Gallstone diseases in pregnancy

INTRODUCTION — Gallstones are more common in pregnant compared with nonpregnant patients. Unlike asymptomatic pregnant patients with gallstones, pregnant patients with gallstone disease (ie, symptoms related to gallstones) are at an increased risk for maternal and neonatal morbidity.

As in nonpregnant patients, gallstone disease is classified into uncomplicated (ie, biliary colic) and complicated (ie, acute cholecystitis, choledocholithiasis, cholangitis, gallstone pancreatitis) disease. In pregnant patients with biliary colic, supportive care will often lead to temporary resolution of symptoms, but symptoms frequently recur later in pregnancy or postpartum. Pregnant patients with repeated attacks of biliary colic or with complicated gallstone disease will require an invasive procedure; cholecystectomy is one of the leading nonobstetrical indications for surgery in pregnant patients, second only to appendectomy (table 1).

Issues related primarily to gallstone disease in pregnant patients will be reviewed here. Detailed discussions on biliary disease in nonpregnant patients, which may also apply to pregnant patients, are reviewed separately.

●(See "Gallstones: Epidemiology, risk factors and prevention".)

●(See "Approach to the management of gallstones".)

●(See "Overview of gallstone disease in adults".)

●(See "Acute calculous cholecystitis: Clinical features and diagnosis".)

●(See "Treatment of acute calculous cholecystitis".)

●(See "Acalculous cholecystitis: Clinical manifestations, diagnosis, and management".)

●(See "Functional gallbladder disorder in adults".)

●(See "Choledocholithiasis: Clinical manifestations, diagnosis, and management".)

●(See "Management of acute pancreatitis", section on 'Gallstone pancreatitis'.)

PATHOPHYSIOLOGY — During pregnancy, increased levels of reproductive hormones (eg, estrogen, progesterone) induce a variety of physiologic changes in the biliary system that promote gallstone formation [1-3]:

●Estrogen increases cholesterol secretion and progesterone reduces bile acid secretion, which ultimately causes bile to become supersaturated with cholesterol. A relative overproduction of hydrophobic bile acids, such as chenodeoxycholate, reduces the ability of bile to solubilize cholesterol.

●Progesterone also slows gallbladder emptying, which further promotes the formation of stones by causing bile stasis.

These changes normalize one to two months following delivery.

Symptoms related to gallstones develop when the gallbladder contracts in response to hormonal or neural stimulation, usually due to a fatty meal. Contraction forces stones (or possibly sludge or microlithiasis) against the gallbladder outlet or cystic duct opening, leading to increased intra-gallbladder pressure and pain (figure 1). The stones often fall back from the cystic duct as the gallbladder relaxes, with amelioration of symptoms.

A stone that passes through the ampulla of Vater can cause acute gallstone pancreatitis, which is the most common cause of acute pancreatitis during pregnancy and is associated with maternal mortality if not recognized and treated appropriately [4-8]. In a meta-analysis including 23 studies and almost 9000 patients with acute pancreatitis in pregnancy, maternal mortality occurred in 23 patients (0.26 percent); maternal mortality rate was higher in the first compared with the second or third trimester [9]. (See 'Gallstone pancreatitis' below and "Management of acute pancreatitis", section on 'Gallstone pancreatitis'.)

RISK FACTORS — Prepregnancy obesity [10,11] and multiparity [12-14] are independent risk factors for gallstones in pregnancy. Other risk factors are similar to those of nonpregnant patients (table 2) [15,16].

Neither dietary fat intake nor physical activity seem to affect risk of gallstone formation in pregnancy or up to four to six weeks postpartum [17]. Likewise, efforts to decrease the likelihood of stones and sludge developing during pregnancy by increasing metabolic expenditure have proven unsuccessful [18].

INCIDENCE AND COURSE — The reported incidence of gallstone-related disease in pregnant patients is low (<1 percent), and rates vary depending on the diagnostic definitions and techniques used, patient selection, and frequency of assessment [4,19-22]. In one of the largest prospective studies including over 3200 pregnant patients without gallstones on the first ultrasound examination, new sludge/stones or progression of baseline sludge was noted in 7.1, 7.9, and 10.2 percent of patients by the second-trimester, third-trimester, or four- to six-week postpartum ultrasound examinations, respectively [11]. However, among patients with sludge or stones, only 1.2 percent of patients developed symptoms attributable to gallstone disease.

In the postpartum period when bile composition and gallbladder function return to normal, prospective studies have shown the following:

●Gallbladder sludge is more likely to resolve than stones (40 to 60 versus 9 percent) [15,23].

●Approximately 30 percent of stones smaller than 10 mm disappeared due to, at least in part, unsaturation of bile [12,15].

●By one year postpartum, most patients with sludge during pregnancy had a normal ultrasound examination, but abnormal ultrasound findings remained in approximately 80 percent of patients with stones [15,24]. Serious complications, such as acute cholecystitis, choledocholithiasis, gangrenous gallbladder, or pancreatitis, developed in <10 percent of symptomatic patients [12,25].

CLINICAL PRESENTATION — The presentation of gallstone disease during pregnancy is similar to that of nonpregnant patients. (See "Overview of gallstone disease in adults", section on 'Clinical manifestations'.)

We categorize the presentation of pregnant patients with gallstone disease into the following clinical groups based on symptoms and ultrasound examination findings:

●Asymptomatic, gallstones visible on ultrasound (incidental gallstones) – An incidental finding of gallstones is not uncommon, as almost all pregnant patients undergo one or more obstetrical ultrasound examinations, which may include the right upper quadrant (RUQ).

