia and optic atrophy. In addition, these individuals can develop Wernicke’s encephalopathy. Classically this condition results in confusion, opthalmoplegia (nystagmus) and ataxia and if untreated carries a
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17% mortality. The end stage of the disease, Korsako¡’s psychosis, is irreversible in up to 50% and characterized by confusion, memory loss and confabulation. The diagnosis can be con¢rmed on ¢nding an elevated erythrocyte transketolase activity and elevated blood pyruvate but this may only be of retrospective diagnostic value. Treatment to prevent Wernicke’s encephalopathy is with thiamine100 mg i.v. diluted in100 ml normal saline infused over 0.5 to1h or 25^50 mg thiamine hydrochloride orally t.d.s. Thiamine replacement should continue until a normal diet is resumed. Wernicke’s encephalopathy can be precipitated by the use of dextrose-containing £uids, particularly if given prior to the replacement of thiamine (thiamine plays an important role in the enzymatic steps involved in glucose metabolism) and these should therefore be avoided. Central pontine myelinolysis (massive progressive demyelination within the central nervous system) can also occur, either as a result of the malnutrition or as a result of too rapid a correction in serum sodium. This causes confusion, cranial nerve palsies (especially of the IVth, Vth and VIth cranial nerves), disturbances of vasomotor control and hypotension. All women admitted with HG should have early appropriate £uid replacement and supplementation with thiamine. Perinatal outcome may be a¡ected in severe HG: growth restriction and intrauterine death. Those with HG (regardless of hospitalization) give birth to a higher proportion of female infants.
Obstetric cholestasis Obstetric cholestasis (OC) is a liver disorder unique to pregnancy. It classically presents with pruritus often involving the palms of the hands and the soles of the feet in the third trimester of pregnancy but has been described in earlier trimesters. On testing liver function transaminases, particularly ALT, are elevated. Less commonly GGT, bilirubin and alkaline phospatase (in excess of the normal pregnancy rise) may be raised. Total bile acids are also elevated and are a sensitive marker for the condition. Women may additionally report dark urine, pale stools, right upper quadrant pain, malaise or an intolerance of fatty foods. The diagnosis is only con¢rmed by excluding other causes of abnormal liver function e.g. hepatitis, biliary obstruction or primary biliary cirrhosis. The condition is more common in multiple pregnancies and women of South American, Scandinavian and Indian descent, and in those with a family history. The pathophysiology of the condition is uncertain, but a genetically inherited susceptibility to oestrogen is likely. Fisk et al analysed all OC case series reported in the English literature from 1966 to 1986 and recorded an overall perinatal mortality rate of 70/1000 and stillbirth rate of 30/1000. Higher incidences of meconium staining (27%) and intrapartum fetal distress (18%) were also noted. By adopting a policy of active management includ-
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ing fetal antenatal monitoring and elective early delivery by 38 weeks, it has been suggested that the perinatal mortality rate can be reduced (18/1000 ^35/1000). However, reported rates of other complications remain high: meconium-stained liquor 16 ^58%, premature delivery 16 ^ 60%, fetal distress 2^33% and postpartum haemorrhage (PPH) 20 ^22% . To date, there is no accurate method of identifying those fetuses at risk of stillbirth but most centres advocate a policy of active management: fetal surveillance and early elective delivery by 38 weeks. A suggested mechanism for the observed risk of PPH is malabsorption of vitamin K and oral supplementation (10 mg water-soluble vitamin K daily) may help to reduce this risk. The pruritus and liver function normalize on delivery (3 days^ 6 weeks) and the recurrence rate in subsequent pregnancies is high (at least 90%).There are no long-term sequelae but a possible association with gallstones has been suggested. There is no correlation between absolute values of liver function or bile acid values and obstetric outcome and liver failure does not occur. Treatment is aimed at controlling pruritus. Initially piriton (4 mg p.o.t.d.s.) and topical emollients can be helpful. Ursodeoxycholic acid (450 mg b.d. Max 1g b.d.) improves liver function and pruritus in some but has not been shown to improve outcome. Reduction in symptom severity has also been reported with dexamethasone (12 mg orally daily for 7 days), S adenosyl methionine and cholestyramine. For the latter two, there are con£icting reports in the literature regarding their bene¢t and cholestyramine may worsen malabsorption of vitamin K. They are no longer widely used.
