A guide to the recognition and management of new-onset or existing disorders affecting the liver and digestive organs supplements the optimal care provided during pregnancy.
Pregnancy is a unique milestone in a woman’s life, marked by significant physiological and sentimental developments. In this article, gastrointestinal and hepato-biliary disorders in pregnancy are reviewed, with a particular focus on inflammatory bowel disease (IBD) and gastro-oesophageal reflux disease.
IBD, manifesting as either Crohn’s disease or ulcerative colitis, requires particular attention in pregnancy. A high proportion of women with IBD are diagnosed around the time of their reproductive years. There can be significant associated complications and complex therapeutic treatment requirements that can cause substantial emotional strain, particularly in those with a recent diagnosis of the condition.
Female fertility rates are relatively equivalent to the general population for both Crohn’s disease and ulcerative colitis (UC), although poorly controlled inflammatory bowel activity can adversely impact on fertility rates.1,2,3 The higher voluntary infertility rate among IBD patients is typically related to concerns regarding the effect of the disease or treatment associated adverse effects on pregnancy outcomes. Surgical procedures such as ileal pouch anal anastomosis (IPAA) following procto-colectomy for severe ulcerative colitis have resulted in significant reduction in fertility.4 When possible, restorative surgery is postponed until completion of pregnancy in order to preserve fertility. Sulfasalazine causes reversible reduction in male sperm count and motility, which returns to normal around three months following drug cessation.5,6
Genetic predisposition, mucosal immune system defects and environmental factors are thought to have contributed to the development of IBD. Having a family member with IBD can increase the comparative risk of disease by up to 20 times that of the general population. Crohn’s disease and ulcerative colitis are heterogeneous polygenic disorders with underlying genetic predisposition in a non-Mendelian fashion as established in familial studies showing monozygotic concordance rate of around 37–58 per cent for Crohn’s disease and 6–17 per cent for UC.7,8
Pregnancy effect on disease
IBD activity can generally flare in the first trimester and postpartum. If conception occurs during quiescent disease state, then the risk of relapse during pregnancy is similar to those non-pregnant patients with IBD.9 Conversely, of those with active disease at conception, two-thirds will have continued or worsening disease activity during pregnancy. This underscores the importance of disease control prior to conception.
Disease effect on pregnancy
There have been variable and conflicting effects on pregnancy outcomes in population studies. However, overall, pregnancies in IBD patients seem to be associated with poorer outcomes. A Northern Californian population study found IBD patients had an increase in the rate of spontaneous abortion (OR: 1.65; 95 per cent CI: 1.09-2.48); adverse pregnancy outcome (stillbirth, preterm birth or small for gestation age infant OR 1.65; 95 per cent CI: 1.00-2.38); and labour complications (OR 1.78; 95 per cent CI: 1.13-2.91).10 Studies from Denmark and Sweden showed higher prevalence of preterm birth (OR 1.77), caesarean section (OR 2.01), small for gestational age (OR 2.78) and neonatal death (OR 1.93) in patients with UC and the risks correlated with disease severity.11 Recent meta-analysis by Cornish et al also found increased premature birth, low birth rate and caesarean section particularly in Crohn’s patients and more congenital abnormalities in UC patients.12
Strong focus has been placed on disease control during pregnancy, as there is evidence to suggest that disease activity has closer association with poor disease outcome than the diagnosis itself.13 Therefore, optimal disease control would have the highest impact in ensuring uncomplicated pregnancy course.
Unless required to make the initial diagnosis, an endoscopic evaluation of IBD is rarely indicated in pregnancy; nevertheless, it generally can be performed safely. When possible it is postponed to the second trimester and often a limited sigmoidoscopy with minimal sedation can provide adequate information. Care is taken to monitor fetal wellbeing, particularly in relation to potential hypoxic effects from sedatives.14
- Optimal disease control of inflammatory bowel disease prior to conception is essential in minimising pregnancy complications.
- Common therapeutic agents in inflammatory bowel disease are generally safe for pregnancy and breastfeeding. Any potential minimal adverse effects are negated by the risks associated with disease flare.
- Hepatic diseases intrinsic to pregnancy can result in significant poor maternal and fetal outcomes which require intensive monitoring, supportive management and expedient delivery.