●Biliary-type symptoms, gallstones visible on ultrasound – For most patients, the first symptoms experienced from gallstones are recurrent pain attacks (biliary colic). Patients with biliary colic complain of epigastric or RUQ pain. The onset of pain is typically between one and three hours postprandially. A history of fatty food ingestion before the initial onset of pain is common. The discomfort progresses in less than one hour to a steady plateau that ranges from moderate to excruciating and remains constant for more than one hour, then slowly subsides over several hours.

Less frequently, the initial symptoms are those of one of the complications of gallstones, most commonly acute cholecystitis. The presentation of acute cholecystitis is similar to that in nonpregnant patients: RUQ or epigastric pain that is steady and severe, prolonged (more than four to six hours), and possibly radiating to the right shoulder or back. Associated symptoms include fever, anorexia, nausea, and vomiting. Abdominal examination usually demonstrates voluntary and involuntary guarding and, frequently, a positive Murphy's sign. The constitutional symptoms and prolonged duration of pain help to distinguish acute cholecystitis from biliary colic. (See "Overview of gallstone disease in adults", section on 'Atypical symptoms' and "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Clinical manifestations'.)

●Biliary-type symptoms, no gallstones visible on ultrasound – Such patients may have a pregnancy-related condition, such as preeclampsia with severe features, or other causes of epigastric or right upper quadrant pain (eg, peptic ulcer disease, choledocholithiasis, recently passed stone, acalculous cholecystitis [which is rare during pregnancy]). (See 'Pregnancy-related conditions' below and 'Non-pregnancy-related conditions' below and "Acalculous cholecystitis: Clinical manifestations, diagnosis, and management".)

DIAGNOSTIC EVALUATION AND FINDINGS

Abdominal imaging — As in nonpregnant patients, imaging is the mainstay of evaluation in pregnant patients in whom gallstone disease is suspected. (See "Overview of gallstone disease in adults", section on 'Evaluation for uncomplicated gallstone disease'.)

Ultrasonography — Ultrasonography is a reliable and safe method for identifying gallstones in pregnant patients. Gallstones and sludge are easily visualized on ultrasound, with sensitivity and specificity approaching 100 percent [20,26,27]. By contrast, ultrasound is relatively insensitive for the detection of common bile duct stones. (See "Overview of gallstone disease in adults", section on 'Transabdominal ultrasound' and "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Ultrasonography'.)

MRCP in select patients — Magnetic resonance cholangiopancreatography (MRCP) is not typically used in the evaluation of biliary colic or acute cholecystitis but may be useful in some complicated cases, such as patients with choledocholithiasis or pancreatitis if ultrasound is nondiagnostic [28,29]. A routine MRCP does not require any contrast agent such as gadolinium, and there are no known harmful fetal effects of noncontrast magnetic resonance during pregnancy. (See "Diagnostic imaging in pregnant and lactating patients".)

Other

●HIDA scan – Cholescintigraphy using 99mTc-hepatic iminodiacetic acid (generically referred to as a HIDA scan) is not a first-line imaging test in patients with suspected gallstone-related disease and is rarely needed for decision making. The fetal dose is <5 mGy (milligray) [30]; there is no evidence of an increased risk of fetal anomalies, intellectual disability, growth restriction, or pregnancy loss at this dose. (See "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Cholescintigraphy (hepatic iminodiacetic acid [HIDA] scan)' and "Diagnostic imaging in pregnant and lactating patients", section on 'Fetal risks'.)

●Computed tomography and plain radiographs are generally avoided in pregnancy for the evaluation of the gallbladder because they are inferior to ultrasound and magnetic resonance imaging and they expose the fetus to ionizing radiation [29]. (See "Diagnostic imaging in pregnant and lactating patients" and "Overview of gallstone disease in adults", section on 'Evaluation for uncomplicated gallstone disease' and "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Diagnostic imaging'.)

Laboratory testing — Laboratory studies should be normal in patients with uncomplicated gallstone disease, both during asymptomatic periods and during attacks of pain; results need to be interpreted with respect to the normal range for pregnant patients, which is sometimes different from the nonpregnant state (table 3).

Thus, laboratories are obtained primarily to aid in the differential diagnosis. Abnormal blood tests such as leukocytosis, elevated liver, or pancreas tests suggest the development of complicated gallstone disease (ie, cholecystitis, cholangitis, pancreatitis) or other pregnancy- or non-pregnancy-related conditions. (See 'Differential diagnosis' below.)

Although the choice and order of testing varies depending on the clinical presentation and suspicion of a particular diagnosis, we perform the following baseline evaluation:

●Complete blood count (to evaluate for infection, HELLP syndrome [Hemolysis, Elevated Liver enzymes, Low Platelet count], preeclampsia with severe features) – The normal range for the white blood cell count is higher in pregnancy (range 5000 to 16,000 cells/microL), which reduces the diagnostic usefulness of this test for infection. However, a left shift and/or bandemia suggests infection. The platelet count may be slightly lower in normal pregnancy but generally remains within the normal range. A low platelet count suggests one of several causes of pregnancy-related thrombocytopenia (eg, HELLP, preeclampsia with severe features). (See "Thrombocytopenia in pregnancy".)

●Aspartate aminotransferase/alanine aminotransferase (AST/ALT), total bilirubin, alkaline phosphatase (to evaluate for complicated gallbladder disease, HELLP, and preeclampsia with severe features).