Research directions . Women heterozygous for defects in the genes coding for proteins involved in bile acid transport from the hepatocyte into the bile canaliculus have been identi¢ed in women with OC and a raised GGT.
Acute fatty liver of pregnancy and HELLP syndrome There is overlap between acute fatty liver of pregnancy (AFLP), HELLP syndrome and liver abnormalities of pre-eclampsia (PET). They are probably a spectrum of diseases with a common aetiology.
HELLP Pre-eclampsia is a multisystem disorder arising as a result of vascular endothelial damage. Abnormalities of liver function may be seen in 20 ^50% of those with PET and are often clinically silent and noted on biochemical screening. However 5^20% of those with PET will develop the more serious complication of haemolysis,
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elevated liver enzymes and low platelets (HELLP) which may be clinically apparent with epigastric pain (65%), nausea and vomiting (35%) and right upper quadrant pain. Hypertension may be seen as with PET but proteinuria may be absent.On testing, liver function transaminases (ALT and AST) are elevated. Bilirubin may also be elevated due to decreased excretion and increased haemolysis which additionally elevates serum lactate dehydrogenase (red blood cell isoenzyme). Platelets are consumed and levels fall. Further endothelial injury releases additional procoagulant substances into the circulation and disseminated intravascular coagulopathy with further consumption of clotting factors and platelets may develop (20%). Fetal growth restriction, placental abruption (16%) and fetal distress are all associated features. Maternal risks are the same as for PET. Rarely, subcapsular liver haematomas, massive hepatic necrosis and liver rupture may occur. Acute renal failure (7%), metabolic acidosis and pulmonary oedema may also be seen. Initial management is resuscitation, correction of coagulopathy, control of blood pressure followed by delivery. Most cases improve after delivery. Some may deteriorate in the ¢rst 48 h and 30% can present postpartum. As with PET meticulous attention to £uid balance is required.The risk of recurrence of HELLP syndrome in subsequent pregnancies is small (4%), however, there is a 25% risk of PETand if there is pre-existing hypertension this rises to 75%.
Acute fattyliver of pregnancy This is a rare (1 in 9000 ^1 in 13 000) but potentially fatal complication of pregnancy for both mother (10 ^20% mortality) and baby (20 ^30% mortality). Untreated, it may cause hepatic failure and encephalopathy. An association with maternal obesity, multiple pregnancy and male fetuses (3 :1) has been observed. It may be more common in ¢rst pregnancies although this association is not as marked as for PET. It usually occurs in the third trimester but has been reported in the second trimester and early postpartum period. It presents with nausea, vomiting, anorexia and malaise. Abdominal pain is a common feature. The disease may initially appear similar to PET but hypertension and proteinuria are usually mild, and hyperuricaemia excessive. Liver function tests (transaminases) are markedly abnormal with values higher than those seen in HELLP and jaundice may be present. White blood cell count may be elevated in excess of the normal pregnancy rise (4156109/l). Hypoglycaemia may be noted. In advanced cases hepatic failure with DIC and renal failure may ensue. The diagnosis can only be con¢rmed on ¢nding microvesicular fatty in¢ltration (steatosis) at liver biopsy but this is rarely performed in those with clotting defects and a clinical diagnosis is su⁄cient. Transient diabetes insipidus has been described in association with AFLP and should be suspected if exces-
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sive thirst or polyuria are noted. Delivery is the only treatment. There is no bene¢t in conservative management. Resuscitation including correction of any coagulopathy and hypoglycaemia should be undertaken prior to delivery and a multidisciplinary team (obstetrician, anaesthetist, and paediatrician) should be involved. The fetus is also at risk and should be carefully monitored. Recovery after delivery may be rapid with no long-term sequelae, but those developing fulminant hepatic failure prior to delivery may require liver transplantation, and haemorrhagic complications secondary to coagulopathy are common. Prompt diagnosis and delivery are essential. The recurrence rate in subsequent pregnancies is not thought to be high (10 ^20%). Subsequent pregnancies should be monitored with serial liver function tests.
