CHAPTER 35 Shivani R. Patel and Richard H. Lee Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA This chapter will focus on cholelithiasis, pancreatitis, intrahepatic cholestasis of pregnancy, inflammatory bowel diseases, and appendicitis. Pregnant women who present with nausea/vomiting, heartburn, and/or right upper quadrant/epigastric pain can be challenging as these symptoms can be normal in pregnancy or may be related to either obstetric or non‐obstetric gastrointestinal conditions. In the setting of these symptoms clinicians must consider either cholelithiasis or cholecystitis as an etiology. Symptomatic cholelithiasis is a common non‐obstetric gastrointestinal condition encountered in pregnancy complicating 1–3% of pregnancies [1]. Acute cholecystitis is less common affecting only 0.1% of pregnancies [1]. Pregnancy increases the risk of gallstone formation due to increased levels of estrogen and progesterone [1]. Additionally the elevated progesterone levels are a risk factor for acute cholecystitis [1]. Cholelithiasis can lead to acute cholecystitis, which can lead to adverse maternal and fetal consequences. In the setting of pregnancy the treatment of cholelithiasis can be challenging, and inadequate treatment can lead to acute cholecystitis. Patients with symptomatic cholelithiasis frequently present with symptoms of right upper quadrant (RUQ) pain, epigastric pain, nausea, and vomiting. In pregnant individuals these symptoms can represent normal changes of pregnancy such as nausea/vomiting of pregnancy or gastritis. Symptomatic cholelithiasis can also be associated with laboratory abnormalities such as leukocytosis and elevated transaminases. Similar to the symptoms described above, mild leukocytosis is a normal physiologic change of pregnancy that can make diagnosis difficult. Many studies have looked at symptomatic cholelithiasis in pregnancy to clarify if the classic symptoms of cholelithiasis along with fever, leukocytosis, and physical exam findings remain reliable in pregnancy. In a retrospective review done by Lu et al. RUQ pain was required for diagnosis of symptomatic cholelithiasis, and of these patients, 52% also reported vomiting [2]. Swisher et al. reported that 96% of cases of symptomatic cholelithiasis in pregnancy presented with complaints of pain and 77.8% of cases reported vomiting [3]. On laboratory evaluation a mild leukocytosis up to 16 900/mm3 can be the result of the normal physiology of pregnancy [4]. It has been shown that symptomatic cholelithiasis in pregnancy is similarly associated with a mild leukocytosis. Swisher et al. found that the mean white blood cell (WBC) count in the confirmed cases of symptomatic cholelithiasis was 10–17.5 × 103/μl while those with acute cholecystitis had a mean WBC count at the upper end of this range at 17.5 × 103/μl [3]. In the study done by Lu et al., the WBC count ranged from 9–12 × 103/μl in patients with symptomatic cholelithiasis, and again acute cholecystitis was associated with a higher WBC (12 × 103/μl) [2]. Frequently transaminases are elevated in patients with acute cholecystitis and can help in making the diagnosis. Lu et al. found them to be mildly elevated at an average of 49 U/l [2]. Similarly, alanine aminotransferase (ALT) values were elevated at 45 U/l [2]. The finding of fever is rare in cases of acute cholecystitis with only 10% of patients having a temperature greater than 38.5°C [2]. In summary, the classic symptoms of symptomatic cholelithiasis are still applicable in the setting of pregnancy. The literature shows that the majority of cases of acute cholecystitis during pregnancy present with some constellation of the symptoms of right upper quadrant pain, nausea, and vomiting. These patients might also have a mild leukocytosis that may be undifferentiable from the normal elevation in WBC count in pregnancy. However, fever is not a reliable marker to diagnose acute cholecystitis in pregnancy. Thus if a pregnant patient presents with any of these signs or symptoms, the medical literature supports that acute cholecystitis must be included in the differential and excluded. Classic ultrasound findings of acute cholecystitis cluster around findings consistent with inflammation of the gallbladder. These findings include gallbladder wall edema defined by a thickness >3 mm, pericholecystic fluid, calculi, and a sonographic Murphy’s sign [5]. Lu et al. reported that 95% of patients with acute cholecystitis had gallstones present on ultrasound [2]. They also found that a thickened gallbladder wall was present in 40% of cases and pericholecystic fluid was found in 15% [2]. Similarly Swisher et al. found that on ultrasound cholelithiasis was present in 100% of cases of acute cholecystitis and 56% concurrently