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Gastrointestinal and liver disease in pregnancy
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Gastrointestinal and liver disease in pregnancy
and 1.6/100,000 and that of UC varies between 0.5 and 24.5/ 100,000. The symptoms associated with IBD include diarrhoea, constipation, increased frequency of bowel movements, cramping abdominal pain, nausea and vomiting. Both CD and UC are also associated with several extra-gastrointestinal manifestations, which can affect almost any other body system. Furthermore, scarring from surgery, fistula formation, fat and vitamin malabsorption may pose complications to pregnancy in women with IBD.
Victoria Geenes Catherine Williamson
Abstract Gastrointestinal and liver disorders of pregnancy may be present before a woman becomes pregnant, or they can be specific to pregnancy. They can be complicated by severe morbidity or mortality. Women with pre-existing disorders should have pre-pregnancy counselling. This will enable the potential risks of pregnancy for the mother and fetus to be evaluated, clinical interventions that improve outcomes to be performed, and drug regimens to be reviewed. Once pregnant, it is important to adopt a multidisciplinary approach with the input of obstetricians, midwives, anaesthetists and physicians with experience and expertise in the management of medical disorders of pregnancy.
Pre-pregnancy care: overall fertility rates among women with active IBD may be reduced compared to unaffected, age matched women. Population studies show infertility rates in CD to be between 5 and 14%. The reasons for this are complex and multifactorial; major factors include dyspareunia resulting from previous pelvic surgery, low libido, depression and active avoidance of pregnancy. Fertility rates in women with inactive disease are comparable to age matched unaffected women. Pre-conceptual counselling for women with IBD should focus on the importance of optimizing their disease control and nutrition. Women with IBD should be advised to take high dose (5 mg) folic acid, and to ensure that their vitamin D levels are optimized. Aminosalicylates, cyclosporin and azathioprine have good safety data for use during pregnancy and can be continued, and courses of steroids should be used if required. Methotrexate should be stopped several months prior to conception due to teratogenic effects. Knowledge about the use of biologic agents in pregnancy is improving, and varies depending upon the mode of action of the drug. If women require biologic agents, they can continue using them for the first two trimesters if required. However, women should be aware that IgG1 antibody therapies (infliximab, adalimumab and golimumab) cross the placenta, and if taken in the 3rd trimester the neonate should not have live vaccinations in the first 6 months of life. The risk and complications arising from previous pelvic/abdominal surgery will vary greatly depending on the exact nature of the surgery, and should be discussed with the surgeon who performed the procedure. There is no increased incidence of congenital malformations in babies born to women with IBD.
Keywords disease; gastrointestinal; liver; pregnancy
Introduction Gastrointestinal and liver diseases in pregnancy may be due to pre-existing conditions or be specific to pregnancy. Many of these conditions are associated with increased risks of maternal and fetal morbidity and mortality. For reasons unknown, some have a more severe course when diagnosed during pregnancy, whilst others have little effect on either the mother or baby. Here we review the presentation, management and perinatal outcomes of common gastrointestinal and liver diseases.
Gastrointestinal disease Inflammatory bowel disease Inflammatory bowel disease is a collective term used to describe the chronic inflammatory conditions, Crohn’s disease (CD) and ulcerative colitis (UC). Both CD and UC are characterised by relapsing and remitting inflammation affecting several parts of the gastrointestinal tract, but there are some important differences that are useful to distinguish them. CD can affect any part of the gastrointestinal tract, although there is often rectal sparing, and involves transmural inflammation. In comparison, UC affects only the colon and rectum and involves the submucosa and mucosa. IBD is more common in women than men, and is most frequently diagnosed in the reproductive years, with at least 50% being diagnosed before the age of 35 years and 25% before conception. The worldwide incidence of CD varies between 0.1
Antenatal care: the course of IBD during a pregnancy appears to be related to the level of disease activity at the time of conception. Women with inactive disease at the time of conception have a similar risk of relapse to non-pregnant women, which is approximately 30% over 12 months. Women with active disease at the time of conception, have an increased risk of flares during pregnancy. These should be managed in conjunction with a gastroenterologist with experience of IBD in pregnancy. Active IBD during pregnancy is associated with increased risk of pre-term delivery, intrauterine growth restriction and low birth weight. These complications are more often seen in women with CD compared to women with UC, but the reasons for this are unclear. In addition, IBD is also associated with increased risks of venous thromboembolism (UC more than CD), antepartum haemorrhage (CD more than UC) and delivery by caesarean section. Women presenting with new symptoms suggestive of IBD during pregnancy, or with flares, can be safely investigated using
Victoria Geenes MBBS PhD is a Clinical Research Fellow at the Maternal and Fetal Disease Group, King’s College London, UK. Conflicts of interest: none declared. Catherine Williamson MBChB MD is Professor of Women’s Health at the Maternal and Fetal Disease Group, King’s College London, UK. Conflicts of interest: none declared.
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Please cite this article in press as: Geenes V, Williamson C, Gastrointestinal and liver disease in pregnancy, Obstetrics, Gynaecology and Reproductive Medicine (2017), http://dx.doi.org/10.1016/j.ogrm.2017.01.005
REVIEW
challenges in antenatal care. Bariatric surgery includes gastric banding, gastric bypass and biliopancreatic diversion surgery. The main benefit is weight loss, but this occurs at the risk of marked malabsorption.
ultrasound or MRI. Flexible sigmoidoscopy is often the endoscopic investigation of choice, but colonoscopy may be used if clinically indicated. The indications for surgery in pregnant women with IBD are the same as those for non-pregnant women.
Pre-pregnancy care: women are generally advised against becoming pregnant in the first year following surgery, due to concerns over conceiving during a period of marked weight loss. However, there are no studies to support or refute this advice. Particular care should be taken in the pre-conceptual period to optimize nutrition, particularly with regards to fat-soluble vitamins, calcium and iron.
Labour and delivery: although there is no specific guidance regarding the optimal mode of delivery, there are some specific considerations. For women with CD and active perianal or rectal disease, an elective caesarean section is almost always advised. Delivery by caesarean section is commonly preferred where there is an ileo-anal pouch or ileo-rectal anastomosis, but it is advisable to have multidisciplinary review of the merits of different modes of delivery for individual cases.
Antenatal care: women who have had bariatric surgery have reduced rates of gestational diabetes mellitus, but have higher rates of small-for-gestational age babies and pre-term delivery. Thus far there are no specific requirements for care during the antenatal period. However, the presentation of a woman with abdominal pain should be taken seriously and the differential diagnosis should include band slippage, herniation or intussusception. Management strategies for other gastrointestinal disorders in pregnancy are summarized in Table 1.
Post-partum care: women should be counselled about the importance of continuing their medications in the post-partum period to reduce the risk of a flare. Most of the medications used to maintain IBD are safe in breastfeeding. Babies born to women treated with infliximab should not receive live vaccines in the first six months of life. Coeliac disease Coeliac disease is a gluten sensitive enteropathy predominantly affecting the small bowel. In affected individuals, exposure to gluten causes an inflammatory reaction, which results in villous atrophy and malabsorption. Characteristic symptoms of coeliac disease are chronic diarrhoea, abdominal distension, malabsorption and loss of appetite. It can present at any age, and is slightly more common in women than men. The only effective treatment of coeliac disease is a life-long gluten free diet. Adherence to this improves symptoms, and reduces the risk of long-term complications including the risk of intestinal lymphoma.
Liver disease The liver undergoes several adaptive changes during normal pregnancy to enable it to cope with increased demands on
Management strategies for pregnant women with gastrointestinal disorders Considerations in pregnancy
Gastrooesophageal reflux
More common in pregnancy.
Management
H2 receptor antagonists and proton pump inhibitors can be safely used in pregnancy. Peptic ulcer Incidence in pregnancy Helicobacter pylori disease unclear, but may be lower. eradication is safe if indicated. Endoscopy can be safely performed in pregnancy. Pancreatitis Incidence of and risk Supportive factors for pancreatitis are management as per unchanged by pregnancy. non-pregnant women. Monitor for malabsorption and gestational diabetes. Appendicitis May present with atypical Surgical management pain and therefore be as per non-pregnant harder to diagnose. women. Location of appendix may be altered in third trimester. Gastroenteritis None Supportive as per nonpregnant women.
