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BILIARY TRACT DISEASE IN PREGNANCY
PREGNANCY AND LIVER DISEASE
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BILIARY TRACT DISEASE IN PREGNANCY Munford R. Yates 111, MD, and Todd H. Baron, MD
Cholelithiasis is a common biliary tract disease in the United States, and more than 75% of the gallstones are composed of cholester01.'~There is considerable evidence that pregnancy is a predisposing factor in the formation of cholesterol gallstones. Sex steroids cause an alteration in biliary lipid composition and gallbladder motility leading to an increase in cholesterol gallstone synthesis. Gallstone disease is observed in 3.3% to 12.2% of pregnant women.9,53, 79, 8a Complications of gallstones represent the second most common nongynecological condition requiring surgery in pregnancya9;yet, clinically apparent disease is rare. The management of symptomatic gallstone disease during pregnancy is controversial. It is important for clinicians caring for pregnant patients to recognize the signs and symptoms of biliary tract disease during pregnancy and understand the management options. EPIDEMIOLOGY
Cholelithiasis is a very common disease in the United States and is estimated to occur in 10% of the adult p o p ~ l a t i o n More . ~ ~ than 75% of gallstones in the United States are made of ch~lesterol.'~ There are numerous studies that have shown that specific conditions predispose patients to cholesterol gallstones.ll Women develop gallstones twice as often as men.I9 The incidence increases with age such that by age 75 years, at least 35% of women and 20% of men have developed gallstones.66Obesity,12, rapid weight 1oss,52 and ileal disease5*21 have inFrom the Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham Hospital (MRY), Birmingham, Alabama; and the Division of Gastroenterology and Hepatology, The Mayo Clinic (THB), Rochester, Minnesota
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creased risk for cholelithiasis. In addition, oral contraceptive estrogen replacement therapy,6O total parenteral nutriti01-1:~certain demographic pop~lations,4~, 73 and elevated triglyceride levelP have also been implicated. Although the epidemiologic evidence between pregnancy and cholesterol gallstone disease has been described as weak," the association is well documented?,74,88 The incidence of gallstone disease in pregnancy ranges from 3.3% to 12.2Y0.9,53, 79, 88 The incidence of disease appears to increase in the final two trimesters of pregnancy; however, it appears that increasing parity (> 2 gestations), particularly in younger women,68,88not only increases the risk of gallstone formation but may also have a role in increasing the likelihood of symptomatic biliary tract di~ease.~ PATHOPHYSIOLOGY
The liver is important in regulating total body cholesterol stores. Cholesterol metabolism is a very complex and highly regulated process.18 Cholesterol secreted in bile is derived from newly synthesized cholesterol (20%), lipoprotein degradation, and sterols from other hepatic stores.81The precise mechanism of biliary cholesterol secretion is not known but appears to be driven by the rate of bile salt and cholesterol ester synthesis and lipoprotein secretion.81Once secreted, cholesterol is solubilized in bile as a result of its association with bile acids and phospholipids in mixed m i ~ e l l e sAn . ~ ~alteration in the hepatic metabolism of cholesterol leads to increased biliary cholesterol secretion. As bile becomes more saturated with cholesterol, vesicles form and become unstable, which leads to cholesterol crystal.growth and stone formation. There appears to be three abnormalities that lead to cholesterol gallstone formation. First, cholesterol supersaturation of bile results from increased biliary cholesterol secretion and bile salt hypo~ecretion.'~ Several mechanisms are important in establishing these secretory abnormalities.41Although supersaturated bile is required for lithogenesis, it is not the only prerequisite for gallstones, as it is found in patients without stones. Second, enhanced nucleation causes the aggregation of cholesterol molecules into coalescent vesicles that ~rystallize.'~ This leads to stone formation. Various endogenous biliary proteins and glycoproteins have been implicated as potential pronucleating agents.4I The third abnormality crucial to cholesterol gallstone formation is related to the gallbladder.I7It is recognized that cholecystectomy patients rarely develop cholesterol gallstones after surgery. There are two theories that explain this phenomenon. First, the gallbladder produces mucus that appears to be a pronucleator and a nidus for crystal Second, impaired gallbladder motility may lead to stasis, which promotes stone formation." Gallbladder emptying is regulated by neural (acetylcholine) and hormonal (cholecystokinin) factors.23Decreased gallbladder emptying not only promotes nucleation by providing a stagnant layer of
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concentrated bile and mucus but also leads to stasis and biliary sludge, a precursor to gallstones.= 74, 88 Pregnancy appears to be a predisposing factor for lithogene~is.~, There are changes in biliary tract and gallbladder physiology during pregnancy that increase the risk of cholesterol gallstones. Kern et a147 noted that as pregnancy progresses into the second and third trimesters, bile became more saturated with cholesterol as a result of an increase in biliary cholesterol secretion and cholic acid synthesis. By shifting bile acid secretion towards an increase in cholic acid at the expense of chenodeoxycholic acid, more cholesterol is secreted into bile. Everson et alz4found that estrogen caused increased biliary secretion of cholesterol and, hence, increased lithogenicity of bile. He proposed three mechanisms for estrogen’s role in altering bile omp position.^^ First, stimulation of hepatic lipoprotein (B and E) receptors leads to increased hepatic cholesterol uptake. Second, estrogen disrupts the feedback inhibition of hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase), the rate limiting enzyme in cholesterol metabolism, such that an increased uptake of lipoprotein cholesterol is not associated with decreased cholesterol synthesis. Lastly, it inhibits cholesterol catabolism into bile acids. As a result, estrogen increases biliary cholesterol Progesterone may also play a role by inhibiting acyl-coenzyme A cholesterol acyltransferase (ACAT) in decreasing cholesterol esterification leading to increased biliary cholesterol ~ e c r e t i o nTherefore, .~~ sex steroids, primarily estrogen, cause alterations in biliary lipid and bile salt composition that increase bile lithogenicity and serve as a prerequisite for cholesterol gallstone formation in pregnancy. Altered gallbladder motility is instrumental in gallstone formation during pregnancy. Ultrasonography data has shown that fasting and residual gallbladder volumes are larger in the second and third trimes79 In addition, incomplete postpranters when compared with dial gallbladder emptying was observed.14 In animal studies, pregnant guinea pigs had decreased gallbladder contractile responses to aceytlcholine and cholecystokinin (CCK).71Ryan71suggests that pregnancy, and more specifically progesterone, affects a step in the excitation-contraction coupling process that is common to both acetylcholine and CCK and results in gallbladder hypomotility and incomplete evacuation of the gallbladder during pregnancy. Although progesterone is a smooth muscle relaxant, it does not appear that there is a generalized decrease in the contractile process in gallbladder smooth muscle.71,7z The mechanism of this dysmotility in pregnancy is unexplained but may be related to changes in the intracellular pool of calciumz3,7z or to the down-regulation of contractile linked G - p r o t e i n ~As . ~ ~expected, the effects of pregnancy on gallbladder volumes are transient and resolve as early as 2 weeks postpartum. Therefore, changes in gallbladder motility during pregnancy lead to bile stasis and resultant sludge formation.53In summary, the increased predisposition to gallstones in pregnancy is caused by estrogen’s effects on increasing bile lithogenicity and progesterone’s effects on promoting gallbladder hypomotility.