Preexisting or coincident liver disease Hepatitis Acute viral hepatitis is the most common cause of jaundice in pregnancy worldwide and may be caused by the hepatitis viruses A, B, C, D, E and G, or by cytomegalovirus (CMV), Epstein Barr virus (EBV) or herpes simplex virus (HSV). Many infections are asymptomatic. Only a third of patients with acute hepatitis A virus infection (HAV) are jaundiced and primary infections with hepatitis C virus (HCV) and hepatitis B virus (HBV) may be asymptomatic except in IVdrug abusers when 30% with a primary infection with HBV are jaundiced.The course is una¡ected by pregnancy except in those with hepatitis E virus (HEV) or disseminated HSV, when mortality for mother and baby are increased. Common symptoms of the acute illness are myalgia, right upper quadrant pain, nausea, vomiting, fatigue and malaise. All may occur prior to the onset of jaundice (preicteric phase).The ALT is raised (may be100 times normal) and alkaline phosphatase and GGTare frequently normal. A few patients may develop cholestasis during the acute phase. This is most common with HAV and can be prolonged. Only HCV, HBV and hepatitis D virus (HDV) result in chronic hepatitis which is a histological diagnosis (¢brosis, cirrhosis) that may only be discovered during the investigation of abnormal liver function (many have a chronically elevated ALT) or because of complications. The course of chronic hepatitis is una¡ected by pregnancy. Liver biopsy is often required in the management of chronic liver disease but should be avoided in pregnancy.
Hepatitis A Transmission is by the orofaecal route and by sexual contact and and may be possible (rarely) after contact with infected blood products. Diagnosis is done by testing for antihepatitis A IgM. Typically, HAV causes a minor illness
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in childhood and the acute illness is often self-limiting. HAVdoes not cause a chronic carrier state and perinatal transmission is extremely rare.
Hepatitis B Transmission is by sexual contact and contact with infected blood products, though orofaecal transmission may be possible. Standard testing is for the surface antigen (HBsAg), other tests determine whether the virus is active or replicating. Testing can detect core antigen (HBc) (found only in liver cells), its blood-borne derivative the e antigen (HBeAg) and later in the disease course their antibodies (antiHBcIgM, antiHBcIgG, antiHBeIgG and antibody to HBsAg (antiHBsIgG)). IgM anti-HBc suggests that an immune response is being mounted within hepatocytes i.e. acute HBV infection. Antigen replacement with antibody can cease at any stage leaving persistent antigenaemia. If the antigen is still detectable after 6 months the individual is said to be a carrier of hepatitis B antigen. Persistant e antigen is associated with a high infectivity and an increased risk of chronic liver disease and eventual hepatocellular carcinoma. The acute illness is usually self-limiting. Those with chronic disease but normal biochemistry and appearance of the liver on ultrasound require no intervention.Those where these features are not normal require liver biopsy. Interferon or lamivudine (DNA replication inhibitor) are e¡ective in treating the disease. Perinatal infection is common especially for those mothers with persisitent e antigenaemia (or lack e antibody). The transmission, however, is thought to occur at delivery and not across the placenta. Neonates should be given Hepatitis B immunoglobulin and hepatitis B vaccine at birth. If immunized, babies may safely be breast-fed. Hepatitis D virus is dependent on co-infection with Hepatitis B virus for replication. Immunoprophylaxis for HBV is e¡ective against HDV.