Pre-pregnancy care: there is conflicting evidence regarding fertility rates and miscarriage rates in women with coeliac disease, but it has been suggested that both can be improved with a gluten free diet. Women with coeliac disease should receive high dose folic acid pre-conceptually, and there should be a focus on optimizing nutrition whilst maintaining a gluten free diet. Antenatal care: coeliac disease is associated with an increased risk of intrauterine growth restriction, low birth weight and preterm delivery. The increased risk for pre-term delivery is significantly reduced in women who are treated with a strict gluten free diet. Women with coeliac disease should therefore be regularly screened for fetal growth, and also monitored for malabsorption. Routine serological testing and endoscopy can be performed during pregnancy in women presenting with symptoms suggestive of coeliac disease for the first time. Labour and delivery: there are no specific considerations for labour or delivery in women with coeliac disease. Bariatric surgery The number of women becoming pregnant with a history of bariatric surgery is increasing, and these women present new
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Condition
Table 1
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following immunosuppressive treatment, and it is estimated that up to 6% of cases present during pregnancy. AIH can be divided into three subtypes: types I, II and III. AIH type I is the most common subtype and is characterised by antinuclear antibodies (ANA, 70%) or anti-smooth muscle antibodies (SMA, 57%). It affects people of any age, unlike type II which predominantly affects children and young women. Type II is characterised by anti-liver kidney microsomal antibodies (LKM1, 3e4%), and seronegativity for ANA and SMA. Type II is associated with a more severe phenotype and a greater risk of extrahepatic autoimmune disease. Type III is characterised by the presence of anti-soluble liver antigen and liver-pancreas antibodies. It accounts for up to 30% of AIH.
metabolism and excretion of endobiotics. These changes mean that the normal ranges for liver function tests are altered, and that some clinical signs that are considered to be pathological outside of pregnancy are not of concern in pregnancy. For example, palmar erythema and spider naevi can be normal in pregnant women. The liver does not change in size during human pregnancy, but it does move to a more superior and posterior position. Liver disease in pregnancy may result from pre-existing conditions or can be the result of pregnancy-specific disorders. In addition, hypertensive disorders may present with abnormal liver function tests, and these are summarized in Table 2. Infective hepatitis Viral hepatitis is becoming an increasingly common problem in obstetrics. The characteristics and effects of the different viruses on pregnancy are described in Table 3.
Pre-pregnancy care: women with AIH should be counselled about the importance of continuing their immunosuppressive treatment, and reassured that azathioprine is not associated with adverse outcomes during pregnancy and is also safe in breastfeeding. Women should be screened for anti-Ro and anti-La antibodies and thyroid function tests should be performed, as AIH is commonly associated with other autoimmune conditions. They should also be offered screening for oesophageal varices prior to conception.
Autoimmune hepatitis Autoimmune hepatitis (AIH) may present as acute hepatitis, chronic hepatitis or even cirrhosis. It is characterized by hepatocellular inflammation and necrosis, and predominantly affects women (3:1 female to male preponderance). There are two peaks of presentation (10e30 years and 40e50 years). Typical symptoms of AIH include fatigue, myalgia, pruritus, nausea, anorexia and upper abdominal pain. Women may also have amenorrhoea and older studies have reported high rates of infertility as a consequence. More recent studies report successful pregnancies
Antenatal care: the risk of adverse perinatal outcomes is increased in poorly controlled disease or cirrhosis. Recent studies have shown that approximately one third of women with AIH will experience a flare of disease during pregnancy, but that this risk can be reduced with good compliance with immunosuppressive therapy. Serious maternal complications, defined as death or liver transplantation with 12 months of delivery, or decompensation of liver disease within 3 months of delivery, occur in up to 11% of women with AIH. The age at diagnosis of AIH, poor compliance with treatment, relapse within 12 months prior to conception, and the presence of cirrhosis are all factors which are associated with an increased risk of maternal and fetal morbidity and mortality. For management of cirrhosis in pregnancy, see later.
Abnormalities in liver function tests as a result of hypertensive disorders of pregnancy Distinguishing feature
Pre-eclampsia HELLP* syndrome
Typical gestational week at onset Symptoms and signs C Headache C Visual disturbance C Abdominal/epigastric pain C Nausea and vomiting C Polyuria/polydipsia C Oedema C Raised blood pressure C Brisk reflexes/clonus C Proteinuria Liver function tests C ALT C AST C gGT C Bilirubin C Bile acids Other tests C Haemoglobin C Platelets C Creatinine C Urate
>20 weeks
36 (25e38)
[ [ [ [ [ [ [[ [ [
[ [[ [[ [ [ [ [ [ [
[ [ [ N N
[[ [ [ [ N
N Y [ [
Y YY [ [
*
Labour and delivery: there is an increased risk of pre-term delivery and admission to SCBU, particularly in women with poorly controlled disease or cirrhosis. There are no specific guidelines regarding the mode of delivery in women with AIH, but the risks of labour should be considered in women with known hepatic cirrhosis or varices. Post-partum care: women should continue to take their immunosuppressive treatments in the post-partum period to reduce the risk of a flare. Azathioprine is safe in breastfeeding. Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is a chronic inflammatory condition affecting the intrahepatic and extrahepatic bile ducts, in which recurrent episodes of cholangitis lead to progressive scarring and obstruction of the bile ducts. It may present with cirrhosis or liver failure. Symptoms are typical of cholestasis, including chronic fatigue jaundice, pruritus and malabsorption. PSC affects males more commonly than females, (2:1 male to female preponderance), with a peak age at diagnosis of 20
The haemolysis, elevated liver enzymes and low platelets syndrome.
Table 2
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Hepatitis viruses in pregnancy: effects and management Virus
Characteristics
Considerations in pregnancy
Hepatitis A Small, non-enveloped RNA virus Faeco-oral transmission Not associated with chronic infection Incubation period 2e7 days
Does not usually cause major maternal or neonatal morbidity. Acute infection in T3 is associated with preterm labour. In utero transmission rare e causes fetal meconium peritonitis in T1 and asymptomatic infection/self-limiting neonatal cholestasis in T3. Hepatitis B Double stranded DNA virus, with eight May present as acute or chronic infection. known serotypes. Screen for virus at booking and in T3 if Transmitted via unprotected sex and ongoing risk of infection. IVDU in low prevalence areas. Anti-HBsAg negative women at high risk MTC transmission in high prevalence should be offered vaccination. areas. Course of acute and chronic infection is unchanged by pregnancy. Not associated with congenital malformation or stillbirth.
Management Vaccination for women at risk. Supportive treatment in acute infection.
Supportive treatment in acute infection. Nucleoside analogues may be used in fulminant infection or protracted severe infection. Limited evidence for anti-virals in pregnancy e generally treatment should be deferred. No evidence to support routine elective caesarean section. Breast milk contains virus, but breastfeeding does not increase risk of transmission. Infants should receive HBV vaccine and immunoglobulin. Hepatitis C RNA virus with six known genotypes. May present as acute or chronic infection. Antiviral treatment is contraindicated in Blood-borne virus most commonly Only screen high risk women for infection. pregnancy due to teratogenicity. acquired via IVDU in adults and MTC Course of infection is unchanged by No evidence to support elective caesarean transmission in children. pregnancy. section. Risk of MTC transmission increased by Associated with increased risk of ICP. MTC transmission is associated with HCV HIV co-infection (3). Not associated with congenital malformation viraemia, prolonged ROM (>6 hours) and or stillbirth. intrapartum exposure to maternal blood. Avoid prolonged ROM and use of fetal scalp electrodes. Breast milk contains virus, but breastfeeding does not increase the risk of transmission. Infants should be tested for HCV antibodies at 16 months of age. Hepatitis E RNA virus. Typically causes acute self-limiting hepatitis, Supportive management. Transmission unclear, but likely water but pregnant women are more susceptible to Post-exposure immunoglobulin treatment borne. does not reduce risk of infection. infection and have higher risk of fulminant hepatic failure. Maternal mortality rate is up to 26%. MTC transmission may occur in utero or directly. Transmission in T3 is associated with a risk of neonatal hepatic necrosis and neonatal death. Not associated with chronic infection, congenital malformation or stillbirth. Associated with pre-term delivery. Abbreviations: T3 e third trimester; T1 e first trimester; IVDU e intravenous drug use; MTC e mother to child; HBsAg e hepatitis B surface antigen; HBV e hepatitis B virus; HIV e human immunodeficiency virus; HCV e hepatitis C virus; ROM e rupture of membranes; ICP e intrahepatic cholestasis of pregnancy.
Table 3
e30 years. Although there are no specific antibodies for PSC, 80% of those affected are positive for peri-nuclear antineutrophil cytoplasmic antibodies (pANCA) and 20e50% are positive for anti-nuclear antibodies (ANA) or anti-smooth muscle antibodies (SMA). PSC is associated with
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inflammatory bowel disease, and ulcerative colitis is present in up to 70%. Pre-pregnancy care: PSC is associated with increased risks of worsening liver function either during pregnancy or in the post-
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REVIEW
partum period. This risk may be ameliorated by treatment with UDCA. Although there are insufficient data to demonstrate a protective effect, UDCA is safe to use during pregnancy, and therefore women should be encouraged to continue taking it. Nutrition should be optimized, and women should be advised to take vitamin supplements to reduce the risk of malabsorption, particularly of fat-soluble vitamins.