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COMPLICATIONS OF GALLSTONE DISEASE Asymptomatic Cholelithiasis
Studies have observed that approximately 60% to 69% of pregnant women with gallstones were asymptomatic?,88 The diagnosis usually is made incidentally during routine prenatal ultrasound. Valdivieso et a P related the lack of symptoms to small gallstone (
Approximately 30% to 40% of pregnant women with gallstones are symptomatic, and about 20% to 50% of those patients have recurrent pain.9,88 The natural history of symptomatic gallstones reveals that the rate of complications (i.e., acute cholecystitis, choledocholithiasis, and gallstone pancreatitis) is 6% per year for 5.years, with a decrease to 1.6% to 1.7% per year for the next 10 to 15 yearsz9Wenckert et a190noted that over a lifetime, 18% patients develop complications that result in a 1.8% per year risk.90More importantly, when a complication of cholelithiasis if left untreated without cholecystectomy, approximately 30% recur over a 3-month period.4Q67 Symptoms of biliary tract disease in pregnant women are similar to those seen in nonpregnant women. Patients present with biliary colic: a sudden, recurrent, severe epigastric or right upper quadrant pain lasting up to 3 hours, with radiation to the right shoulder or interscapular region. It may be accompanied by nausea, vomiting, and anorexia. Biliary colic is caused by transient obstruction of the cystic duct. It may be precipitated by a large meal but not necessarily a fatty meal. Although the interval between attacks is variable, in pregnancy it is thought that symptoms worsen with advancing gestation and even into puerperium period. Although gallbladder and bile physiology revert to normal within a few weeks after delivery, it is apparent that postpartum women continue to have symptomatic gallstone disease.87,88 Epidemiologic data have recognized that women have an increased risk of symptomatic
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gallstone disease up to 5 years after their last pregnancy.84Maringhini et a153ultrasonographically assessed postpartum women for the presence of sludge and gallstones. Immediately postpartum, 26% of women had sludge, whereas 5% of patients had gallstone^.^^ At the 1-year followup, 95.6% of women with sludge initially had normal gallbladders, whereas only 13% of women with gallstones had normal gallbladder^?^ Valdivieso et aP8 noted that 29% of postpartum women initially with gallstones (<6 mm) had a disappearance of these gallstones within the follow-up of 6 to 24 months. The investigators related this phenomenon to either silent migration or spontaneous dissolution.88Therefore, gallbladder sludge resolves within 1 year of delivery, whereas most patients with gallstones may become symptomatic up to 5 years after pregnancy. Acute Cholecystitis
Acute cholecystitis is a rare complication of cholelithiasis in pregnancy, with an estimated rate of 1 to 8 cases per 10000 patients22,49; however, cholecystitis is second only to appendicitis as the most common nongynecological abdominal condition requiring surgery in pregn a n ~ y Almost .~~ always, an antecedent history of biliary colic can be elicited. In over 90% cases, prolonged stone obstruction of the cystic duct is the cause of acute inflammation of the gallbladder. The symptoms of acute cholecystitis during pregnancy are no different than in nonpregnant patients. It results in severe right upper quadrant pain worsened with inspiration, fever, nausea, and vomiting. Leukocytosis is ccmmon. Although acute cholecystitis occurs with similar frequency in each trimester, it may be more common in the postpartum period. Choledocholithiasis
Choledocholithiasis, common bile duct stones, is a rare occurrence in pregnancy. It is observed in 10% of pregnant patients undergoing cholecystectomy33and accounts for 7% of cases of jaundice in pregnancya Gallstones pass from the gallbladder into the common bile duct leading to obstruction of bile flow with resultant biliary ductal dilatation. The clinical presentation of choledocholithiasis is right upper quadrant tenderness, fever, and jaundice (Charcot’s triad), indicative of acute cholangitis. Pancreatitis may also occur. Laboratory studies reveal hyperbilirubinemia and mild transaminase and alkaline phosphatase elevation. Gallstone Pancreatitis
The incidence of acute pancreatitis complicating pregnancy is very rare and ranges from 1 in 1000 to 1 in 10000 deliveries.%,55 The most common cause of acute pancreatitis in pregnancy is gallstone disease,
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which represents 70% to 90% of patients.55,74 Additionally, 1.2% to 11% of symptomatic gallstone patients are complicated by acute pancreatitis.l3sS9 It is caused by common bile duct stones that transiently obstruct the main pancreatic duct, where it passes near the common bile duct at the ampulla of Vater. Historically, pregnancy was deemed a predisposing condition for pancreatitis, but this has not been pr0ved.5~Other, less common causes of pancreatitis in pregnancy include hyperlipipancreas divis~m,6~ idi~pathic,'~, 74 demia,55,74 hyperparath~roidism,6~ and alcohol ( Although pancreatitis presents at any time during pregnancy, it is most common in the third trimester. There is no relation to parity. The clinical manifestations of pancreatitis are similar to those in nonpregnant women. Patients appear ill with midepigastric pain, classically with radiation to the back, nausea, vomiting, fever, and anorexia. Jaundice may occur if there are common bile duct stones. The laboratory studies in patients with pancreatitis may reveal leukocytosis, hyperglycemia, hypoalbuminemia, or hypocalcemia. The majority of patients have elevated serum amylase and lipase levels. Overall, patients with acute pancreatitis have a 10% mortality.80 Earlier studies estimated that the maternal mortality from acute pancreatitis was approximately 37Y0.~'A recent study reviewed 43 pregnant women with acute pancreatitis of undefined severity5; however, no maternal deaths and minimal morbidity were observed.65Fetal loss rate ranges from 10% to 6O%, most of the deaths reflecting neonatal mortality following preterm delivery.",55,65, 74 Ramin et aP5reported 13% of infants died, a majority of which were preterm deaths. The decrease in maternal and fetal morbidity and mortality in gallstone pancreatitis during pregnancy is attributed to better recognition, diagnosis, and management. DIFFERENTIAL DIAGNOSIS
Conditions to consider in the differential diagnosis of cholelithiasis should include peptic ulcer disease, gastroesophageal reflux disease, nephrolithiasis, preeclampsia, acute fatty liver of pregnancy (AFLP), and HELLP (hemolysis, elevated liver enzymes, and low platelets) synd r ~ m eThe . ~ ~differential diagnosis of biliary tract disease in pregnancy also includes: Cholelithiasis Peptic ulcer disease GERD Nephrolithiasis Preeclampsia AFLP HELLP Cholecystitis Perforated duodenal ulcer
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Pancreatitis Pyelonephritis Hepatitis Hepatic abscess Fitz-Hugh-Curtis syndrome Appendicitis Pneumonia Pancreatitis Cholecystitis Cholangitis Appendicitis Perforated ulcer Preeclampsia Perinephric abscess Ectopic pregnancy Hyperemesis gravidarum Peptic ulcer disease (PUD) has a lower incidence in pregnancy than in the general population.15The symptoms of PUD are similar in pregnancy with epigastric pain, postprandial nausea and vomiting, and abdominal distention. It may worsen in the third trimester. Gastroesophageal reflux disease (GERD) is common in pregnant women starting in the initial trimester and progressing through gestat i ~ n Its . ~ classic presentation is heartburn, a substernal burning that radiates from the xiphoid, up through the chest, and into the throat. It is precipitated by lying down, bending over, and large meals. GERD improves following delivery. Nephrolithiasis presents as renal colic, a severe unilateral flank pain .that radiates to the ipsilateral lower quadrant or groin.s2 It may be associated with nausea and vomiting and urinary symptoms. Hematuria and pyuria are not uncommon. Preeclampsia occurs in 2% to 10% of all pregnancies, manifesting in the late second and third trimesters.s The patient presents with hypertension, proteinuria, and edema.45It may affect the liver in up to 50% cases and is accompanied by right upper quadrant or epigastric pain, nausea, and vomiting. Preeclampsia resolves with delivery in most cases. AFLP occurs in 1 in 13000 pregnancies, with manifestations in the third t r i m e ~ t e r .Patients ~~ present with anorexia, headaches, malaise, nausea, and vomiting. This is followed by epigastric and or right upper quadrant pain and jaundice. Concomitant preeclampsia is present in about 50% cases.54Elevated transaminases, leukocytosis, thrombocytopenia, or disseminated intravascular coagulation are observed. Fulminant hepatic failure is a potential HELLP syndrome is rare but occurs in 4% to 12% of patients with preeclampsia. It usually manifests in the third trimester and sometimes in the postpartum period.77Symptoms include right upper quadrant or epigastric pain with nausea and vomiting, visual changes, and jaundice. The disease processes that should be considered in the differential
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diagnosis of acute cholecystitis during pregnancy include perforated duodenal ulcer, pancreatitis, pyelonephritis, hepatitis, hepatic abscess, Fitz-Hugh-Curtis syndrome, appendicitis, and pneumonia. Other, less common conditions to consider include herpes zoster infection, pulmonary infarction, and various cardiac diseases.74 Complications of peptic ulcer disease during pregnancy are extremely rare?* Perforation is suggested by peritoneal signs of inflammation such as rebound tenderness, involuntary abdominal muscle guarding, and lack of bowel sounds. Pyelonephritis is common and occurs in 1%to 2% of pregnan~ies.~~ It is manifested by fever, rigors, unilateral flank or costovertebral angle pain, nausea, and vomiting. Bacteriuria usually is present. Perinephric abscess formation is a potential complication. Hepatitis is characterized by a prodromal syndrome with constitutional symptoms followed by right upper quadrant pain and jaundice.70 It is caused by viruses, drugs, or autoimmune-mediated processes. Hepatic abscesses are rare in pregnancy. Common symptoms include right upper quadrant pain, fever, and jaundice. Fitz-Hugh-Curtis syndrome is a perihepatitis syndrome that is caused by a gonococcal or chlamydia1 infection. It occurs in the setting The patient of acute pelvic inflammatory disease in 3% to 10% of presents with acute right upper quadrant pain and fever that may overshadow the pelvic complaints. Appendicitis is the most common nongynecologic abdominal condition requiring surgery in pregnancy and occurs in 1 in 1500 deli~eries.~ It usually presents in the second trime~ter.5~ Appendicitis is characterized initially by periumbilical pain that later localizes to the right lower quadrant. Anorexia with nausea, vomiting, and fever accompanies this abdominal pain. As gestation progresses, the appendix changes position within the abdomen: the gravid uterus pushes it superiorly then laterally into the right upper quadrant.54The diagnosis of appendicitis during pregnancy can be difficult and is mistaken for acute cholecystitis. It is imperative to make the correct diagnosis because of the high rate of fetal mortality in the setting of a perforated appendix. Pneumonia in the right lower lobe is an extra-abdominal disease that may present with right upper quadrant pain. The pain is pleuritic in nature and accompanied by cough and fever. Pancreatitis should be considered in any pregnant patient with nausea, vomiting, and abdominal pain. Other conditions that need consideration include cholecystitis, cholangitis, appendicitis, perforated duodenal ulcer, preeclampsia, perinephric abscess, ruptured ectopic pregnancy, and hyperemesis g r a v i d a r ~ m . ~ ~ An ectopic pregnancy is one that occurs outside of the uterus. The fallopian tubes are the most common site of an ectopic pregnancy. Women present with acute, diffuse, abdominal pain in the first trimester. Intra-abdominal bleeding may lead to shock. Hyperemesis gravidarum is a condition of intractable vomiting in the first trimester. Elevated transaminases, alkaline phosphatase, and
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bilirubin may occur.' It resolves as gestation progresses into the second trimester. DIAGNOSIS
