Acute Biliary Tract Diseases - Acute Abdomen During Pregnancy

Acute Abdomen During Pregnancy

2. Acute Biliary Tract Diseases

Goran Augustin^{1, 2}

(1)

Department of Surgery Division of Gastrointestinal Surgery, University Hospital Center Zagreb, Zagreb, Croatia

(2)

School of Medicine University of Zagreb, Zagreb, Croatia

Abstract

A notable discovery in the last century by Von Recklinghausen that 90 % of women having gallstones have been gravid at least once, and the subsequent findings by Courvoisier in autopsy studies that three times as many women have gallstones as men hinted at the possibility of pregnancy being one of the major factors in the development of cholelithiasis [1].

2.1 Acute Cholecystitis/Biliary Colic

2.1.1 History

2.1.2 Incidence

The prevalence of gallbladder disease differs in several populations. In the United States, 10–15 % of the adult population has gallstones. In other populations, such as those of Latin American countries, the prevalence of gallstones is up to 50 % in adult women [2].

In 1910, Peterson collected 25 cases of cholecystitis during pregnancy, ten of these were during puerperium [3]. In 25 cases of gallstones complicating pregnancy, the ages of the patients were recorded in 21 instances. The age distribution of patients where gallstones complicated pregnancy was: 20–25 years, four cases; 25–30 years, eight cases; 30–35 years, six cases; and 35–40 years, three cases. The ages of the patients suffering from gallstones during the puerperium are the following: 20–25 years, three cases; 25–30 years, one case; 30–35 years, one case; 35–40 years, one case; and over 40 years, one case.

The most common causes of the gallbladder disease in pregnancy are gallstones and biliary sludge. The incidence of gallbladder disease in pregnancy is 0.05–0.3 % [4–6], and asymptomatic gallstones occur in 3.5–10 % of all pregnancies. Incidence of acute cholecystitis during pregnancy is 1/1,600–1/10,000 pregnancies [7–9], and 40 % of pregnant patients with symptomatic cholelithiasis require cholecystectomy during pregnancy [10–12]. Higher incidence of gallbladder disease of 0.39 % is found in Saudi Arabia. This is attributed to (1) high number of repeated pregnancies and (2) genetic predisposition because higher percentages (7.5 %) of pregnant women harbor silent gallstones in comparison to 3.5 % in the Western countries [13]. There is no statistically significant difference in the prevalence rates for gallstones between Mexican-born and non-Mexican-born pregnant Hispanic women in the 20-year to 49-year age group [14]. In a study by the University of Southern California, ultrasonography initially revealed biliary sludge in 15 % and gallstones in 6 % of the pregnant women examined. New sludge or stones were found in 30 and 2 % of the women, respectively, at the end of their pregnancies. Postpartum sonography revealed the disappearance of the sludge in 61 % of those women who had previously demonstrated sludge and the disappearance of stones in 28 % of those who had had stones. Therefore, some patients who have symptomatic cholelithiasis during pregnancy may not have it after delivery [15].

Biliary sludge, a potential precursor to gallstones, forms in up to 30 % of women during pregnancy, and gallstones form in 2–4 % [16, 17]. Biliary sludge, or microlithiasis, in pregnancy consists of clusters of cholesterol crystals in the bile. Although not all cases of sludge will necessarily evolve to become gallstones, sludge is believed to be the initial step in gallstone formation and is regarded as the earliest recognizable stage of lithogenesis [18]. Pregnancy, however, does not seem to increase the severity of gallstone complications. Most gallstones are asymptomatic during pregnancy [16, 17, 19, 20]. Despite the rarity of the condition, complications of gallstones represent the second most common non-gynecologic condition requiring surgery in pregnancy [21] with cholecystectomy performed in 1–8/10,000 pregnancies [22]. Cholelithiasis is the cause of cholecystitis in over 90 % of cases. The incidence of cholelithiasis in pregnant women undergoing routine obstetric ultrasound examinations is 3.5–12 % versus 1.3 % of nonpregnant controls [17, 19].

It should be noted that the number of children a woman has increases her risk of gallbladder disease and that compared with nulliparous women, the risk rises incrementally by 8 % with each additional birth. It is also interesting that after accounting for the number of children, 12 months of breastfeeding reduces the risk of gallbladder disease in parous women by 7 % [23]. As estrogen levels are known to fall during lactation, it is possible that the protective effect of breastfeeding could be mediated through estrogen [24], although there are other hormonal changes that occur with lactation that may also have an effect.

2.1.3 Risk Factors

2.1.3.1 Multiparity

Risk factor for cholelithiasis is multiparity due to hormonal changes that directly influence on gallstone formation [25]. Pregnancy increases prevalence from 1.3 % in nulliparous females to 12.2 % in multiparous females [26]. Early marriage and repeated pregnancies until menopause make the probability of gallstone disease occurring in pregnancy higher. A cross-sectional study found following incidence of gallstones: 21–30 years age group of 1.37 % in patients having no pregnancy, 9.62 % in patients having one pregnancy, 7.14 % in patients having two pregnancies, 6.04 % in patients having three pregnancies, and 3.3 % in patients having four and more pregnancies; in the 31–40 years age group, 0.55 % in patients having no pregnancy, 1.37 % in patients having one pregnancy, 6.04 % in patients having two pregnancies, 8.24 % in patients having three pregnancies, and 12.64 % in patients having four and more pregnancies; in the 41–50 years age group, 0.82 % in patients having no pregnancy, 0.55 % in patients having one pregnancy, 4.4 % in patients having two pregnancies, 4.4 % in patients having three pregnancies, and 12.91 % in patients having four and more pregnancies; and in the 51–60 years age group, 0.55 % in patients having one pregnancy, 1.1 % in patients having two pregnancies, 2.47 % in patients having three pregnancies, and 14.29 % in patients having four and more pregnancies. The number of pregnancies is associated with gallstone disease. The risk of developing gallstone disease increases in association with increased number of parity, particularly among the younger women [27]. Valdivieso found that 12 % of women immediately after delivery had gallstones compared to 1.3 % nulliparous control group [17]. This finding is explained by the increase in progesterone secretion which remains high during the second and third trimesters leading to smooth muscle relaxation and hence gallbladder dilatation and stasis [28]. It is important to note that the incidence of gallbladder disease in the asymptomatic category was higher in patients of higher age and parity [3, 29]. Young patients with a higher parity are more prone to gallbladder disease [29, 30].

2.1.3.2 Obesity and Diabetes Mellitus

The risk of forming gallbladder sludge or stones during pregnancy is significantly higher in obese women (BMI ≥30 kg/m²) than in normal weight (BMI <25 kg/m²) or overweight (BMI 25.0–29.9 kg/m²) women [4, 31]. Insulin resistance, which increases with BMI, is one possible mechanism linking obesity to gallstones [32–36]. However, not all studies confirm this association [37, 38]. Studies showing that fasting serum insulin, which may be used as a surrogate measure for insulin resistance, is a risk factor for prevalent gallstones [33, 35, 39–41]. Women who formed gallbladder sludge or stones were significantly more insulin resistant. This association remained strong even after adjusting for possible confounding factors including prepregnancy BMI, lipid and glucose levels, waist-hip ratio, and physical activity during pregnancy. This association was strongest for women whose prepregnancy BMI was <30 kg/m² [42]. Multiple autopsy studies have documented a statistically significant increase in the incidence of gallstones in diabetes mellitus [2, 39, 43]. Epidemiological studies in Mexican Americans [32] and in Caucasian Americans [44] have shown diabetes mellitus to be a significant risk factor for gallstones.

2.1.3.3 Oral Contraceptives

Strong association of the oral contraceptives usage and gallbladder disease shows that all pregnant patients with history of having used oral contraceptives in the past must be submitted to ultrasound examination of the gallbladder [29]. These findings are consistent with those of Thijs and Knipschild who have suggested that modern low-dose oral contraceptives may be safer than older formulas, but the safety of oral contraceptives should be evaluated by studying bile saturation and biliary function rather than waiting for gallbladder disease to develop [45].

2.1.4 Pathophysiology

2.1.4.1 Estrogens/Progesterone

As found by epidemiological and clinical investigations in every population studied, cholesterol gallstones are more common in women than men, and this gender difference begins since puberty and continues through the childbearing years [2, 46]. It has been postulated that pregnancy is associated with an increased percentage of colic acid, increased cholesterol secretion, increased bile acid pool size, decreased enterohepatic circulation, and decreased percentage of chenodeoxycholic acid [47]. The progesterone-induced smooth muscle relaxation of the gallbladder promotes stasis of the bile and increases the risk of cholelithiasis and subsequently of acute cholecystitis [48]. Ultrasound findings of the gallbladder in pregnant women show a decrease in the emptying rate and an increase in residual volume after emptying. Additionally, elevated levels of estrogen during pregnancy increase the lithogenicity of the bile, which further increases the risk of cholelithiasis and acute cholecystitis [49]. Therefore, the most common type of stones in pregnancy is yellow cholesterol stones [2, 31]. Bile becomes more lithogenic as a result of increased estrogen levels, which results in increased hepatic secretion of biliary cholesterol and cholesterol-supersaturated bile. Additionally, high levels of estrogen could impair gallbladder motility function and consequently induce gallbladder hypomotility [50]. These changes promote the formation of sludge and stones. Increased plasma levels of progesterone also reduce gallbladder motility [51, 52]. Since plasma hormone concentrations increase linearly with duration of gestation, the risk of gallstone formation is especially hazardous in the third trimester of pregnancy. Most, but not all, studies have found that the use of oral contraceptive steroids and conjugated estrogens in premenopausal women doubles the incidence of cholesterol gallstones [53–56]. In addition, the administration of estrogen to postmenopausal women and estrogen therapy to men with prostatic carcinoma displays similar lithogenic effects [57–62]. These observations support the concept that higher risks for cholesterol gallstones in women than in men are related to differences in how the liver handles cholesterol in response to estrogen [56].

