Hyperemesis, Gastrointestinal and Liver Disorders in Pregnancy
During pregnancy, there is generalized relaxation of smooth muscle resulting in relaxation of the oesophageal sphincter, reduced gastric peristalsis, and delayed gastric emptying. Small and large bowel transit times are increased. There is increased blood flow to the liver and increased production of fibrinogen, transferrin and many other binding proteins. Reference ranges for many liver function tests are altered. Gestation-specific alkaline phosphatase is increased, mainly from increased placental production, and aminotransferases and γ-glutamyltransferase are reduced.
Nausea, Vomiting and Hyperemesis Gravidarum
Background: nausea is experienced by up to 90% of women during pregnancy, and 50% complain of vomiting. Symptoms can start from 5 weeks and usually resolve by the end of the first trimester. Persistent vomiting in pregnancy is termed hyperemesis gravidarum (HG) when the woman is unable to maintain adequate hydration and nutrition. The cause of HG is incompletely understood, but hormonal, mechanical and psychological factors have been implicated. Biochemical thyrotoxicosis (raised free thyroxine and suppressed thyroid-stimulating hormone [TSH]) is thought to occur by the stimulatory action of human chorionic gonadotrophin (hCG) on the thyroid (hCG shares a common α-subunit with TSH).
Features: signs of HG include weight loss, muscle wasting, ptyalism (inability to swallow saliva resulting in spitting and drooling) tachycardia, and postural hypotension. Biochemical findings may include hyponatraemia, hypokalaemia, abnormal thyroid function and liver function, and metabolic hypochloraemic alkalosis (loss of HCl from stomach).
Complications: if inadequately treated HG can lead to significant maternal and fetal morbidity.
Severe hyponatraemia or its over rapid correction can lead to central pontine myelinolysis or osmotic myelinolysis (presents with confusion, horizontal gaze paralysis, and spastic quadriplegia).
Wernicke’s encephalopathy (Vitamin B1 deficiency) can occur in any condition of unbalanced nutrition, which lasts for 2–3 weeks. This presents with a triad of confusion, ataxia, and ophthalmople-gia. It carries a mortality of between 10% and 15%, and incomplete recovery can lead to Korsakoff’s psychosis where the patient develops anterograde and retrograde amnesia and confabulation.
Thromboembolism is a risk due to dehydration and immobility in hospital.
Others include vitamin deficiencies and aspiration of vomitus.
Severe HG (abnormal biochemistry and/or Wernicke’s) can result in intrauterine growth restriction or even intrauterine death, but overall there are lower risks of miscarriage, stillbirth and preterm delivery.
Diagnosis & investigations: it is a diagnosis of exclusion, and other causes must be considered especially if the vomiting starts after the first trimester. The possible differential diagnoses of nausea and vomiting in pregnancy are given in Table 1.
Management: a protocol for management of hyperemesis is given in Table 2. It is important to give the patient adequate reassurance as to the safety of anti-emetics in pregnancy as poor compliance is a major reason for failure of treatment. Mild cases can be managed as day cases, giving intravenous rehydration and anti-emetics, and continuing with buccal medication, or suppositories then oral once vomiting is under control. It is usual to advise continuing regular anti-emetics for 7 days following admission to prevent a recurrence of symptoms. Intravenous thiamine should be given to moderate to severe cases. Inpatients should be given anti-embolic stockings and low-molecular-weight heparin, and serum electrolytes should be checked daily. Refractory cases not responding to conventional anti-emetics should prompt further investigation for another cause, and a trial of corticosteroids should be considered. Biochemical thyrotoxicosis does not require treatment unless there are clinical signs of hyperthyroidism and TSH receptor antibodies are present.
Gastric reflux is a common condition affecting two-thirds of pregnant women especially in the third trimester. It is exacerbated by changes in pregnancy, including pressure from the enlarging uterus, increased gastric transit time, and reduced lower oesophageal sphincter pressure. These lead to reflux of gastric contents into the lower oesophagus and inflammation of the mucosa. Features include retrosternal and epigastric pain, and dyspepsia. The differential diagnosis includes peptic ulcer disease. Management includes non-pharmacological (such as sleeping semi-recumbent and avoiding food and fluids immediately before bed) and pharmacological measures. Drugs that are safe to use in pregnancy are antacids (aluminium salts cause constipation and magnesium diarrhoea); Antacids with alginic acid; metoclopramide; sucralfate; H2-receptor blockers (ranitidine is safe but avoid cimetidine because of its effect on androgen receptors); and proton-pump inhibitors. Avoid misoprostol as it is an abortifacient, and it is also associated with congenital abnormalities, fetal death, and uterine perforation.