Biliary atresia Biliary atresia may be congenital or acquired, and it is a progressive inflammatory disease of the bile ducts that leads to cholestasis. The aetiology of biliary atresia is unknown, but is likely to be multi-factorial. Treatment is with surgical reconstruction of the bile ducts (Kasai procedure) in the first instance. This procedure is not curative, but delays the need for liver transplantation.
Antenatal care: there is no increase in the risk of low birth weight or stillbirth, and therefore no specific role for additional antenatal fetal surveillance. PSC is not associated with an increased risk of congenital malformation, stillbirth or neonatal death. Successful endoscopic retrograde pancreatography (ERCP) and stenting during pregnancy have been performed.
Pre-pregnancy care: women with biliary atresia should be counselled about the risk of deteriorating liver function during pregnancy. Women with portal hypertension and oesophageal varices appear to have an increased risk of bleeding. Maternal nutrition should be optimized, with particular attention paid to fat-soluble vitamins due to the risk of malabsorption.
Labour and delivery: in relation to fetal outcomes, PSC is associated with an increased risk of pre-term delivery (both iatrogenic and spontaneous) and delivery by caesarean section, mainly elective. There are no specific recommendations relating to the mode of delivery but consideration should be given to the risks of labour in the presence of cirrhosis.
Antenatal care: perinatal outcomes in women with biliary atresia appear to be good, and in the small numbers of cases reported there does not seem to be an association with any particular adverse outcome. Biliary atresia has not been associated with congenital malformations. There is one case report of an intrauterine death in a woman with cholangitis and portal hypertension.
Post-partum care: women with PSC remain at high risk of a flare of their disease in the post-partum period. UDCA is safe to use in breastfeeding, and women should be counselled to continue taking it.
Labour and delivery: there is no specific guidance on the mode of delivery for women with biliary atresia, but consideration should be given to the potential risks of labour in women with portal hypertension.
Primary biliary cirrhosis Primary biliary cirrhosis (PBC) is an autoimmune disease characterised by the progressive destruction of small bile ducts leading to cirrhosis. The symptoms are similar to those of PSC, but in contrast PBC is a disease that predominantly affects women (9:1 female to male preponderance). It typically presents in middle age (35e55 years), but may be diagnosed in women of reproductive age. PBC is commonly associated with extrahepatic autoimmune diseases, and up to 80% of those affected have another autoimmune condition. Antimitochondrial antibodies (AMA) are characteristic in PBC and are positive in 90e95%. Anti-nuclear antibodies (ANA) are also positive in up to 35% of cases.
Post-partum care: in the majority of cases, maternal liver function improves rapidly post-partum, although it is possible that prolonged cholestasis may result in the need for urgent liver transplantation. Wilson’s disease Wilson’s disease is a rare genetic (autosomal recessive) disorder of copper metabolism. It is characterised by an accumulation of copper in the liver and other organs, resulting predominantly in cirrhosis, liver failure, neurological and psychiatric symptoms. Infertility and recurrent miscarriage are common in women with Wilson’s disease and may be the presenting features of the disease. Pre-pregnancy care: women with Wilson’s disease should be counselled about the risks of discontinuing treatment, which include deterioration of liver function, haemolysis and maternal death. The main treatments used in Wilson’s disease are Dpenicillamine, trientine and zinc, the former of which are known to be teratogenic at high doses. However, the doses used in the treatment of Wilson’s disease are much lower and appear to be safe in pregnancy. Furthermore, cessation of treatment can cause severe deterioration of disease and women should be encouraged to continue taking therapy for Wilson’s disease in pregnancy.
Pre-pregnancy care: there are few reports of pregnancy in women with PBC, and there is no clear consensus of the effect of the disease on pregnancy outcomes. The drugs commonly used to treat PBC, including UDCA, cholestyramine and rifampicin are safe in pregnancy and it therefore seems judicious to continue them to reduce the risk of deterioration in maternal liver function. As with PSC, maternal nutritional status should be optimized and women should be given vitamin supplementation. Antenatal care: several case reports have suggested that there is an increased risk of adverse perinatal outcomes in women with PBC, including intrauterine fetal death. However, the numbers of women in the studies are too small to be conclusive.
Antenatal care: perinatal outcomes in women with Wilson’s disease are reported to be good, and there are no specific considerations for antenatal care beyond compliance with treatment.
Labour and delivery: there is no specific guidance on the mode of delivery for women with PBC, but consideration should be given to the potential risks of labour in women with cirrhosis.
Labour and delivery: there are no specific guidelines for labour and delivery, but consideration should be given to the potential risks of labour in women with Wilson’s disease and cirrhosis.
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REVIEW
Post-partum care: infants born to women typically have normal levels of copper and caeruloplasmin.
Cirrhosis is also associated with increased risks of preeclampsia, placental abruption, post-partum haemorrhage and maternal death, and therefore women should be closely monitored in specialist units to mitigate against these risks.
Hereditary haemochromatosis Hereditary haemochromatosis is an inherited disorder of iron metabolism. Clinical presentations are variable, and depend on the predominant organ affected, but may be asymptomatic in the early stages. Chronic haemochromatosis is associated with cirrhosis and hepatocellular carcinoma, dilated cardiomyopathy or cardiac conduction disturbances, pancreatic dysfunction or diabetes, hypogonadism, non-inflammatory osteoarthritis and bronzing of the skin. Women of reproductive age may be protected from the clinical manifestations of haemochromatosis by regular menstruation.
Labour and delivery: there are very limited data regarding the optimal way to delivery women with cirrhosis, but there are concerns over allowing women to labour as the process involves repeated Valsalva manoeuvres which raise intra-abdominal pressure and therefore increase the risk of variceal rupture. Therefore an assisted second stage of labour is advisable. Liver transplantation Pre-pregnancy care: data relating to pregnancy in women with previous liver transplants are limited, but outcomes are likely to be improved in women with adequate immunosuppression. Women should therefore be counselled about the importance of continuing their immunosuppressive regimens, and should also be treated with high dose (5 mg) folic acid.
Pre-pregnancy care: women should be counselled about the risks of end-organ dysfunction in pregnancy. These should be discussed on an individualized basis depending on the organs affected, but may include the risks of glycaemic control at the time of conception, the presence of cardiomyopathy or cirrhosis.
Antenatal care: perinatal outcomes in women with a history of liver transplantation are reported to be good, especially if pregnancy is delayed for 12 months after surgery, or after an episode of rejection. Furthermore, the live birth rate is reported to be 70 e90%. There is an increased risk of hypertensive disorders and pre-eclampsia and women should be closely monitored for these and other complications. There are also increased risks of preterm birth and low birth weight infants. Graft survival does not appear to be affected by pregnancy, despite the reported incidence of rejection during pregnancy being between 2 and 17%. Episodes of rejection should be managed as they are in non-pregnant women i.e. with appropriate investigations and changes to the immunosuppressive regimen if necessary.
Antenatal care: women with haemochromatosis should be monitored for fetal growth, particularly in the presence of diabetes. Glycaemic control should be tightly maintained throughout pregnancy to reduce the associated risks of adverse perinatal outcomes. Labour and delivery: there are no specific guidelines for labour and delivery, but consideration should be given to the potential risks of labour in women with haemochromatosis and cirrhosis. Cirrhosis and portal hypertension Cirrhosis is the common end point of many liver diseases, and is defined as permanent scarring of the liver from continuous longterm insults. The majority of cases of cirrhosis in the UK are the result of excessive alcohol consumption and hepatitis C infection. It is associated with portal hypertension, oesophageal varices and hypersplenism.
Labour and delivery: there are no specific considerations regarding the mode of delivery in women with previous liver transplantation, but the underlying pathology should be taken into consideration.
Pre-pregnancy care: data relating to pregnancy in women with cirrhosis are sparse. Studies of women with alcoholic liver disease or viral hepatitis have suggested that there are higher rates of both maternal and neonatal mortality, and the risk is further increased in those with portal hypertension and oesophageal varices. Women should therefore be offered screening and treatment for oesophageal varices prior to conception.