Accumulated evidence has revealed that estrogen increases the risk for the formation of cholesterol gallstones by promoting hepatic secretion of biliary cholesterol that induces an increase in cholesterol saturation of the bile [57, 59, 61, 63, 64]. In addition, studies show that high levels of estrogen significantly enhance the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis, even under high dietary cholesterol loads [64–67]. These findings suggest that there could be an increased delivery of cholesterol to the bile from de novo synthesis in the liver. Furthermore, some studies show that estrogen could augment the capacity of dietary cholesterol to induce cholesterol supersaturation of the bile [65, 68–70]. It is also found that high doses of estrogen augment intestinal cholesterol absorption [68] contributable in part to an upregulated expression of intestinal sterol influx transporter Niemann-Pick C1-like 1 protein (NPC1L1) via the intestinal ESR1 pathway [71]. Furthermore, studies show that during estrogen treatment, mice continue to synthesize cholesterol in the face of its excess availability from the high cholesterol diet. It suggests that there is a loss in the negative feedback regulation of cholesterol biosynthesis, which results in excess secretion of newly synthesized cholesterol and supersaturation of the bile that predisposes to cholesterol precipitation and gallstone formation [64]. In addition, estrogen could decrease plasma low-density lipoprotein (LDL) cholesterol and increase plasma high-density lipoprotein (HDL) cholesterol because high doses of E2 amplify expression levels of HDL receptor SR-BI and LDL receptor [72–75]. The decrease in plasma LDL is a result of increased hepatic LDL receptor expression, which increases the clearance of plasma LDL. Therefore, the increased uptake of LDL by the liver may result in increased secretion of cholesterol into the bile. These alterations could induce an apparent increase in hepatic output of biliary cholesterol derived from circulating lipoproteins such as HDL and LDL, although LDL cholesterol could have a less effect on biliary secretion. These observations suggest that the hepatic estrogen receptor ESR1 is an important, selective target for the treatment of cholesterol gallstones. Figure 2.1 illustrates the potential lithogenic mechanisms of estrogen through the ESR1 pathway in the liver. Complete discussion of molecular mechanisms of estrogen effect on gallstone formation that are out of scope of this topic could be found in Wang et al. [76].

Fig. 2.1

The proposed model underlying the potential lithogenic mechanisms of estrogen through the estrogen receptor 1 (ESR1) pathway in the liver. In the liver there is a possible “estrogen-ESR1-SREBP-2” pathway promoting cholesterol biosynthesis and hepatic secretion of biliary cholesterol. The negative feedback regulation of cholesterol biosynthesis (as shown in a dashed line) is inhibited by ESR1 that is activated by estrogen, mostly through stimulating the activity of sterol regulatory element-binding protein-2 (SREBP-2) with the resulting activation of the SREBP-2 responsive genes for the cholesterol biosynthetic pathway. Consequently, these alterations induce excess secretion of newly synthesized cholesterol and supersaturation of the bile that predisposes to cholesterol precipitation and gallstone formation. Moreover, the hepatic ESR1 activated by estrogen could stimulate the activity of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 on the canalicular membrane of the hepatocyte and promote biliary cholesterol secretion. Of special note is that these lithogenic effects of estrogen are inhibited by the antiestrogenic ICI 182,780. In addition, the estrogen effects on increasing cholesterol biosynthesis and promoting cholesterol gallstone formation are, in part, blocked by deletion of the ESR1 gene [76]

It is interesting that there is a high rate of gallstone/sludge dissolution in the 1st month after delivery. The rate of disappearance of gallstones and biliary sludge is 15–28 % and 39–68 %, respectively [16, 77]. Observation is that spontaneous disappearance of gallstones after delivery is significantly more frequent in older women [16]. Speculation is that a few young women eject small gallstones from the gallbladder during the postpartum period when gallbladder contraction restores, and some of these women develop an attack of acute pancreatitis (AP). In contrast, in older women with reduced gallbladder contractility, most gallstones likely remain in the gallbladder until dissolved by less lithogenic bile. Thus, AP associated with pregnancy usually occurs in young postpartum women and is usually due to gallstones [16].

2.1.4.2 Insulin

Apart from hormone, insulin resistance is also responsible for gallstone formation. The exact mechanisms are not clear. Cholesterol is the primary constituent of gallstones formed during pregnancy. Cholesterol gallstone formation requires several pathogenic factors, including supersaturation of hepatic bile with cholesterol and altered gallbladder motility. Hyperinsulinemia and insulin resistance may affect either of these factors. Hyperinsulinemia has direct effects on hepatic lipid metabolism, increasing cholesterol synthesis via activity of the hydroxyl-methylglutaryl coenzyme A reductase enzyme [78] and increasing hepatic uptake of LDL cholesterol [79]. Insulin resistance is also associated with lower serum levels of HDL cholesterol, a known risk factor for prevalent gallstones [80]. In one study, administration of insulin in diabetics increased biliary cholesterol saturation [81]. Some, but not all, studies have shown greater degrees of biliary cholesterol saturation in patients with type II diabetes compared with controls [82, 83]. Insulin inhibits basal and cholecystokinin-stimulated gallbladder motility, and gallbladder dysmotility has been documented in patients with clinically diagnosed type II diabetes [84, 85]. In animal models, nonobese, diabetic mice have diminished gallbladder contractility and rapid formation of cholesterol crystals [86], while gallbladder contractility correlates inversely with glucose and insulin levels in obese animals [87]. Insulin resistance is associated with gallbladder dysmotility in nonobese, nondiabetic humans [88]. Therefore, insulin resistance, even in the absence of obesity, may lead to gallbladder sludge and stone formation, either by causing gallbladder dysmotility or by altering biliary lipid secretion. Insulin resistance may be a surrogate for other, undefined pathophysiologic mechanisms that lead to gallstone formation rather than a direct underlying cause [42]. For example, other, undefined abnormalities in lipid metabolism may lead to gallstone formation and also lead independently to insulin resistance.

Diabetics have been shown to have an increased cholesterol saturation index in the bile compared with nondiabetics [89]. In addition, gallbladder fasting volumes have been shown to be larger, and gallbladder motility is diminished in non-insulin-dependent diabetics compared with nondiabetics [90, 91]. Hyperinsulinemia is characteristically found in persons with non-insulin-dependent diabetes as a result of insulin resistance. Several authors have documented an association between hyperinsulinemia and an increased prevalence of gallbladder disease [32, 35, 36, 92]. Both hyperglycemia and euglycemic hyperinsulinemia have been shown to inhibit CCK-stimulated gallbladder motility [84]. Hyperinsulinemia may also be a key factor in these observations because insulin regulates the Na⁺-K⁺ pump, which may adversely affect the ionic and osmotic homeostasis of smooth muscle cells including gallbladder myocytes [93]. The Na⁺-K⁺ pump of presynaptic nerve terminals is also regulated by insulin [93]. Moreover, decreased Na⁺-K⁺ pump activity can result in increased intracellular Na⁺, which in turn increases the Na⁺-Ca⁺⁺exchange, thereby increasing intracellular calcium. Increased intracellular calcium will alter both smooth muscle tone and release of neurotransmitters. Moreover, we have demonstrated that gallbladder myocytes from obese, diabetic mice are foreshortened and respond poorly to cholecystokinin (CCK) [94]. Thus, the abnormal gallbladder emptying seen in response to a test meal in the nondiabetic lean subjects investigated in this study may be related to a state of relative hyperinsulinemia as a result of insulin resistance. Insulin resistance and/or diabetes may also affect alterations in the density or sensitivity of acetylcholine or CCK receptors or prevent neurotransmitters from accessing their receptors. Sugars can react nonenzymatically with amino groups in proteins, lipids, and nucleic acids to form advanced glycation end products [95, 96]. These products are thought to have many effects, including covalent cross-linking of collagen and protein matrix [96]. The cross-linking of the matrix may lead to stiffening of the gallbladder wall itself, limiting its contraction, or may impair CCK egress through blood vessel basement membranes, preventing CCK interaction with neural or myocyte receptors.

2.1.4.3 Obesity

One potential explanation for the differences in gallbladder dynamics observed between obese and lean individuals may be due to the differences in serum and, perhaps, gallbladder wall lipids [97–99]. As a result, the cholesterol/phospholipids ratio increases and membrane fluidity decreases. Smooth muscle cells from human gallbladders with cholesterol stones have increased cholesterol and cholesterol/phospholipids ratios [97]. In addition, this group has demonstrated decreased membrane fluidity in these gallbladders. Therefore, these obese subjects with high serum total and LDL cholesterols as well as triglycerides may also have high gallbladder lipids, which may play a role in gallbladder function.

2.1.5 Clinical Presentation

Symptoms of gallstone disease during pregnancy are the same as in nonpregnant patients [17, 20]. The following features suggest biliary colic or acute cholecystitis:

· History of previous episodes or known gallbladder stones

· Nausea, dyspepsia, and intolerance of fatty foods

· Vomiting (50 % of patients)

· Abdominal pain in the right hypochondrium or epigastrium

· Pain radiating to the back around the right scapula

During physical examination there are several signs that can be elicited:

· Direct abdominal tenderness in the upper right quadrant. Due to different locations of the enlarging uterus and gallbladder, there is no significant blunting of symptoms.

· Murphy’s sign (cessation of inspiration during palpation of inflamed gallbladder) may be elicited less frequently in pregnant patients and are indicating acute cholecystitis [100].