Peptic Ulcer Disease
Peptic ulcer disease is uncommon in pregnancy, and this may in part be owing to a protective effective of oestrogens and prostaglandins on the gastric mucosa. It usually presents with epigastric pain. Complications such as haemorrhage and perforation are rare in pregnancy, but significant symptoms such as haematemesis should be investigated with upper gastrointestinal endoscopy, which can be safely performed in pregnancy. Pharmacological treatment includes H2-receptor blockers (eg, ranitidine) or proton-pump inhibitors (eg, omeprazole). Misoprostol is avoided, and Helicobacter pylori eradication can usually be delayed until after pregnancy. Constipation
This is another common condition in pregnancy affecting 40% of women, as physiological changes lead to decreased colonic motility and pressure of the gravid uterus on rectosigmoid colon. Risk factors include dehydration, poor dietary intake, opiate analgesia, and iron supplements.
Non-pharmacological measures such as increased fluid intake and dietary fibre are usually sufficient, with temporary cessation of oral iron. Laxatives may be required if these other measures fail, and both osmotic (lactulose, magnesium hydrochloride) and stimulant (senna, glycerol supposito-ries) types are safe.
DISORDERS OF THE LIVER AND BILIARY TRACT
There are several disorders of the liver, which are specific to pregnancy and are important to recognize as they are associated with significant morbidity and mortality for the mother and her fetus and delivery is the only cure. Some pre-existing conditions may only become clinically evident during pregnancy, and others such as hepatitis E have a predilection for pregnant women in whom the prog-nosis is significantly worse.
Liver Disorders Specific to Pregnancy
Haemolysis Elevated Liver Enzymes and Low Platelets (HELLP)
Background – HELLP is thought to be a severe form of pre-eclampsia, affecting 5–20% of these pregnancies, with one-third post partum. Hepatic damage is thought to occur as a result of increased sinusoidal pressure, hypovolaemia, and fibrin deposition.
Features and investigations – the condition can be asymptomatic or present with right upper quadrant or epigastric pain, nausea, vomiting, and general malaise.
In most cases, hypertension and proteinuria are present, and there is a mild to moderate elevation of aminotransferases and bilirubin. Blood film will reveal true thrombocytopenia and red cell frag-ments indicative of haemolysis.
Complications – HELLP is associated with significant maternal (1%) and perinatal (10–60%) mortality. Maternal complications include liver infarction and rupture, subcapsular liver haematoma, acute renal failure, and placental abruption.
Management – the mainstay of management involves stabilizing the patient, including control of blood pressure and giving magnesium sulphate for prevention of eclampsia. Prompt delivery is usually required if it presents antenatally. Clotting times should be monitored and correction of thrombocytopenia (platelets, < 50 × 109/L) is required to cover delivery.
Studies vary on the recurrence rate of HELLP in a future pregnancy, with figures of 2–27% quoted. The risk of pre-eclampsia is higher and may be up to 75% if background hypertension is present. Many women choose not to have a further pregnancy.
Acute Fatty Liver of Pregnancy
Background – this rare disorder is associated with abnormalities in mitochondrial β oxidation and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. There is considerable overlap of the symptoms and signs with pre-eclampsia and HELLP syndrome. It is more common in multiple pregnancies, primiparae, obese women, and with a male fetus.
Features and investigations – the presentation is similar to that in HELLP syndrome with nausea, vomiting and abdominal pain, although the rise in serum transaminases, creatinine and leucocytosis tends to be more marked. Other discriminating features are hypoglycaemia and coagulopathy, which are much more evident in acute fatty liver of pregnancy (AFLP). It may present post partum with severe haemorrhage. Table 3 gives the diagnostic criteria for AFLP.
Complications – AFLP carries a high maternal and fetal mortality of between 2–18% and 7–58%, respectively. Maternal complications include disseminated intravascular coagulation, renal failure, pancreatitis, and (transient) diabetes insipidus. There is also a risk of progression to hepatic encephalopathy and fulminant liver failure.Management – if AFLP presents antenatally, then coagulopathy and hypoglycaemia should be treated aggressively and delivery expedited. High dependency unit and/or intensive therapy unit involvement are/is usually required and early liaison with a specialist liver unit in case of progression to liver failure.