Acute fatty liver of pregnancy Acute fatty liver of pregnancy (AFLP) is a rare cause of acute liver failure in pregnancy. It most commonly occurs in the third trimester, but up to 20% of cases present following delivery. Nulliparity and multiple pregnancy are recognized as risk factors, and there is an association between AFLP and disorders of betafatty acid oxidation, most commonly fetal homozygosity for long chain 3 hydroxyl-acyl-coenzyme A dehydrogenase (LCHAD) deficiency. LCHAD deficient fetuses have a reduced capacity to oxidise long chain fatty acids in the liver and placenta, and therefore there is an accumulation of hepatotoxic metabolites in the maternal liver. AFLP is characterised by microvesicular steatosis and affects approximately 1 in 7000e16,000 pregnancies. AFLP typically presents with vomiting, reduced appetite, midepigastric or right upper quadrant abdominal pain, headache and jaundice. Hyperlactaemia, hypoglycaemia, hypertension, proteinuria, ascites and bleeding secondary to coagulopathy may also be present. These clinical features are included in the ‘Swansea Criteria’ (Table 4), a set of symptoms, signs and
Antenatal care: the management of the underlying disease should be optimized, and particular attention should be paid to maternal nutritional and iron status, given the risks of malabsorption and anaemia. Up to 78% of women with pre-existing oesophageal varices will have a bleed during pregnancy, most commonly in the second or third trimester. Endoscopy in the 2nd trimester is often advised, as existing oesophageal varices can worsen, and new varices can appear in pregnancy. Endoscopy, sclerotherapy and ligation banding appear to be safe, and reduce the risk of a potentially life-threatening haemorrhage, but data are limited and there are no randomized controlled trials.
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REVIEW
women in the UK. Characteristically it presents in the third trimester with maternal pruritus and raised serum bile acid levels. Symptoms of cholestasis (dark urine, pale stools and steatorrhoea) may also be present and the liver transaminases (ALT, AST) are usually elevated. Clinical jaundice is rare. The diagnosis of ICP is one of exclusion, and women should be investigated for other causes of cholestasis or hepatic impairment. Serum bile acids are the most sensitive and specific test for the diagnosis and monitoring of the condition.
Swansea criteria for acute fatty liver of pregnancy Six or more of the following in the absence of an alternative cause should be present to make the diagnosis Symptoms and signs
Laboratory abnormalities
Other
Vomiting Abdominal pain Polydipsia/polyuria Encephalopathy Elevated bilirubin (>14 mmol/L) Hypoglycaemia (<4 mmol/L) Elevated urate (>340 mmol/L) Leucocytosis (>11 109/L) Elevated transaminases (ALT or AST, >42 IU/L) Elevated ammonia (>47 mmol/L) Renal impairment (creatinine >150 mmol/L) Coagulopathy (PT > 14 second or APTT >34 second) Ascites or bright liver on ultrasound Microvesicular steatosis on liver biopsy
Pre-pregnancy care: ICP is reported to be more common in women with a personal or family history of the condition, gallstones or multiple pregnancy. No other specific risk factors have been identified. Antenatal care: ICP is usually a benign condition for the mother, but severe disease (defined as serum bile acid concentrations greater than 40 mmol/L) is associated with an increased risk of adverse fetal outcomes, including pre-term delivery (both spontaneous and iatrogenic), prolonged admission to the neonatal unit and stillbirth. There is no evidence that increased fetal surveillance can predict or prevent these adverse outcomes, but women often find it reassuring. The perinatal outcomes in women with serum bile acids levels below 40 mmol/L are less clear, but the evidence suggests that the risks are similar to those in women with uncomplicated pregnancy. ICP is not associated with intrauterine growth restriction or low birth weight. Following diagnosis, women should be treated with UDCA, which is the only drug that has been shown to have beneficial effects on maternal symptoms and biochemistry, and possible beneficial effects on perinatal outcomes. Other drugs including cholestyramine, S-adenosyl L-methionine and dexamethasone are less effective than UDCA at reducing pruritus or improving liver function. Rifampicin may be a useful adjunct to UDCA in women with severe or refractory disease, but should only be used if the liver transaminases are not markedly raised, and there have been no randomised controlled trials of this treatment.
Numbers in brackets are the ranges used in Knight et al. 2008. ALT e alanine transaminase; AST e aspartate transaminase; PT e prothrombin time; APTT e activated partial thromboplastin time.
Table 4
biochemical changes that are valuable for diagnosis, and can be useful in distinguishing AFLP from the HELLP (haemolysis, elevated liver enzymes and low platelets syndrome) syndrome. Pre-pregnancy care: AFLP is more common in nulliparous women, and also in multiple pregnancy. Women with previous AFLP are at an increased risk of recurrence, particularly if LCHAD mutations are identified. There are no other clinical features that have been identified as risk factors for AFLP. Antenatal care: AFLP is associated with a high risk of maternal and fetal mortality, and therefore early recognition and diagnosis are vital. The ‘Swansea Criteria’ are valuable for diagnosis, and are present in almost all cases.
Labour and delivery: there are no specific guidelines relating to the timing or mode of delivery in women with ICP. There appears to be a clustering of stillbirths associated with ICP at around 38 weeks, and this has lead to the adoption of policies of elective early term delivery in many centres. However, the evidence for this practice is limited. There are no specific contraindications to induction of labour or vaginal delivery, but the literature suggests that many women with ICP are delivered by caesarean section.
Labour and delivery: maternal resuscitation and treatment of coagulopathy should be followed by urgent delivery, typically by caesarean section, although there are no specific contraindications to vaginal delivery if this can be achieved rapidly. Spinal and epidural anaesthesia are contraindicated in the presence of coagulopathy.
Post-partum care: the maternal symptoms and biochemical abnormalities of ICP typically resolve rapidly following delivery, although there are reports of a more protracted course in the literature. Women should have serum bile acid levels and liver function tests repeated at 6e8 weeks post-partum, and if there is incomplete resolution referral to a hepatologist for investigation of underlying cholestatic liver disease should be considered. There is a high risk of recurrent ICP in subsequent pregnancies, and a subgroup of women also get recurrent cholestasis with their menstrual cycle or when taking the oral contraceptive pill. For this reason, women should be advised to avoid oestrogen-containing preparations.
Post-partum care: liver function tests and coagulopathy typically resolve within 2e3 days after delivery. A small proportion of women with AFLP develop liver failure, and should be transferred to a specialist liver unit for consideration of liver transplantation. AFLP is not associated with the sequelae of chronic liver disease, and recovery is usually complete. Infants born to women with AFLP should be screened for fatty acid oxidation disorders. Intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder that affects approximately 1 in 140 pregnant
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There is emerging evidence of a higher risk of hepatobiliary disease and metabolic syndrome in later life in women with a history of ICP.
Trivedi PJ, Kumagi T, Al-Harthy N, et al. Good maternal and fetal outcomes for pregnant women with primary biliary cirrhosis. Clin Gastroenterol Hepatol 2014; 12. 1179e1185 e1171. Van der Woude CJ, Ardizzone S, Bengtson MB, et al. The second European evidence-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis 2015; 9: 107e24. Walker I, Chappell L, Williamson C. Rational testing: abnormal liver function tests in pregnancy. BMJ 2013; 25: 347. Westbrook RH, Yeoman AD, Kriese S, Heneghan MA. Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun 2012; 38: J239e44. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol 2014; 124: 120e33.
Summary There is a broad spectrum of gastrointestinal and liver disease in pregnancy, some of which is evident prior to conception and some of which presents for the first time during pregnancy. Many of the drugs used outside of pregnancy are safe in pregnancy, and should be continued to reduce the risks of maternal and fetal morbidity. If gastrointestinal or liver disease are suspected a pregnant woman prompt diagnosis and intervention with appropriate management, and in co-ordination with a specialist with experience of managing these disorders in pregnancy will reduce maternal and fetal morbidity and mortality. A
Practice points C
FURTHER READING Knight M, Nelson-Piercy C, Kurinczuk JJ, Spark P, Brocklehurst P. A prospective national study of acute fatty liver of pregnancy in the UK. Gut 2008; 57: 951e6. McKay DB, Josephson MA. Pregnancy in recipients of solid organs eeffects on mother and child. N Engl J Med 2006; 354: 1281e93. Narayanan RP, Syed AA. Pregnancy following bariatric surgery e medical complications and management. Obes Surg 2016; 26: 2523e9. Rasheed SM, Abdel Monem AM, Abd Ellah AH, Abdel Fattah MS. Prognosis and determinants of pregnancy outcome among patients with post-hepatitis liver cirrhosis. Int J Gynaecol Obstet 2013; 121: 247e51. Saccone G, Berghella V, Sarno L, et al. Celiac disease and obstetric complications: a systematic review and metaanalysis. Am J Obstet Gynecol 2016; 214: 225e34.
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Women with pre-existing gastrointestinal and liver disease should have pre-pregnancy counselling by a doctor with experience in the management of these disorders in pregnancy It is important to have prompt multidisciplinary review for pregnant women with pre-existing gastrointestinal and liver diseases that could have an adverse impact on maternal or fetal mortality and morbidity Clinicians should be aware of alterations in normal ranges of LFT and other blood parameters in pregnancy when managing women with gestational medical disease The commonest cause of newly identified abnormal liver function tests in pregnancy is pre-eclampsia associated disease Azathioprine can be taken in pregnancy and when breastfeeding Advice on continuation of drugs in pregnancy should be given by a clinician with knowledge about the maternal as well as fetal risks and benefits associated with the use of drugs to treat liver and gastrointestinal disease in pregnancy and lactation
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Gastrointestinal and liver disease in pregnancy
and 1.6/100,000 and that of UC varies between 0.5 and 24.5/ 100,000. The symptoms associated with IBD include diarrhoea, constipation, increased frequency of bowel movements, cramping abdominal pain, nausea and vomiting. Both CD and UC are also associated with several extra-gastrointestinal manifestations, which can affect almost any other body system. Furthermore, scarring from surgery, fistula formation, fat and vitamin malabsorption may pose complications to pregnancy in women with IBD.