Hepatitis C Transmission is by contact with infected blood products. Sexual contact may rarely account for some cases but orofaecal transmission is not thought to occur. Following the introduction of screening pregnant women for HBV (and vaccination of their o¡spring), HCV is emerging as a more signi¢cant form of liver disease and can be detected in 0 ^ 4.3% of pregnant women. This ¢gure varies across geographic regions. Testing is by enzyme-linked immunosorbent assay, measuring binding of an antigen with antiHCV antibodies in the patient’s serum. Acute HCV infection, however cannot be reliably diagnosed in this way because tests may not become positive for up to three months. In chronic HCV, detection of antibodies is
CURRENT OBSTETRICS & GYNAECOLOGY
not su⁄cient and persisting viral RNA can be detected in the serum by PCR. Those with detectable virus or those with abnormal liver function test require a liver biopsy to assess the stage of disease. Since the introduction of HCV screening of blood products vertical transmission is now a major route of transmission and is the most common cause of infection in children. Transmission via infected drug-abusing individuals is, however, still an important cause. The rate of mother-to-infant transmission is about 5% where the mother is not co-infected with HIV when the risk of transmission is 3^5 times higher. Transmission rates may also be higher if the maternal viral load (as measured by HCV-RNA) is high. Passive transfer means that HCV material can be detected in fetal blood for up to 18 months. Testing of the fetus should therefore be done after this time. Breast-feeding and vaginal delivery do not in£uence the rate of transmission. It is important to arrange follow-up of both the woman and her o¡spring if HCV is diagnosed during pregnancy, for there is strong evidence to suggest that early treatment with interferon alpha and tribavarin reduces the risk of chronic infection (80% to 50% with treatment). Disease progression is slow, with a median of 30 years between infection and cirrhosis. Age 40 or over at the time of infection, high alcohol consumption and male sex are all associated with an increased risk of progressive liver disease. In patients with chronic HCV, serum transaminases may return to normal during pregnancy. An association between HCV and OC has been reported and screening for HCV should be undertaken in anyone with OC, particularly if the OC is early in onset. No immunoprophylaxis for HCV is available.
Hepatitis E HEV is rare in the United Kingdom (UK). The importance of this condition is the apparent predilection of the virus for pregnant women, in whom infection can be fatal. It is particularly dangerous if contracted in the third trimester and may result in hepatic encephalopathy and liver failure. Outside pregnancy the primary infection is mild and self-limiting. It is transmitted via the orofaecal route. There is no chronic carrier state and perinatal transmission does not occur. HGV is related to HCV and has only recently been identi¢ed.
Herpes simplex virus Primary infection with HSV type 2 (sexually transmitted compared with type 1 that is usually acquired in childhood) can cause fulminant hepatic failure in a pregnant woman and is associated with a high mortality. The disease is often disseminated and pneumonitis or encephalitis may co-exist. Diagnosis is made on liver biopsy (focal haemorrhagic necrosis, intranuclear inclusion bodies)
HYPEREMESIS GRAVIDARUM,GASTROINTESTINAL AND LIVER DISEASE IN PREGNANCY
and treatment should be with intravenous antiviral therapy.
Other causes of viral hepatitis Acute hepatitis is common in infections with EBV and rare with CMV. Jaundice is uncommon. EBV is transmitted by close oral contact and may be acquired asymptomatically. If symptoms occur they are usually those of a sore throat and generalized lymphadenopathy (glandular fever/infectious mononucleosis).The average age of infection is 20 years. Perinatal transmission does not occur. 50% to 60% of women of childbearing age in the UK will have antibodies to CMV indicating past infection. In primary CMV infection, the virus is present in the circulation and is shed from the cervix, crosses the placenta and is found in the urine. IgG and IgM against CMV can be detected in the maternal serum. IgM may remain positive for several months. Signs and symptoms include a sore throat, generalized lymphadenopthy or splenomegally and may occur in association with a mild febrile illness.The average age of infection is 30 years.Overt disease occurs in only a few patients and the immunocompromised are particularly at risk. Primary infection in the pregnant woman at any gestation may a¡ect the fetus (30 ^ 40%) causing congenital abnormalities and growth restriction. Problems are rare after reactivation or reinfection with a di¡erent strain. Five to 7% will be symptomatic at birth (of which 20% die) with e.g. jaundice, hepatosplenomegally, rash, chorioretinitis, intracranial calci¢cation, encephalitis or microcephally and 10 ^15% may have abnormalities later e.g. psychomotor delay, sensorineural hearing loss.