•Transaminases and bilirubin are not affected by normal pregnancy; in addition, elevation in the serum total bilirubin is not common in acute cholecystitis, since biliary obstruction is limited to the gallbladder. However, mild elevations in serum aminotransferases, along with hyperbilirubinemia and jaundice, may occur as a result of the passage of small stones, sludge, or pus [31]. (See "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Laboratory findings'.)

•Significant elevations of the transaminases and alkaline phosphatase or direct bilirubin should raise the possibility of a common bile duct stone, cholangitis, or Mirizzi syndrome (ie, a gallstone impacted in the distal cystic duct causing extrinsic compression of the common bile duct). It should be noted that transaminases are elevated to at least twice normal in HELLP syndrome and can be elevated in preeclampsia with severe features, and the normal alkaline phosphatase level may be markedly elevated in pregnancy. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management" and "Acute cholangitis: Clinical manifestations, diagnosis, and management" and "Mirizzi syndrome".)

●Serum amylase and lipase (to evaluate for pancreatitis) – Serum amylase and lipase levels remain in the normal range or increase slightly in pregnancy [32-35]. Elevations in serum amylase and lipase may occur as a result of the passage of small stones, sludge, or gallstone pancreatitis [31].

●Urine protein (to evaluate for preeclampsia) – Urine protein is not affected by gallstone disease. Proteinuria is a frequent finding in preeclampsia but is no longer considered necessary for the diagnosis if features of severe disease are present (table 4).

DIAGNOSIS — The criteria for diagnosis of gallstone-related diseases in pregnancy are the same as in nonpregnant patients.

●Biliary colic (see "Overview of gallstone disease in adults", section on 'Evaluation for uncomplicated gallstone disease')

●Acute cholecystitis (see "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Diagnostic approach')

●Choledocholithiasis (see "Choledocholithiasis: Clinical manifestations, diagnosis, and management", section on 'Initial diagnostic evaluation')

●Acute cholangitis (see "Acute cholangitis: Clinical manifestations, diagnosis, and management", section on 'Diagnostic approach')

●Biliary pancreatitis (see "Clinical manifestations and diagnosis of acute pancreatitis", section on 'Diagnosis')

DIFFERENTIAL DIAGNOSIS — In pregnant patients with right upper quadrant (RUQ) or epigastric pain, both pregnancy-related and non-pregnancy-related clinical diagnoses must be considered, even when gallstones are observed on ultrasound examination, since they may be an incidental finding (algorithm 1).

Pregnancy-related conditions — Pregnancy-related conditions that may be associated with RUQ or epigastric pain include preeclampsia with severe features and HELLP syndrome (ie, Hemolysis, Elevated Liver enzymes, Low Platelet count), acute fatty liver, abruptio placentae, uterine rupture, and intra-amniotic infection. These conditions can usually be differentiated from gallstone disease by the clinical setting in which they occur and by obtaining the appropriate diagnostic studies. (See "Approach to acute abdominal/pelvic pain in pregnant and postpartum patients".)

●Preeclampsia/HELLP – Hypertension is the requisite criterion for preeclampsia (table 4) and is common in HELLP syndrome (table 5). Thrombocytopenia is a requisite criterion for HELLP syndrome and is common in preeclampsia. Both disorders occur after 20 weeks of gestation. Gallbladder disease is not associated with either hypertension or thrombocytopenia and can occur anytime in pregnancy. Patients with preeclampsia with severe features or HELLP syndrome can have elevated liver enzymes (typically at least twice normal), which can also occur with complicated gallstone disease. (See "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

●Acute fatty liver – Acute fatty liver occurs in the second half of pregnancy, usually in the third trimester. The most frequent initial symptoms are nausea or vomiting (approximately 75 percent of patients), abdominal pain (particularly epigastric, 50 percent), anorexia, and jaundice. Serum aminotransferase elevations are usually higher in fatty liver than in gallbladder disease, ranging from modest increases to up to 1000 IU/L. About one-half of patients have signs of preeclampsia at presentation or at some time during the course of illness. Hypoglycemia is a feature of severe acute fatty liver but is not present in preeclampsia, HELLP syndrome, or gallbladder disease. Severe acute fatty liver is also characterized by renal failure and disseminated intravascular coagulation, which are not features of gallbladder disease. (See "Acute fatty liver of pregnancy".)

●Abruption – An acute abruption (ie, decidual hemorrhage leading to the premature separation of the placenta prior to delivery) classically presents with vaginal bleeding, uterine contractions, and abdominal/uterine pain that is typically not limited to the RUQ or epigastrium. In severe cases, the fetal heart rate pattern is abnormal, and disseminated intravascular coagulation occurs. These features distinguish abruption from gallbladder disease. (See "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".)

●Uterine rupture – Most uterine ruptures occur in laboring patients with a prior cesarean delivery or prior transmyometrial surgery. Signs and symptoms of uterine rupture can include an abnormal fetal heart rate tracing or fetal death, uterine tenderness, peritoneal irritation, vaginal bleeding, and shock. Uterine rupture prior to the onset of labor is rare and usually due to sharp or blunt abdominal trauma. This clinical setting is quite different from that in biliary disease. (See "Uterine rupture: After previous cesarean birth".)

●Intra-amniotic infection – Signs and symptoms of intra-amniotic infection include fever, abdominal pain, uterine tenderness, leukocytosis, maternal and fetal tachycardia, and uterine contractions. Intra-amniotic infection is common after premature rupture of the fetal membranes. Patients with acute cholecystitis have some of these signs and symptoms, but the location of pain is different (RUQ/epigastrium versus uterine) and the fetal membranes are typically intact. (See "Clinical chorioamnionitis".)