- Reflux symptoms are common during pregnancy and they usually respond well to lifestyle modifications and simple therapeutic agents.
Medication safety is frequently a major cause of apprehension among pregnant IBD patients and the primary care providers who lack familiarity with biologic drugs and immunomodulators. Pharmacotherapy in IBD generally involves the use of corticosteroids for induction followed by maintenance therapy with aminosalicylates and immunomodulators such as thiopurine analogues. Biological agents in the form of anti-tumour necrosis factor-alpha (TNF-α) can also be used as induction and maintenance therapy for both Crohn’s and UC.
Corticosteroids are generally safe to be used for induction therapy during pregnancy. There is a possible minor association with cleft palate and reduction in birthweight.15,16 Long-term adverse steroid effects are similar to those in non-pregnant patients.
Aminosalicylates (sulfasalazine/mesalazine/balsalazide/olsalazine) do not incur significant adverse risk in pregnancy or for breastfeeding.17 Reports of diarrhoea in breastfeeding infants of women taking rectal 5-ASA has prompted monitoring the infant’s stool consistency. The sulfapyridine component of sulfasalazine does cross the placenta and may affect folic acid metabolism. The usual supplementation with folic acid is recommended. Owing to limited evidence, the concerns regarding aminosalicylates causing premature closure of the ductus arteriosus has not led to established restrictions in the third trimester.
Thiopurine analogues – azathioprine and 6-mercaptopurine – have historically been assigned as Category D drugs in pregnancy; however, this was based on extrapolation from animal data and high-dose usage in oncology settings. With an increasing duration of experience, recent evidence suggests they are well tolerated when used for IBD in pregnancy and any minimal increase in adverse outcomes is negated by the risk associated with poor disease control.18 Furthermore, potential adverse effects are lowered in the fetus due to a deficit of the enzyme inosinate phosphorylase required to convert thiopurine analogues to harmful active metabolites.
The use of biologics has revolutionised IBD management in recent years, with significant improvement in clinical response and remission rates. Two anti-TNF-α agents, infliximab and adalimumab, are approved for use in Australia. Administration of these agents during conception and pregnancy are considered to be low risk.19 High levels of infliximab can be found in infants owing to placental transfer and thus treatments during the third trimester are sometimes withheld due to potential risk. A minimal amount of infliximab is secreted in breastmilk and breastfeeding is not contraindicated, however the data on adalimumab are limited.
Cyclosporine is a Category C drug that can be used as rescue induction therapy for those with fulminant ulcerative colitis. It is not strongly associated with adverse pregnancy outcomes, although breastfeeding is contraindicated owing to high levels present in breastmilk.20 Methotrexate is contraindicated in pregnancy as it is a proven abortifacient and causes congenital defects.
Requirement for surgery in pregnant IBD patients is similar to non-pregnant patients and usually relates to complications of poorly controlled disease. Indications include bowel perforation, drainage of abscesses, intestinal obstruction and management of enterocutaneous fistulae. There are very limited data examining the role of surgery in pregnancy.
Mode of delivery
The mode of delivery in an IBD patient is based on obstetric considerations. Caesarean section is preferred in those with peri-anal or rectal disease.21 Similarly, concerns about anal sphincter disturbance with vaginal delivery may prompt caesarean section in patients who already have borderline continence from altered anatomy following ileal-pouch anal anastomoses.22 Use of episiotomy is minimised, if possible, with the risk of perineal involvement with Crohn’s leading to delayed healing.