Victoria Geenes Catherine Williamson
Abstract Gastrointestinal and liver disorders of pregnancy may be present before a woman becomes pregnant, or they can be specific to pregnancy. They can be complicated by severe morbidity or mortality. Women with pre-existing disorders should have pre-pregnancy counselling. This will enable the potential risks of pregnancy for the mother and fetus to be evaluated, clinical interventions that improve outcomes to be performed, and drug regimens to be reviewed. Once pregnant, it is important to adopt a multidisciplinary approach with the input of obstetricians, midwives, anaesthetists and physicians with experience and expertise in the management of medical disorders of pregnancy.
Pre-pregnancy care: overall fertility rates among women with active IBD may be reduced compared to unaffected, age matched women. Population studies show infertility rates in CD to be between 5 and 14%. The reasons for this are complex and multifactorial; major factors include dyspareunia resulting from previous pelvic surgery, low libido, depression and active avoidance of pregnancy. Fertility rates in women with inactive disease are comparable to age matched unaffected women. Pre-conceptual counselling for women with IBD should focus on the importance of optimizing their disease control and nutrition. Women with IBD should be advised to take high dose (5 mg) folic acid, and to ensure that their vitamin D levels are optimized. Aminosalicylates, cyclosporin and azathioprine have good safety data for use during pregnancy and can be continued, and courses of steroids should be used if required. Methotrexate should be stopped several months prior to conception due to teratogenic effects. Knowledge about the use of biologic agents in pregnancy is improving, and varies depending upon the mode of action of the drug. If women require biologic agents, they can continue using them for the first two trimesters if required. However, women should be aware that IgG1 antibody therapies (infliximab, adalimumab and golimumab) cross the placenta, and if taken in the 3rd trimester the neonate should not have live vaccinations in the first 6 months of life. The risk and complications arising from previous pelvic/abdominal surgery will vary greatly depending on the exact nature of the surgery, and should be discussed with the surgeon who performed the procedure. There is no increased incidence of congenital malformations in babies born to women with IBD.
Keywords disease; gastrointestinal; liver; pregnancy
Introduction Gastrointestinal and liver diseases in pregnancy may be due to pre-existing conditions or be specific to pregnancy. Many of these conditions are associated with increased risks of maternal and fetal morbidity and mortality. For reasons unknown, some have a more severe course when diagnosed during pregnancy, whilst others have little effect on either the mother or baby. Here we review the presentation, management and perinatal outcomes of common gastrointestinal and liver diseases.
Gastrointestinal disease Inflammatory bowel disease Inflammatory bowel disease is a collective term used to describe the chronic inflammatory conditions, Crohn’s disease (CD) and ulcerative colitis (UC). Both CD and UC are characterised by relapsing and remitting inflammation affecting several parts of the gastrointestinal tract, but there are some important differences that are useful to distinguish them. CD can affect any part of the gastrointestinal tract, although there is often rectal sparing, and involves transmural inflammation. In comparison, UC affects only the colon and rectum and involves the submucosa and mucosa. IBD is more common in women than men, and is most frequently diagnosed in the reproductive years, with at least 50% being diagnosed before the age of 35 years and 25% before conception. The worldwide incidence of CD varies between 0.1
Antenatal care: the course of IBD during a pregnancy appears to be related to the level of disease activity at the time of conception. Women with inactive disease at the time of conception have a similar risk of relapse to non-pregnant women, which is approximately 30% over 12 months. Women with active disease at the time of conception, have an increased risk of flares during pregnancy. These should be managed in conjunction with a gastroenterologist with experience of IBD in pregnancy. Active IBD during pregnancy is associated with increased risk of pre-term delivery, intrauterine growth restriction and low birth weight. These complications are more often seen in women with CD compared to women with UC, but the reasons for this are unclear. In addition, IBD is also associated with increased risks of venous thromboembolism (UC more than CD), antepartum haemorrhage (CD more than UC) and delivery by caesarean section. Women presenting with new symptoms suggestive of IBD during pregnancy, or with flares, can be safely investigated using
Victoria Geenes MBBS PhD is a Clinical Research Fellow at the Maternal and Fetal Disease Group, King’s College London, UK. Conflicts of interest: none declared. Catherine Williamson MBChB MD is Professor of Women’s Health at the Maternal and Fetal Disease Group, King’s College London, UK. Conflicts of interest: none declared.
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challenges in antenatal care. Bariatric surgery includes gastric banding, gastric bypass and biliopancreatic diversion surgery. The main benefit is weight loss, but this occurs at the risk of marked malabsorption.
ultrasound or MRI. Flexible sigmoidoscopy is often the endoscopic investigation of choice, but colonoscopy may be used if clinically indicated. The indications for surgery in pregnant women with IBD are the same as those for non-pregnant women.
Pre-pregnancy care: women are generally advised against becoming pregnant in the first year following surgery, due to concerns over conceiving during a period of marked weight loss. However, there are no studies to support or refute this advice. Particular care should be taken in the pre-conceptual period to optimize nutrition, particularly with regards to fat-soluble vitamins, calcium and iron.
Labour and delivery: although there is no specific guidance regarding the optimal mode of delivery, there are some specific considerations. For women with CD and active perianal or rectal disease, an elective caesarean section is almost always advised. Delivery by caesarean section is commonly preferred where there is an ileo-anal pouch or ileo-rectal anastomosis, but it is advisable to have multidisciplinary review of the merits of different modes of delivery for individual cases.
Antenatal care: women who have had bariatric surgery have reduced rates of gestational diabetes mellitus, but have higher rates of small-for-gestational age babies and pre-term delivery. Thus far there are no specific requirements for care during the antenatal period. However, the presentation of a woman with abdominal pain should be taken seriously and the differential diagnosis should include band slippage, herniation or intussusception. Management strategies for other gastrointestinal disorders in pregnancy are summarized in Table 1.
Post-partum care: women should be counselled about the importance of continuing their medications in the post-partum period to reduce the risk of a flare. Most of the medications used to maintain IBD are safe in breastfeeding. Babies born to women treated with infliximab should not receive live vaccines in the first six months of life. Coeliac disease Coeliac disease is a gluten sensitive enteropathy predominantly affecting the small bowel. In affected individuals, exposure to gluten causes an inflammatory reaction, which results in villous atrophy and malabsorption. Characteristic symptoms of coeliac disease are chronic diarrhoea, abdominal distension, malabsorption and loss of appetite. It can present at any age, and is slightly more common in women than men. The only effective treatment of coeliac disease is a life-long gluten free diet. Adherence to this improves symptoms, and reduces the risk of long-term complications including the risk of intestinal lymphoma.
Liver disease The liver undergoes several adaptive changes during normal pregnancy to enable it to cope with increased demands on
Management strategies for pregnant women with gastrointestinal disorders Considerations in pregnancy
Gastrooesophageal reflux
More common in pregnancy.
Management
H2 receptor antagonists and proton pump inhibitors can be safely used in pregnancy. Peptic ulcer Incidence in pregnancy Helicobacter pylori disease unclear, but may be lower. eradication is safe if indicated. Endoscopy can be safely performed in pregnancy. Pancreatitis Incidence of and risk Supportive factors for pancreatitis are management as per unchanged by pregnancy. non-pregnant women. Monitor for malabsorption and gestational diabetes. Appendicitis May present with atypical Surgical management pain and therefore be as per non-pregnant harder to diagnose. women. Location of appendix may be altered in third trimester. Gastroenteritis None Supportive as per nonpregnant women.