had gallbladder wall thickening [3]. In the literature the diagnostic value of ultrasound in the setting of acute cholecystitis is clearly reliable if a constellation of findings is used. It appears that when gallstones are visible it is a reliable method for diagnosing acute cholecystitis in pregnancy. Additionally the findings of gallbladder wall thickening and pericholecystic fluid can further bolster ones diagnosis. Thus, in pregnancy, ultrasound can aid in making the diagnosis when physical exam and laboratory findings are suggestive of acute cholecystitis. The treatment options of acute cholecystitis include both nonsurgical conservative management and cholecystectomy. Nonsurgical management consists of bowel rest, intravenous hydration, intravenous antibiotics, and analgesia for pain [5]. In the setting of pregnancy conservative management can pose risks to both the mother and the fetus. Maternal risks include treatment failure, recurrent episodes, need for emergency surgery, and longer hospital stay. The risks of treatment failure include gangrenous cholecystitis, gallbladder perforation, cholecystoenteric fistulas, choledocholithiasis, and ascending cholangitis [1, 3, 5]. Fetal risks include spontaneous abortion, intrauterine fetal demise, and premature birth. Swisher et al. reviewed maternal and fetal outcomes in patients with acute cholecystitis compared to those with biliary colic [3]. They found that 44% of patients with acute cholecystitis fail initial conservative therapy [3]. The relapse rate requiring hospitalization during pregnancy with conservative management is 22–58% [2, 3, 6]. Muench et al. describe a series in which delay in operative management resulted in multiple admissions for recurrent episodes [7]. As the number of episodes of recurrence increase, the number of additional hospital days increases by 2–11 days [2, 3]. Rates of relapse appear to be higher in patients who present earlier in pregnancy; 65% in the first and second trimesters compared 35% in the third trimester [2]. Swisher et al. found that the rate of relapse was highest in the first trimester and lowest if they presented in the third trimester [3]. Preterm contractions are experienced by 28% of patients managed conservatively compared to 31% who underwent cholecystectomy [2]. There is a higher rate of preterm delivery in patients managed nonoperatively (17% vs. 0%) [2]. There is also a higher rate of induction of labor (7–10%) in patients conservatively to aid in alleviation of symptoms [2, 3, 6]. Dixon et al. reported that spontaneous abortion occurred in 12% of patients with symptomatic cholelithiasis [6]. Maternal and fetal mortality are rare events with no studies describing maternal mortality and only one study finding a fetal mortality rate of 4.7% [2, 3]. Conservative management remains the initial treatment of choice in the pregnant population. However, given the increased risks to both the mother and fetus consideration should be given to operative management, especially when the patient’s initial presentation is early in pregnancy. Cholecystectomy is the definitive treatment for acute cholecystitis. It is well known that definitive treatment prevents maternal and fetal morbidity and mortality associated with conservative management. In the era of minimally invasive surgery laparoscopy is increasingly being used in the pregnant population. Barone et al. found that patients undergoing lupus anticoagulant (LAC) are more likely to be earlier in gestation (16 weeks) compared to those undergoing OC (23 weeks) [8]. They reported one maternal death (5%) two weeks after surgery in the LAC group secondary to intra‐abdominal hemorrhage and one spontaneous abortion five weeks after surgery [8]. Barone et al. also reported that 30% of patients in the OC group required treatment for preterm contractions with 3.8% experiencing preterm delivery. This was compared to 5% in the LAC group receiving treatment for preterm contractions and 0% delivering prematurely [8]. In the same paper a review of studies showed only 1/61 patients experienced a spontaneous abortion after LAC [8]. Similarly Cosenza et al. found that there was no difference in fetal loss when comparing LAC to OC, and also found no difference in operative time and blood loss [9]. In a small series comparing LAC to OC, those who underwent LAC were able to tolerate regular diet faster compared to OC (0.3 vs. 0.6 days) [2]. They found no increased risk of preterm delivery or preterm contractions in the LAC group [2]. Affleck et al. also reported no difference in preterm delivery rates between a laparoscopic approach versus an open approach, and Gouldman et al. reported no preterm births in their study of patients undergoing LAC [10, 11]. Muench et