Post delivery, most women recover quickly, and management is conservative and supportive. Liver function may take up to 4 weeks to recover, and liver transplantation should be considered in those with liver rupture, severe encephalopathy, or failure of liver recovery. The recurrence rate for AFLP is around 25%, but many women avoid a further pregnancy. The baby should be screened for LCHAD deficiency.
Features and investigations – Obstetric cholestasis (OC) is a pregnancy-specific condition, which occurs in approximately 0.7% of pregnant women in the UK, and the main features are maternal pruritus and impaired liver function. In most cases, the serum bile acids are elevated, but derangement in other markers of liver function such as transaminases, bilirubin and γ-glutamyltransferase also occurs. Other maternal symptoms include steatorrhoea, pale stools, and dark urine.
The aetiology of the condition is incompletely understood but is thought to be due to the chole-static effect of oestrogens, which is supported by the higher incidence in twin pregnancy and occur-rence of similar symptoms in some individuals taking the oral contraceptive pill.
Complications – the major risks associated with this condition are to the fetus and include pre-term delivery, meconium staining of the liquor, and intrauterine fetal death, which is reported to be 2–12% depending on the studies reviewed. The risk of stillbirth is difficult to predict despite cardiotocography monitoring and ultrasound for fetal well-being. One prospective cohort study of 693 cases of OC has shown that the risk to the fetus occurs when the serum bile acids are above 40 μmol/L and that there is a 1–2% increase in fetal complications for every 1 μmol/L increase in the serum bile acid level.
Management – involves excluding other causes for liver function derangement as OC is a diagnosis of exclusion. Itching can be severe, causing marked skin excoriation, insomnia, and maternal distress. It is important to take a proper history in these cases as a rash is not a feature of OC and the patient will report that the itching preceded the skin changes. Mild symptoms can be managed with antihistamines and emollients containing 1–2% menthol. For more severe cases, ursodeoxycholic acid is the most effective treatment for ameliorating the symptoms and may improve the biochemical picture. It is not known whether treatment with ursodeoxycholic acid improves the outcome for the fetus or whether cases in which the serum bile acids are below 40 μmol/L can be managed expectantly, and this is the subject of ongoing research. Vitamin K 10 mg orally should be given to the mother from time of diagnosis to delivery to reduce the risk of post-partum haemorrhage.
Most units advocate delivery at around 37–38 weeks, and one study examining 352 pregnancies complicated by OC found that over 90% of intrauterine deaths occurred after 37 weeks, which sup-ports this practice. In resistant cases, rifampicin can be used under the guidance of a liver specialist although published data on its use in pregnancy is limited.
Maternal liver function tests usually return to normal post partum with no long-term liver damage, but should be monitored to ensure this happens. Women who have had OC should avoid the combined oral contraceptive pill. Recurrence risk of OC in a future pregnancy is high at > 90%.
Non-pregnancy-specific Liver Disease
Gall Bladder Disease (Gallstones and Cholecystitis)
Pregnancy increases the risk of gallstone formation, as oestrogen increases the cholesterol content of the liver and progesterone increases bile secretion. This results in increased saturation of the bile with cholesterol and gallstone formation. Cholecystitis should be treated promptly with broad-spectrum intravenous antibiotics and fluids, as it can precipitate pre-term labour. Pancreatitis is another serious complication of gallstones and again management is usually conservative as discussed below.
Pancreatitis rarely occurs in pregnancy and is most commonly due to gallstones. Hypertriglyceridaemia and hypercalcaemia of primary hyperparathyroidism are other causes. The presentation and symptoms are similar to the non-pregnant patient, and the diagnosis is usually made when the serum amylase > 1,000 U/L. Management is supportive with intravenous fluids and analgesia. Most cases will resolve spontaneously, but around 10% will develop severe complications needing intensive therapy unit support. Careful assessment of renal and liver function, clotting, glucose, full blood count and oxygen saturation will help to distinguish those needing intensive care.
Hepatitis B – transmission of hepatitis B occurs mainly by sexual contact or infected blood products. Acute infection usually presents with mild symptoms. Fulminant liver failure can occur in around 1%. Usually less than 5% remain as carriers which is associated with a risk of cirrhosis, chronic active hepatitis, and liver cancer. The risk of vertical transmission is low unless the mother develops the acute infection during the pregnancy (90% in the third trimester). High vertical transmission rates also occur in mothers who are positive for the hepatitis B e antigen which is a marker of high infectivity.