· Abdominal muscle rigidity is present only with gallbladder perforation and biliary peritonitis. A rigid abdomen with rebound tenderness remains a valid indicator of peritonitis during pregnancy, but abdominal wall laxity in late pregnancy might mask the classical signs of peritonitis [101, 102].

· Fever and tachycardia are variably present and are not sensitive signs. The more advanced the disease, the more pronounced these symptoms and signs are.

2.1.6 Differential Diagnosis

There are many diseases that can present with the pain in the upper right quadrant. But with adequate history taking and clinical examination, most of them could be easily excluded. Complete list of differential diagnoses is found in Table 2.1.

Table 2.1

Differential diagnosis of right upper quadrant pain

Diaphragmatic myocardial infarction

Acute fatty liver in pregnancy

HELLP syandrome

Preeclampsia-eclampsia

Acute appendicitis

Acute hepatitis

Pancreatitis

Symptomatic/perforated peptiac ulcer

Pyelonephritis

Nephrolithiasis

Herpes zoster

Hepatitis

Perihepatitis (Fitz-Hugh-Curtis syndrome)

Hepatic vascular engorgement

Hepatic hematoma

Hepatic malignancy

Choledocholithiasis

Cholangitis

Rib fracture

Shingles

Pneumonia

Pulmonary embolus or infarct

Pleural effusion

Radiculopathy

Colon cancer (hepatic flexure)

2.1.6.1 Hyperemesis Gravidarum

Hyperemesis gravidarum can be defined as persistent vomiting associated with weight loss greater than 5 % of prepregnancy body weight and ketonuria [103]. It occurs in 0.5–1.5 % of pregnancies [103, 104] and is more common in nulliparous in contrast to multiparous women that are prone to cholelithiasis and cholecystitis [105]. Hyperemesis gravidarum leads to dehydration, and hospitalization is usually required for intravenous fluid therapy. Indeed, the necessity of hospital admission is commonly included in the definition of hyperemesis gravidarum [105]. This disorder presents early in the first trimester of pregnancy, with intractable nausea and vomiting. As a rule, symptoms resolve before the second part of pregnancy, regardless of therapy. Jaundice is uncommon and, if present, is not associated with abdominal pain or fever. Abnormal liver tests are common, but the exact frequency is unknown. A frequency of 16 % has been found in a retrospective study [106]. The most striking abnormality is elevation of aminotransferases with ALT levels exceeding AST levels as it is usual in nonalcoholic and noncirrhotic liver diseases [106]. ALT levels are variable, and hepatitis serologies are useful in the differential diagnosis especially when ALT levels are above 10 times the upper normal limit or when it is the first affected pregnancy. Associated drug-liver injury should be systematically searched, especially when jaundice is present. Liver biopsy is not needed to confirm the diagnosis. Pregnancies complicated by hyperemesis gravidarum have been associated with transient hyperthyroidism, which usually requires no specific therapy [105].

2.1.6.2 Perihepatitis (Fitz-Hugh-Curtis Syndrome)

Perihepatitis (Fitz-Hugh-Curtis syndrome) is the result of early bacteremic or retroperitoneal lymphatic dissemination of Chlamydia trachomatis or gonococcal pelvic infection [107]. The syndrome is most frequently seen in young women and is more common in the second and third trimesters and puerperium. Inflammation in the right upper quadrant produces perihepatic adhesions. Classically, there is sudden onset of sharp right upper quadrant pain, often pleuritic in quality. Nausea and hiccups are occasionally noted. Physical findings include tenderness under the right costal margin, occasional hepatic friction rub, and fever. Pelvic examination may be normal or may reveal signs of cervicitis or pelvic inflammatory disease. Liver function tests and cholecystogram may be transiently abnormal. The diagnosis is suggested by a history of recent pelvic infection, but the syndrome can be a sequela of latent or asymptomatic infection. The diagnosis is further supported by isolation of gonococcus on cervical culture and improvement on appropriate antibiotics [107]. It is important to exclude other etiologies because there is no specific diagnostic marker of this syndrome.

2.1.6.3 Costal Margin Pain

Costal margin pain and tenderness due to stretching of muscular attachments are not uncommon during pregnancy, and consequently the pain of biliary disease may be brushed aside as insignificant.

2.1.7 Diagnosis

2.1.7.1 Laboratory Findings

If there is clinical suspicion of acute biliary colic or cholecystitis after history taking and clinical examination in primary care, the patient should be sent to hospital for further evaluation. The difficulty in establishing the diagnosis is physiological leukocytosis up to 20,000/ml at labor in normal pregnancy and is not diagnostic. Only granulocytosis (left shift) indicates bacterial infection. C-reactive protein (CRP) is elevated and significant, and bacterial infection is expected if values over 40 are expected. The erythrocyte sedimentation rate (ESR) is physiologically elevated and thus is a less reliable monitor of inflammatory activity during pregnancy [108]. Serum bilirubin and transaminases may be elevated, as in nonpregnant women. Serum alkaline phosphatase is less helpful because estrogen causes its elevation (levels may double during normal pregnancy). Serum amylase levels are elevated transiently in up to 33 %.

2.1.7.2 Transabdominal Ultrasound

Successful visualization of the gallbladder itself in pregnancy is 97 % [29, 109]. The remaining 2.5 % of the patients, whose gallbladder could not be visualized initially, were diagnosed as having chronic cholecystitis with contracted gallbladder and thickened gallbladder wall on the rescan [29, 110]. Gallbladder sludge, a mixture of cholesterol and calcium bilirubinate crystals in the bile, can be detected ultrasonographically and represent a precursor stage potentially leading to the formation of actual gallstones [18]. It is sonographically visible as the accumulation of the bile and is reported in as many as 30 % of gravid patients with a similar proportion of women affected by the postpartum period [31]. Sonography performed in early pregnancy has confirmed the physiological expansion of the gallbladder and the accumulation of stones, debris, and bile. Ultrasound findings of the gallbladder in healthy pregnant women show a decrease in the emptying rate and an increase in residual volume after emptying. Gallstones are detected with accuracy of 95–98 % [111]. If gallstones are an isolated finding, then only biliary colic is present in patients with pain in the right upper quadrant. If acute cholecystitis is present, there are several characteristics present on ultrasound:

· Gallbladder calculi

· Wall thickening (>3 mm)

· Pericholecystic fluid

· Sonographic Murphy’s sign (focal tenderness under the ultrasound transducer positioned over the gallbladder)

Another finding that should be ruled out is common bile duct (CBD) obstruction because confirmation or suspicion changes therapeutic approach. It is suspected or confirmed if these characteristics are present:

· CBD over 7 mm in diameter

· Dilatation of intra- and extrahepatic ducts

· Gallbladder calculi smaller than cystic duct diameter

Ultrasound and magnetic resonance cholangiopancreatography (MRCP) may be particularly helpful in differentiating choledocholithiasis from intrahepatic cholestasis of pregnancy because the clinical and biochemical presentation of these two entities overlap [112].

A patient with abdominal pain from a suspected urinary tract calculus disease is better evaluated with ultrasound. Although the diagnosis of calculus is complicated by the presence of pregnancy-related hydronephrosis, addition of color Doppler imaging of the bladder to identify ureteral jets and transvaginal ultrasound to detect stones in the distal third of the ureter has helped in the evaluation [113].

2.1.7.3 Endoscopic Ultrasound

Endoscopic ultrasound (EUS) is rarely used as a definitive diagnostic tool for identification of stones in the distal CBD. Mostly it is used before ERCP for therapeutic strategy or as confirmatory tool after sphincterotomy stone extraction.

2.1.7.4 Magnetic Resonance Cholangiopancreatography

MRCP is indicated if dilatation of intrahepatic and extrahepatic ducts (Fig. 2.2) is present on abdominal ultrasound (see “Common Bile Duct Stones, Cholangitis, and Biliary Pancreatitis”). It can also differentiate between common bile duct stones and external compression due to Mirizzi syndrome (Fig. 2.3). Additionally, because the pancreas is frequently obscured by overlying bowel gas during ultrasound evaluation, MRCP can often better evaluate the pancreas for edema, the pancreatic duct for obstruction in the setting of gallstone pancreatitis, and the peripancreatic tissues for inflammation.

Fig. 2.2

Choledocholithiasis in a patient in the second trimester of pregnancy. Magnetic resonance cholangiopancreatography (MRCP) shows distal common bile duct obstruction due to a calculus (arrowhead), gravid uterus (curved arrow), and physiological right hydronephrosis and hydroureter (arrows) [114]

Fig. 2.3

A 27-year-old female at 36 weeks gestation who had obstructive jaundice and right upper quadrant pain. (a) Coronal T2-weighted single-shot fast spin-echo image shows distended gallbladder with cholelithiasis (arrow) and intrahepatic biliary dilatation (arrowheads). (b) Thin-slice MR cholangiopancreatography (MRCP) images showed that the distal common bile duct is normal in caliber, and the common hepatic duct was compressed by the inflamed and distended gallbladder. Maximum intensity projection reconstruction of thin-slice MRCP images demonstrates the distended gallbladder fundus compressing the proximal common bile duct (arrow), causing intrahepatic biliary dilatation, and a normal caliber distal common bile duct (arrowheads), consistent with Mirizzi syndrome [115]

The European Society of Urogenital Radiology (ESUR) established its Contrast Media Safety Committee in 1994. Table 2.2 presents the ESUR guidelines for the use of iodinated and gadolinium contrast media during pregnancy [116].