al. determined that LAC was safe in pregnancy with favorable short‐term and long‐term fetal outcomes, including no spontaneous abortions or preterm births [7]. LAC is safe in pregnancy and can provide more favorable maternal and fetal outcomes than an open approach. Given the above evidence, a LAC should be considered in patients with acute cholecystitis. Pancreatitis has an incidence of approximately 1 per 1000–10 000 pregnancies [12, 13]. It is most commonly caused by cholelithiasis [14]. It is associated with an increased risk for preterm birth and maternal/fetal morbidity and mortality [15]. Treatment for pancreatitis revolves around treating the cause. The mainstay of treatment for biliary pancreatitis includes conservative management, LAC, or endoscopic retrograde cholangiopancreatography. If left untreated, biliary pancreatitis has a high risk of recurrence during the pregnancy and puerperium [16, 17]. The symptoms of acute pancreatitis are non‐specific and can mimic other diseases seen in pregnancy. The differential diagnosis of acute pancreatitis includes preeclampsia, acute fatty liver of pregnancy, HELLP syndrome, appendicitis, gastritis, peptic ulcer disease, ovarian torsion, cholelithiasis, bowel obstruction, chorioamnionitis, and placental abruption. There is a third trimester prominence in incidence although it can occur at any time during pregnancy [12, 18]. The majority of cases of acute pancreatitis in pregnancy are caused by choledocholithiasis and less likely from alcohol abuse, hypertriglyceridemia, idiopathic, and medications [13, 14]. Symptoms of acute pancreatitis include nausea and vomiting, severe upper abdominal pain, and fever. Signs can include fever, jaundice, upper abdominal tenderness to palpation, and guarding. Laboratory findings that may be elevated include: WBC count, amylase, lipase, serum transaminases, glucose, lactate dehydrogenase, blood urea nitrogen, and base deficit. Findings that may be decreased include: serum calcium and partial pressure of oxygen. The serum lipase has a sensitivity of 94% and specificity of 96% for acute pancreatitis [19]. Ranson’s criteria which is used to assess disease severity and risk for mortality from pancreatitis has not be subjugated to validation in pregnancy [20]. Upper abdominal ultrasound is a safe and sensitive method of diagnosing cholelithiasis in the setting of acute pancreatitis. When the diagnosis is uncertain consideration should be made for magnetic resonance imaging (MRI) of the abdomen. MRI can also provide further detail on the pancreas such as the presence of pseudocysts or hemorrhage within the pancreas [21–24]. The management of patients with pancreatitis involves restricting oral intake, providing pain control and nutritional support. Antibiotics are no longer recommended. Definitive treatment for pancreatitis is dependent on the cause. If pancreatitis is caused by choledocholithiasis (i.e. biliary pancreatitis) the mainstays of treatment have included conservative management, OC, LAC, and endoscopic‐retrograde cholangiopancreatography (ERCP). Data are limited to retrospective case–control studies or small case series. Conservative management may be associated with an increased risk for fetal mortality (8.0 vs. 2.6%, P = 0.28) [25]. There is no evidence to suggest superiority of cholecystectomy over ERCP [25]. Data regarding the recurrence of symptoms and hospitalizations is largely extrapolated from patients with cholelithiasis. Conservative management is associated with an increased risk of recurrence on the order of 70%. Intervention with either ERCP or cholecystectomy has been shown to reduce the risk of subsequent hospitalization and recurrent symptoms. One small case‐series of seven pregnant patients showed successful treatment of biliary pancreatitis with the use of magnetic resonance cholangiopancreatography, ERCP and sphincterotomy, then LAC [26]. Treatment ultimately depends on a combination of disease severity, maternal/fetal status, gestational age, and the experience of the surgeon or gastroenterologist. Ducarme et al. suggest the following: conservative treatment in the first trimester and LAC in the second trimester; in the second trimester, LAC; in the third trimester, conservative treatment or ERCP with biliary endoscopic sphincterotomy, and LAC postpartum [19]. For the treatment of pancreatitis in pregnancy induced by hypertriglyceridemia, there are limited data to provide recommendations. Options in this setting include treatments used for non‐pregnant patients which include fat restriction, nutritional supplements, plasma exchange, heparin, and insulin. Pseudocysts rarely develop but if they do, the majority can be observed as spontaneous resolution is on the order of 