The diagnosis of cholelithiasis and its complications is made after a thorough history and physical examination are performed, coupled with a laboratory and radiologic evaluation. The clinical symptoms of biliary tract disease in pregnancy are not highly specific, which may be difficult to differentiate from other disorders. The effects of pregnancy further compound the uncertainty. For example, because of the anatomic disturbances by the gravid uterus, certain disorders like appendicitis can present very differently in pregnancy than in nonpregnancy. In addition, laboratory studies during normal pregnancy in the third trimester may reveal a mild leukocytosis and mild elevations of alkaline phosphatase.'O Therefore, unique anatomic and laboratory changes in pregnancy can make the diagnosis of biliary tract disease difficult. As a result, radiologic imaging studies are necessary in most cases to make the diagnosis. Ultrasonography should be performed in every patient suspected of gallstone-related disease.4l It is a safe, rapid, and portable procedure but is operator dependent (Table 1). Ultrasound uses high frequency sound waves to provide anatomic information without the possible teratogenic effects of radiation. As a result, there are no adverse effects on the fetus or the mother. Gallstones greater than 1 to 2 mm and biliary ductal dilatation can be detected with a diagnostic accuracy close to 97?0 ' 41; however, it has poor accuracy for detecting choledocholithiasis.54 Ultrasound has a high positive predictive value at diagnosing acute cholecystitis when the criteria of pericholecystic fluid and increased gallbladder wall thickness are seen in combination with a sonographic Murphy's sign. Additionally, it can be used to evaluate other intraabdominal pathology. Nuclear cholescintography is used to diagnose acute cholecystitis. It uses technetium-99m-labeled iminodiacetic acids (HIDA), which are secreted in the bile ducts. Gamma rays are emitted by the tracer, and images are taken. If there is no tracer uptake into the gallbladder, it signifies a gallbladder neck obstruction, indicative of acute cholecystitis. A drawback It has a 95% sensitivity and specificity for diagn~sis.~'
Table 1. THE SAFETY OF DIAGNOSTIC TOOLS FOR BILIARY TRACT DISEASE IN PREGNANCY First Trimester
Ultrasound HIDA scan ERCP
Yes No Unknown
Second Trimester
Third Trimester
Yes
Yes
No Yes
No Unknown
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for the HIDA scan is that no anatomic information is obtained. It is contraindicated during pregnancy (Table 1). Endoscopic retrograde cholangiopancreatography (ERCP) is a diagnostic and therapeutic study that has greatest use in choledocholithiasis and gallstone pancreatitis (Table 1).Under conscious sedation, a sideviewing endoscope is passed into the duodenum to the papilla. The bile duct is cannulated with a catheter and radiopaque contrast is injected to image the biliary system. In pregnancy, precautions can be taken to decrease the radiation exposure to the uterus. This is discussed later in this article. TREATMENT
The treatment for gallstones and their complications is reserved for symptomatic disease. The initial therapy for biliary tract disease in pregnancy is nonoperative. There are three medical treatments for recurrent biliary colic. First, oral therapy with bile acids dissolves cholesterol gallstones. These bile acids decrease cholesterol saturation in bile, prolong the nucleation time of bile, competitively block reabsorption of bile acids in the terminal ileum, decrease the synthesis of cholesterol by the liver, and decrease cholesterol secretion in the bile.37,41, This therapy is suitable for a minority of patients with noncalcified cholesterol gallstones and a patent cystic Sixty percent success can be achieved in patients with a few, small stones (<1 cm)62;however, once treatment is stopped, stones recur. Currently, two bile acids are used: chenodiol and ursodiol. The former bile acid is toxic to the fetus and a contraindication in pregnancy.62Ursodiol has been used effectively and safely in women with cholestasis of pregnancy.59There are no published experiences with ursodiol for gallstone dissolution therapy in pregnancy. Contact dissolution of gallstones with solvents is another potential medical therapy for the treatment of symptomatic biliary colic. Methyltert-butyl ether or a-propyl acetate is instilled into the gallbladder either through percutaneous or endoscopically placed catheters. Dissolution may require multiple sessions and achieves 95% success.85Unfortunately, stones recur after treatment. This therapy is investigational and its role in pregnancy is undefined.66 The last medical therapy for cholelithiasis is extracorporeal shock wave lithotripsy (ESWL). It relies on focused, high amplitude sound waves to fragment gallstones. ESWL requires a functioning gallbladder and works optimally in patients with a few radiolucent small Multiple sessions usually achieve adequate fragmentation. Complications include soft tissue damage and recurrent biliary colic as fragments migrate into the common bile duct. Satisfactory fragmentation with ESWL occurs in 50% cases, with 20% recurrence at 4 years.61 It is contraindicated in pregnancy. The initial management for complicated biliary tract disease in pregnancy is conservative medical treatment. In cholecystitis and cholan-
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gitis, patients are given intravenous fluids, antibiotics, and bowel rest. Likewise, pregnant women with pancreatitis are managed with analgesics, intravenous fluids, and bowel rest. Patients usually respond clinically with conservative therapy. Although recurrence of complicated disease has been reported as high as 69%, approximately 10% to 35% of patients fail medical treatment and require more invasive endoscopic or 36, 49, 67 surgical management.20, The indications for surgical intervention for gallstone disease in pregnancy are recurrent episodes of biliary colic and complications such as cholecystitis, choledocholithiasis, and pancreatitis after conservative treatment has failed. Historically, surgery was avoided for biliary tract disease in pregnancy because of the complications associated with surgery.36KammereP noted that the severity of the surgical disease, not the surgery itself, impacted fetal and maternal morbidity and mortality. In addition, in patients operated for uncomplicated cholecystitis, there was no increase in maternal morbidity and mortality, and fetal loss occurred at a rate of 59'0.~ Early studies have noted high rates of fetal loss in the first trimester and recommended delaying pera at ion.^^, 49, 56 McKellar et a156observed that there is a high rate of fetal loss (12%) in pregnant women who have cholecystectomy for complicated biliary tract disease during the first t r i m e ~ t e r .But ~ ~ this rate decreased through Others have reported high rates of preterm labor with resultant preterm delivery when surgery is performed during the third 56 Although tocolytics have been successful at delaying delivtrime~ter.~~, ery in patients with symptomatic gallstones who have undergone surthe timing of cholecystectomy is felt to be gery in the third the safest for the fetus and the mother in the second trimester.20,56, 67 Theories to explain a safer second trimester include the completion of fetal organogenesis, the relatively small uterus allowing a technically easier operation, and the lower rate of spontaneous ab0rti0n.I~Reports of open cholecystectomy in the second trimester without fetal loss or 67* 83 preterm labor have been encouraging.2o, Laparoscopic cholecystectomy is now the standard of care for the 35, 57 Initially, pregsurgical treatment of complicated gallstone disease.22, nancy was felt to be a contraindication for laparoscopic cholecystectomy because of the unknown effects of carbon dioxide pneumoperitoneum on the fetus.78Since 1991, successful laparoscopic cholecystectomy during pregnancy has been performed during all trimesters in over 60 patients without complication^.^^, 50 Morrell et a157devised a strategy to improve the safety of the procedure, which includes constant fetal monitoring, pneumatic compression hose, a decreased insufflation pressure (12 mm Hg), left tilt position of the patient, which decreases inferior vena caval compression, and a Hasson cannula for initial trocar insertion to avoid the gravid uterus.57Recently Amos et a12 described seven patients that were treated laparoscopically in the second trimester. Four fetal deaths occurred despite these precautions. He theorized that the effects of the carbon dioxide might have negatively affected fetal physiology.2 More studies are needed to address this potentially hazardous problem.*,78
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The surgical management of symptomatic, complicated biliary tract disease in pregnancy is evolving. The strategy (Table 2) involves conservative management of first trimester disease, allowing elective surgery in the second trimester; surgery for symptomatic disease during the second trimester; and medical management of third trimester symptoms to allow elective postpartum surgery.13,2o In summary, laparoscopic cholecystectomy appears safest and most successful during the second trimester of pregnancy. Further investigation is needed to determine if laparoscopic cholecystectomy is as safe during the first and third trimesters of pregnancy.35,57, 78 The role of ERCP during pregnancy is not fully defined. Recently, it has been successfully used to treat cholangitis and gallstone pancreatitis resulting from choledocholithiasis during pregnancy?, 34, 39 This therapy evolved as nonoperative management is traditionally favored for treatment of complicated biliary tract disease in pregnancy. In nonpregnant patients, ERCP is considered a safe and effective therapy for cholangitis secondary to common bile duct however, the use of ERCP in gallstone pancreatitis is controversial except in documented cases of biliary obstruction with sepsis.25,26, 58 In addition, ERCP is a relatively safe procedure, with an overall complication rate for treatment of choledocholithiasis and gallstone pancreatitis of 8%.27 The use of ERCP with endoscopic biliary sphincterotomy as a nonoperative method to prevent further episodes of gallstone pancreatitis may be useful in selected patients. Multiple studies have investigated ERCP in pregnancy4,16, 34, 39 Jamidar et a139reported 29 procedures in 23 pregnant women for a variety of pancreaticobiliary diseases.39 Fifteen patients underwent biliary sphincterotomy, with stone extraction resulting in two fetal losses and one procedure-related pan~reatitis.~~ In most studies of ERCP during pregnancy, the investigators have advocated endoscopic sphincterotomy with stone extraction when common bile ducts stones are present.16 Alternatively, some investigators have used biliary stents to maintain bile duct patency until cholecystectomy can be performed in the postpartum period.77Others have stented the gallbladder to prevent possible cholecystitis in patients with symptomatic cholelithiasis.M The timing of ERCP in pregnancy is controversial. No large series have evaluated the safest time for the procedure. As previously noted, the surgical literature suggests that the second trimester is the safest for invasive procedures.20,56, 67 In the first trimester, there are concerns about the teratogenic effects of radiation and fetal loss resulting from spontaneTable 2. SURGICAL STRATEGY FOR COMPLICATED GALLSTONE DISEASE IN PREGNANCY First trimester: Medical management with elective surgery in the second trimester Second trimester: Surgery Third trimester: Medical management with elective surgery postpartum
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ous abortion^.^, 39 Baillie et a14 described successful strategies to limit radiation exposure during ERCP using lead shielding of the uterus, avoiding spot radiographs, and limiting fluoroscopic time. Others suggest that additional precautions such as radiation dosimetry badges, photography of fluoroscopic images, and obstetric consultation are needed to decrease the radiation risks of ERCP.3,16Likewise, because of the increased risk of preterm labor for women in their third trimester, tocolytics have been used successfully during ERCP in pregnancy.I6 ERCP with endoscopic biliary sphincterotomy may be used safely to treat choledocholithiasis and gallstone pancreatitis in pregnancy if proper precautions are implemented. The second trimester appears to be the safest time interval to perform ERCP. Although ERCP has been done safely and successfully in the first and third trimesters, further studies are needed to determine the issue of optimal timing.