Mode of delivery does not alter the vertical transmission rate. Invasive procedures in labour, such as applying fetal scalp electrodes or fetal blood sampling, should be avoided. Neonates should be given hepatitis B immunoglobulin and vaccinated at birth and usually again at 1 month and 6 months. Giving this combined regimen protects against neonatal infection in 93% of cases. Breastfeeding should be encouraged as this also does not alter the risk of neonatal infection provided vaccination is given.
Mothers with hepatitis B should also be screened for hepatitis C and human immunodeficiency virus and have their baseline liver function checked.
Hepatitis C – Hepatitis C is a blood-borne infection and is common amongst intravenous drug users. At least 85% of infected individuals will develop chronic liver disease with around 30% developing cirrhosis after 10 years. Women should be under the care of a hepatologist.
Pregnancy has no effect on the disease; however, patients are more at risk of OC which is often more severe.
The risk of vertical transmission is low if the mother has a low viral titre. Mode of delivery and breastfeeding do not influence the rate of neonatal infection.
Hepatitis E – Hepatitis E is spread by the faeco–oral route and, in the non-pregnant population, is usually a self-limiting illness. Pregnant women are more severely infected with 20% developing acute liver failure. The maternal mortality rate is 12 times higher than in the non-pregnant population. Vertical transmission was approximately 30% in one small study with a fetal mortality rate of 50% in those affected.
Herpes Simplex Virus –HSV hepatitis occurs more commonly in pregnant women than the general population and has a maternal mortality rate of 39%. It can occur through primary infection or by reactivation of a latent disease and can be caused by serotypes HSV 1 and 2. Mucocutaneous lesions are present in only 50% of cases. Definitive diagnosis is made on liver biopsy, but computed tomographic scan is of value, showing multiple low-density areas within the liver. Treatment with aciclovir improves survival and should not be delayed if the diagnosis is suspected.
The differential diagnosis of abnormal liver function in pregnancy and a guide to investigations are given in Table 4.
PREGNANCY FOLLOWING LIVER TRANSPLANTATION
The chance of successful pregnancy in women following transplantation is around 70%, although the risk of complications such as miscarriage, intrauterine growth restriction, pre-term delivery and pre-eclampsia is increased. Ideally, pregnancy should be deferred until at least 1 year following liver transplantation to allow the graft function to stabilize and when lower doses of immunosuppressants can be used. Also, there is an increased risk of infection with cytomegalovirus immediately follow transplantation, which may result in congenital abnormalities if it occurs in early pregnancy. Graft function and survival are not affected by pregnancy though. The immunosuppressant agents, tac-rolimus, prednisolone and ciclosporin, are generally well tolerated in pregnancy and are not associated with fetal malformations. Mycophenolate mofetil is teratogenic in animals, and there are reported cases of congenital malformations in babies born to mothers taking this drug and it therefore should be avoided. Rates of caesarean section are high amongst this group of women although vaginal de-livery is not contraindicated. Inflammatory Bowel Disease
Features and investigations: inflammatory bowel disease (IBD) usually presents in young adulthood. The incidence of ulcerative colitis is higher in women than in men whereas Crohn’s disease affects both sexes equally. The course of disease is usually unaffected by pregnancy, although Crohn’s may flare post partum. Symptoms suggestive of active disease should be investigated with full blood count, serum albumin level and stool culture, and sigmoidoscopy or proctoscopy.
Management: obstetric outcome is related to disease activity at the time of conception, and women should be encouraged to conceive during periods of remission. Active disease is a risk factor for pre-term delivery and low birth weight. The management of IBD during pregnancy is frequently compromised owing to patient fears regarding congenital malformations and sometimes similar concerns or lack of experience of physicians in dealing with pregnant women. In general, attacks should be managed the same as in the non-pregnant patient.
The aminosalicylates, sulfasalazine and mesalazine, are safe for use throughout pregnancy and breastfeeding. Sulfasalazine is a dihydrofolate reductase inhibitor, which blocks the conversion of folate to its more active metabolites; therefore, supplementation with 5 mg folic acid is advised preconceptually and during pregnancy.
Corticosteroids are also safe although there is some evidence for an increased risk of cleft lip and palate in animals and humans. For acute colonic disease, topical steroid enemas can be used. Pred-nisolone is the corticosteroid of choice as > 90% is metabolized by the placenta, thus lowering the amount reaching the fetus.