30–40%. Laparoscopic, endoscopic, and percutaneous drainage of pseudocysts have been reported. The prognosis for spontaneous resolution is greater if the pseudocyst is asymptomatic, <6 cm, and has been present for less than six weeks [27]. Intrahepatic cholestasis of pregnancy (ICP) has a prevalence of approximately 1% [28]. The clinical manifestation of ICP is pruritus in the absence of rash. The pruritus has been described as total‐body itching with a predilection for the palms of the hands and soles of the feet. Laboratory values that are associated with ICP include elevated total serum bile acid concentration, transaminitis, hyperbilirubinemia, or alterations in the bile acid ratios. Maternal outcome is generally good, but there is an association with sudden fetal death. The most concerning aspect of ICP is its association with adverse perinatal outcome [28]. Although maternal complications from ICP are rare, there are several adverse fetal effects including preterm labor, meconium aspiration, and fetal death [29]. Reid et al. analyzed complications in 56 pregnancies with ICP and reported an astonishingly high rate of adverse outcomes (e.g. perinatal mortality rate 11%, meconium staining 27%, abnormal antepartum fetal heart rate pattern 14%, preterm delivery rate 36%) [30]. Similarly, Fisk et al. reported a 45% incidence of meconium staining, 44% incidence of preterm labor, 22% incidence intrapartum fetal distress, and a 3.5% perinatal mortality rate. The most important observations noted by Fisk et al. were twofold. Firstly, given the absence of growth restriction in cases with fetal deaths, chronic uteroplacental insufficiency was believed to be less likely a cause for this complication in ICP. Secondly, the lower perinatal mortality rate compared to previous reports was attributed to closer surveillance during pregnancy with induction of labor by 37 weeks or earlier if there were any signs of fetal distress [31]. Williamson et al. reported an overall intrauterine death rate of 7% with 90% (18/20) of the deaths occurring after 37 weeks gestation [32]. To date, the exact mechanism of fetal death is unknown. Glantz et al. demonstrated bile acid concentrations ≥40 μmol l−1 to be associated with an increased risk for adverse complications (i.e. preterm delivery, asphyxial events, meconium staining) [33]. Alternatively, there are reports of fetal death occurring with lower or normalized bile acid concentrations [34, 35]. Ursodeoxycholic acid (UDCA) is the main treatment given for ICP. It has been superior to other agents in reducing pruritus, lowering the bile acid concentration, and improving liver transaminase profiles (e.g. S‐adenosyl‐L‐methionine, cholestyramine, dexamethasone) [36–45]. There are no randomized controlled trials addressing this. Some experts recommend delivery at or around 36 weeks of gestation based on increased observation of fetal and neonatal deaths to those fetuses delivered after 36 weeks gestation [46]. Fetal deaths attributed to ICP do occur prior to 36 weeks gestation; however, the risk of prematurity vs. the risk of stillbirth need to be weighed when making delivery plans. To date, there are no antepartum testing measures to predict or reduce the risk of stillbirth from ICP. Inflammatory bowel disease (IBD) in pregnancy consists of Crohn’s disease and ulcerative colitis. The majority of patients with IBD are diagnosed before 35 years of age and will therefore affect women of reproductive age. Crohn’s disease is characterized by transmural, granulomatous inflammation anywhere along the gastrointestinal tract. Ulcerative colitis involves mucosal inflammation primarily of the rectum but can extend to the rest of the colon. Retrospective nature of studies investigating pregnancy outcomes in IBD, many data are conflicting. Nevertheless, the effect of IBD on pregnancy depends primarily on disease activity at the time of conception. Women with quiescent disease that is well‐controlled appear to have similar pregnancy outcomes as the general population [47, 48]. However, if there is active disease at conception there are some data to suggest an increased risk for spontaneous abortion, late preterm birth and low birth weight [49–53]. Patient’s with IBD can be reassured there does not appear to be an increased risk stillbirth or congenital anomalies [54].
Gastrointestinal disorders
Cholelithiasis
Background
Clinical questions
Critical appraisal of the literature
Pancreatitis
Background
Clinical questions
Critical appraisal of the literature
Intrahepatic cholestasis of pregnancy
Background
Clinical questions
Critical appraisal of the literature
Inflammatory bowel disease
Background
Clinical questions
Critical appraisal of the literature
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