Cholelithiasis Cholesterol and triglycerides accumulate in the liver during normal pregnancy, perhaps to sustain the fetus during periods of starvation. Serum cholesterol levels rise by 25^50% and serum triglycerides by150% from the fourth month of pregnancy to their peak at term. This, in association with the enlarged gallbladder and supersaturation of bile with cholesterol, contributes to the increased gallstone formation seen in pregnant women. During routine obstetric ultrasound 2^ 4% of women are found to have asymptomatic gallstones. Symptomatic disease occurs in only 0.5^1%. Features are much the same as outside pregnancy and include right upper quadrant pain and nausea and vomiting.Those with acute cholecystitis may also have tenderness and pyrexia. Investigations should include an ultrasound of the gallbladder (distension or thickening of the wall or a £uid collection), white cell count (may be raised), liver function tests and a serum amylase. Pancreatitis must be excluded although mild elevations of serum amylase are seen with acute cholecystitis. Management is the same as in the non-pregnant
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patient and is medical initially (intravenous £uids, analgesia,+antibiotics) with those who have persisting symptoms or complicated gallstone disease (i.e. cholangitis/ cholecystitis, acute pancreatitis) being referred for early ERCP or surgery. Laparoscopic surgery is safe in pregnancy. It has been suggested that it should be performed with fetal monitoring and supraumbilical open cannulation for insu¥ation.The woman should be adequately hydrated preoperatively.
Coeliac disease Coeliac disease is a permanent gluten-sensitive enteropathy possibly of immunological, autoimmune origin resulting in in£ammation of the small bowel. It a¡ects 1: 300 of the general population. Many present in adulthood with malaise, nausea, vomiting, abdominal pain, bloating or diarrhoea. Diagnosis is now made easier due to the availability of testing for endomysial autoantibodies. However, biopsy of the small bowel mucosa remains the de¢nitive diagnostic test. A gluten-free diet is an effective treatment and if strict can lead to complete remission. Prolonged breast-feeding during the period at which gluten rich foods would normally be introduced, reduces the risk. Large amounts of gluten in the diet increases the risk.The condition frequently leads to malabsorption of many nutrients such as iron, folic acid, calcium and fat-soluble vitamins. The disease itself is una¡ected by pregnancy but women with CD should pay careful attention to diet and receive adequate supplementation with iron and folate.
In£ammatory bowel disease: ulcerative colitis and Crohn’s disease Crohn’s Disease Crohn’s Disease (CD) is a progressive, granulomatous, in£ammatory disorder of the intestine, most commonly the terminal ileum. Short a¡ected segments of bowel are often separated by normal bowel i.e. skip lesions. Its prevalence is 40 ^ 80 per 100 000 and it commonly presents in the teens and early twenties with cramping abdominal pain and diarrhoea. There may be associated anaemia and weight loss (50%), fresh blood or melaena per rectum (40%), ¢stulae or perianal sepsis (15^20%). Intermittent intestinal obstruction or strictures may occur.Occasionally uveitis, arthritis, skin rashes (erythema nodosum and pyoderma) or renal stones may occur. Diagnosis is made on the basis of the clinical picture, radiological ¢ndings (‘rose thorn’, ‘skip lesions’, cobblestone, ¢brosis or ‘string sign’ on barium enema) or biopsy (laparotomy or endoscopy). Some cases remit spontaneously. Long-term management for recurrent disease includes attention to diet and vitamin supplementation (folic acid, vitamin B12, iron, Vitamins A, D, E, K,
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potassium, zinc and calcium). Steroids in low doses orally may reduce recurrence rates and may suppress acute intestinal symptoms (i.v. or orally, depending on disease severity) in those with ileal or colonic disease. Mesalazine (an antiin£ammatory agent: 5 amino salicylic acid (5ASA), or azathioprin (cytotoxic immunosuppressant) are also of use in ileal and colonic disease but an elemental diet is usually only helpful in ileal disease and sulphasalazine (an antibiotic compound, sulphapyridine and an antiin£ammatory agent, 5ASA, in combination) in colonic disease. Sulphasalazine is associated with side e¡ects (marrow supresssion, haemolysis, skin rashes, gastrointestinal symptoms) and 5ASA alternatives (which lack the sulphapyridine) such as mesalazine are often better tolerated and are available in slow release, targeted release and enema formulations. Anal disease and ¢stulae may be treated with metronidazole. Surgery is reserved for emergencies (obstruction), those failing to settle with conservative management or to treat abscesses and ¢stulae.
