GI Consult: GI Disorders During Pregnancy

Does the pregnant patient miserable with nausea and vomiting have the classic first-trimester syndrome, or hyperemesis gravidarum, or worse? What are the warning signs of liver disease during pregnancy? The authors cover the spectrum of possible GI-related problems and discuss their therapies.

By Christine L. Frissora, MD, Mark W. Russo, MD, and Kenneth L. Koch, MD

Dr. Frissora and Dr. Russo are assistant professors of medicine in the division of gastroenterology at the Weill Medical College of Cornell University in New York City. Dr. Koch is professor of medicine in the gastroenterology division at Hershey Medical Center, Penn State University, Hershey, Pennsylvania.

What drugs are safe to use for gastroesophageal reflux disease (GERD) during pregnancy?

The H2-receptor blockers ranitidine, famotidine, and nizatidine have been used in pregnancy and are classified as pregnancy category B drugs, meaning there is no animal data to suggest teratogenicity and no human data available. However, in clinical experience, there have been birth defects in 4% to 6% of children born to women who have taken these drugs to treat GERD. While that rate is no higher than the normal rate of birth defects, this class of agents still should not be used during pregnancy. All drugs should be avoided, if possible, in the first trimester, when fetal organs are forming. Calcium carbonate tablets can be taken to relieve GERD symptoms; they are also an acceptable form of calcium intake during pregnancy.

How should constipation be treated during pregnancy?

The best way to treat constipation during pregnancy is with diet. Fruits such as papaya, prunes, pears, plums, and peaches—and plenty of water—are helpful. High doses of magnesium are controversial because of the risk of central nervous system (CNS) problems in infants and therefore should not be used in excess during pregnancy. If constipation does not resolve with dietary modifications, low doses of senna or cascara can be taken twice a week.

Can celiac sprue develop during pregnancy?

Celiac sprue can develop during pregnancy, typically causing anorexia, diarrhea, and dehydration that can lead to persistent nausea and vomiting. The electrolyte abnormalities may be confused with hyperemesis gravidarum. The diagnosis of celiac sprue can be made by using antibody blood tests; the tissue transglutaminase IgA and antiendomysial IgA are virtually 100% specific for sprue. Their sensitivity, however, is only about 80%. Other serologic tests can detect antigliadin antibodies, which are IgA and IgG. However, these antibodies are not as sensitive or specific as the tissue transglutaminase and endomysial antibodies.

Because all serologies will normalize after the patient goes on a gluten-free diet, they are useful for monitoring compliance with such a diet. It is important to note that selective IgA deficiency is ten times more common in celiac sprue than in the general population. An IgA-deficient individual will always test negative for antigliadin IgA antibodies, and in these cases an upper endoscopy with biopsy can be performed if needed. This can be done without sedation during pregnancy if the patient can tolerate it; otherwise, midazolam 2 to 4 mg IV can probably be used safely if an endoscopy is truly necessary.

What kind of evaluation should a nauseated pregnant patient undergo?

Severe nausea in a pregnant patient may reflect one end of the spectrum of nausea and vomiting typically seen in pregnancy—that is, hyperemesis gravidarum. However, a careful history may uncover clues that suggest other diagnoses. The key is to determine if there is pain associated with the nausea and vomiting. Any pain in the abdomen must be investigated separately. Right upper quadrant pain or epigastric pain may indicate cholecystitis or pancreatitis. An ultrasound may be warranted in such instances. If there is a history of regurgitation and heartburn, then a diagnosis of GERD can be made. Flank pain may indicate pyelonephritis, another cause of nausea and vomiting, which is diagnosed by an elevated white blood cell count and pyuria. Gestational diabetes may present with nausea, vomiting, hyperglycemia, and glycosuria. New onset of migraine headache, visual disturbances, or other neurologic findings suggest CNS abnormalities. A computed tomography scan of the head or neurologic consultation may be indicated.

What is the treatment for nausea and vomiting during pregnancy?

If secondary causes are excluded, then the patient has the nausea of pregnancy, a well-known but poorly understood condition associated with the first trimester that often lasts all day. The treatment varies according to the severity of the nausea. Mild to moderate nausea can be treated with changes in diet such as increasing carbohydrates and decreasing fatty foods. Ginger tablets (250 mg orally three times daily as necessary) may also help. Acupressure and acustimulation bands placed on the P6 acupuncture point have proved beneficial in many women. Vitamin B6, antihistamines, and motion sickness drugs may also be useful. For more severe nausea, the prokinetic drug metoclopramide 10 mg may be administered orally or intravenously (IV) three to four times daily. Ondansetron may also be used. These drugs have no known adverse effects on the fetus.