Table 2.2

ESUR guidelines for the use of iodinated and gadolinium contrast media during pregnancy and lactation

	Iodinated agents	Gadolinium agents
Pregnancy	(a) In exceptional circumstances, when radiographic examination is essential, agents may be given to the pregnant female	(a) When MR examination is necessary, agents may be given to the pregnant female
Pregnancy	(b) Following administration to the mother, thyroid function should be checked in the neonate during the first week	(b) Following administration of agents to the mother, no neonatal tests are necessary
Lactation	Breastfeeding may be continued normally when agents are given to the mother	Breastfeeding may be continued normally when agents are given to the mother
Pregnant or lactating mother with renal impairment	No additional precautions are necessary for the fetus or neonate. Follow ESUR guidelines for contrast media administration when renal function is impaired	No additional precautions are necessary for the fetus or neonate. Follow ESUR guidelines for contrast media administration when renal function is impaired

It should be noted that using modern diagnostic modalities for correct diagnosis of biliary origin of acute abdomen during pregnancy is very high. It can be presented as index of wrong diagnosis:

Index of wrong diagnosis (%) = provisionally diagnosed cases – confirmed cases × 100 provisionally diagnosed cases

For acute appendicitis in pregnancy, it is around 40 % and only 8.5 % for acute cholecystitis in pregnancy [117].

2.1.8 Treatment

2.1.8.1 Historical Perspective

Discussion of this pathology dates from 1890 when Robert Barnwell Rhett, Jr. (Fig. 2.4), wrote of a cholecystotomy on a pregnant woman. In 1893, Boorse mentioned a case of pregnancy complicated by the expression of biliary calculi. In 1893, Willien reported a cholecystotomy in the 3rd month of pregnancy. In 1895, Vineberg reported two cases of cholecystitis in the puerperium and said that he was able to find but four cases previous to his article. In 1895, Davis AB reported a case of cholecystectomy in the 7th month without interrupting pregnancy. Ploger in 1910 gave a record of 42 cases, of these 22 had gallstone colic in the puerperium, and in 19 of these it was the first attack. The remaining 20 attributed the beginning or increase in the severity of their gallstone pains to some pregnancy [119]. Peterson collected 25 cases complicating pregnancy including his own case and ten complicating the puerperium. These are cases proved by operation or through finding of calculi in the stool [3]. Otherwise he could have included 20 cases of Huchard and 51 of Berline-Herwig. Since 1910, Green reported two cases following miscarriage [120]; Branson, four cases [121]; Audebert, one case; and Graham, six cases, a rather meager list when the frequency of gallstone operation is considered [122].

Fig. 2.4

Robert Barnwell Rhett Jr. (1853–1901), President of the Medical Society of South Carolina and Dean of the Charleston Medical School, performed first cholecystotomy on a pregnant patient [118]

This relationship is suggested by the relative frequency of gallstones in para women to the occurrence in men on the one hand and virgins or sterile women on the other. Ochsner reported 50 cases in which there were four times as many females as males. Kehr reports a series of 720 laparotomies upon 655 patients of which 536 were women and 119 men. Mayo makes the statement that gallstones occur three times more frequent in women. Schroeder says that 90 % of women operated upon have borne children. Peterson found that 75 % had children. Grube proves that of 657 cases of gallstone, 613 cases had children. There were 183 married and 33 unmarried or sterile women [123]. Authur’s collection tends to the same conclusions that there is sufficient evidence positively to state that pregnancy produces changes in the biliary system which favors the invasion of microorganisms. Grube concisely states that these changes are (1) stasis of the bile, (2) increase of cholesterin in the bile, (3) protein decomposition, (4) cell desquamation, and (5) hyperemia of the mucosa of the bile ducts [123]. He agrees with Hofbauer that cholelithiasis is due to the above processes plus bacterial infection and says that as a result of investigations of the livers of women who have died during or just before or after labor all of the above-named conditions are characteristic of pregnancy [124]. M’Nee says that on the basis of investigation carried on by himself and Ashoff, some forms of stones originate in the aseptic and uninflamed bladder. M’Nee believes there is a definite relationship between gallstones and pregnancy taking into consideration that the most common age of onset corresponds to the period of childbearing and the number of cases of gallstones in women who have borne children [125]. He believed that the pressure of the uterus causes stasis. He also found that the cholesterme contents of the bile were greatly increased in five women who died during, just before, or after labor. These findings coincide with those of Grube. Peterson says that in pregnancy, it is significant that in nearly one-third of the cases the period of onset is at that time of gestation when the uterus is approaching the level of the umbilicus, sending the intestines upward, and when the growing fetus is beginning to hamper the eliminative powers of the liver. In the puerperium in one-half of the cases, the attacks occurred during the first 7 days postpartum suggesting traumatism of the biliary passages during labor. He quotes Vineberg who says the great eliminative processes going on at this period, the change in the intra-abdominal pressure, and the forced rest in bed with the attendant constipation all favor these attacks.

The occurrence of jaundice is most important as its presence materially affects the uterine contents, and the nearer to term, the greater the possibility of exciting labor. Peterson found that in 15 cases of his series of 25, jaundice was present. He seems to prove by a study of the cases with reference to the location of the gallstones and jaundice that pregnancy can produce jaundice in a constitutional way without the aid of obstruction in the shape of calculi. Peterson’s bibliography shows that in this country, IUoway, 1889, reported a case of icterus gravidarum.

The operative mortality is 13 %, for 23 cases [3]. This is influenced by the complications of common duct involvement and the degree and extent of inflammatory processes. The condition of pregnancy seems to have but little effect. The deaths reported were from rupture of the gallbladder, cases of empyema, or extensive or prolonged operative procedures required by the conditions found. The occurrence of miscarriage is dependent upon the pathology present more than upon the effect of the operation. In Peterson’s cases, two started before operation and three after. All of the latter were cases of extreme infection with chills, fever, and jaundice. Graham reports a case in the 6th month in which the gallbladder was ruptured by a blow on the abdomen. At operation, three gallstones were found in the abdomen, one in the gallbladder and two in the cystic duct. He gives detailed histories of four others, which were operated upon during pregnancy, all of whom went to term. One other case refused operation and died 2 years later from complete obstruction of the common bile duct. Luiz in discussing Graham’s paper describes a case with gallbladder rupture during labor. The patient died of general peritonitis, and postmortem, 250 gallstones were found scattered through the abdominal cavity. There is evidence to believe that operation on the gallbladder in which complications are not marked has but little effect in producing abortion and that recovery may be expected as in the ordinary case. This fact justifies us in advising removal at any time when the symptoms become frank and at any time during the pregnant state, especially when a history of frequent and recurrent attacks is obtained. The tendency of cholecystitis to subside for long periods is to be remembered so that in mild and short attacks operation may be postponed until after delivery with a minimum risk.

2.1.8.2 Conservative Treatment

Interests of both the mother and the fetus must be considered in therapy during pregnancy. Usually, these interests do not conflict, because what is good for the mother is generally good for the fetus. Sometimes, however, maternal therapy must be modified to substitute alternative but safer therapy because of concerns about drug teratogenicity (e.g., substituting a histamine two receptor antagonist for misoprostol, an abortifacient that is contraindicated during pregnancy) [126, 127]. Rarely, the maternal and fetal interests are diametrically opposed, as in the use of chemotherapy for maternal cancer, a therapy that is potentially life saving to the mother but life threatening to the fetus [128]. These conflicts raise significant medical, legal, and ethical issues.

The first available large studies on pregnancy-related gallbladder disease showed fetal loss of 12–15 % [3, 129]. A study by Greene et al. noted fetal loss of 24 % after cholecystectomy [130]. If one of four patients with fetal loss (of total 17 patients) is excluded due to postoperative peritonitis (cholecystectomy and appendectomy were performed during initial operation), then the fetal rate is 18 %. In that time 10 % of all pregnancies ended in abortion [131, 132]. Greene et al. also concluded that the causal relationship to surgery is not clear, because of the varied time lapse between surgery and abortion. Even in 1997 a study in British Journal of Surgery recommended conservative treatment [10].

It is known that there is significant difference between biliary colic and acute cholecystitis. The diagnosis of biliary colic requires right upper quadrant pain and gallstones documented by ultrasound in the absence of ultrasonographic signs of gallbladder inflammation. Traditionally, medical treatment is almost always used first especially in biliary colic. The therapy could be initiated or continued by primary care physician but only after the consultation with the gastroenterologist or abdominal surgeon. This recommendation is due to the fact that even after biliary colic, there were 28 % of premature contractions [133] and in the study by Dixon et al. even three fetal deaths [134]. Initially, the patients should be seen every day for the first several days then once a week. The patients with significant comorbidities should be hospitalized even for medical therapy.

Another traditional indication for medical therapy is to delay the cholecystectomy until the second trimester because spontaneous abortion rate after open cholecystectomy is 12 % in the first trimester and 5.6 % in the second trimester [135]. On the other hand, delay of surgery until the second trimester in patients with symptomatic gallstone disease during pregnancy may lead to further complications of gallstone disease such as acute cholecystitis and gallstone pancreatitis, risk of maternal malnutrition, and reduction in fetal growth rate caused by lack of maternal oral intake leading to higher spontaneous abortion rates and preterm labor [20, 136–138]. In addition, the rates of preterm labor and premature delivery are 0 % during the second trimester compared to 40 % in the third trimester [135].

Total Parenteral Nutrition

Total parenteral nutrition has been used as an effective alternative to surgical treatment of chronic cholecystitis in the second and third trimesters [139]. A study of ten pregnant patients with severe hyperemesis managed with parenteral nutrition found no adverse effect on maternal weight gain and fetal growth [140]. The growing fetus requires essential fatty acids and amino acids for development and maturity of vital organs like the brain and lungs. Parenteral nutrition provides a viable means for the fetus to receive these supplements. There has been recent trend toward the use of peripherally inserted central catheters (PICC) because of lower rate of major complications and relative ease of insertion compared to central venous catheters [141]. PICCs should always be considered particularly in high-risk populations like pregnant women. Several studies, however, have shown a higher rate of minor complications like thrombophlebitis in patients with PICCs [142, 143]. PICC insertion is highly operator dependent, and lowest complication rates have been reported in the most experienced centers [144].