References 1. Adams RH, Gordon J, and Combes B Hyperemesis Gravidarum. I. Evidence of hepatic dysfunction. Obstet Gynecol 11:659, 1968 2. Amos JD, Schorr SJ, Norman PF, et al: Laparoscopic surgery during pregnancy. Am J Surg 171:435, 1996 3. Axelrad AM, Fleischer DE, Strack LL, et al: Performance of ERCP for symptomatic cholelithiasis: Techniques to increase safety and improve patient management. Am J Gastro 89:109, 1994 4. Baillie J, Cairns SR, and Putnam WS, et al: Endoscopic management of choledocholithiasis during pregnancy. Surg Gynecol Obstet 171:1, 1990 5. Baker AL, Kaplan MM, Norton RA, et al: Gallstones in inflammatory bowel disease. Am J Dig Dis 19:109, 1975 6. Baker A L Liver and biliary tract disease. In Barron WM, Lindheimer MD (eds): ' Medical Disorders During Pregnancy. St. Louis, Mosby-Year Book, 1995, p 284 7. Baron TH, Richter JE: Gastroesophageal reflux diseases in pregnancy. Gastroenterol Clin North Am 21:777, 1992 8. Barron W The syndrome of preeclampsia. Gastroenterol Clin North Am 21:851, 1992 9. Basso L, McCollum PT, Darling MRN, et al: A study of cholelithiasis during pregnancy and its relationship with age, parity, menarche, breast-feeding, dysmenorrhea, oral contraception and a maternal history of cholelithiasis. Surg Gynecol Obstet 175:41,1992 10. Bacq Y, Zarka 0, Brechot J-F, et al: Liver function tests in normal pregnancy: A prospective study of 103 pregnant women and 103 matched controls. Hepatology 23:1030, 1996 11. Bennion LJ, Grundy SM: Risk factors for the development of cholelithiasis in man. N Engl J Med 299:1221, 1978 12. Bernstein RA, Werner LH, R i m AA: Relationship of gallbladder disease to parity, obesity, and age. Health Serv Res 88:925, 1973 13. Block P, Kelly T R Management of gallstone pancreatitis during pregnancy and the postpartum period. Surg Gynecol Obstet 168:426, 1989 14. Braverman DZ, Johnson ML, and Kern F Effects of pregnancy and contraceptive steroids on gallbladder function. N Engl J Med 302362, 1980 15. Cappell MS, Garcia A: Gastric and duodenal ulcers during pregnancy. Gastroenterol Clin North Am 27169, 1998 16. Cappell MS: Safety of gastrointestinal endoscopy during pregnancy. Gastroenterol Clin North Am 2754, 1998 17. Carey MC: Pathogenesis of gallstones. Am J Surg 165:410, 1993
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18. Cooper A D The metabolic basis of cholesterol gallstone disease. Gastroenterol Clin North Am 20:21, 1991 19. Diehl AK Epidemiology and natural history of gallstone disease. Gastroenterol Clin North Am 201, 1991 20. Dixon NP, Faddis DM, Silberman H: Aggressive management of cholecystitis during pregnancy. Am J Surg 154:292,1987 21. Dowling RH, Bell GD, White J: Lithogenic bile in patients with ileal dysfunction. Gut 13415, 1972 22. Elderling SC: Laparoscopic cholecystectomy in pregnancy. Am J Surg 165:625, 1993 23. Everson GT Gastrointestinal motility in pregnancy. Gastroenterol Clin North Am 21:751, 1992 24. Everson GT, McKinley C, Kern F: Mechanisms of gallstone formation in women: Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Invest 87237, 1991 25. Fan S-T, Lai ECS, Mok FPT, et al: Early treatment of active biliary pancreatitis by endoscopic papillotomy. N Engl J Med 328:228, 1993 26. Folsch UR, Nitsche R, Liidtke R, et al: Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. N Engl J Med 336237, 1997 27. Freeman ML, Nelson DB, Sherman S, et al: Complications of endoscopic biliary sphincterotomy. N Engl J Med 335:909, 1996 28. Friedman G D Natural history of asymptomatic and symptomatic gallstones. Am J Surg 165:399, 1993 29. Friedman GD, Raviola CA, Firenan B: Prognosis of gallstones with mild or no symptoms: 25 years of follow-up in HMO. J Clin Epidemiol42127, 1989 30. Gadacz TR, Talamini MA, Lillemoe KD, et a1 Laparoscopic cholecystectomy.Surg Clin North Am 701249, 1990 31. Gilstrap LC, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: An anterospective study. Obstet Gynecol 57409, 1981 32. Ghumman E, Barry M, Grace PA: Management of gallstones in pregnancy. Br J Surg 841646, 1997 33. Glenn F, McSherry CK Gallstones and pregnancy among 300 young women treated with cholecystectomy. Surg Gynecol Obstet 1271067, 1968 34. Goldschmiedt M, Wolf L, Shires T Treatment of symptomatic choledocholithiasis during pregnancy. Gastro Intest Endosc 39512, 1993 35. Gouldman JW,Sticca RP, Rippon MB, et al: Laparoscopic cholecystectomy in pregnancy. Am Surg 64:93, 1998 36. Hiatt JR, Hiatt JCG, Williams RA, et a1 Biliary disease in pregnancy: Strategy for surgical management. Am J Surg 151:263, 1986 37. Hirota I, Chijiiwa K, Noshiro H, et a1 Effect of chenodeoxycholic acid and ursodeoxycholic acid on nucleation time in human gallbladder bile. Gastroenterology 102:1668, 1992 38. Holmes K Pelvic inflammatory disease. In Fauci AS, Braunwald E, Isselbacher KJ, et a1 (eds): Harrison's Principles of Internal Medicine. New York, McGraw-Hill, 1998, p 814 39. Jamidar PA, Beck GJ, Hoffman BJ, et al: Endoscopic retrograde cholangiopancreatography in pregnancy. Am J Gastro 901263, 1995 40. Jarvinen HJ, Hastbacka J: Early cholecystectomy for acute cholecystitis: A prospective randomized study. Ann Surg 191:501, 1980 41. Johnston DE, Kaplan M M Pathogenesis and treatment of gallstones. N Engl J Med 328:412, 1993 42. Jones PF, McEwan AB, Bernard RM: Hemorrhage and perforation complicating peptic ulcer in uremancv. Lancet 2:350. 1969 43. Jorgenson T Prevalence of gallstones in a Danish population. Am J Epidemiol 126:912, 1987 44. Kammerer WS: Nonobstetric surgery during pregnancy. Med Clin North Am 63:1157, 1979 45. Knox TA, Olans LB: Liver disease in pregnancy. N Engl J Med 335:569, 1996 1
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46. Kopemik G, Mazur M, Lieberman JR, et a1 Pyogenic liver abscess in pregnancy. Isr J Med Sci 24245, 1988 47. Kern F, Everson GT, DeMark B, et al: Biliary lipids, bile acids, and gallbladder function in the female: Effects of pregnancy and the ovulatory cycle. J Clin Invest 68:1229, 1981 48. Lai ECS, Mok FPT, Tan ESY, et al: Endoscopic drainage for severe acute cholangitis. N Engl J Med 326:1582, 1992 49. Landers D, Carmona R, Crombleholme W, et al: Acute cholecystitis in pregnancy. Obstet Gynecol 69331, 1987 50. Lanzafame RJ: Laparoscopic cholecystectomy during pregnancy. Surgery 118:627, 1995 51. Levy PF, Smith BF, Lamont J T Human gallbladder mucin accelerates nucleation of cholesterol in artificial bile. Gastroenterology 87270, 1984 52. Liddle RA, Goldstein RB, and Saxton J: Gallstone formation during weight-reduction dieting. Arch Intem Med 149:1750, 1989 53. Maringhini A, Marceno MP, Lanzarone F, et al: Sludge and stones in gallbladder after pregnancy: Prevalence and risk factors. J Hepatol 5:218, 1987 54. Mayer IE, Hussain H: Abdominal pain in pregnancy. Gastroenterol Clin North Am 271, 1998 55. McKay AJ, ONeill, Imrie C W Pancreatitis, pregnancy, and gallstones. Br J Obstet Gynecol 8747, 1980 56. McKellar DP, Anderson CT, and Boynton CJ: Cholecystectomy during pregnancy without fetal loss. Surg Obstet Gynecol 174:465, 1992 57. Morrell DG, Mullins JR, Harrison PB: Laparoscopic cholecystectomy during pregnancy in symptomatic patients. Surgery 112856, 1992 58. Neoptolemos JP, Carr-locke DL, London NJ,et a1 Controlled trial of urgent ERCP and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 2979, 1988 59. Palma J, Reyes H, Ribalta J, et a1 Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: A randomized, double-blind study controlled with placebo. J Hepatol 271022, 1997 60. Petitti DB, Sidney S, Perlman JA: Increased risk of cholecystitis in users of supplemental estrogen. Gastroenterology 94:91, 1988 61. Petitti DB, Sidney S Obesity and cholelithiasis among women: Implication for prevention. Am J Prev Med 4:327, 1988 62. Plaisier PW, van der Hul RL, Terpstra OT, et al: Current treatment modalities for . symptomatic gallstones. Am J Gastro 88633, 1993 63. Pockros PJ, Peters RL, Reynolds TB: Idiopathic fatty liver of pregnancy: Findings in ten cases. Medicine 63:1, 1984 64. Printen JJ, Ott RA: Cholecystectomy during pregnancy. Am Surg 44:432, 1978 65. Ramin KD, Ramin SM, Richey SD, et al: Acute pancreatitis in pregnancy. Am J Obstet Gynecol 173187, 1995 66. Ransohoff DF, Gracie WA Treatment of gallstones. Ann Intem Med 119:606, 1993 67. Ranson JH: The timing of biliary surgery in acute pancreatitis. Ann Surg 189:654,1979 68. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO): The epidemiology of gallstone disease in Rome Italy part 11: Factors associated with the disease. Hepatology 8:907, 1988 69. Roslyn JJ, Pitt HA, Mann LL, et al: Gallbladder disease in patients with long-term parenteral nutrition. Gastroenterology 84:148, 1983 70. Rustgi VK, Hoofnagle JH: Viral hepatitis during pregnancy. Semin Liver Dis 740, 1987 71. Ryan JP: Effect of pregnancy on gallbladder contractility in guinea pig. Gastroenterology 87674, 1984 72. Ryan JP, Pellecchia D: Effect of progesterone pretreatment on guinea pig gallbladder motility in vitro. Gastroenterology 8381, 1982 73. Sampliner RE, Bennett PH, Comess LJ, et al: Gallbladder disease in Pima Indians: Demonstration of high prevalence and early onset. N Engl J Med 283:1358, 1970 74. Scott L D Gallstone disease and pancreatitis in pregnancy. Gastroenterol Clin North Am 21:803, 1992 75. Scragg RKR, McMichall AJ, Seamark RF: Oral contraceptives, pregnancy, and endogenous oestrogen in gallbladder disease-A case control study. Brit Med J 288:1995, 1984