Non-pregnancy-related conditions — Non-pregnancy-related conditions include non-gallstone-related biliary disease, gastroesophageal reflux, peptic ulcer disease, hepatitis, and right-sided pneumonia. Of note, the location of the appendix migrates cephalad with the enlarging uterus as shown in the figure (figure 2); thus, appendicitis may be more likely to present with RUQ pain in pregnancy. The differential diagnosis of RUQ or epigastric pain unrelated to pregnancy is reviewed separately. (See "Causes of abdominal pain in adults" and "Approach to acute abdominal/pelvic pain in pregnant and postpartum patients", section on 'Upper abdominal pain'.)

MANAGEMENT — Most pregnant patients with gallstones are asymptomatic and do not require further evaluation or treatment.

The management of symptomatic gallstone diseases during pregnancy is evolving. In the past, nonoperative management was usually recommended, especially during the first and third trimester. At present, early surgical or endoscopic intervention is the treatment of choice for those with complicated gallstone diseases (acute cholecystitis, choledocholithiasis/cholangitis, gallstone pancreatitis), as well as those with progressive, intractable, or recurrent biliary colic symptoms (algorithm 1) [36].

However, management should be individualized based on the clinical scenario (ie, uncomplicated versus complicated disease), gestational age, and other factors (eg, local expertise, patient preference).

Treatment setting — Most pregnant patients with right upper abdominal pain should be admitted to the hospital for pain control and fluid therapy and to rule out other conditions, although some patients with mild biliary colic symptoms may be initially managed in an outpatient setting.

Supportive care — Supportive care for all patients with symptomatic gallstone diseases includes pain control, intravenous fluid therapy, and antibiotic therapy (when clinically indicated). During an acute attack, patients should avoid eating, which may exacerbate the pain by releasing cholecystokinin. (See 'Antibiotic therapy' below and 'Pathophysiology' above.)

Pain control — Acetaminophen can be used to manage mild pain. More severe pain can usually be controlled with opioids. Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally avoided in pregnancy, especially after 32 weeks of gestation, because of potential adverse fetal effects when used for more than 48 hours (eg, premature closure of the ductus arteriosus, oligohydramnios).

Antibiotic therapy — While empiric antibiotic therapy is generally not required for biliary colic or mild gallstone pancreatitis, it is required for patients with acute cholecystitis, cholangitis, or severe gallstone pancreatitis. Although acute cholecystitis is primarily an inflammatory process, secondary infection of the gallbladder can occur as a result of cystic duct obstruction and bile stasis. The approach to antibiotic therapy in patients with acute cholecystitis and cholangitis is discussed separately. (See "Treatment of acute calculous cholecystitis", section on 'Antibiotics' and "Acute cholangitis: Clinical manifestations, diagnosis, and management", section on 'Management'.)

The most frequent isolates from the gallbladder or common bile duct are Escherichia coli, Enterococcus, Klebsiella, and Enterobacter.

Monotherapy with a beta-lactam/beta-lactamase inhibitor, such as one of the following, is appropriate in pregnancy:

●Ampicillin-sulbactam 3 g intravenously every six hours, or

●Piperacillin-tazobactam 3.375 g intravenously every six hours, or

●An acceptable alternative is a third-generation cephalosporin, such as ceftriaxone 1 g intravenously every 24 hours, plus metronidazole 500 mg intravenously every eight hours. In patients who cannot take a penicillin or cephalosporin, vancomycin 15 to 20 mg/kg/dose intravenously every 8 to 12 hours initially (adjust based on therapeutic monitoring) plus aztreonam 1 to 2 g intravenously every 8 hours (maximum 8 g/day) plus metronidazole is an accepted alternative.

Cephalosporins, clindamycin, and aztreonam have a good safety profile in pregnant patients. Aminoglycosides are relatively safe but carry a risk of fetal (and maternal) ototoxicity and nephrotoxicity, so drug levels should be monitored. Fluoroquinolones and carbapenems are generally avoided in pregnant patients because of potential fetal toxicity.

Additional information about perioperative antibiotic use in pregnant patients is available elsewhere. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

Biliary colic — The initial supportive management of biliary colic is usually successful; patients are then encouraged to eat a well-balanced diet. Whether or not a particular diet may reduce the formation and future risk of biliary colic is unknown. Although ursodeoxycholic acid (UDCA) has been administered in the management of intrahepatic cholestasis of pregnancy and has a good fetal safety profile, its efficacy for the treatment of gallbladder stones during pregnancy has not been well studied, and we do not use it in our practice. (See "Intrahepatic cholestasis of pregnancy", section on 'Ursodeoxycholic acid'.)

For patients in whom supportive management is not successful, additional imaging and repeat laboratory studies should be performed to exclude complicated gallstone disease. If a complicated gallstone disease is diagnosed, or symptoms of biliary colic (eg, pain, nausea/vomiting) cannot be controlled with supportive care and dietary modification, gallbladder surgery should be promptly offered and can be performed during any trimester. (See 'Cholecystectomy during pregnancy' below.)

Whether all pregnant patients require gallbladder surgery after recovering from a single bout of biliary colic is controversial (algorithm 1):

●Some of our contributors offer all such patients gallbladder surgery [37]. Rationale supporting this practice includes the following:

•Delaying gallbladder surgery until after delivery incurs a high rate of recurrences that require emergency room visits and/or hospitalization [38-40]. Gallstone-related symptoms recur in 92, 64, and 44 percent of patients who initially present in the first, second, and third trimester, respectively [20,41].