Diet

Low fat diet is essential, minimizing intake of cholesterol-rich foods like foods of animal origin, pork and red meat, with slow reduction of body weight and by indulging in more fruits and fiber intake. Potent natural remedies minimize the abnormal concentration of bile acids (acids that help in fat digestion), keep cholesterol level in check, heal inflammation, clear out toxins, and eliminate excess of lipids from the body.

Beetroot juice is high in fiber and has carotenoids and flavonoids that reduce the cholesterol from entering the gallbladder and thus stops the formation of solid pear-shaped gallstones. It has betaine that supports liver function and tames high sugar level.

Apple juice has unique compound – malic acid – that helps in softening the gallstones and disintegrates.

Mix of raw juice comprises of carrot juice, cucumber juice, and beetroot juice. The maximum concentration should be of carrot juice. Cucumber juice has silica that prevents overformation of calcium stones in the body.

Analgesia

Nonsteroidal anti-inflammatory drugs are the first choice treatment for symptomatic relief:

· Ibuprofen 400–600 mg three times a day

· Naproxen 250 mg up to four times a day

· Diclofenac 25–50 mg up to three times a day

Increased risks of miscarriage and malformations are not proved with NSAID use in early pregnancy. Conversely, exposure to NSAIDs after 30 weeks gestation is associated with an increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. NSAIDs should be given in pregnancy only if the maternal benefits outweigh the potential fetal risks, at the lowest effective dose, and for the shortest duration possible. If indicated, ibuprofen is the preferred agent.

Paracetamol and weak opioids such as codeine may be used as additional treatments to help control the pain. They are also useful if nonsteroidal anti-inflammatory drugs are not tolerated or are contraindicated as in patients with peptic ulceration.

Anticholinergic Antispasmodics

Dicyclomine (Bentyl) is classified as FDA type B drug which means that it could be used in pregnancy, if clearly needed. It passes into breast milk and could affect a nursing infant. Dicyclomine can suppress the production of breast milk in nursing mothers.

Antibiotics

The US Food and Drug Administration has categorized all antibiotics according to the risks associated with their use in pregnancy. Two categories are important:

· Category A: studies in pregnant women do not demonstrate any risks to the mother or fetus.

· Category B: while animal studies show no risk, human studies are inadequate or animal toxicity has been noted, but the studies on humans show no risk

There are no antibiotics in category A. In category B are penicillins and cephalosporins. The first-line treatments are ampicillin and sulbactam or cefoxitin/cefuroxime.

There is no consensus on the duration of antibiotic use. The most precise method is to use it until the patient becomes afebrile and does not show evidence of leukocytosis or elevated CRP.

Ursodeoxycholic Acid

Ursodeoxycholic acid, a naturally occurring bile acid agent, can dissolve gallstones by changing the composition of the bile, and it has been used in nonpregnant patients for this indication. Although ursodeoxycholic acid has been administered in pregnancy in the management of intrahepatic cholestasis, its safety and efficacy for the treatment of gallstones during pregnancy has not been established [145].

2.1.8.3 Percutaneous Biliary Drainage

Pregnant patients presenting with recurrent gallbladder colic during the first or third trimester or high-risk patients could be managed with percutaneous transhepatic gallbladder aspiration (drainage). Under ultrasound guidance and local anesthesia, a pigtail drainage tube is inserted through the liver and into the distended gallbladder. Essentially, it is recommended that the drainage tube should not be extracted until a fistula forms around the tube (around 2 weeks) in severe cases where changing of the drainage tube is necessary. Major disadvantages of this procedure are bile leakage, bile duct injury, and abdominal abscess [146]. Although the patients both delivered without neonatal complications and subsequently underwent LC postpartum, not enough data are available for recommending this approach routinely [147].

2.1.8.4 Operative Treatment

Recommendations for General Population

According to Tokyo guidelines for surgical treatment of patients with acute cholecystitis [148], there are several statements that should be followed in nonpregnant population. Randomized controlled trials in the open cholecystectomy era, comparing early surgery with delayed surgery in the 1970s–1980s, found that early surgery had the advantages of less blood loss, a shorter operation time, a lower complication rate, and a briefer hospital stay (level 1b) [28, 149–151] and (level 3b) [152]. Recent randomized clinical trials (level 1b) [153–157] have addressed the timing of and surgical approach to the gallbladder in patients with acute cholecystitis, and the results have indicated that laparoscopic cholecystectomy performed during the first admission was associated with a shorter hospital stay, quicker recovery, and reduction in overall cost of treatment compared to open cholecystectomy. Early laparoscopic cholecystectomy is now accepted to be sufficiently safe for routine use, because earlier reports of increased risk of bile duct injury (level 4) [158] have not been substantiated by more recent experience (level 1b) [154, 155, 157, 159, 160].

According to the Tokyo guidelines [148], acute cholecystitis has three grades related to severity of the disease:

· Mild (grade I): early laparoscopic cholecystectomy is the preferred procedure.

· Moderate (grade II): early cholecystectomy is performed. However, if patients have severe local inflammation, early gallbladder drainage (percutaneous or surgical) is indicated. Because early cholecystectomy may be difficult, medical treatment and delayed cholecystectomy are necessary.

· Severe (grade III): urgent management of organ dysfunction and management of severe local inflammation by gallbladder drainage and/or cholecystectomy should be carried out. Delayed elective cholecystectomy should be performed later, when cholecystectomy is indicated.

Indications in Pregnant Population

The most common cause of biliary surgery during pregnancy is repeated biliary colic in 37–70 % of cases, followed by acute cholecystitis in 20–32 %, choledocholithiasis in 7 % and acute biliary pancreatitis in the remaining 3 % of cases, and olecystitis with 32 % of cases [10, 161]. In contrast to the generally favorable published fetal-maternal outcomes following cholecystectomy during pregnancy, conservative medical management of symptomatic cholelithiasis in pregnant women often leads to suboptimal clinical outcomes. Maternal illness may pose a greater threat to the fetus than surgery. Three published studies have shown the readmission rate for pregnant patients with biliary tract disease to be greater than 50 % in patients managed conservatively, and 16 % of the patients had either spontaneous abortions or preterm births [20, 134].

Recurrence rate during pregnancy is 31–38 % for symptomatic cholelithiasis, and patients in the second trimester had the highest rate of relapse, followed with first and then the third trimester [133, 162]. There are reports with even higher recurrence rates (40–92 %) after conservative treatment confirming that it is trimester dependent [136, 163, 164]. Also, pregnant patients often had more severe disease at the time of relapse [133]. Swisher et al. [164] reported an average of 2–6 relapses during pregnancy; Elamin et al. reported an average of 4 ± 1.3 admissions for relapse [165]; and Lu et al. reported 1-3 additional admissions, each lasting 5–8 days [133]. Patients with symptomatic cholelithiasis at first presentation with each subsequent relapse had more severe disease than the previous episode [133]. The most common causes of biliary surgery during pregnancy were repeated biliary colic in 37.5–70 % of cases, followed by acute cholecystitis in 20–32 %, and choledocholithiasis in 7–17 % [10, 161]. If the disease progresses to AP, the rate of fetal loss may be increased. Jouppila et al. reported three episodes of fetal death in a series of eight pregnant patients with AP [166]. However, not all of their patients had gallstones. Another important observation is that the majority of patients with complicated gallstone disease who do not undergo antepartum cholecystectomy have recurrent postpartum symptoms often within 3 months postpartum. When appropriate, physicians should advocate for antepartum or early postpartum cholecystectomy to minimize symptom recurrence and unplanned hospitalizations [167].

Compared with patients managed surgically, nonoperative management was associated with a significantly higher rate of labor induction and preterm delivery requiring neonatal intensive care [133]. Also a recent report suggests that fetal death rate is higher after conservative treatment than after laparoscopic cholecystectomy for symptomatic benign biliary disease [163]. A spontaneous abortion rate of 12 % is associated with the nonoperative management of symptomatic cholelithiasis in the first trimester [5]. The effects of any medical intervention on fetal mortality have to be considered in the context of certain preexisting background risks that are common to all pregnancies. These include a 3 % risk for birth defects, 15 % for miscarriage, 4 % for prematurity, 4 % for growth retardation, and 1 % for mental retardation or neurological developmental problems.