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76. Sibai BM, Ramadan MK, Usta I, et al: Maternal morbidity in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) Am J Obstet Gynecol 169:1000, 1993 77. Siegel JH, Cohen S A ERCP in a pregnant patient [letter]. Am J Gastro 89:1596,1994 78. Soper NJ: Effect of nonbiliary problems on laparoscopic cholecystectomy. Am J Surg 165:522, 1993 79. Stauffer RA, Adams A, Wygal J, et al: Gallbladder disease in pregnancy. Am J Obstet Gynecol 144:661, 1982 80. Steinberg W, Tenner S Acute pancreatitis. N Engl J Med 330:1198, 1994 81. Stone BG, Erickson SK, Craig WY, et al: Regulation of rat biliary cholesterol secretion by agents that alter intrahepatic cholesterol metabolism: Evidence for a distinct biliary precursor pool. J Clin Invest 761773, 1985 82. Stothers L, Lee L M Renal colic in pregnancy. J Urol 1481383, 1992 83. Swisher SG, Schmit PJ, Hunt KK, et al: Biliary disease during pregnancy. Am J Surg 168:576, 1994 84. Thijs C, Knipschild P, Leffers l? Pregnancy and gallstone disease: An empiric demonstration of the importance of specification of risk periods. Am J Epidemiol 134:186,1991 85. Thistle JL, May GR, Bender CE, et a1 Dissolution of cholesterol gallstones by methylter-butyl ether administered by percutaneous transhepatic catheter. N Engl J Med 320633,1989 86. Thistle JL, Cleary PA, Lachin JM, et al: The natural history of cholelithiasis: The national cooperative gallstone study. Ann Intern Med 101:171, 1984 87. Tsimoyiannis E, Antoniou NC, Tsaboulas C, et al: Cholelithiasis during pregnancy and lactation. Eur J Surg 160:627, 1994 88. Valdivieso V, Covarrubias C, Siegel F, et a1 Pregnancy and cholelithiasis: Pathogenesis and natural course of gallstones diagnosed in early peurperium. Hepatology 171,1993 89. Weingold AB: Appendicitis in pregnancy. Clin Obstet Gynecol26:801, 1983 90. Wenckert A, Robertson B: The natural course of gallstone disease: 11 year review of 781 nonoperated cases. Gastroenterology 50:376, 1966 91. Wilkinson EJ: Acute pancreatitis in pregnancy: A review of 98 cases and a report of 8 new cases. Obstet Gynecol Surv 28:281, 1978 92. Xiao ZL, Chin Q, Biancani P, et al: Mechanisms of pregnancy-induced gallbladder hypomotility in guinea pigs. Gastroenterology 114:A549, 1998
Address reprint requests to Todd H. Baron, MD 200 First Street SW Division of Gastroenterology and Hepatology The Mayo Clinic Rochester, MN 55905 e-mail: [email protected]
1089-3261/99 $8.00
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BILIARY TRACT DISEASE IN PREGNANCY Munford R. Yates 111, MD, and Todd H. Baron, MD
Cholelithiasis is a common biliary tract disease in the United States, and more than 75% of the gallstones are composed of cholester01.'~There is considerable evidence that pregnancy is a predisposing factor in the formation of cholesterol gallstones. Sex steroids cause an alteration in biliary lipid composition and gallbladder motility leading to an increase in cholesterol gallstone synthesis. Gallstone disease is observed in 3.3% to 12.2% of pregnant women.9,53, 79, 8a Complications of gallstones represent the second most common nongynecological condition requiring surgery in pregnancya9;yet, clinically apparent disease is rare. The management of symptomatic gallstone disease during pregnancy is controversial. It is important for clinicians caring for pregnant patients to recognize the signs and symptoms of biliary tract disease during pregnancy and understand the management options. EPIDEMIOLOGY
Cholelithiasis is a very common disease in the United States and is estimated to occur in 10% of the adult p o p ~ l a t i o n More . ~ ~ than 75% of gallstones in the United States are made of ch~lesterol.'~ There are numerous studies that have shown that specific conditions predispose patients to cholesterol gallstones.ll Women develop gallstones twice as often as men.I9 The incidence increases with age such that by age 75 years, at least 35% of women and 20% of men have developed gallstones.66Obesity,12, rapid weight 1oss,52 and ileal disease5*21 have inFrom the Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham Hospital (MRY), Birmingham, Alabama; and the Division of Gastroenterology and Hepatology, The Mayo Clinic (THB), Rochester, Minnesota
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creased risk for cholelithiasis. In addition, oral contraceptive estrogen replacement therapy,6O total parenteral nutriti01-1:~certain demographic pop~lations,4~, 73 and elevated triglyceride levelP have also been implicated. Although the epidemiologic evidence between pregnancy and cholesterol gallstone disease has been described as weak," the association is well documented?,74,88 The incidence of gallstone disease in pregnancy ranges from 3.3% to 12.2Y0.9,53, 79, 88 The incidence of disease appears to increase in the final two trimesters of pregnancy; however, it appears that increasing parity (> 2 gestations), particularly in younger women,68,88not only increases the risk of gallstone formation but may also have a role in increasing the likelihood of symptomatic biliary tract di~ease.~ PATHOPHYSIOLOGY
The liver is important in regulating total body cholesterol stores. Cholesterol metabolism is a very complex and highly regulated process.18 Cholesterol secreted in bile is derived from newly synthesized cholesterol (20%), lipoprotein degradation, and sterols from other hepatic stores.81The precise mechanism of biliary cholesterol secretion is not known but appears to be driven by the rate of bile salt and cholesterol ester synthesis and lipoprotein secretion.81Once secreted, cholesterol is solubilized in bile as a result of its association with bile acids and phospholipids in mixed m i ~ e l l e sAn . ~ ~alteration in the hepatic metabolism of cholesterol leads to increased biliary cholesterol secretion. As bile becomes more saturated with cholesterol, vesicles form and become unstable, which leads to cholesterol crystal.growth and stone formation. There appears to be three abnormalities that lead to cholesterol gallstone formation. First, cholesterol supersaturation of bile results from increased biliary cholesterol secretion and bile salt hypo~ecretion.'~ Several mechanisms are important in establishing these secretory abnormalities.41Although supersaturated bile is required for lithogenesis, it is not the only prerequisite for gallstones, as it is found in patients without stones. Second, enhanced nucleation causes the aggregation of cholesterol molecules into coalescent vesicles that ~rystallize.'~ This leads to stone formation. Various endogenous biliary proteins and glycoproteins have been implicated as potential pronucleating agents.4I The third abnormality crucial to cholesterol gallstone formation is related to the gallbladder.I7It is recognized that cholecystectomy patients rarely develop cholesterol gallstones after surgery. There are two theories that explain this phenomenon. First, the gallbladder produces mucus that appears to be a pronucleator and a nidus for crystal Second, impaired gallbladder motility may lead to stasis, which promotes stone formation." Gallbladder emptying is regulated by neural (acetylcholine) and hormonal (cholecystokinin) factors.23Decreased gallbladder emptying not only promotes nucleation by providing a stagnant layer of
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concentrated bile and mucus but also leads to stasis and biliary sludge, a precursor to gallstones.= 74, 88 Pregnancy appears to be a predisposing factor for lithogene~is.~, There are changes in biliary tract and gallbladder physiology during pregnancy that increase the risk of cholesterol gallstones. Kern et a147 noted that as pregnancy progresses into the second and third trimesters, bile became more saturated with cholesterol as a result of an increase in biliary cholesterol secretion and cholic acid synthesis. By shifting bile acid secretion towards an increase in cholic acid at the expense of chenodeoxycholic acid, more cholesterol is secreted into bile. Everson et alz4found that estrogen caused increased biliary secretion of cholesterol and, hence, increased lithogenicity of bile. He proposed three mechanisms for estrogen’s role in altering bile omp position.^^ First, stimulation of hepatic lipoprotein (B and E) receptors leads to increased hepatic cholesterol uptake. Second, estrogen disrupts the feedback inhibition of hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase), the rate limiting enzyme in cholesterol metabolism, such that an increased uptake of lipoprotein cholesterol is not associated with decreased cholesterol synthesis. Lastly, it inhibits cholesterol catabolism into bile acids. As a result, estrogen increases biliary cholesterol Progesterone may also play a role by inhibiting acyl-coenzyme A cholesterol acyltransferase (ACAT) in decreasing cholesterol esterification leading to increased biliary cholesterol ~ e c r e t i o nTherefore, .