•Up to 27 percent of recurrences may involve complications such as acute cholecystitis, cholangitis, or pancreatitis [38]. Complicated gallstone diseases have been associated with preterm labor in 20 percent and fetal loss in 10 to 60 percent of the patients [42].

●Other contributors offer gallbladder surgery selectively to patients with recurrent bouts of bothersome pain or those who are unable to gain weight at an acceptable rate due to the symptoms [36].

If biliary colic occurs near term, another reasonable option is to avoid cholecystectomy and reevaluate the patient after delivery (see 'Incidence and course' above). In that case, we suggest reimaging those who had uncomplicated biliary colic during pregnancy with abdominal ultrasound four to six weeks postpartum. Further management depends on findings on follow-up imaging studies:

●If sludge/stones persist, we suggest performing cholecystectomy at least six weeks after delivery to allow the mother to recover from the delivery and bond with the infant but before three months after delivery to prevent recurrent attacks of biliary colic or more severe complications. In such patients, postpartum restoration of gallbladder motility may exacerbate passage of sludge or stones from the gallbladder.

●If sludge/stones disappear postpartum, it is reasonable to take a watchful waiting approach while maintaining a low threshold for reimaging and surgical intervention should any suggestion of symptoms recur. Dietary and lifestyle measures that may reduce the risk of new gallstone formation are reviewed separately. (See "Gallstones: Epidemiology, risk factors and prevention", section on 'Prevention of gallstones'.)

Postpartum cholecystectomy rates in patients with biliary colic during pregnancy vary widely (0.8 to 56 percent) [11,23,43].

Acute cholecystitis — One of the most common clinical scenarios is a patient with symptoms of cholecystitis and gallstones on ultrasound. Following supportive care including antibiotic therapy, gallbladder surgery is indicated for any pregnant patient with acute cholecystitis and can be safely performed during any trimester (algorithm 1). For patients near term, a reasonable alternative is to defer gallbladder surgery until after delivery, assuming that symptoms can be controlled with antibiotics and supportive care. However, the risk of persistent, worsening, or recurrent symptoms in such patients is unknown. (See 'Cholecystectomy during pregnancy' below.)

In a National Inpatient Sample (NIS) study including 23,939 pregnant patients with acute cholecystitis from 2003 to 2015, approximately 36 percent were managed nonoperatively while 60 and 4 percent underwent laparoscopic and open cholecystectomy, respectively [44]. Compared with nonoperative management, laparoscopic cholecystectomy for acute cholecystitis was associated with lower rates of preterm delivery, labor, or abortion (odds ratio [OR] 0.41), and each day that laparoscopic cholecystectomy was delayed was associated with an increased risk of fetal complications (OR 1.17).

In a propensity score-matched study including 2719 pregnant patients with cholecystitis, those who did not undergo cholecystectomy were more likely to have maternal-fetal complications than those who underwent cholecystectomy both during the index admission (27.6 versus 8 percent) and on 30 day readmission (7.9 versus 3.7 percent) [45]. Specifically, patients who did not undergo cholecystectomy were over 6 times more likely to have poor fetal growth and over 3 times more likely to have either premature delivery or undergo cesarean delivery. The readmission rate was higher among those who did not undergo cholecystectomy (18.7 versus 10.7 percent), whereas the hospital stay was slightly shorter (3.7 versus 4.5 days).

Other studies of pregnant patients with acute cholecystitis also associated early cholecystectomy with reduced preterm delivery rate and readmission rate compared with conservative management [46].

Choledocholithiasis/cholangitis — Patients with choledocholithiasis and/or cholangitis are managed with supportive care (including antibiotic therapy) and either (1) preoperative endoscopic retrograde cholangiopancreatography (ERCP) followed by gallbladder surgery or (2) gallbladder surgery with either common bile duct exploration or postoperative ERCP (algorithm 1).

The two approaches are equally effective in the general population [47,48] but have not been directly compared in pregnant patients. Both gallbladder surgery and ERCP can be safely performed during any trimester, and the choice should be based on local expertise [37].

●ERCP with sphincterotomy can be performed with low rates of maternal or fetal morbidity [49-52]. The efficacy of preoperative ERCP followed by laparoscopic cholecystectomy has been validated by multiple studies in the pregnant population [53-59]. ERCP generally uses fluoroscopy for imaging, which can be accomplished safely during pregnancy with fetal shielding. Exposure to ionizing radiation during ERCP can also be minimized or eliminated by using specific techniques [60], which are discussed in detail elsewhere. (See "Endoscopic retrograde cholangiopancreatography (ERCP) in pregnancy".)

●Good outcomes have been described with intraoperative common bile duct exploration, but few cases have been reported for pregnant patients [61-64]. As with ERCP, the fetus should be shielded during intraoperative cholangiography [65]. (See "Surgical common bile duct exploration".)

For patients who are near term, a reasonable option is to perform ERCP to extract the common bile stone and relieve the common bile duct obstruction but defer gallbladder surgery until after delivery. However, the risk of a recurrent episode of choledocholithiasis is unknown.

Gallstone pancreatitis — Management of gallstone pancreatitis consists of initial supportive care with hospitalization, pain control, intravenous fluid therapy, and nutritional support (algorithm 1). In a patient with biliary pancreatitis, antibiotics are not required unless there is evidence of infection. (See "Management of acute pancreatitis", section on 'Antibiotics' and 'Supportive care' above.)