Surgical advances made over the last two decades shifted the management toward a multidisciplinary and minimally invasive approach. Interventional radiology, endoscopic retrograde cholangiography (ERCP), and laparoscopic surgery are commonly employed, but their timing and indications need to be properly defined. The advantages of operative treatment could be summarized in the following:

· Lower consumption of medications

· Lower hospital stay and number of hospitalizations

· Lower incidence of potentially life-threatening complications:

· Perforation

· Biliary sepsis

· Peritonitis

· Lower incidence of gallstone pancreatitis

· Lower incidence of spontaneous abortions, preterm labor, and preterm delivery

Open Versus Laparoscopic Cholecystectomy

On the basis of four retrospective studies comparing laparoscopic cholecystectomy (LC) with open cholecystectomy (OC), it is difficult to recommend any particular treatment because these studies did not specifically look at the physiological effects of pneumoperitoneum or CO₂-induced acidosis on the fetus during LC or the effects of uterine manipulation during OC [15, 135, 168, 169]. These studies did not show any significant difference in maternal and fetal outcome. There were 6.74 % preterm deliveries in the LC group compared with 2.90 % in the OC group (p = 0.27). One fetal death occurred in the LC group compared with two in the OC group (p = 0.41). The fetal death reported by Cosenza et al. occurred on postsurgical day 6. This woman underwent LC converted to OC for gallstone-induced AP in the 14th week of gestation. In a report by Barone et al. a 27-year-old woman died from postsurgical hemorrhage after undergoing LC in the 20th week of gestation. The source of bleeding was not identified. The other fetal death in this series occurred 4 weeks after surgery after the mother underwent OC in the 16th week of gestation. The absence of morbidity and mortality with the LC [15, 16] or just minor mortality including several wound infections [161] is stated in several studies. The largest study estimated a rate of 7 % for fetal mortality and by-trimester recurrence rates of 55, 55, and 40 % for nonoperative management. The rate of emergent surgery following nonoperative management was calculated to be 19.5 %. For LC the aggregate data suggest a fetal death rate of 2.5 % [163]. It should be noted that the analysis included 277 patients, and only one fetal death in the second trimester occurred.

LC in pregnant women provides all of the advantages of laparoscopic surgery – such as significantly reduced hospitalization, decreased narcotic use, and quicker return to a regular diet [135]. Other advantages of LC include less manipulation of the uterus and detection of other pathology that may be present [168]. It also decreases the possibility of postoperative deep vein thrombosis because of improved early mobility in such patients.

As in nonpregnant population, if LC cannot be completed successfully, conversion to OC is mandatory [170].

Contraindications for Laparoscopic Surgery

Contraindications for laparoscopic surgery in pregnancy are principally the same as in nonpregnant population [171]:

Absolute Contraindications

· Hypovolemic shock, massive bleeding, or hemodynamic instability

· Severe cardiorespiratory disease

· Uncontrolled coagulopathy

Relative Contraindications

· Peritonitis

· Portal hypertension

· Multiple previous procedures/extensive intra-abdominal adhesions

2.1.8.5 Specific Considerations

Symptomatic Cholelithiasis in Diabetic Pregnant Patient

The serious consequences of cholelithiasis in diabetics are well established [172–174]. There is only one article published with the analysis of diabetic subgroup of pregnant patients with symptomatic cholelithiasis. A total of 35.8 % of the patients in this study had established diabetes mellitus. This is greater than the finding in general population of gallstone patients, among whom diabetes mellitus is only 11.1 % [172]. This may suggest that patients with diabetes have a greater tendency to symptomatic gallstones in pregnancy. A more plausible explanation is that diabetic patients, educated to the tendency of diabetes mellitus to exacerbate the seriousness of many illnesses and already accustomed to the hospital, sought medical attention more often than the nonpregnant patients. The reported prevalence of diabetes mellitus in the Saudi Arabian population varies from 4.1 to 7.2 % [175, 176]. The recommendation is to perform LC during pregnancy even if biliary colic in such patients is present.

Cholecystitis in IVF Pregnancy

The number of IVF pregnancies is constantly increasing (see “Acute Appendicitis”); therefore, it is expected that the number of cases with acute cholecystitis during IVF pregnancy will also increase, especially because patient during assisted reproduction are exposed to higher doses of female hormones which are known risk factors for the genesis and progression of biliary sludge and stones. Currently there is only one case report of laparoscopic cholecystectomy in a 16-week IVF pregnancy [177]. There were no intra- or postoperative complications, and the baby was born normal with APGAR 10/10 in the 39th week of pregnancy.

Spontaneous Biliary Tract Perforations

Biliary tract perforations are unusual causes of peritonitis in pregnancy. The symptoms and signs are often nondiagnostic, especially during pregnancy, and diagnosis may be delayed with possible fatal consequences [178]. Gallbladder or common bile duct (CBD) perforations as a cause of peritonitis in pregnancy have been rarely reported in literature, and their exact incidence in pregnancy is not known.

Gallbladder Perforation

Even when the gallbladder perforates, the usual outcome is a local abscess, on account of the adhesion that forms between the gallbladder, the greater omentum, and the parietal peritoneum [179]. Although gallbladder perforation has been reported to occur in 3–10 % cases of acute cholecystitis in adults, free gallbladder perforation into the peritoneal cavity is even rarer, occurring in only 0.5 % of the patients undergoing conservative management for acute cholecystitis. Risk factors for gallbladder perforation in adults include age greater than 60 years, immunosuppression, steroid use, and severe systemic disease [178].

The initiating event in majority of these patients is impaction of the stone leading to epithelial injury and ischemia due to distension of the gallbladder. The site of perforation is either at the fundus, which is farthest away from the blood supply, or less commonly at the neck from the pressure of an impacted stone [180].

Perforation of the Common Bile Duct

Spontaneous perforation of the CBD is even a rarer event in adults, with only 45 cases reported [178, 181]. Bile duct perforation is most commonly described in infants related to congenital biliary system anomalies. As early as 1882, Freeland [182] reported the first case of extrahepatic biliary system rupture in an adult (diagnosed at autopsy), an entity that was subsequently first described in pregnancy by Hogan in 1957 [183], and currently there are only nine case reports published in pregnancy [183–190].

Pathogenesis, Diagnosis, and Treatment

Although the pathogenesis of spontaneous biliary perforation in the adult is poorly understood, recognized mechanisms include the following: calculous perforation at the site of impaction; calculous erosion without impaction; increased canalicular pressure due to obstruction by tumor, stone, or spasm of the sphincter of Oddi; intramural infection; mural vessel infarction leading to mural necrosis; or rupture of a biliary tract anomaly such as cyst or diverticulum [189]. The obstruction leads to an increase in intraductal pressure. This leads to dilatation of the biliary tree and subsequent stasis and infection, ascending cholangitis, and thrombosis of intramural vessels. The end result is necrosis and perforation of the duct wall. One postulated cause is increased hemodynamic changes associated with higher pressure in the vena cava during pregnancy. Overall, 70 % of cases are related to calculi [188].

Since this condition is unusual during pregnancy, accurate diagnosis and treatment may be delayed resulting in perinatal morbidity and mortality. Abdominal paracentesis is helpful in diagnosis of biliary peritonitis. It is extremely difficult to diagnose it preoperatively, but free fluid in the abdomen with signs of acute abdomen and elevated liver function test should raise suspicion [187].

The surgical management of gallbladder perforation consists of cholecystectomy, copious irrigation, and drainage of the abdominal cavity [178]. Recommended treatment for CBD perforation includes cholecystectomy and decompression of the biliary tree in the form of CBD exploration with T-tube drainage in cases of small perforations. Roux-en-Y biliary-enteric anastomosis is indicated if the ductal disruption is large [189]. If CBD perforation is detected during diagnostic evaluation, endoscopic CBD stent placement followed by biliary surgery (if necessary) is indicated [191]. If general or hepatobiliary surgeon is not reachable in emergency setting, subhepatic drainage with several large diameter drains is recommended and the patient is transferred to adequate surgical facilities [187].

2.1.8.6 Surgical Procedures

Open Cholecystectomy

There are two skin abdominal wall incisions used as in nonpregnant population:

· Right subcostal incision

· Upper midline incision

Both incisions are well known and performed in standard fashion, and the technique could be found in any abdominal surgery textbook or atlas. As in any other operation during pregnancy, it is important to eliminate or minimize uterine manipulation to exclude the possibility of uterine contractions and possible preterm labor or abortion depending on the trimester of the operation.

Laparoscopic Cholecystectomy

At the beginning of laparoscopy, cholecystectomy during pregnancy was considered as a relative contraindication, mainly because of the lack of knowledge of the effects of CO₂ to the fetus. Fear of surgical treatment was based on the potential risk of abortion or malformations if done during the first trimester or preterm labor when done in the last one. Direct uterine trauma, decreased uterine blood flow due to the pneumoperitoneum, and toxic narcotics drugs were suggested as possible causes of fetal morbidity [192–194]. In Reddick and Olsen’s 1989 article [195], pregnancy was said to be a contraindication to LC. First published case of LC on a 27-year-old patient who was 31 weeks pregnant was in 1991 by Pucci and Seed [196]. Several series of laparoscopy for the management of cholecystitis have shown no negative side effects on fetal outcome [197–199].

Up to 2008 there are 277 reported cases of LC in pregnant patients in the English literature. The data from these reports are retrospective, uncontrolled, and unblinded and surely represent only a fraction of the pregnant women who have undergone LC. Nevertheless, these data provide the best evidence available to determine how to treat a pregnant woman with biliary tract disease [163]. Potential advantages of LC in the pregnant patient include decreased fetal depression due to lessened postoperative narcotic requirements, lower risks of wound complications, and diminished postoperative maternal hypoventilation [200]. A study by Barone et al. showed almost significantly lower incidence of premature contractions (p = 0.057) in LC compared to OC group [169]. The only significant differences between the LC and OC groups were that patients underwent laparoscopic surgery at a mean of 5 weeks of gestation earlier than those who had open procedures and the serum alkaline phosphatase was significantly higher in the open group. In a small case control study by Curet et al. 12 LC were compared with 11 OC. There were no spontaneous abortions or episodes of premature labor in the LC group and one preterm labor in the OC group [135].

Pneumoperitoneum

Despite the conventional dogma that the first and third trimesters are higher risk periods for LC, there have been no reported fetal deaths after LC was carried out in either of these trimesters. The use of LC for patients in the first trimester of pregnancy is controversial [201] because of the unknown effects of the CO₂ pneumoperitoneum on the developing fetus [202, 203], but no problems have been encountered in clinical series so far [204].