Ulcerative Colitis Ulcerative Colitis (UC) is a chronic in£ammatory disease primarily of the colonic mucosa and usually presents with frequent, loose, small-volume motions with mucus and blood in those aged 20 ^ 40 years. It may present after a single short episode of diarrhoea, years of general ill health with continuous or intermittent diarrhoea or a severe acute episode of bloody diarrhoea, fever, abdominal distension (toxic megacolon) that may be fatal. A mild attack may involve ¢ve motions a day, a moderate attack 10 and a severe attack in excess of 10 times a day. Stool microscopy and culture are important to exclude an infection as the cause of symptoms. It is usual to see rectal disease that spreads continuously but for a variable distance proximally up the large bowel (Unlike CD where there are skip lesions). Diagnosis is based on clinical ¢ndings, radiology (‘hosepipe’ bowel, ulcers, pseudopolyps on barium enema), endoscopy ¢ndings (granular mucosa, pus, blood) and biopsy. Complications include anaemia, weight loss, protein loss, hypoalbuminaemia (and oedema), electrolyte loss, carcinoma of the colon (10% after 10 years; this is not a risk if disease is con¢ned to the rectum), toxic megacolon and subsequent perforation, skin rashes, arthropathy, liver disease, iritis and venous thrombosis. Acute attacks require treatment with steroids. Mild attacks of distal disease may respond to steroid or 5ASA enemas. More extensive disease requires oral 5ASA preparations (sulphasalazine 1g b.d, mesalazine 400 mg t.d.s) or prednisolone (30 ^ 40 mg daily). Severe attacks will require intravenous hydrocortisone (100 mg t.d.s.). Use of 5ASA preparations during times of remission may reduce relapse rates. Patients with toxic megacolon, extensive
CURRENT OBSTETRICS & GYNAECOLOGY
unremitting disease or long-standing disease (and risk of cancer) may bene¢t from surgery, either panproctocolectomy and ileostomy or subtotal colectomy and later terminal ileal pouch formation.
In£ammatory bowel disease in pregnancy Fertility is normal in UC but impaired in CD. Sulphasalazine may cause a reversable reduction in male fertility. In£ammatory bowel disease (IBD) is largely una¡ected by pregnancy.Well-controlled disease prior to pregnancy is likely to remain so.One-third of those in whom disease was active at the time of conception improve but the remainder will have ongoing symptoms throughout pregnancy despite medical treatment. Active disease at the time of conception is associated with an increased risk of miscarriage. IBD is associated with an increased risk of preterm birth and the risk is further increased if there is active disease at any time during the pregnancy. It has been suggested that IBD may £are in the postpartum period due to falling steroid levels.This is probably more common in CD than UC. Azathioprine, steroids and 5ASA-type drugs including sulphasalzine are safe. The prompt treatment of exacerbations is as important in pregnancy as it is outside pregnancy. Careful monitoring for anaemia and high-dose prophylactic folic acid (5 mg daily), especially in those with ileal disease or on sulphasalzine, should be recommended. Active perianal CD at the time of delivery is an indication for Caesarean section but those with no perianal disease, or those with inactive disease, do not require CS unless scarring has resulted in an inelastic perineum. Those with stomas, previous colectomies, ileoanal anastomoses are not known to be at increased risk of complications apart from surgical complications possible at the time of CS. Those women on steroids at a dose 7.5 mg or more for 2 weeks or more require prophylactic steroids during labour (100 mg hydrocortisone 100 mg i.v. or i.m.t.d.s). Breast-feeding is not usually recommended in those on azathioprine.