Gallstone pancreatitis will improve or resolve rapidly in many patients with supportive treatment. A systematic review identified 12 studies that included a total of 113 patients with confirmed gallstone-induced acute pancreatitis (study dates: 1972 to 2004) [53,66-76]. Maternal mortality was no different for conservative compared with surgical management, but fetal mortality trended higher with conservative management compared with surgery (six versus two cases) in patients who did not improve quickly [20]. Thus, patients who do not respond promptly to supportive medical care, and those with concomitant cholangitis, should undergo prompt ERCP and sphincterotomy with or without biliary stent placement.

Cholecystectomy is also indicated, usually during the same hospitalization, for patients with mild disease that resolves to prevent recurrence (up to 70 percent [4]) and reduce costs [77]. Given that acute pancreatitis in pregnancy most commonly occurs during the third trimester [4], for patients who are near term, delaying gallbladder surgery until after delivery is a reasonable option [4,78].

CHOLECYSTECTOMY DURING PREGNANCY — Cholecystectomy can be performed safely and effectively during pregnancy. In current practice, laparoscopic cholecystectomy is the preferred treatment for all symptomatic gallstone diseases [37].

Timing — Traditionally, surgery was avoided during the first and third trimester to minimize the risk of spontaneous abortion and preterm delivery, respectively [79]. Cholecystectomy, when indicated, was preferentially performed during the second trimester [20,66,80-85]. This practice, however, was not evidence based.

Contemporary literature supports that laparoscopic surgery performed during any trimester is safe for the mother and fetus [86,87]. Cholecystectomies performed during the first trimester were not associated with a higher rate of complications compared with those performed during the second trimester (adjusted odds ratio [OR] 0.88, 95% CI 0.47-1.63) [88]. Laparoscopic cholecystectomy and appendectomy performed late in the third trimester have also been reported [86,87,89,90]. Consequently, major surgical [37] and obstetrical societies [91,92] have switched their positions to endorsing necessary laparoscopic surgery during any trimester.

However, cholecystectomy in the third trimester has been associated with increased preterm delivery in several population studies:

●In an administrative database study of the California statewide data, those who underwent cholecystectomy during the third trimester had higher rates of preterm delivery (OR 2.05), hospitalization (85 versus 63 percent), readmission (OR 2.05), and open cholecystectomy (13 versus 2 percent), as well as a longer hospital stay (+0.83 days), compared with patients who underwent cholecystectomy postpartum [93].

●In a similar study of the New York statewide data, patients who underwent cholecystectomy during the third trimester also had a higher rate of preterm delivery (OR 2.54) and a longer hospital stay (OR 1.44) compared with patients who underwent cholecystectomy postpartum, but other outcomes (eg, composite maternal outcomes, fetal demise, overall complication rate) were not statistically different [94].

●In a study of 819 patients from the National Inpatient Sample who underwent cholecystectomy during pregnancy, cholecystectomies performed during the third trimester were associated with a higher rate of preterm delivery (adjusted OR 7.20, 95% CI 3.09-16.77) and overall maternal/fetal complications (adjusted OR 2.78, 95% CI 1.71-4.53) compared with those performed during the second trimester [88].

Thus, while surgical management is the preferred approach for patients with symptomatic gallstone disease near term, another option is to delay gallbladder surgery until after delivery, as long as the presenting symptoms have been adequately addressed by nonsurgical methods (eg, supportive treatment for gallstone pancreatitis, endoscopic retrograde cholangiopancreatography [ERCP] for choledocholithiasis or cholangitis). Patients should be explained the risks and benefits of late-term versus postpartum gallbladder surgery to facilitate an informed decision jointly with the treating surgeon and obstetrician.

Personnel and preparations — An experienced surgeon and anesthesiologist, and early involvement of the patient's obstetrician, are important for providing optimal outcomes for the mother and baby.

●In a review of the Nationwide Inpatient Sample (NIS) database, surgical treatment by high-volume surgeons (≥75^th percentile) was associated with fewer maternal complications and fetal complications than treatment by low-volume surgeons (maternal complications 0.9 versus 14.3 percent; fetal complications 3.9 versus 9.5 percent) [82].

●Patients with uncomplicated gallbladder disease should be administered prophylactic antibiotics prior to cholecystectomy, and those already receiving antibiotics for complicated gallbladder disease should be re-dosed prior to surgery. Appropriate antibiotic choices are discussed above. (See 'Antibiotic therapy' above.)

●Other anesthetic and preoperative considerations in the pregnant patient, including positioning, fetal monitoring, thromboprophylaxis, and pharmacologic management of preterm labor, are discussed in detail elsewhere. Prophylactic tocolytic agents are not necessary [65]. (See "Anesthesia for nonobstetric surgery during pregnancy" and "Nonobstetric surgery in pregnant patients: Patient counseling, surgical considerations, and obstetric management".)

Surgical approaches — In contemporary surgical practice, laparoscopic cholecystectomy is the recognized standard for removal of the gallbladder and is also the preferred technique in pregnant patients [37,65]. However, either an open or laparoscopic approach to cholecystectomy may be chosen based upon uterine size, maternal body habitus, past surgical history, surgeon experience, and the availability of appropriate staff and equipment.

In general, a laparoscopic approach provides better surgical exposure than the open approach during pregnancy and reduces the need to manipulate the uterus away from the operative field. It also offers earlier recovery, reduced postoperative pain with a reduction in opioid usage, smaller incisions, and fewer wound complications such as hernia or surgical site infections [95,96].

Reviews of older studies comparing open with laparoscopic cholecystectomy found no significant differences in maternal or fetal outcomes [8,20,53,79,82,96-104]. In a 2016 systematic review and meta-analysis of 11 observational studies (10,632 patients), laparoscopic compared with open cholecystectomy was associated with decreased risks for fetal (OR 0.42, 95% CI 0.28-0.63), maternal (OR 0.42, 95% CI 0.33-0.53), and surgical (OR 0.45, 95% CI 0.25-0.82) complications and a shorter length of stay (3.2 versus 6.0 days) [105]. However, 91 percent of the patients underwent surgery during the first and second trimester.