What type of evaluation should be done for a patient with prolonged vomiting during pregnancy?

The patient should be evaluated in the emergency department for evidence of dehydration and orthostatic hypotension. She may have hyperemesis gravidarum, but other causes of prolonged vomiting must be considered. Abdominal pain suggestive of bowel obstruction, pancreatitis, or cholecystitis should be considered. Pyelonephritis and sepsis may also cause recurrent vomiting. Central nervous system diseases, such as migraine, meningitis, and brain tumor, should be considered. Depending on the patient's history and results of the physical examination, blood tests and urinalysis may be warranted. In emergent cases, an ultrasound of the abdomen or an upper endoscopy should be performed. Pregnant women with recurrent vomiting often must be admitted for observation.

What is the difference between the nausea and vomiting of pregnancy and hyperemesis gravidarum?

When pregnant women develop severe vomiting that leads to dehydration, electrolyte abnormalities, or weight loss, the disorder is referred to as hyperemesis gravidarum, previously known as pernicious vomiting of pregnancy. Hyperemesis gravidarum has a reported incidence of between 3 and 20 per 1,000 pregnancies, with 5 per 1,000 being the most commonly accepted figure. The condition can coexist with gestational diseases and potentially life-threatening diseases of the liver associated with pregnancy, which must be accurately diagnosed on initial presentation. Rarely, if untreated, hyperemesis gravidarum can lead to significant morbidity, including maternal and fetal death.

What causes hyperemesis gravidarum? And what is the differential diagnosis?

Hyperemesis gravidarum is a neurohormonal disorder of unknown etiology. Whatever the cause, the end result is activation of the central emesis center and abnormal motility and emptying of the stomach. Electrolyte abnormalities and dehydration always ensue.

Hyperemesis gravidarum is more common in trophoblastic diseases of pregnancy and certain fetal abnormalities such as triploidy, trisomy 21, and hydrops fetalis. These conditions must be excluded before attributing the nausea and vomiting to nonobstetric causes. Hyperemesis gravidarum also must not be confused with pre-eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), or acute fatty liver of pregnancy, all of which are potentially life-threatening if unrecognized.

The most common trophoblastic disease of pregnancy is hydatidiform mole (or molar pregnancy). The diagnosis of molar pregnancy can be made if the uterus is unusually large and firmer than in a normal pregnancy. A positive diagnosis can be made by sonography, which would show cystic lesions; also, human chorionic gonadotropin levels are higher than in a normal pregnancy. The uterus should be evacuated as soon as the diagnosis is made.

What are the most serious sequelae in hyperemesis gravidarum?

The most common serious sequela is Wernicke's encephalopathy, which results from thiamine (vitamin B1) deficiency and which is sometimes associated with central pontine myelinolysis. Rarely, serious events have occurred as a result of severe vomiting. Yamamoto described a patient who developed esophageal rupture and presented with pneumomediastinum as a result of severe vomiting.

What is the therapeutic strategy for hyperemesis gravidarum?

The first step in the treatment of hyperemesis gravidarum is hydration. Prolonged loss of gastric contents results in a hypochloremic metabolic alkalosis. Intravenous hydration is needed early in the course of this condition to replete intravascular volume and restore electrolyte levels. If the patient is otherwise healthy, IV fluid can be given rapidly. Because of the risk of Wernicke's encephalopathy, it is essential to administer thiamine 100 mg IV prior to giving dextrose. After thiamine replacement, dextrose can be administered as 100 mg in 100 ml normal saline, infused over a 30-minute period. Ringer's lactate, an isotonic solution that contains electrolytes, is also given IV, initially at a wide-open rate, which is typically 350 ml/hour. After two liters have been infused, the rate can usually be decreased to 200 ml/hr. After 24 hours of hydration, the rate is adjusted to maintain fluid status, which will depend upon urine output and other fluid losses. Many patients improve promptly after rehydration and can be maintained on biweekly IV hydration as outpatients.

Sodium, potassium, and magnesium levels must be continuously monitored. When checking calcium levels, it is essential to correct for the low albumin that is common in pregnancy due to fluid shifts. A simple formula is: True serum calcium level = 0.8 x (3.5 - albumin level) + measured serum calcium level. An ionized calcium level can be obtained, but it requires a special laboratory test that may not be readily available.

When oral hydration can be tolerated, it is best to begin with small, frequent amounts of salty fluids such as homemade chicken soup. Patients can then try crackers, noodles, and smooth natural peanut butter. Preservatives and chemicals such as monosodium glutamate must be avoided.