CONCLUSION Most women with gastrointestinal or liver disease have successful pregnancies. Those women a¡ected by pregnancy- speci¢c gastrointestinal and liver diseases require their early detection and appropriate management. PRACTICE POINTS
Hyperemesis gravidarum . Aims: Accurate diagnosis of HG, improvement of symptoms and correction of dehydration and
HYPEREMESIS GRAVIDARUM,GASTROINTESTINAL AND LIVER DISEASE IN PREGNANCY
malnutrition. Prevention of thiamine de¢ciency and Wernicke’s encephalopathy. . Management: Stop iron supplements; rehydrate with normal saline or Hartmann’s solution adding potassium chloride as required. Avoid dextrosecontaining £uid. Supplement with thiamine. Prescribe regular antiemetic. Emotional support. . Investigations: Weigh on admission and repeat weekly. Daily pulse, lying and standing blood pressure and urinalysis. Urea and electrolyte, liver function, calcium, blood glucose and thyroid function tests. Full blood count, midstream urine for microscopy and culture. Pelvic ultrasound.
Obstetric cholestasis . Aims: To screen all women with pruritus in pregnancy for OC. To exclude any other liver abnormality. To observe those women with OC closely because of the risk of stillbirth. . Management: Explain risks of OC: Stillbirth, fetal distress, meconium-stained liquor, preterm labour and postpartum haemorrhage.O¡er treatment for pruritus (emollients, piriton, ursodeoxycholic acid). O¡er vitamin K if labour is anticipated. (534 weeks is suggested). O¡er delivery at 37^38 weeks gestation. . Investigations: Liver function tests, total serum bile acid measurement, ultrasound of the liver and biliary tree. Screen for hepatitis A, B, and C, Epstein Barr virus. Cytomegalovirus, primary biliary cirrhosis (antimitochondrial antibodies) chronic active hepatitis (antismooth-muscle antibodies).
PRACTICE POINTS
AFLP . Aims: To identify AFLP in those with anorexia, nausea, vomiting or abdominal pain. To resuscitate mother and deliver fetus. . Management: Fetal monitoring. Correct hypoglycaemia with I.V. 50% glucose. Correct any coagulopathy with fresh frozen plasma or platelet transfusion as required. Deliver fetus. Caution with £uid replacement: Large volumes of dilute urine (diabetes insipidus) should be replaced, maintainence £uid should be limited because of risk of £uid overload and pulmonary oedema . Investigations: Blood pressure, urinalysis, full blood count, clotting screen, blood glucose, liver and renal function tests, uric acid, hourly urine output measurement, serum and urine osmolality (if urine output is excessive).
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RESEARCH DIRECTIONS . An association between HELLP and AFLP and asymptomatic maternal heterozygosity for a defect in mitrochondrial fatty acid oxidation (long c 3hydroxyacyl CoA dehydrogenase (LCHAD) de¢ciency) has been proposed. . Mortality is high for homozygous children (metabolic derangement, liver disease, cardiomyopathy or neuropathy in the ¢rst 2 years of life) and may present as sudden infant death in the neonatal period. Observation of the fetuses for this disorder may be indicated in children born to mothers a¡ected by AFLP or HELLP. . What is unclear is what contribution an a¡ected fetus plays in the maternal development of these conditions. Maternal disease may be more severe in those carrying a¡ected babies.
FURTHER READING Girling J C, Dow E, Smith J H (1997) Liver function tests in pre-eclampsia: importance of comparison with a reference range derived for normal pregnancy. Br J Obstet Gynaecol 104, 246^250. David A L, Kotecha M, Girling J C (2000) Factors in£uencing postnatal liver function tests. Br J Obstet Gynaecol 107,1421^1426. Nelson-Piercy C, Fayers P, de Swiet M (2001) Randomised, doubleblind, placebo-controlled trial of corticosteroids for the treatment of hyperemesis gravidarum. Br J Obstet Gynaecol 108, 9^15. Raine Fleming N, Kilby M (1997) Obstetric Cholestasis. Fetal Maternal Med Rev 9,1^17. Ryder S D, Beckingham I J (1901b) ABC of diseases of liver, pancreas, and biliary system ö Acute hepatitis. Br Med J 322,151^153. Ryder S D, Beckingham I J (1901a) ABC of diseases of liver, pancreas, and biliary system ö Chronic viral hepatitis. Br Med J 322, 219^221.