If the laparoscopic procedure cannot be safely and/or effectively completed, the approach should be converted to an open cholecystectomy to avoid injury to surrounding structures. This reflects good judgment and should not be viewed as a failure or complication of the laparoscopic approach. Indications for choosing an open surgical approach or conversion to an open procedure are discussed in detail elsewhere. (See "Complications of laparoscopic surgery", section on 'Conversion to an open procedure'.)

Laparoscopic cholecystectomy — A few modifications to standard techniques for laparoscopic cholecystectomy are needed when the patient is pregnant.

●Patients should be placed slightly head-up and tilted to their left, allowing the uterus to fall away from the vena cava.

●We prefer to use the open (Hasson) technique to gain initial access to the abdomen. An alternative during the later stages of pregnancy is subcostal access [65].

●The trocars are generally placed in the usual locations, although as the uterus enlarges in the third trimester (figure 3), it can be advantageous to move the epigastric port into the left upper quadrant to provide greater perspective (figure 4). This modification should be determined after pneumoperitoneum has been established.

The remainder of the technique of laparoscopic cholecystectomy, including intraoperative evaluation and laparoscopic management of common bile duct stones, is similar to surgery in nonpregnant patients, as is shown in the figures and discussed in detail elsewhere (figure 5 and figure 6). (See "Laparoscopic cholecystectomy", section on 'Evaluation for choledocholithiasis' and "Surgical common bile duct exploration".)

Intraoperative cholangiography should be considered if the biliary anatomy is unclear and/or if there is a substantial possibility of common bile duct stones. Radiation exposure to the fetus is not significant if shielded by a lead apron (figure 7) [65]. If available, intraoperative ultrasound of the bile duct can be performed as an alternative to cholangiography and has equivalent diagnostic accuracy for common duct stones in experienced hands.

Open cholecystectomy — The surgical technique of open cholecystectomy is modified only slightly during pregnancy.

●Patients are placed slightly head-up and tilted toward the left, allowing the uterus to fall away from the inferior vena cava.

●A subcostal incision is preferred as it allows an easier approach to the gallbladder when the uterus is very large.

●The procedure is otherwise performed in standard fashion, as discussed in detail elsewhere. (See "Open cholecystectomy".)

Postoperative care — General considerations for the postoperative care of pregnant patients are reviewed separately. Fetal heart rate and uterine activity should be assessed in the recovery room, as appropriate for gestational age. (See "Laparoscopic surgery in pregnancy", section on 'Postoperative care' and "Anesthesia for nonobstetric surgery during pregnancy", section on 'Postoperative care'.)

Following cholecystectomy, the patient can usually resume drinking clear liquids once the effects of anesthesia have worn off and then advance as tolerated to a low-fat diet. Patients who have had laparoscopic surgery can usually be discharged home on the day of surgery or the following day unless there are extenuating circumstances, such as uterine contractions, vaginal bleeding, pain, or unremitting nausea. A two- to four-day stay is usually necessary after open surgery.

Opioids and antiemetics can be used, as needed, to control postoperative pain and nausea. Analgesic requirements should be met in consultation with the obstetrician. Short-term use of acetaminophen or narcotics is safe in pregnancy, although prolonged use of these medications (>2 weeks) postoperatively should be avoided. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, especially after 32 weeks of gestation, because they may cause premature closure of the fetal ductus arteriosus. Epidural analgesia is an option for postoperative pain control after an open procedure and carries less risk of opioid-induced hypoventilation when compared with intravenous opioids. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Pain and fever medications'.)

Outcomes

Maternal-fetal safety — Cholecystectomy during pregnancy appears to be safe for the mother and fetus [39]. Specifically, surgical intervention is not associated with a higher risk of premature labor and/or delivery (prevalence 0 to 10 percent) than that in the general obstetrical population [20,66,84,106,107]. Nor is cholecystectomy associated with a higher risk of maternal or fetal mortality than nonoperative management of symptomatic gallstone disease during pregnancy [107]. In a 2009 study of 9714 pregnant patients who underwent cholecystectomy, the overall rates of maternal or fetal complications were 4.3 and 5.8 percent, respectively [82].

Surgical complications — Pregnancy alone does not appear to increase postoperative surgical morbidity for cholecystectomy in pregnant compared with nonpregnant patients [108,109].

●In a review of data from the American College of Surgeons database from 2005 to 2009, composite 30 day major morbidity was similar after cholecystectomy between pregnant and nonpregnant patients at 1.8 percent [108].

●In a review of the NIS that compared cholecystectomy in 9714 pregnant with 53,598 nonpregnant female controls from 1996 to 2006, pregnant patients had higher rates of unadjusted surgical complications (10.7 versus 9.6 percent) [82]. However, after adjustment for patient and provider characteristics, pregnancy was not a significant predictor for having a surgical complication but was an independent predictor for longer adjusted length of stay.

Comparison with nonoperative treatment — Although randomized trials of the surgical treatment of biliary disease in pregnant patients have never been performed, observational data support that an early intervention approach is equally safe and more effective than expectant management/supportive medical therapy [110,111]. This conclusion is congruent with similar findings in the general population where higher-quality evidence exists.