Pre-pregnancy care: there is conflicting evidence regarding fertility rates and miscarriage rates in women with coeliac disease, but it has been suggested that both can be improved with a gluten free diet. Women with coeliac disease should receive high dose folic acid pre-conceptually, and there should be a focus on optimizing nutrition whilst maintaining a gluten free diet. Antenatal care: coeliac disease is associated with an increased risk of intrauterine growth restriction, low birth weight and preterm delivery. The increased risk for pre-term delivery is significantly reduced in women who are treated with a strict gluten free diet. Women with coeliac disease should therefore be regularly screened for fetal growth, and also monitored for malabsorption. Routine serological testing and endoscopy can be performed during pregnancy in women presenting with symptoms suggestive of coeliac disease for the first time. Labour and delivery: there are no specific considerations for labour or delivery in women with coeliac disease. Bariatric surgery The number of women becoming pregnant with a history of bariatric surgery is increasing, and these women present new
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Condition
Table 1
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following immunosuppressive treatment, and it is estimated that up to 6% of cases present during pregnancy. AIH can be divided into three subtypes: types I, II and III. AIH type I is the most common subtype and is characterised by antinuclear antibodies (ANA, 70%) or anti-smooth muscle antibodies (SMA, 57%). It affects people of any age, unlike type II which predominantly affects children and young women. Type II is characterised by anti-liver kidney microsomal antibodies (LKM1, 3e4%), and seronegativity for ANA and SMA. Type II is associated with a more severe phenotype and a greater risk of extrahepatic autoimmune disease. Type III is characterised by the presence of anti-soluble liver antigen and liver-pancreas antibodies. It accounts for up to 30% of AIH.
metabolism and excretion of endobiotics. These changes mean that the normal ranges for liver function tests are altered, and that some clinical signs that are considered to be pathological outside of pregnancy are not of concern in pregnancy. For example, palmar erythema and spider naevi can be normal in pregnant women. The liver does not change in size during human pregnancy, but it does move to a more superior and posterior position. Liver disease in pregnancy may result from pre-existing conditions or can be the result of pregnancy-specific disorders. In addition, hypertensive disorders may present with abnormal liver function tests, and these are summarized in Table 2. Infective hepatitis Viral hepatitis is becoming an increasingly common problem in obstetrics. The characteristics and effects of the different viruses on pregnancy are described in Table 3.
Pre-pregnancy care: women with AIH should be counselled about the importance of continuing their immunosuppressive treatment, and reassured that azathioprine is not associated with adverse outcomes during pregnancy and is also safe in breastfeeding. Women should be screened for anti-Ro and anti-La antibodies and thyroid function tests should be performed, as AIH is commonly associated with other autoimmune conditions. They should also be offered screening for oesophageal varices prior to conception.
Autoimmune hepatitis Autoimmune hepatitis (AIH) may present as acute hepatitis, chronic hepatitis or even cirrhosis. It is characterized by hepatocellular inflammation and necrosis, and predominantly affects women (3:1 female to male preponderance). There are two peaks of presentation (10e30 years and 40e50 years). Typical symptoms of AIH include fatigue, myalgia, pruritus, nausea, anorexia and upper abdominal pain. Women may also have amenorrhoea and older studies have reported high rates of infertility as a consequence. More recent studies report successful pregnancies
Antenatal care: the risk of adverse perinatal outcomes is increased in poorly controlled disease or cirrhosis. Recent studies have shown that approximately one third of women with AIH will experience a flare of disease during pregnancy, but that this risk can be reduced with good compliance with immunosuppressive therapy. Serious maternal complications, defined as death or liver transplantation with 12 months of delivery, or decompensation of liver disease within 3 months of delivery, occur in up to 11% of women with AIH. The age at diagnosis of AIH, poor compliance with treatment, relapse within 12 months prior to conception, and the presence of cirrhosis are all factors which are associated with an increased risk of maternal and fetal morbidity and mortality. For management of cirrhosis in pregnancy, see later.
Abnormalities in liver function tests as a result of hypertensive disorders of pregnancy Distinguishing feature
Pre-eclampsia HELLP* syndrome
Typical gestational week at onset Symptoms and signs C Headache C Visual disturbance C Abdominal/epigastric pain C Nausea and vomiting C Polyuria/polydipsia C Oedema C Raised blood pressure C Brisk reflexes/clonus C Proteinuria Liver function tests C ALT C AST C gGT C Bilirubin C Bile acids Other tests C Haemoglobin C Platelets C Creatinine C Urate
>20 weeks
36 (25e38)
[ [ [ [ [ [ [[ [ [
[ [[ [[ [ [ [ [ [ [
[ [ [ N N
[[ [ [ [ N
N Y [ [
Y YY [ [
*
Labour and delivery: there is an increased risk of pre-term delivery and admission to SCBU, particularly in women with poorly controlled disease or cirrhosis. There are no specific guidelines regarding the mode of delivery in women with AIH, but the risks of labour should be considered in women with known hepatic cirrhosis or varices. Post-partum care: women should continue to take their immunosuppressive treatments in the post-partum period to reduce the risk of a flare. Azathioprine is safe in breastfeeding. Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is a chronic inflammatory condition affecting the intrahepatic and extrahepatic bile ducts, in which recurrent episodes of cholangitis lead to progressive scarring and obstruction of the bile ducts. It may present with cirrhosis or liver failure. Symptoms are typical of cholestasis, including chronic fatigue jaundice, pruritus and malabsorption. PSC affects males more commonly than females, (2:1 male to female preponderance), with a peak age at diagnosis of 20
The haemolysis, elevated liver enzymes and low platelets syndrome.
Table 2
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Hepatitis viruses in pregnancy: effects and management Virus
Characteristics
Considerations in pregnancy
Hepatitis A Small, non-enveloped RNA virus Faeco-oral transmission Not associated with chronic infection Incubation period 2e7 days
Does not usually cause major maternal or neonatal morbidity. Acute infection in T3 is associated with preterm labour. In utero transmission rare e causes fetal meconium peritonitis in T1 and asymptomatic infection/self-limiting neonatal cholestasis in T3. Hepatitis B Double stranded DNA virus, with eight May present as acute or chronic infection. known serotypes. Screen for virus at booking and in T3 if Transmitted via unprotected sex and ongoing risk of infection. IVDU in low prevalence areas. Anti-HBsAg negative women at high risk MTC transmission in high prevalence should be offered vaccination. areas. Course of acute and chronic infection is unchanged by pregnancy. Not associated with congenital malformation or stillbirth.
Management Vaccination for women at risk. Supportive treatment in acute infection.
Supportive treatment in acute infection. Nucleoside analogues may be used in fulminant infection or protracted severe infection. Limited evidence for anti-virals in pregnancy e generally treatment should be deferred. No evidence to support routine elective caesarean section. Breast milk contains virus, but breastfeeding does not increase risk of transmission. Infants should receive HBV vaccine and immunoglobulin. Hepatitis C RNA virus with six known genotypes. May present as acute or chronic infection. Antiviral treatment is contraindicated in Blood-borne virus most commonly Only screen high risk women for infection. pregnancy due to teratogenicity. acquired via IVDU in adults and MTC Course of infection is unchanged by No evidence to support elective caesarean transmission in children. pregnancy. section. Risk of MTC transmission increased by Associated with increased risk of ICP. MTC transmission is associated with HCV HIV co-infection (3). Not associated with congenital malformation viraemia, prolonged ROM (>6 hours) and or stillbirth. intrapartum exposure to maternal blood. Avoid prolonged ROM and use of fetal scalp electrodes. Breast milk contains virus, but breastfeeding does not increase the risk of transmission. Infants should be tested for HCV antibodies at 16 months of age. Hepatitis E RNA virus. Typically causes acute self-limiting hepatitis, Supportive management. Transmission unclear, but likely water but pregnant women are more susceptible to Post-exposure immunoglobulin treatment borne. does not reduce risk of infection. infection and have higher risk of fulminant hepatic failure. Maternal mortality rate is up to 26%. MTC transmission may occur in utero or directly. Transmission in T3 is associated with a risk of neonatal hepatic necrosis and neonatal death. Not associated with chronic infection, congenital malformation or stillbirth. Associated with pre-term delivery. Abbreviations: T3 e third trimester; T1 e first trimester; IVDU e intravenous drug use; MTC e mother to child; HBsAg e hepatitis B surface antigen; HBV e hepatitis B virus; HIV e human immunodeficiency virus; HCV e hepatitis C virus; ROM e rupture of membranes; ICP e intrahepatic cholestasis of pregnancy.
Table 3
e30 years. Although there are no specific antibodies for PSC, 80% of those affected are positive for peri-nuclear antineutrophil cytoplasmic antibodies (pANCA) and 20e50% are positive for anti-nuclear antibodies (ANA) or anti-smooth muscle antibodies (SMA). PSC is associated with
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inflammatory bowel disease, and ulcerative colitis is present in up to 70%. Pre-pregnancy care: PSC is associated with increased risks of worsening liver function either during pregnancy or in the post-
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partum period. This risk may be ameliorated by treatment with UDCA. Although there are insufficient data to demonstrate a protective effect, UDCA is safe to use during pregnancy, and therefore women should be encouraged to continue taking it. Nutrition should be optimized, and women should be advised to take vitamin supplements to reduce the risk of malabsorption, particularly of fat-soluble vitamins.
Biliary atresia Biliary atresia may be congenital or acquired, and it is a progressive inflammatory disease of the bile ducts that leads to cholestasis. The aetiology of biliary atresia is unknown, but is likely to be multi-factorial. Treatment is with surgical reconstruction of the bile ducts (Kasai procedure) in the first instance. This procedure is not curative, but delays the need for liver transplantation.