Liver disease unique to pregnancy
Intrahepatic cholestasis of pregnancy
This disorder occurs in around 0.5–1.5 per cent of European pregnancies (15 per cent in Chilean population) and seems to have some genetic predisposition.23 Cholestasis typically develops during the second to third trimester, with higher prevalence in twin pregnancy is presumed to be related to the effect of elevated oestrogen levels. The usual manifestations of this disease include pruritus, particularly in soles and palms, along with elevation of serum bile acid and aminotransferases. High maternal bile acid levels are associated with poor fetal outcomes including premature birth, fetal distress and intrauterine death.24
Cholestasis commonly resolves after delivery and does not affect the long-term maternal prognosis. Ursodeoxycholic acid is safe and well tolerated for alleviating marked pruritus and biochemical abnormalities.25 Some obstetric units electively induce labour at around 37 weeks of gestation to prevent fetal death; however, there are no randomised controlled trials to support this intervention and management should be considered on an individual, case-by-case basis.26
Pre-eclampsia / HELLP
Pre-eclampsia is a multi-system disorder of unclear aetiology characterised by hypertension, oedema and proteinuria along with transaminitis as a hepatic component of multi-organ dysfunction. The HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) is considered to be part of a spectrum of disease that complicates 20 per cent of severe pre-eclampsia during pregnancy.27 Presenting in the second and third trimester and sometimes postpartum, patients may develop abdominal pain, nausea and vomiting, occasionally jaundice or may be completely asymptomatic. They may also have other features of pre-eclampsia such as hypertension and proteinuria. Severe cases may progress to develop acute liver failure, hepatic haematoma and rupture along with eclamptic complications.28 Fetus prematurity and intrauterine growth retardation are common adverse outcomes seen in HELLP. Treatment of pre-eclampsia and HELLP mainly revolves around intensive monitoring and support, including correction of coagulopathy, hypertension management and electrolyte normalisation, until expedited delivery. Risk of recurrent HELLP is increased in subsequent pregnancies; however, long-term complications are generally uncommon.
Acute fatty liver of pregnancy
Acute fatty liver of pregnancy (AFLP) is a rare disorder occurring in late pregnancy with significant maternal and neonatal mortality. Patients present with non-specific symptoms including right upper quadrant pain, nausea, vomiting, jaundice and encephalopathy. They will typically demonstrate transaminitis, hyperbilirubinaemia, leucocytosis and elevated serum creatinine.29
Often it may be difficult to distinguish between HELLP, AFLP and other acute liver disorders such as viral hepatitis. AFLP seems to be associated with more severe hypoglycaemia, hyperuricaemia and coagulopathy or disseminated intravascular coagulopathy (DIC). Delayed management leads to fulminant hepatic failure and life-threatening complications.
An association has been found between AFLP and deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD).30 This enzyme is involved in glucose production through fatty acid oxidation during times of fasting. An increased incidence of AFLP is reported in those women who are heterozygous for LCHAD and babies with homozygous LCHAD deficiency. Although the mechanism of AFLP is yet to be elucidated it has been postulated that there is increased fetal fatty acid cross over to the maternal circulation resulting in microvesicular steatosis and liver injury. Nevertheless, neonatal screening for LCHAD deficiency is recommended following development of AFLP. Once again the management of AFLP focuses on expedient timely delivery to minimise long-term maternal and neonatal complications.
This does not result in any significant hepatic disorder; however, some patients may have non-specific elevation of aminotransferases. Some of these patients may require hydration and electrolytes support. Most conventional anti-emetics – including dopamine agonists (metoclopramide/domperidone), phenothiazines (prochloperazine) and H1 antagonists – are safe to use in pregnancy.
Concurrent or existing liver disease
Acute viral hepatitis can occur at any time during pregnancy. Hepatitis A is the most common pathogen; however, hepatitis B, hepatitis C, Epstein-Barr and cytomegalovirus can also be involved. Of note, herpes simplex virus infections rarely result in fulminant hepatitis. Generally only supportive measures are required as treatment. Acute Hepatitis E, although rarely seen in Australia, can also cause fulminant hepatitis during pregnancy, with a maternal mortality rate of 15–25 per cent as well as resulting in poor obstetric and fetal outcomes.
Chronic hepatitis B patients with highly active disease or advanced liver disease are encourage to receive anti-viral therapy prior to conception.31 Until the recent introduction of Tenofovir, there have been no agents with proven safety in pregnancy. Pegylated interferon is contraindicated during conception and pregnancy. Those with mild disease but high viral load can be treated with lamivudine in the third trimester to minimise vertical transmission.Furthermore, hepatitis B vaccination and immunoglobulin should be provided to neonates with an HBsAg-positive mother as these are highly effective ways to reduce vertical transmission. Mode of delivery and breastfeeding do not affect the rate of transmission.