●A retrospective analysis of hospital discharges from 1999 to 2006 from the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) identified 36,929 pregnant patients hospitalized with biliary tract disease (eg, gallstones, cholecystitis, cholangitis, biliary pancreatitis, other biliary diseases) [82]. Of these, 9714 underwent cholecystectomy; most (89 percent) were performed laparoscopically. Surgical treatment was associated with lower complication rates than nonoperative management (maternal complication rate 4.3 versus 16.5 percent; fetal complication rate 5.8 versus 16.5 percent). However, the choice of surgery versus nonoperative management and laparoscopic versus open surgery in this retrospective study likely reflects patient-specific factors, such as the type and severity of gallstone-related disease; thus, the results cannot be used alone to guide decision making [112].

●Medical management of symptomatic gallstone diseases has been associated with an increased risk of cesarean delivery. In one small retrospective review of 112 pregnant patients who presented with complications of gallstone disease (eg, acute cholecystitis, choledocholithiasis, pancreatitis), the cesarean delivery rate was significantly higher in those treated conservatively (n = 68) compared with those undergoing surgery, ERCP, or both (34 versus 8 percent) [39]. This may have been due to an increased frequency of labor induction in conservatively treated patients.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gallbladder surgery" and "Society guideline links: Gallstones".)

SUMMARY AND RECOMMENDATIONS

●Gallstones are common during pregnancy due to decreased gallbladder motility and increased cholesterol saturation of bile. The major independent risk factors for gallstones are prepregnancy obesity and multiparity. (See 'Pathophysiology' above and 'Risk factors' above.)

●The clinical presentation of gallstone disease during pregnancy is similar to that of nonpregnant patients. Among pregnant patients who develop gallstones or have sludge, approximately 1 percent develop symptoms. In most patients, recurrent right upper quadrant (RUQ) pain (biliary colic) is the first symptom related to gallstones. Less frequently, initial manifestations may be related to complications of gallstones (ie, acute cholecystitis, cholangitis, gallstone pancreatitis). (See 'Clinical presentation' above.)

●The criteria for diagnosis of gallstone-related diseases in pregnancy are the same as in nonpregnant patients. Ultrasonography is a reliable and safe method for identifying stones in the gallbladder. Common bile duct stones are poorly identified with transabdominal ultrasound. Other imaging that may be useful and is considered safe in pregnancy includes magnetic resonance cholangiopancreatography (MRCP) and cholescintigraphy (HIDA scan). (See 'Diagnosis' above and 'Abdominal imaging' above.)

●Laboratory studies can be helpful for diagnosing complicated gallbladder disease and excluding other pregnancy- and non-pregnancy-related conditions. Routine laboratory studies are generally normal in patients with uncomplicated biliary colic. Significant elevations of the transaminases and alkaline phosphatase or direct bilirubin should raise the possibility of a common bile duct stone, cholangitis, or Mirizzi syndrome; results need to be interpreted with respect to the normal range for pregnant patients, which is sometimes different from the nonpregnant state (table 3). (See 'Laboratory testing' above.)

●In pregnant patients with RUQ or epigastric pain, pregnancy-related conditions (eg, preeclampsia with severe features and HELLP syndrome [ie, Hemolysis, Elevated Liver enzymes, Low Platelet count], acute fatty liver, abruptio placentae, uterine rupture, and intra-amniotic infection) must be considered, even if gallstones are observed on ultrasound examination, since they may be an incidental finding. These conditions can usually be differentiated from gallstone disease using the clinical setting in which they occur. (See 'Differential diagnosis' above.)

●Most gallstones in pregnancy are asymptomatic and require no further evaluation or treatment. Pregnant patients who are symptomatic are typically admitted to the hospital for pain control, intravenous fluid therapy, antibiotic therapy (for acute cholecystitis or cholangitis only), and possible surgical intervention (algorithm 1). (See 'Treatment setting' above and 'Supportive care' above.)

●Most patients with uncomplicated gallstone disease (ie, biliary colic) improve with supportive therapy, which includes pain control and intravenous fluid. Subsequent management and timing of elective surgery is controversial; some of our contributors offer cholecystectomy during pregnancy to all symptomatic patients (even if only a single episode), while others offer cholecystectomy only to those with progressive, intractable, or recurrent symptoms (algorithm 1). (See 'Biliary colic' above.)

●For most pregnant patients with complicated gallstone diseases (acute cholecystitis, choledocholithiasis or cholangitis, gallstone pancreatitis), we suggest early intervention (gallbladder surgery or endoscopic retrograde cholangiopancreatography [ERCP]) rather than nonoperative medical management (algorithm 1) (Grade 2C). However, delaying gallbladder surgery until after delivery is a reasonable alternative for some patients near term. In several population studies, cholecystectomy during the third trimester has been associated with increased risk of preterm delivery compared with postpartum surgery. Additional considerations include disease severity and surgical expertise as well as patient preferences. (See 'Acute cholecystitis' above and 'Choledocholithiasis/cholangitis' above and 'Gallstone pancreatitis' above and 'Timing' above.)

●Cholecystectomy can be performed safely and effectively during any trimester of pregnancy but requires an experienced surgeon, anesthesia provider, and early involvement of an obstetrician. Pregnancy alone does not appear to increase postoperative morbidity for cholecystectomy, nor does cholecystectomy jeopardize maternal-fetal safety. (See 'Cholecystectomy during pregnancy' above.)

●For pregnant patients who undergo cholecystectomy, we suggest a laparoscopic approach rather than open surgery, when feasible and available (Grade 1B). Laparoscopic surgery has been shown to improve patient outcomes without increasing surgical, maternal, or fetal complication rates. (See 'Surgical approaches' above.)