Antenatal care: there is no increase in the risk of low birth weight or stillbirth, and therefore no specific role for additional antenatal fetal surveillance. PSC is not associated with an increased risk of congenital malformation, stillbirth or neonatal death. Successful endoscopic retrograde pancreatography (ERCP) and stenting during pregnancy have been performed.
Pre-pregnancy care: women with biliary atresia should be counselled about the risk of deteriorating liver function during pregnancy. Women with portal hypertension and oesophageal varices appear to have an increased risk of bleeding. Maternal nutrition should be optimized, with particular attention paid to fat-soluble vitamins due to the risk of malabsorption.
Labour and delivery: in relation to fetal outcomes, PSC is associated with an increased risk of pre-term delivery (both iatrogenic and spontaneous) and delivery by caesarean section, mainly elective. There are no specific recommendations relating to the mode of delivery but consideration should be given to the risks of labour in the presence of cirrhosis.
Antenatal care: perinatal outcomes in women with biliary atresia appear to be good, and in the small numbers of cases reported there does not seem to be an association with any particular adverse outcome. Biliary atresia has not been associated with congenital malformations. There is one case report of an intrauterine death in a woman with cholangitis and portal hypertension.
Post-partum care: women with PSC remain at high risk of a flare of their disease in the post-partum period. UDCA is safe to use in breastfeeding, and women should be counselled to continue taking it.
Labour and delivery: there is no specific guidance on the mode of delivery for women with biliary atresia, but consideration should be given to the potential risks of labour in women with portal hypertension.
Primary biliary cirrhosis Primary biliary cirrhosis (PBC) is an autoimmune disease characterised by the progressive destruction of small bile ducts leading to cirrhosis. The symptoms are similar to those of PSC, but in contrast PBC is a disease that predominantly affects women (9:1 female to male preponderance). It typically presents in middle age (35e55 years), but may be diagnosed in women of reproductive age. PBC is commonly associated with extrahepatic autoimmune diseases, and up to 80% of those affected have another autoimmune condition. Antimitochondrial antibodies (AMA) are characteristic in PBC and are positive in 90e95%. Anti-nuclear antibodies (ANA) are also positive in up to 35% of cases.
Post-partum care: in the majority of cases, maternal liver function improves rapidly post-partum, although it is possible that prolonged cholestasis may result in the need for urgent liver transplantation. Wilson’s disease Wilson’s disease is a rare genetic (autosomal recessive) disorder of copper metabolism. It is characterised by an accumulation of copper in the liver and other organs, resulting predominantly in cirrhosis, liver failure, neurological and psychiatric symptoms. Infertility and recurrent miscarriage are common in women with Wilson’s disease and may be the presenting features of the disease. Pre-pregnancy care: women with Wilson’s disease should be counselled about the risks of discontinuing treatment, which include deterioration of liver function, haemolysis and maternal death. The main treatments used in Wilson’s disease are Dpenicillamine, trientine and zinc, the former of which are known to be teratogenic at high doses. However, the doses used in the treatment of Wilson’s disease are much lower and appear to be safe in pregnancy. Furthermore, cessation of treatment can cause severe deterioration of disease and women should be encouraged to continue taking therapy for Wilson’s disease in pregnancy.
Pre-pregnancy care: there are few reports of pregnancy in women with PBC, and there is no clear consensus of the effect of the disease on pregnancy outcomes. The drugs commonly used to treat PBC, including UDCA, cholestyramine and rifampicin are safe in pregnancy and it therefore seems judicious to continue them to reduce the risk of deterioration in maternal liver function. As with PSC, maternal nutritional status should be optimized and women should be given vitamin supplementation. Antenatal care: several case reports have suggested that there is an increased risk of adverse perinatal outcomes in women with PBC, including intrauterine fetal death. However, the numbers of women in the studies are too small to be conclusive.
Antenatal care: perinatal outcomes in women with Wilson’s disease are reported to be good, and there are no specific considerations for antenatal care beyond compliance with treatment.
Labour and delivery: there is no specific guidance on the mode of delivery for women with PBC, but consideration should be given to the potential risks of labour in women with cirrhosis.
Labour and delivery: there are no specific guidelines for labour and delivery, but consideration should be given to the potential risks of labour in women with Wilson’s disease and cirrhosis.
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Post-partum care: infants born to women typically have normal levels of copper and caeruloplasmin.
Cirrhosis is also associated with increased risks of preeclampsia, placental abruption, post-partum haemorrhage and maternal death, and therefore women should be closely monitored in specialist units to mitigate against these risks.
Hereditary haemochromatosis Hereditary haemochromatosis is an inherited disorder of iron metabolism. Clinical presentations are variable, and depend on the predominant organ affected, but may be asymptomatic in the early stages. Chronic haemochromatosis is associated with cirrhosis and hepatocellular carcinoma, dilated cardiomyopathy or cardiac conduction disturbances, pancreatic dysfunction or diabetes, hypogonadism, non-inflammatory osteoarthritis and bronzing of the skin. Women of reproductive age may be protected from the clinical manifestations of haemochromatosis by regular menstruation.
Labour and delivery: there are very limited data regarding the optimal way to delivery women with cirrhosis, but there are concerns over allowing women to labour as the process involves repeated Valsalva manoeuvres which raise intra-abdominal pressure and therefore increase the risk of variceal rupture. Therefore an assisted second stage of labour is advisable. Liver transplantation Pre-pregnancy care: data relating to pregnancy in women with previous liver transplants are limited, but outcomes are likely to be improved in women with adequate immunosuppression. Women should therefore be counselled about the importance of continuing their immunosuppressive regimens, and should also be treated with high dose (5 mg) folic acid.
Pre-pregnancy care: women should be counselled about the risks of end-organ dysfunction in pregnancy. These should be discussed on an individualized basis depending on the organs affected, but may include the risks of glycaemic control at the time of conception, the presence of cardiomyopathy or cirrhosis.
Antenatal care: perinatal outcomes in women with a history of liver transplantation are reported to be good, especially if pregnancy is delayed for 12 months after surgery, or after an episode of rejection. Furthermore, the live birth rate is reported to be 70 e90%. There is an increased risk of hypertensive disorders and pre-eclampsia and women should be closely monitored for these and other complications. There are also increased risks of preterm birth and low birth weight infants. Graft survival does not appear to be affected by pregnancy, despite the reported incidence of rejection during pregnancy being between 2 and 17%. Episodes of rejection should be managed as they are in non-pregnant women i.e. with appropriate investigations and changes to the immunosuppressive regimen if necessary.
Antenatal care: women with haemochromatosis should be monitored for fetal growth, particularly in the presence of diabetes. Glycaemic control should be tightly maintained throughout pregnancy to reduce the associated risks of adverse perinatal outcomes. Labour and delivery: there are no specific guidelines for labour and delivery, but consideration should be given to the potential risks of labour in women with haemochromatosis and cirrhosis. Cirrhosis and portal hypertension Cirrhosis is the common end point of many liver diseases, and is defined as permanent scarring of the liver from continuous longterm insults. The majority of cases of cirrhosis in the UK are the result of excessive alcohol consumption and hepatitis C infection. It is associated with portal hypertension, oesophageal varices and hypersplenism.
Labour and delivery: there are no specific considerations regarding the mode of delivery in women with previous liver transplantation, but the underlying pathology should be taken into consideration.
Pre-pregnancy care: data relating to pregnancy in women with cirrhosis are sparse. Studies of women with alcoholic liver disease or viral hepatitis have suggested that there are higher rates of both maternal and neonatal mortality, and the risk is further increased in those with portal hypertension and oesophageal varices. Women should therefore be offered screening and treatment for oesophageal varices prior to conception.
Acute fatty liver of pregnancy Acute fatty liver of pregnancy (AFLP) is a rare cause of acute liver failure in pregnancy. It most commonly occurs in the third trimester, but up to 20% of cases present following delivery. Nulliparity and multiple pregnancy are recognized as risk factors, and there is an association between AFLP and disorders of betafatty acid oxidation, most commonly fetal homozygosity for long chain 3 hydroxyl-acyl-coenzyme A dehydrogenase (LCHAD) deficiency. LCHAD deficient fetuses have a reduced capacity to oxidise long chain fatty acids in the liver and placenta, and therefore there is an accumulation of hepatotoxic metabolites in the maternal liver. AFLP is characterised by microvesicular steatosis and affects approximately 1 in 7000e16,000 pregnancies. AFLP typically presents with vomiting, reduced appetite, midepigastric or right upper quadrant abdominal pain, headache and jaundice. Hyperlactaemia, hypoglycaemia, hypertension, proteinuria, ascites and bleeding secondary to coagulopathy may also be present. These clinical features are included in the ‘Swansea Criteria’ (Table 4), a set of symptoms, signs and
Antenatal care: the management of the underlying disease should be optimized, and particular attention should be paid to maternal nutritional and iron status, given the risks of malabsorption and anaemia. Up to 78% of women with pre-existing oesophageal varices will have a bleed during pregnancy, most commonly in the second or third trimester. Endoscopy in the 2nd trimester is often advised, as existing oesophageal varices can worsen, and new varices can appear in pregnancy. Endoscopy, sclerotherapy and ligation banding appear to be safe, and reduce the risk of a potentially life-threatening haemorrhage, but data are limited and there are no randomized controlled trials.