~~ sex steroids, primarily estrogen, cause alterations in biliary lipid and bile salt composition that increase bile lithogenicity and serve as a prerequisite for cholesterol gallstone formation in pregnancy. Altered gallbladder motility is instrumental in gallstone formation during pregnancy. Ultrasonography data has shown that fasting and residual gallbladder volumes are larger in the second and third trimes79 In addition, incomplete postpranters when compared with dial gallbladder emptying was observed.14 In animal studies, pregnant guinea pigs had decreased gallbladder contractile responses to aceytlcholine and cholecystokinin (CCK).71Ryan71suggests that pregnancy, and more specifically progesterone, affects a step in the excitation-contraction coupling process that is common to both acetylcholine and CCK and results in gallbladder hypomotility and incomplete evacuation of the gallbladder during pregnancy. Although progesterone is a smooth muscle relaxant, it does not appear that there is a generalized decrease in the contractile process in gallbladder smooth muscle.71,7z The mechanism of this dysmotility in pregnancy is unexplained but may be related to changes in the intracellular pool of calciumz3,7z or to the down-regulation of contractile linked G - p r o t e i n ~As . ~ ~expected, the effects of pregnancy on gallbladder volumes are transient and resolve as early as 2 weeks postpartum. Therefore, changes in gallbladder motility during pregnancy lead to bile stasis and resultant sludge formation.53In summary, the increased predisposition to gallstones in pregnancy is caused by estrogen’s effects on increasing bile lithogenicity and progesterone’s effects on promoting gallbladder hypomotility.
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COMPLICATIONS OF GALLSTONE DISEASE Asymptomatic Cholelithiasis
Studies have observed that approximately 60% to 69% of pregnant women with gallstones were asymptomatic?,88 The diagnosis usually is made incidentally during routine prenatal ultrasound. Valdivieso et a P related the lack of symptoms to small gallstone (
Approximately 30% to 40% of pregnant women with gallstones are symptomatic, and about 20% to 50% of those patients have recurrent pain.9,88 The natural history of symptomatic gallstones reveals that the rate of complications (i.e., acute cholecystitis, choledocholithiasis, and gallstone pancreatitis) is 6% per year for 5.years, with a decrease to 1.6% to 1.7% per year for the next 10 to 15 yearsz9Wenckert et a190noted that over a lifetime, 18% patients develop complications that result in a 1.8% per year risk.90More importantly, when a complication of cholelithiasis if left untreated without cholecystectomy, approximately 30% recur over a 3-month period.4Q67 Symptoms of biliary tract disease in pregnant women are similar to those seen in nonpregnant women. Patients present with biliary colic: a sudden, recurrent, severe epigastric or right upper quadrant pain lasting up to 3 hours, with radiation to the right shoulder or interscapular region. It may be accompanied by nausea, vomiting, and anorexia. Biliary colic is caused by transient obstruction of the cystic duct. It may be precipitated by a large meal but not necessarily a fatty meal. Although the interval between attacks is variable, in pregnancy it is thought that symptoms worsen with advancing gestation and even into puerperium period. Although gallbladder and bile physiology revert to normal within a few weeks after delivery, it is apparent that postpartum women continue to have symptomatic gallstone disease.87,88 Epidemiologic data have recognized that women have an increased risk of symptomatic
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gallstone disease up to 5 years after their last pregnancy.84Maringhini et a153ultrasonographically assessed postpartum women for the presence of sludge and gallstones. Immediately postpartum, 26% of women had sludge, whereas 5% of patients had gallstone^.^^ At the 1-year followup, 95.6% of women with sludge initially had normal gallbladders, whereas only 13% of women with gallstones had normal gallbladder^?^ Valdivieso et aP8 noted that 29% of postpartum women initially with gallstones (<6 mm) had a disappearance of these gallstones within the follow-up of 6 to 24 months. The investigators related this phenomenon to either silent migration or spontaneous dissolution.88Therefore, gallbladder sludge resolves within 1 year of delivery, whereas most patients with gallstones may become symptomatic up to 5 years after pregnancy. Acute Cholecystitis
Acute cholecystitis is a rare complication of cholelithiasis in pregnancy, with an estimated rate of 1 to 8 cases per 10000 patients22,49; however, cholecystitis is second only to appendicitis as the most common nongynecological abdominal condition requiring surgery in pregn a n ~ y Almost .~~ always, an antecedent history of biliary colic can be elicited. In over 90% cases, prolonged stone obstruction of the cystic duct is the cause of acute inflammation of the gallbladder. The symptoms of acute cholecystitis during pregnancy are no different than in nonpregnant patients. It results in severe right upper quadrant pain worsened with inspiration, fever, nausea, and vomiting. Leukocytosis is ccmmon. Although acute cholecystitis occurs with similar frequency in each trimester, it may be more common in the postpartum period. Choledocholithiasis
Choledocholithiasis, common bile duct stones, is a rare occurrence in pregnancy. It is observed in 10% of pregnant patients undergoing cholecystectomy33and accounts for 7% of cases of jaundice in pregnancya Gallstones pass from the gallbladder into the common bile duct leading to obstruction of bile flow with resultant biliary ductal dilatation. The clinical presentation of choledocholithiasis is right upper quadrant tenderness, fever, and jaundice (Charcot’s triad), indicative of acute cholangitis. Pancreatitis may also occur. Laboratory studies reveal hyperbilirubinemia and mild transaminase and alkaline phosphatase elevation. Gallstone Pancreatitis
The incidence of acute pancreatitis complicating pregnancy is very rare and ranges from 1 in 1000 to 1 in 10000 deliveries.%,55 The most common cause of acute pancreatitis in pregnancy is gallstone disease,
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which represents 70% to 90% of patients.55,74 Additionally, 1.2% to 11% of symptomatic gallstone patients are complicated by acute pancreatitis.l3sS9 It is caused by common bile duct stones that transiently obstruct the main pancreatic duct, where it passes near the common bile duct at the ampulla of Vater. Historically, pregnancy was deemed a predisposing condition for pancreatitis, but this has not been pr0ved.5~Other, less common causes of pancreatitis in pregnancy include hyperlipipancreas divis~m,6~ idi~pathic,'~, 74 demia,55,74 hyperparath~roidism,6~ and alcohol ( Although pancreatitis presents at any time during pregnancy, it is most common in the third trimester. There is no relation to parity. The clinical manifestations of pancreatitis are similar to those in nonpregnant women. Patients appear ill with midepigastric pain, classically with radiation to the back, nausea, vomiting, fever, and anorexia. Jaundice may occur if there are common bile duct stones. The laboratory studies in patients with pancreatitis may reveal leukocytosis, hyperglycemia, hypoalbuminemia, or hypocalcemia. The majority of patients have elevated serum amylase and lipase levels. Overall, patients with acute pancreatitis have a 10% mortality.80 Earlier studies estimated that the maternal mortality from acute pancreatitis was approximately 37Y0.~'A recent study reviewed 43 pregnant women with acute pancreatitis of undefined severity5; however, no maternal deaths and minimal morbidity were observed.65Fetal loss rate ranges from 10% to 6O%, most of the deaths reflecting neonatal mortality following preterm delivery.",55,65, 74 Ramin et aP5reported 13% of infants died, a majority of which were preterm deaths. The decrease in maternal and fetal morbidity and mortality in gallstone pancreatitis during pregnancy is attributed to better recognition, diagnosis, and management. DIFFERENTIAL DIAGNOSIS
Conditions to consider in the differential diagnosis of cholelithiasis should include peptic ulcer disease, gastroesophageal reflux disease, nephrolithiasis, preeclampsia, acute fatty liver of pregnancy (AFLP), and HELLP (hemolysis, elevated liver enzymes, and low platelets) synd r ~ m eThe . ~ ~differential diagnosis of biliary tract disease in pregnancy also includes: Cholelithiasis Peptic ulcer disease GERD Nephrolithiasis Preeclampsia AFLP HELLP Cholecystitis Perforated duodenal ulcer