The use of ginger for hyperemesis gravidarum has been investigated. Thirty women participated in a double-blind randomized crossover trial of a natural product, the powdered root of ginger, 250 mg orally four times daily compared to placebo. The ginger was taken for four days with a two-day washout period between the placebo and ginger groups. Patients reported significantly greater relief with ginger (p=0.035). The degree of nausea and the episodes of vomiting were reduced. No side effects were observed.

What is the difference between pre-eclampsia, eclampsia, and toxemia of pregnancy?

Pre-eclampsia is a multisystem disease of unclear etiology that affects 3% to 10% of all pregnancies, typically starting in the second half of pregnancy and occurring more commonly in primiparous women. The usual criteria used to diagnose pre-eclampsia include sustained hypertension after the 20th week of pregnancy (greater than 140/90 mm Hg) in a woman known to be previously normotensive, with proteinuria of 500 mg/L or higher on 24-hour urine testing. Patients experience nausea, vomiting, epigastric or right upper quadrant pain, thirst, headache, and blurred vision. These symptoms overlap with those of hyperemesis gravidarum, and it is essential to make an accurate diagnosis. Many patients with pre-eclampsia are hyperreflexic and edema is common. Liver disease is a common and ominous complication; it usually takes the form of HELLP syndrome.

When seizures occur in patients with pre-eclampsia, the disorder is called eclampsia. Toxemia of pregnancy is simply the old name for pre-eclampsia.

What is the best approach with a patient who has abnormal liver function test (LFT) results during pregnancy?

A pregnant patient with abdominal pain may have elevated LFTs, indicating liver disease associated with pregnancy, viral hepatitis, or cholelithiasis. An ultrasound of the abdomen with a Doppler scan of the portal vein is sometimes necessary. Any elevation in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels, especially in the third trimester, is a red flag for fatty liver of pregnancy, a potentially life-threatening disorder. A hepatologist should be consulted when abnormal LFTs are found during pregnancy.

What kinds of liver function abnormalities are expected in pregnancy?

Alkaline phosphatase may be elevated because of the placenta, which produces the enzyme. The AST, ALT, and bilirubin levels should be normal. Albumin may be slightly low due to the expansion of intravascular volume during pregnancy. An albumin level of less than 3 should prompt an evaluation for malabsorption or malnutrition.

When is induced delivery or emergent cesarean section indicated?

Acute fatty liver (and liver failure) of pregnancy is an emergent condition that typically occurs in the third trimester. About 50% of women with this condition are nulliparous. Induced delivery (if the mother and fetus are stable) or an emergent cesarean section is sometimes necessary.

This condition is associated with nausea, vomiting, fever, epigastric pain, and jaundice. Pruritus may also be a symptom. Laboratory findings may show prolonged prothrombin time, decreased fibrinogen level, and moderate to high elevations of transaminases. (Rarely, patients may have normal transaminases.) Elevated uric acid, blood urea nitrogen, and creatinine levels may reveal renal failure. (Creatinine levels above 1.2 mg/dl are not normal in pregnancy.) Leukocytosis is common. Hypoglycemia may occur and should be suspected in all patients with altered mental status. The hallmark on liver biopsy is microvesicular fat, most prominent in the central zone and sparing the periportal hepatocytes.

Patients with acute fatty liver of pregnancy may need to be treated in an intensive care unit, preferably at a liver transplant center. A hepatologist must be consulted immediately. Because the condition is often fatal and may recur, patients should be cautioned against future pregnancies.

When is hepatic rupture a concern?

It is essential to differentiate hyperemesis gravidarum from prolonged vomiting associated with HELLP syndrome and acute fatty liver of pregnancy because the latter two disorders will lead to significant maternal mortality if unrecognized and untreated. The HELLP syndrome is presumed to underlie hepatic hematoma and hepatic rupture in pregnancy. Transaminase elevations can range from modest to levels of several thousand, without significant elevations in the alkaline phosphatase or bilirubin. Treatment of choice is induced delivery or cesarean section. Most patients present after the 27th week of pregnancy; 11% present earlier and up to 30% present after delivery. The HELLP syndrome can recur in subsequent pregnancies, and patients should be advised of this risk.

What is Budd Chiari disorder?

Budd Chiari is a disorder in which there is thrombosis of the hepatic vein, resulting in abdominal pain, ascites, anorexia, and vomiting. This can occur in pregnant or postpartum women who have a hypercoagulable state, such as those induced by smoking or factor V Leidin, protein C, or protein S deficiency. Diagnosis may be made by ultrasound of the liver with Doppler scan or magnetic resonance angiography. Early diagnosis may avoid morbidity. The patient should be transferred to a liver transplant center immediately.

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