There is extensive data on the safety of azathioprine in pregnancy, and there are no harmful effects on the fetus when adequate doses are used. Second-line immunosuppressants such as 6-mer-captopurine as well as metronidazole and vitamin B12 can also be used safely.
Conversely, methotrexate is contraindicated because of teratogenicity, and patients should be advised not to conceive within 3 months of taking this drug.
Infliximab is a chimeric monoclonal antibody against tumor necrosis factor-α and has revolution-ized the course of refractory IBD. In a case series of 96 pregnant women with Crohn’s disease or rheu-matoid arthritis treated with infliximab, the pregnancy outcomes were not different between the two groups or compared with the general population. A small study in breastfeeding mothers has also shown that infliximab was undetectable in the breast milk and in the sera of newborn infants.
Mode of delivery: most women with IBD can deliver normally. Indications for Caesarean section include active or severe perianal disease and ileoanal pouch anastomosis. Where surgery has been performed, it is recommended that the obstetrician obtain information from the surgeon to define the risks of vaginal delivery.
Coeliac disease: this is an abnormality of the small intestinal mucosa caused by the ingestion of gluten-containing substances in susceptible individuals. Diagnosis is made by jejunal or duodenal biopsy, which shows subtotal villous atrophy. Up to 80% of patients are positive for HLA B8, and there is a familial link. Features include diarrhoea, malabsorption, anorexia, and weight loss. Haematological disorders are common, and other complications include osteoporosis and osteomalacia due to malabsorption of vitamin D and calcium, muscle weakness, peripheral neuropathy, encephalopathy, and other mineral and vitamin deficiencies (vitamin B6, B12, zinc, folate, ferritin).
Exacerbation of symptoms may occur in pregnancy, and the rates of miscarriage and stillbirth are increased in those with untreated disease. Strict adherence to a gluten-free diet can reduce poor fetal outcomes. Careful attention must be paid to replacing essential minerals and vitamins, and women should be encouraged to breastfeed as this can reduce the incidence or delay the onset of coeliac disease in the neonate in those with a strong family history.
The incidence of appendicitis in pregnancy is similar to that in the non-pregnant population (1 in 500–1,500). Presentation may be atypical in pregnancy and therefore the diagnosis may be delayed. The appendix is shifted superiorly and therefore classic pain over McBurney’s point may be absent. Vomiting may be the only symptom. Leucocytosis is common in pregnancy, and symptoms such as fever or extreme leucocytosis are suggestive of perforation. Ultrasound has high sensitivity and specificity for the detection of appendicitis although clinical assessment should be used to guide management. Broad-spectrum antibiotics should be given pre-operatively. Prompt diagnosis and treatment are mandatory as the perinatal death rate is 20% in cases of perforation. Pre-term labour occurs in 11% of cases in the second trimester, and this risk decreases considerably in the first week after surgery.
© 2011 Elsevier Ltd. Initially published in Obstetrics, Gynaecology & Reproductive Medicine 2011;21(3):80–85. FURTHER READING
Bottomley C, Bourne T. Management strategies for hyperemesis. Best Pract Res Clin Obstet Gynaecol 2009;23:549–564.
Caprilli R, Gassull MA, Escher JC, et al. European Crohn’s and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations. Gut 2006;55(suppl 1):i36– i58.
Ch’ng CL, Morgan M, Hainsworth I, Kingham JG. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002;51:876–880.
Joshi D, James A, Quaglia A, Westbrook RH, Heneghan M. Liver disease in pregnancy. Lancet 2010;375:594–605.
McKillop L, Williamson C. Liver disease in pregnancy. Postgrad Med J 2010;86:160–164.
Nelson Piercy C. Handbook of Obstetric Medicine. Informa Healthcare; 2009:241–261.
Nelson-Piercy C, Williamson C. Gastrointestinal and hepatic disorders. In: Greer IA, Nelson-Piercy C, Walters B, eds. Maternal medicine. London: Churchill Livingstone; 2007:171–190.
Royal College of Obstetricians and Gynaecologists. Green top guideline number 43, January 2006.
Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007;109:956–966.
About the Authors
Clare Cuckson is a Specialist Registrar Obstetrics at Queen Charlotte’s and Chelsea Hospital, London, UK. Sarah Germain is a Specialist Registrar in Obstetric Medicine/Diabetes and Endocrinology at Queen Charlotte’s Hospital and St. Thomas’ Hospital, London, UK.