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Pancreatitis Pyelonephritis Hepatitis Hepatic abscess Fitz-Hugh-Curtis syndrome Appendicitis Pneumonia Pancreatitis Cholecystitis Cholangitis Appendicitis Perforated ulcer Preeclampsia Perinephric abscess Ectopic pregnancy Hyperemesis gravidarum Peptic ulcer disease (PUD) has a lower incidence in pregnancy than in the general population.15The symptoms of PUD are similar in pregnancy with epigastric pain, postprandial nausea and vomiting, and abdominal distention. It may worsen in the third trimester. Gastroesophageal reflux disease (GERD) is common in pregnant women starting in the initial trimester and progressing through gestat i ~ n Its . ~ classic presentation is heartburn, a substernal burning that radiates from the xiphoid, up through the chest, and into the throat. It is precipitated by lying down, bending over, and large meals. GERD improves following delivery. Nephrolithiasis presents as renal colic, a severe unilateral flank pain .that radiates to the ipsilateral lower quadrant or groin.s2 It may be associated with nausea and vomiting and urinary symptoms. Hematuria and pyuria are not uncommon. Preeclampsia occurs in 2% to 10% of all pregnancies, manifesting in the late second and third trimesters.s The patient presents with hypertension, proteinuria, and edema.45It may affect the liver in up to 50% cases and is accompanied by right upper quadrant or epigastric pain, nausea, and vomiting. Preeclampsia resolves with delivery in most cases. AFLP occurs in 1 in 13000 pregnancies, with manifestations in the third t r i m e ~ t e r .Patients ~~ present with anorexia, headaches, malaise, nausea, and vomiting. This is followed by epigastric and or right upper quadrant pain and jaundice. Concomitant preeclampsia is present in about 50% cases.54Elevated transaminases, leukocytosis, thrombocytopenia, or disseminated intravascular coagulation are observed. Fulminant hepatic failure is a potential HELLP syndrome is rare but occurs in 4% to 12% of patients with preeclampsia. It usually manifests in the third trimester and sometimes in the postpartum period.77Symptoms include right upper quadrant or epigastric pain with nausea and vomiting, visual changes, and jaundice. The disease processes that should be considered in the differential
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diagnosis of acute cholecystitis during pregnancy include perforated duodenal ulcer, pancreatitis, pyelonephritis, hepatitis, hepatic abscess, Fitz-Hugh-Curtis syndrome, appendicitis, and pneumonia. Other, less common conditions to consider include herpes zoster infection, pulmonary infarction, and various cardiac diseases.74 Complications of peptic ulcer disease during pregnancy are extremely rare?* Perforation is suggested by peritoneal signs of inflammation such as rebound tenderness, involuntary abdominal muscle guarding, and lack of bowel sounds. Pyelonephritis is common and occurs in 1%to 2% of pregnan~ies.~~ It is manifested by fever, rigors, unilateral flank or costovertebral angle pain, nausea, and vomiting. Bacteriuria usually is present. Perinephric abscess formation is a potential complication. Hepatitis is characterized by a prodromal syndrome with constitutional symptoms followed by right upper quadrant pain and jaundice.70 It is caused by viruses, drugs, or autoimmune-mediated processes. Hepatic abscesses are rare in pregnancy. Common symptoms include right upper quadrant pain, fever, and jaundice. Fitz-Hugh-Curtis syndrome is a perihepatitis syndrome that is caused by a gonococcal or chlamydia1 infection. It occurs in the setting The patient of acute pelvic inflammatory disease in 3% to 10% of presents with acute right upper quadrant pain and fever that may overshadow the pelvic complaints. Appendicitis is the most common nongynecologic abdominal condition requiring surgery in pregnancy and occurs in 1 in 1500 deli~eries.~ It usually presents in the second trime~ter.5~ Appendicitis is characterized initially by periumbilical pain that later localizes to the right lower quadrant. Anorexia with nausea, vomiting, and fever accompanies this abdominal pain. As gestation progresses, the appendix changes position within the abdomen: the gravid uterus pushes it superiorly then laterally into the right upper quadrant.54The diagnosis of appendicitis during pregnancy can be difficult and is mistaken for acute cholecystitis. It is imperative to make the correct diagnosis because of the high rate of fetal mortality in the setting of a perforated appendix. Pneumonia in the right lower lobe is an extra-abdominal disease that may present with right upper quadrant pain. The pain is pleuritic in nature and accompanied by cough and fever. Pancreatitis should be considered in any pregnant patient with nausea, vomiting, and abdominal pain. Other conditions that need consideration include cholecystitis, cholangitis, appendicitis, perforated duodenal ulcer, preeclampsia, perinephric abscess, ruptured ectopic pregnancy, and hyperemesis g r a v i d a r ~ m . ~ ~ An ectopic pregnancy is one that occurs outside of the uterus. The fallopian tubes are the most common site of an ectopic pregnancy. Women present with acute, diffuse, abdominal pain in the first trimester. Intra-abdominal bleeding may lead to shock. Hyperemesis gravidarum is a condition of intractable vomiting in the first trimester. Elevated transaminases, alkaline phosphatase, and
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bilirubin may occur.' It resolves as gestation progresses into the second trimester. DIAGNOSIS
The diagnosis of cholelithiasis and its complications is made after a thorough history and physical examination are performed, coupled with a laboratory and radiologic evaluation. The clinical symptoms of biliary tract disease in pregnancy are not highly specific, which may be difficult to differentiate from other disorders. The effects of pregnancy further compound the uncertainty. For example, because of the anatomic disturbances by the gravid uterus, certain disorders like appendicitis can present very differently in pregnancy than in nonpregnancy. In addition, laboratory studies during normal pregnancy in the third trimester may reveal a mild leukocytosis and mild elevations of alkaline phosphatase.'O Therefore, unique anatomic and laboratory changes in pregnancy can make the diagnosis of biliary tract disease difficult. As a result, radiologic imaging studies are necessary in most cases to make the diagnosis. Ultrasonography should be performed in every patient suspected of gallstone-related disease.4l It is a safe, rapid, and portable procedure but is operator dependent (Table 1). Ultrasound uses high frequency sound waves to provide anatomic information without the possible teratogenic effects of radiation. As a result, there are no adverse effects on the fetus or the mother. Gallstones greater than 1 to 2 mm and biliary ductal dilatation can be detected with a diagnostic accuracy close to 97?0 ' 41; however, it has poor accuracy for detecting choledocholithiasis.54 Ultrasound has a high positive predictive value at diagnosing acute cholecystitis when the criteria of pericholecystic fluid and increased gallbladder wall thickness are seen in combination with a sonographic Murphy's sign. Additionally, it can be used to evaluate other intraabdominal pathology. Nuclear cholescintography is used to diagnose acute cholecystitis. It uses technetium-99m-labeled iminodiacetic acids (HIDA), which are secreted in the bile ducts. Gamma rays are emitted by the tracer, and images are taken. If there is no tracer uptake into the gallbladder, it signifies a gallbladder neck obstruction, indicative of acute cholecystitis. A drawback It has a 95% sensitivity and specificity for diagn~sis.~'
Table 1. THE SAFETY OF DIAGNOSTIC TOOLS FOR BILIARY TRACT DISEASE IN PREGNANCY First Trimester
Ultrasound HIDA scan ERCP
Yes No Unknown
Second Trimester
Third Trimester
Yes
Yes
No Yes
No Unknown
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for the HIDA scan is that no anatomic information is obtained. It is contraindicated during pregnancy (Table 1). Endoscopic retrograde cholangiopancreatography (ERCP) is a diagnostic and therapeutic study that has greatest use in choledocholithiasis and gallstone pancreatitis (Table 1).Under conscious sedation, a sideviewing endoscope is passed into the duodenum to the papilla. The bile duct is cannulated with a catheter and radiopaque contrast is injected to image the biliary system. In pregnancy, precautions can be taken to decrease the radiation exposure to the uterus. This is discussed later in this article. TREATMENT