Vertical transmission of chronic hepatitis C occurs in five per cent of those with positive hepatitis C virus (HCV) RNA and is accentuated by high viral load and co-infection with HIV. Currently, there is no proven method of risk reduction other than HCV eradication. Pegylated interferon-based regimens once again are contraindicated in pregnancy. There is no clear evidence-based consensus on the mode of delivery in reducing transmission risk.32
Autoimmune / Wilson / Haemochromatosis
Autoimmune liver diseases, including primary biliary cirrhosis and primary sclerosing cholangitis along with metabolic hepatic disorders, often affect patients during childbearing years. Control of disease prior to conception with multidisciplinary management between obstetricians and gastroenterologists is essential in lowering complications during pregnancy.
Risk of biliary lithogenesis increases during pregnancy and pregnant women may present with biliary and pancreatic complications such as cholecystitis, cholangitis and pancreatitis. Abdomen ultrasound and magnetic resonance cholangio-pancreatography (MRCP) are useful non-invasive diagnostic imaging modalities. Endoscopic retrograde cholangio-pancreatography (ERCP) can be safely performed for extra-hepatic biliary obstructions, provided care is taken to minimise fetal radiation exposure.33 If necessary, laparoscopic cholecystectomy can be undertaken in the second trimester.
Pregnancy in cirrhotic patients is generally considered high risk with significant maternal morbidity and mortality resulting from potential hepatic decompensation as well as gastrointestinal tract bleeding.34 It is also associated with increase in spontaneous abortions, preterm deliveries and stillbirth. Management of pregnant cirrhotic patients is similar to those non-pregnant patients with optimal medical optimisation. Patients should receive endoscopic variceal surveillance and prophylaxis. Close monitoring of antenatal liver function is recommended. Coagulopathy may need to be corrected prior to labour.
Gastro-oesophageal reflux disease
Reflux in pregnancy
Gastro-oesophageal reflux disease (GORD) is a common disorder in pregnancy and may be present in up to 50 per cent of all pregnancies. There is evidence to suggest that the lower oesophageal sphincter pressure is abnormally low during pregnancy and it has been postulated that this is the result of the hormonal influence of progesterone.35 Animal studies have shown altered sphincter response to physiological stimuli with relaxation of sphincter tone. Acid reflux symptoms are similar to those in non-pregnant patients, with heartburn, regurgitation and dyspepsia being the most common complaints. Symptoms generally become more prevalent through to the third trimester and generally settle postpartum.36
Reflux disease can be reliably diagnosed based on clinical history alone. Endoscopic evaluation is rarely required unless there are severe symptoms not responding to maximal medical therapy. Contrast barium studies should be avoided due to radiation exposure.
Lifestyle and dietary modifications are generally recommended as first-line treatment for reflux disease in pregnancy. This includes elevation of the upper torso during sleep, small frequent meals and avoidance of alcohol and acid-inducing food groups.
Over-the-counter antacid formulations are mostly safe and effective in pregnancy. Calcium- and magnesium-based compounds are favoured as there are some data suggesting possible risk reduction of hypertension/pre-eclampsia and eclampsia, respectively. These compounds can result in constipation with long-term use. Excess sodium bicarbonate formulation should not be used as it may lead to metabolic alkalosis.
For those with troublesome reflux symptoms, histamine receptor antagonists such as ranitidine and cimetidine can be trialled. Most of the studies did not find any significant increase of maternal complication or fetal malformations in pregnant women exposed to these agents.37 The FDA classifies all of them as category B drugs. Use during lactation is acceptable except for nizatidine.
Proton pump inhibitors
Caution should be exercised when using proton pump inhibitors (PPI) in patients with severe dyspeptic and acid reflux symptoms not amenable to above therapy. Omeprazole may have some fetal risks in animal studies; however large observation studies did not conclusively show significant risk of malformation.38 It is currently assigned class C by the FDA. More data are required to fully assess the safety of other PPI agents and although the overall risk is probably low this class of drugs are only used in carefully selected cases. In light of their low molecular weight properties, high concentration can be found in breastmilk and hence avoidance during lactation is recommended.
Common gastroenterological disorders may be associated with a multitude of pregnancy-related issues and potentially significant adverse pregnancy outcomes. Emphasis placed on prompt recognition and management in a multidisciplinary approach in consultation between obstetric and gastroenterology teams will result in improved maternal and fetal outcomes.
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