Limited published physiological data exist concerning fetal-maternal interactions during laparoscopy. As a general principle, when the fetal-maternal unit is stressed, the mother is “conserved” at the expense of the fetus. For example, the normally decreased maternal PaCO₂ during pregnancy may be important in assuring adequate transplacental CO₂ diffusion from the fetus to the mother for subsequent pulmonary excretion. CO₂ pneumoperitoneum may cause maternal and subsequent fetal hypercarbia, due to decreased maternal ventilation and increased transperitoneal CO₂ absorption by the mother. In a study of pregnant ewes by Hunter and Swanstrom [202], CO₂pneumoperitoneum induced progressive, albeit reversible, fetal hypercarbia, acidosis, and tachycardia when pneumoperitoneum pressures exceeded 15 mmHg. These effects were minimized by using low pneumoperitoneum pressures or by using nitrous oxide as the insufflation gas [202]. The potential deleterious effects of short-term fetal hypercarbia are unknown. However, in high-risk mothers prone to hypercarbia (e.g., chronic lung disease, massive obesity), precautions to decrease maternal hypercarbia by using low-pressure pneumoperitoneum (12 mmHg or less) or nitrous oxide as the insufflation gas might be considered. Nitrous oxide has been safely employed during gynecologic laparoscopy. Nitrous oxide requires the presence of either hydrogen gas or methane (such as from colonic origin) to be combustible during electrosurgical procedures [202].

Introduction of gas into peritoneum (closed cavity) has two immediate effects: (1) increase in intra-abdominal pressure and (2) gaseous exchange leading to equilibrium with gases in the blood [205]. Increased intra-abdominal pressure can decrease cardiac output by several mechanisms, including direct alteration of venous resistance in the inferior vena cava, total peripheral resistance, and mean systemic pressure [205]. Impaired venous return via compression of the inferior vena cava is of particular concern in the second half of pregnancy since the enlarged uterus can also limit venous return. The uterine compression of vena cava can be minimized by slight lateral positioning of the mother [206]. The CO₂ that is absorbed across the peritoneal surface first equilibrates within the bloodstream, then with longer operative time with the skeletal muscle, viscera, and finally bone. The patients who undergo a prolonged laparoscopic procedure are at risk of maintaining hypercarbia and acidosis postoperatively until all excess CO₂ is eliminated from the tissue.

Hypercarbia and respiratory acidosis can be monitored to some extent by capnography which measures end-tidal CO₂ concentration in the endotracheal tubes. If a rise in end-tidal CO₂ is detected, CO₂elimination via the alveoli can be increased using controlled hyperventilation. The limitation of capnography is that while it is sensitive, end-tidal CO₂ is not foolproof in estimating CO₂ arterial pressure. When ventilation-perfusion mismatch is present and the amount of ventilation is greater relative to perfusion, gas from such ventilation will contain less pCO₂ than the actual PaCO₂, resulting in falsely normal or low end-tidal CO₂ readings [207]. Similar discrepancy between end-tidal CO₂ and PaCO₂, and subsequent acidosis, has been demonstrated also in operative laparoscopy patients with compromised cardiopulmonary status [208]. For such patients, monitoring of arterial PaCO₂ and pH is preferable to limit the risk of hypercarbia and acidosis. The close monitoring of CO₂ is also important considering the potential direct effect of CO₂ in increasing the mean arterial pressure and total peripheral resistance index, leading to increased afterload which could limit cardiac output [209].

Limited studies of pneumoperitoneum in pregnant sheep have demonstrated increased fetal arterial blood pressure, tachycardia, and respiratory acidosis, which were only partially corrected with alteration in ventilator settings based on maternal capnography results [202, 210, 211].

Working pressures of CO₂ are recommended to be below 12 mmHg in order to prevent fetal acidosis [212]. Hunter et al. investigated the physiological impact of a CO₂ pneumoperitoneum in these clinical settings. They concluded that a CO₂ pneumoperitoneum created minimal impact on the patient and the fetus when using intra-abdominal pressure of 15 mmHg or less, also confirmed by others [202, 213, 214]. In accordance with Steinbrook et al. [204], some authors use a pneumoperitoneum of 10 mmHg – low enough to be in the safe range and high enough to gain adequate visualization for a safe procedure [47].

Third Trimester

When LC is necessary, the recommendation is to perform it in the second trimester. This is due to the belief that in the second trimester, organogenesis is complete and the risk of spontaneous abortion as seen in the first trimester and the risk of spontaneous labor as in the third trimester are significantly reduced in the second trimester [163, 215, 216]. The third trimester, however, poses certain potential difficulties mainly in terms of the diminished working space available owing to the enlarging uterus, the risk of injuring the uterus, and the perceived risk for excessive manipulation of the gravid uterus leading to preterm labor. The most serious complication of the uterine injury includes that of fetal loss owing to pneumoamnion resulting from inadvertent injury during Veress needle insertion for pneumoperitoneum [217]. A near-term gravid uterus makes an LC technically impossible, and near-term pregnancy is the only absolute indication for OC [12,142]. Specific problem poses patients with indication for elective or emergent Cesarean section. After Cesarean section, depending on the severity of cholecystitis, one can decide between open and laparoscopic operation and conservative treatment with elective cholecystectomy after 6 weeks.

In 1991, Pucci and Seed published a case report of a successful LC for a 27-year-old patient who was 31 weeks pregnant [196]. Furthermore, in one of the largest single institution series of 15 cases of the third trimester laparoscopic surgery, Affleck et al. reported a preterm delivery rate to be similar in both the LC and OC groups [218]. There were no fetal losses, uterine injuries, or spontaneous abortions in the LC group. In fact most of the reports in the literature suggest the safety of laparoscopic approach in pregnant women including the third trimester [163, 168, 215, 216, 219–224]. Some authors are publishing data about laparoscopy in the third trimester combining acute appendicitis and cholecystitis with excellent outcome [225]. It should be stressed that appendicitis and cholecystitis as specific pathologies have different influence on uterine irritability possibly because of different nature of local peritonitis and also due to different location (the appendix is in contact with the uterus). The upper gestational limit for laparoscopic surgery is not defined. Upadhyay et al. have shown that laparoscopic surgery up to 34 weeks can be performed [216]. For patients with potentially viable fetuses managed surgically, steroids were generally administered 24 h preoperatively to speed fetal lung maturation.

Open (Hasson) Technique

According to an NIH statement, patients in the third trimester of pregnancy should generally not undergo LC, because of the risk of damage to the uterus and the difficulty presented by the large and gravid uterus, which can obstruct safe access to the abdomen and gallbladder fossa [226]. Fatum and Rojansky suggest a gestational age limit of 26-28 weeks for laparoscopic surgery in general [193]. Although in the past Society of American Gastrointestinal Endoscopic Surgery (SAGES) recommended an open technique of initial port placement, in a revision of their guidelines (year 2007), they have suggested that the initial access could be safely accomplished by open (Hasson) technique, Veress needle, or optical trocar technique, the location of trocar placement being adjusted according to the fundal height, earlier incisions, and experience of the surgeon [227].

When Veress needle is used for initial insufflation, it could be safely carried out by inserting it in either the left or the right upper quadrant in the midclavicular line approximately 1-3 cm below the costal margin [216, 228]. It should be noted that there are two reports of Veress needle insufflating intrauterine cavity, resulting in CO₂ embolism [223, 229], and one during laparoscopic appendectomy, injuring the uterine wall with the mandrel of the 5 mm trocar. There was loss of a little amniotic fluid, but there was no severe bleeding. The remainder of the pregnancy was without complications [230]. After inserting a 5 mm trocar at this site, a 5 mm camera is then used to guide the insertion of the rest of the ports under direct vision [216].

The usual umbilical port for the camera is placed few centimeters cephalad beyond the fundus of the gravid uterus in the midline usually in supraumbilical position. The insufflation pressure is around 12–15 mmHg. A pressure of 15 mmHg should not be of concern as in the third trimester, as at times the uterine pressures can reach very high during spontaneous intermittent contractions [216]. Currently, optical trocars or the so-called Direct Vision Initial Ports (Opti-view, by Ethicon, Cincinnati, OH, USA; Visiport, by US Surgical, Norwalk, CT, USA) have become available. They can be used with or without pneumoperitoneum. These kinds of trocars are introduced under direct vision.

Laparolift

To eliminate the possible influence of CO₂ pneumoperitoneum on the fetus, some authors used the laparoscopic technique without the use of pneumoperitoneum [231]. This method is not well accepted in pregnant as in nonpregnant population.

Local Anesthesia

Local anesthesia with prolonged duration of action could be utilized in port sites for improved postoperative analgesia, which minimizes narcotic requirements after surgery.

2.1.8.7 Perioperative Management

Intraoperative CO₂ Monitoring

Intraoperative CO₂ monitoring by capnography should be used during laparoscopy in the pregnant patient (level III). Fetal acidosis with insufflation has not been documented in the human fetus, but concerns over potential detrimental effects of acidosis have led to the recommendation of maternal CO₂ monitoring [203, 232]. Initially, there was a debate over maternal blood gas monitoring of arterial carbon dioxide (PaCO₂) versus end-tidal carbon dioxide (ETCO₂) monitoring, but the less invasive capnography has been demonstrated to adequately reflect maternal acid-base status in humans [233]. Several large studies have documented the safety and efficacy of ETCO₂measurements in pregnant women [168, 193, 225] making routine blood gas monitoring unnecessary.