The treatment for gallstones and their complications is reserved for symptomatic disease. The initial therapy for biliary tract disease in pregnancy is nonoperative. There are three medical treatments for recurrent biliary colic. First, oral therapy with bile acids dissolves cholesterol gallstones. These bile acids decrease cholesterol saturation in bile, prolong the nucleation time of bile, competitively block reabsorption of bile acids in the terminal ileum, decrease the synthesis of cholesterol by the liver, and decrease cholesterol secretion in the bile.37,41, This therapy is suitable for a minority of patients with noncalcified cholesterol gallstones and a patent cystic Sixty percent success can be achieved in patients with a few, small stones (<1 cm)62;however, once treatment is stopped, stones recur. Currently, two bile acids are used: chenodiol and ursodiol. The former bile acid is toxic to the fetus and a contraindication in pregnancy.62Ursodiol has been used effectively and safely in women with cholestasis of pregnancy.59There are no published experiences with ursodiol for gallstone dissolution therapy in pregnancy. Contact dissolution of gallstones with solvents is another potential medical therapy for the treatment of symptomatic biliary colic. Methyltert-butyl ether or a-propyl acetate is instilled into the gallbladder either through percutaneous or endoscopically placed catheters. Dissolution may require multiple sessions and achieves 95% success.85Unfortunately, stones recur after treatment. This therapy is investigational and its role in pregnancy is undefined.66 The last medical therapy for cholelithiasis is extracorporeal shock wave lithotripsy (ESWL). It relies on focused, high amplitude sound waves to fragment gallstones. ESWL requires a functioning gallbladder and works optimally in patients with a few radiolucent small Multiple sessions usually achieve adequate fragmentation. Complications include soft tissue damage and recurrent biliary colic as fragments migrate into the common bile duct. Satisfactory fragmentation with ESWL occurs in 50% cases, with 20% recurrence at 4 years.61 It is contraindicated in pregnancy. The initial management for complicated biliary tract disease in pregnancy is conservative medical treatment. In cholecystitis and cholan-
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gitis, patients are given intravenous fluids, antibiotics, and bowel rest. Likewise, pregnant women with pancreatitis are managed with analgesics, intravenous fluids, and bowel rest. Patients usually respond clinically with conservative therapy. Although recurrence of complicated disease has been reported as high as 69%, approximately 10% to 35% of patients fail medical treatment and require more invasive endoscopic or 36, 49, 67 surgical management.20, The indications for surgical intervention for gallstone disease in pregnancy are recurrent episodes of biliary colic and complications such as cholecystitis, choledocholithiasis, and pancreatitis after conservative treatment has failed. Historically, surgery was avoided for biliary tract disease in pregnancy because of the complications associated with surgery.36KammereP noted that the severity of the surgical disease, not the surgery itself, impacted fetal and maternal morbidity and mortality. In addition, in patients operated for uncomplicated cholecystitis, there was no increase in maternal morbidity and mortality, and fetal loss occurred at a rate of 59'0.~ Early studies have noted high rates of fetal loss in the first trimester and recommended delaying pera at ion.^^, 49, 56 McKellar et a156observed that there is a high rate of fetal loss (12%) in pregnant women who have cholecystectomy for complicated biliary tract disease during the first t r i m e ~ t e r .But ~ ~ this rate decreased through Others have reported high rates of preterm labor with resultant preterm delivery when surgery is performed during the third 56 Although tocolytics have been successful at delaying delivtrime~ter.~~, ery in patients with symptomatic gallstones who have undergone surthe timing of cholecystectomy is felt to be gery in the third the safest for the fetus and the mother in the second trimester.20,56, 67 Theories to explain a safer second trimester include the completion of fetal organogenesis, the relatively small uterus allowing a technically easier operation, and the lower rate of spontaneous ab0rti0n.I~Reports of open cholecystectomy in the second trimester without fetal loss or 67* 83 preterm labor have been encouraging.2o, Laparoscopic cholecystectomy is now the standard of care for the 35, 57 Initially, pregsurgical treatment of complicated gallstone disease.22, nancy was felt to be a contraindication for laparoscopic cholecystectomy because of the unknown effects of carbon dioxide pneumoperitoneum on the fetus.78Since 1991, successful laparoscopic cholecystectomy during pregnancy has been performed during all trimesters in over 60 patients without complication^.^^, 50 Morrell et a157devised a strategy to improve the safety of the procedure, which includes constant fetal monitoring, pneumatic compression hose, a decreased insufflation pressure (12 mm Hg), left tilt position of the patient, which decreases inferior vena caval compression, and a Hasson cannula for initial trocar insertion to avoid the gravid uterus.57Recently Amos et a12 described seven patients that were treated laparoscopically in the second trimester. Four fetal deaths occurred despite these precautions. He theorized that the effects of the carbon dioxide might have negatively affected fetal physiology.2 More studies are needed to address this potentially hazardous problem.*,78
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The surgical management of symptomatic, complicated biliary tract disease in pregnancy is evolving. The strategy (Table 2) involves conservative management of first trimester disease, allowing elective surgery in the second trimester; surgery for symptomatic disease during the second trimester; and medical management of third trimester symptoms to allow elective postpartum surgery.13,2o In summary, laparoscopic cholecystectomy appears safest and most successful during the second trimester of pregnancy. Further investigation is needed to determine if laparoscopic cholecystectomy is as safe during the first and third trimesters of pregnancy.35,57, 78 The role of ERCP during pregnancy is not fully defined. Recently, it has been successfully used to treat cholangitis and gallstone pancreatitis resulting from choledocholithiasis during pregnancy?, 34, 39 This therapy evolved as nonoperative management is traditionally favored for treatment of complicated biliary tract disease in pregnancy. In nonpregnant patients, ERCP is considered a safe and effective therapy for cholangitis secondary to common bile duct however, the use of ERCP in gallstone pancreatitis is controversial except in documented cases of biliary obstruction with sepsis.25,26, 58 In addition, ERCP is a relatively safe procedure, with an overall complication rate for treatment of choledocholithiasis and gallstone pancreatitis of 8%.27 The use of ERCP with endoscopic biliary sphincterotomy as a nonoperative method to prevent further episodes of gallstone pancreatitis may be useful in selected patients. Multiple studies have investigated ERCP in pregnancy4,16, 34, 39 Jamidar et a139reported 29 procedures in 23 pregnant women for a variety of pancreaticobiliary diseases.39 Fifteen patients underwent biliary sphincterotomy, with stone extraction resulting in two fetal losses and one procedure-related pan~reatitis.~~ In most studies of ERCP during pregnancy, the investigators have advocated endoscopic sphincterotomy with stone extraction when common bile ducts stones are present.16 Alternatively, some investigators have used biliary stents to maintain bile duct patency until cholecystectomy can be performed in the postpartum period.77Others have stented the gallbladder to prevent possible cholecystitis in patients with symptomatic cholelithiasis.M The timing of ERCP in pregnancy is controversial. No large series have evaluated the safest time for the procedure. As previously noted, the surgical literature suggests that the second trimester is the safest for invasive procedures.20,56, 67 In the first trimester, there are concerns about the teratogenic effects of radiation and fetal loss resulting from spontaneTable 2. SURGICAL STRATEGY FOR COMPLICATED GALLSTONE DISEASE IN PREGNANCY First trimester: Medical management with elective surgery in the second trimester Second trimester: Surgery Third trimester: Medical management with elective surgery postpartum
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ous abortion^.^, 39 Baillie et a14 described successful strategies to limit radiation exposure during ERCP using lead shielding of the uterus, avoiding spot radiographs, and limiting fluoroscopic time. Others suggest that additional precautions such as radiation dosimetry badges, photography of fluoroscopic images, and obstetric consultation are needed to decrease the radiation risks of ERCP.3,16Likewise, because of the increased risk of preterm labor for women in their third trimester, tocolytics have been used successfully during ERCP in pregnancy.I6 ERCP with endoscopic biliary sphincterotomy may be used safely to treat choledocholithiasis and gallstone pancreatitis in pregnancy if proper precautions are implemented. The second trimester appears to be the safest time interval to perform ERCP. Although ERCP has been done safely and successfully in the first and third trimesters, further studies are needed to determine the issue of optimal timing.
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Address reprint requests to Todd H. Baron, MD 200 First Street SW Division of Gastroenterology and Hepatology The Mayo Clinic Rochester, MN 55905 e-mail: [email protected]