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women in the UK. Characteristically it presents in the third trimester with maternal pruritus and raised serum bile acid levels. Symptoms of cholestasis (dark urine, pale stools and steatorrhoea) may also be present and the liver transaminases (ALT, AST) are usually elevated. Clinical jaundice is rare. The diagnosis of ICP is one of exclusion, and women should be investigated for other causes of cholestasis or hepatic impairment. Serum bile acids are the most sensitive and specific test for the diagnosis and monitoring of the condition.
Swansea criteria for acute fatty liver of pregnancy Six or more of the following in the absence of an alternative cause should be present to make the diagnosis Symptoms and signs
Laboratory abnormalities
Other
Vomiting Abdominal pain Polydipsia/polyuria Encephalopathy Elevated bilirubin (>14 mmol/L) Hypoglycaemia (<4 mmol/L) Elevated urate (>340 mmol/L) Leucocytosis (>11 109/L) Elevated transaminases (ALT or AST, >42 IU/L) Elevated ammonia (>47 mmol/L) Renal impairment (creatinine >150 mmol/L) Coagulopathy (PT > 14 second or APTT >34 second) Ascites or bright liver on ultrasound Microvesicular steatosis on liver biopsy
Pre-pregnancy care: ICP is reported to be more common in women with a personal or family history of the condition, gallstones or multiple pregnancy. No other specific risk factors have been identified. Antenatal care: ICP is usually a benign condition for the mother, but severe disease (defined as serum bile acid concentrations greater than 40 mmol/L) is associated with an increased risk of adverse fetal outcomes, including pre-term delivery (both spontaneous and iatrogenic), prolonged admission to the neonatal unit and stillbirth. There is no evidence that increased fetal surveillance can predict or prevent these adverse outcomes, but women often find it reassuring. The perinatal outcomes in women with serum bile acids levels below 40 mmol/L are less clear, but the evidence suggests that the risks are similar to those in women with uncomplicated pregnancy. ICP is not associated with intrauterine growth restriction or low birth weight. Following diagnosis, women should be treated with UDCA, which is the only drug that has been shown to have beneficial effects on maternal symptoms and biochemistry, and possible beneficial effects on perinatal outcomes. Other drugs including cholestyramine, S-adenosyl L-methionine and dexamethasone are less effective than UDCA at reducing pruritus or improving liver function. Rifampicin may be a useful adjunct to UDCA in women with severe or refractory disease, but should only be used if the liver transaminases are not markedly raised, and there have been no randomised controlled trials of this treatment.
Numbers in brackets are the ranges used in Knight et al. 2008. ALT e alanine transaminase; AST e aspartate transaminase; PT e prothrombin time; APTT e activated partial thromboplastin time.
Table 4
biochemical changes that are valuable for diagnosis, and can be useful in distinguishing AFLP from the HELLP (haemolysis, elevated liver enzymes and low platelets syndrome) syndrome. Pre-pregnancy care: AFLP is more common in nulliparous women, and also in multiple pregnancy. Women with previous AFLP are at an increased risk of recurrence, particularly if LCHAD mutations are identified. There are no other clinical features that have been identified as risk factors for AFLP. Antenatal care: AFLP is associated with a high risk of maternal and fetal mortality, and therefore early recognition and diagnosis are vital. The ‘Swansea Criteria’ are valuable for diagnosis, and are present in almost all cases.
Labour and delivery: there are no specific guidelines relating to the timing or mode of delivery in women with ICP. There appears to be a clustering of stillbirths associated with ICP at around 38 weeks, and this has lead to the adoption of policies of elective early term delivery in many centres. However, the evidence for this practice is limited. There are no specific contraindications to induction of labour or vaginal delivery, but the literature suggests that many women with ICP are delivered by caesarean section.
Labour and delivery: maternal resuscitation and treatment of coagulopathy should be followed by urgent delivery, typically by caesarean section, although there are no specific contraindications to vaginal delivery if this can be achieved rapidly. Spinal and epidural anaesthesia are contraindicated in the presence of coagulopathy.
Post-partum care: the maternal symptoms and biochemical abnormalities of ICP typically resolve rapidly following delivery, although there are reports of a more protracted course in the literature. Women should have serum bile acid levels and liver function tests repeated at 6e8 weeks post-partum, and if there is incomplete resolution referral to a hepatologist for investigation of underlying cholestatic liver disease should be considered. There is a high risk of recurrent ICP in subsequent pregnancies, and a subgroup of women also get recurrent cholestasis with their menstrual cycle or when taking the oral contraceptive pill. For this reason, women should be advised to avoid oestrogen-containing preparations.
Post-partum care: liver function tests and coagulopathy typically resolve within 2e3 days after delivery. A small proportion of women with AFLP develop liver failure, and should be transferred to a specialist liver unit for consideration of liver transplantation. AFLP is not associated with the sequelae of chronic liver disease, and recovery is usually complete. Infants born to women with AFLP should be screened for fatty acid oxidation disorders. Intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder that affects approximately 1 in 140 pregnant
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There is emerging evidence of a higher risk of hepatobiliary disease and metabolic syndrome in later life in women with a history of ICP.
Trivedi PJ, Kumagi T, Al-Harthy N, et al. Good maternal and fetal outcomes for pregnant women with primary biliary cirrhosis. Clin Gastroenterol Hepatol 2014; 12. 1179e1185 e1171. Van der Woude CJ, Ardizzone S, Bengtson MB, et al. The second European evidence-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis 2015; 9: 107e24. Walker I, Chappell L, Williamson C. Rational testing: abnormal liver function tests in pregnancy. BMJ 2013; 25: 347. Westbrook RH, Yeoman AD, Kriese S, Heneghan MA. Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun 2012; 38: J239e44. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol 2014; 124: 120e33.
Summary There is a broad spectrum of gastrointestinal and liver disease in pregnancy, some of which is evident prior to conception and some of which presents for the first time during pregnancy. Many of the drugs used outside of pregnancy are safe in pregnancy, and should be continued to reduce the risks of maternal and fetal morbidity. If gastrointestinal or liver disease are suspected a pregnant woman prompt diagnosis and intervention with appropriate management, and in co-ordination with a specialist with experience of managing these disorders in pregnancy will reduce maternal and fetal morbidity and mortality. A
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FURTHER READING Knight M, Nelson-Piercy C, Kurinczuk JJ, Spark P, Brocklehurst P. A prospective national study of acute fatty liver of pregnancy in the UK. Gut 2008; 57: 951e6. McKay DB, Josephson MA. Pregnancy in recipients of solid organs eeffects on mother and child. N Engl J Med 2006; 354: 1281e93. Narayanan RP, Syed AA. Pregnancy following bariatric surgery e medical complications and management. Obes Surg 2016; 26: 2523e9. Rasheed SM, Abdel Monem AM, Abd Ellah AH, Abdel Fattah MS. Prognosis and determinants of pregnancy outcome among patients with post-hepatitis liver cirrhosis. Int J Gynaecol Obstet 2013; 121: 247e51. Saccone G, Berghella V, Sarno L, et al. Celiac disease and obstetric complications: a systematic review and metaanalysis. Am J Obstet Gynecol 2016; 214: 225e34.
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Women with pre-existing gastrointestinal and liver disease should have pre-pregnancy counselling by a doctor with experience in the management of these disorders in pregnancy It is important to have prompt multidisciplinary review for pregnant women with pre-existing gastrointestinal and liver diseases that could have an adverse impact on maternal or fetal mortality and morbidity Clinicians should be aware of alterations in normal ranges of LFT and other blood parameters in pregnancy when managing women with gestational medical disease The commonest cause of newly identified abnormal liver function tests in pregnancy is pre-eclampsia associated disease Azathioprine can be taken in pregnancy and when breastfeeding Advice on continuation of drugs in pregnancy should be given by a clinician with knowledge about the maternal as well as fetal risks and benefits associated with the use of drugs to treat liver and gastrointestinal disease in pregnancy and lactation
Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Geenes V, Williamson C, Gastrointestinal and liver disease in pregnancy, Obstetrics, Gynaecology and Reproductive Medicine (2017), http://dx.doi.org/10.1016/j.ogrm.2017.01.005