Fetal Heart Monitoring

Fetal heart monitoring should occur pre- and postoperatively in the setting of urgent abdominal surgery during pregnancy (level III). While intraoperative fetal heart rate monitoring (every 5 min) by surface ultrasound was once thought to be the most accurate method to detect fetal distress during laparoscopy, no intraoperative fetal heart rate abnormalities have been reported in the literature [11, 136]. Lu et al. found that external monitors of uterine contractions were variably effective in the insufflated abdomen [133]. This has led some to recommend only pre- and postoperative monitoring of the fetal heart rate as no increased fetal morbidity has been reported [168, 225].

Special monitoring precautions beyond those usually employed during general anesthesia – continuous maternal pulse oximetry, end-tidal CO₂, monitoring, electrocardiography, and pulse rate measurements, combined with frequent blood pressure measurements – have generally not been employed. Transabdominal monitoring of fetal heart rate is usually not technically feasible during laparoscopic surgery in advanced pregnancy. In high-risk pregnancy, transvaginal fetal monitoring can be employed [204]. In addition, in women predisposed to significant hypercarbia, changes in end-tidal CO₂ may lag significantly behind maternal PaCO₂. Frequent direct measurements of maternal PaCO₂ via an arterial catheter may be warranted [204].

Thromboprophylaxis

Many factors can alter postoperative coagulation changes. These include the type of operation performed [234] and the type of anesthesia [235]. Postoperative changes in cytokine level are affected by even more factors. They include the type of procedure and anesthetic technique or anesthetic agent used [236], the duration of operation [237], and the use of autologous or allogenic transfusion [238].

Caprini et al. [234] reported a marked hypercoagulable state after LC, as seen by an increase in the thromboelastographic index, on the first postoperative day compared with preoperative values. Other reports have documented a reduction in postoperative hypercoagulability after LC compared with after OC [239, 240]. Prisco et al. reported a significant increase in F1.2 levels after LC, but these levels were significantly lower than OC [240]. Conversely, other investigators have demonstrated no difference in postoperative hemostasis between laparoscopic and open surgery [241, 242], and fibrinogen levels increased and reached maximum levels at 72 h, but significantly less so after LC than after OC, while plasminogen levels decreased postoperatively without a significant difference between groups [243]. Laparoscopic surgery is associated with a lesser degree of thromboembolic complications despite pneumoperitoneum which, by reducing venous inflow toward the heart, promotes venous stasis of the legs and predisposes to deep venous thrombosis [244, 245].

In a nonrandomized trial, Shietroma et al. [243] compared TAT, F1, FIB, soluble fibrin, and D-dimer plasma levels until 72 h after surgery between patients assigned to open or laparoscopic cholecystectomy and found that levels of the aforementioned markers were significantly higher in the open surgery group than in the laparoscopic surgery group, implying significantly higher activation of coagulation and fibrinolysis in the open surgery group. Three other nonrandomized studies compared fibrinolytic activity between OC and LC and found insignificant differences between the two groups of patients [241, 242, 246].

Results of the study by Tsiminikakis et al. showed that open surgery, as compared with laparoscopic procedures, leads to activation of the clotting system of a higher degree than in the laparoscopic surgery group, implying thus greater thromboembolic risk for patients undergoing open surgery. Subclinical fibrinolysis was also more profound in the open surgery group. Although of a lower degree, hypercoagulability is still observed in patients undergoing laparoscopic surgery. This fact, combined with the pneumoperitoneum-induced venous stasis of the legs, explains the reduced, but not negligible, rate of thromboembolic complications after laparoscopic surgery. Therefore, routine thromboembolic prophylaxis (low-molecular-weight subcutaneous heparin, elastic compression stockings, intraoperative pneumatic stockings, and early postoperative patient mobilization) should be considered for patients undergoing laparoscopic surgery [247].

Gestational hormones, particularly estrogen, contribute to a mild hypercoagulopathy during pregnancy by increasing the synthesis of clotting factors [248]. Thromboembolic phenomena are also promoted by intra-abdominal vascular stasis resulting from compression by the enlarged gravid uterus. If a laparotomy can be avoided, recovery time is greatly reduced; thus, postoperative complications due to immobilization, such as deep vein thrombosis and pulmonary embolism, are less likely. Prophylaxis with pneumatic compression devices both intraoperatively and postoperatively and early postoperative ambulation are recommended as in the nonpregnant patients.

Tocolysis

Current SAGES and EAES guidelines recommend tocolytics only if uterine contractions are present. In other words, tocolytics should not be used for prevention of uterine contractions. Tocolytics were thought to calm the uterus from the insult of acute abdomen and the intraoperative uterine manipulation, but their benefit is equivocal [249]. Figure 2.5 stratifies the different tocolytics used and their effect on the fetal outcome [117]. Authors show that there is no significant difference in efficacy of different tocolytics and no significant difference in outcome when tocolytics are used or not, the finding confirmed by others [250]. These findings are different from those which Allen et al. reported, as they recorded a 100 % success rate of tocolysis in prevention of labor [251].

Fig. 2.5

Effects of specific tocolytics, all tocolytics, and no tocolytics on fetal outcome during acute abdomen [117]

Tocolytics not only fail to improve fetal outcome but also had serious maternal and fetal side effects, which could contraindicate their use, especially ritodrine and prostaglandin synthetase inhibitors. Ritodrine causes maternal and fetal tachycardia, nausea, and vomiting as recorded in this study, and so it impaired very important signs for managing acute abdomen. Prostaglandin synthetase inhibitors are blamed for constriction of ductus arteriosus when used as a tocolytic, but recently it was found that when used between 26 and 34 weeks of pregnancy, the danger is minimal [252]. In the study by El-Amin Ali et al. [117], no teratogenesis due to prostaglandin synthetase inhibitor was detected, and the reported complications of altered hematological indices, transient renal insufficiency, and necrotizing enterocolitis [253] were not detected. Another drawback of the use of prostaglandin synthetase inhibitor is its anti-inflammatory and antipyretic effect, which might mask important clinical parameters for acute abdomen case management and give the surgeon a false sense of security. Unlike ritodrine and prostaglandin synthetase inhibitor, nifedipine is safer and does not alter the disease symptomatology [249]. Although nifedipine was blamed for causing hypotension, this proved to be insignificant [254, 255]. Albeit feared for teratogenicity [256], the evidence is not conclusive [257], and no malformations were reported in the study by El-Amin Ali [117]. In the study by Lu et al. 14 out of 53 (26 %) patients with symptomatic cholelithiasis developed preterm contractions requiring treatment with tocolytic agents. One patient with biliary colic failed tocolysis and delivered a 1,250 g infant at 32 weeks gestation, and another with acute cholecystitis had pulmonary edema as a complication of tocolysis [133]. Selective use is recommeded, only if uterine contractions are present, as proposed in the study by Sungler et al. [47]. Both patients receiving tocolysis (25th and 32nd weeks of gestation) had preterm labor on admission for 6 and 9 days, respectively.

Folic Acid/Multivitamin Supplementation

A study by Acsa et al. showed that symptomatic cholelithiasis and/or cholecystitis in pregnant women is associated with a higher risk for neural tube defects in their offspring [258]. However, this finding was based on 11 cases, and of these cases, two had alternative possible causes (diabetes and high fever-related influenza) as well. Thus, this finding is only a signal, which needs confirmation or rejection. There is no similar report published regarding the association between symptomatic cholelithiasis and cholecystitis and neural tube defects. At the evaluation of this association, microbial agents, related drug treatments, other confounders, and chance effects should be considered. Previous studies indicated an association between neural tube defects or other congenital anomalies and high fever during the critical period [259–264]. Some pregnant women with symptomatic cholelithiasis and/or cholecystitis reported fever in the study. Currently there are no data regarding the possible association between the bacterial causes of cholecystitis and neural tube defects [164]. The drugs used for the treatment of symptomatic cholelithiasis and/or cholecystitis have no role in the origin of neural tube defects [265, 266]. The use of folic acid and folic acid-containing multivitamins was less frequent symptomatic cholelithiasis and/or cholecystitis group. Authors’ hypothesis for the explanation of possible association between symptomatic cholelithiasis and/or cholecystitis and neural tube defects is based on the observation that the chronic condition of symptomatic cholelithiasis and/or cholecystitis frequently includes fever, and this fever may have a role in the origin of neural tube defects. Thus, periconceptional folic acid/multivitamin supplementation in pregnant women with symptomatic cholelithiasis and/or cholecystitis is particularly important [258, 263].

Duration of Hospitalization

In the study by Lu et al. patients who underwent LC were able to tolerate clear liquids 0.6 days sooner and regular diet 0.3 days sooner than patients who underwent OC [133]. Curet et al. demonstrated, in a retrospective study, a significant reduction in hospitalization time for LC in comparison with OC [135]. Mean hospitalization was 2 [161] to 4.5 [220] days for acute cholecystitis treated with LC and 3 days for common bile duct exploration [161].

2.1.8.8 Surgical Considerations in the Postpartum Period

The abdominal wall also undergoes significant change during pregnancy, with muscle tone reduction and skin elasticity to accommodate the enlarging uterus. The abdominal wall tone remains lax for several weeks postpartum, returning to a near-nonparous level in 6-7 weeks. The hallmarks of acute surgical disease, abdominal guarding and rigidity, do not occur during the early puerperium. This single feature of the puerperium is responsible for confusion and delay in proper surgical diagnosis. Puerperal changes in blood components may be confusing as well. During the first 10–14 days of the puerperium, WBC counts of 20,000–25,000/mm³ are not unusual; there is also a predominant increase in neutrophils. The erythrocyte sedimentation rate may increase to 50–60 mm/h. Reliance on either the erythrocyte sedimentation rate or the WBC count for the diagnosis of acute infection may be misleading.

The postpartum patient can be operated upon without the added concerns of the fetus; however, several unique characteristics apply to this group. In the early postpartum period, the enlarged uterus is a potential technical factor. In the Cesarean section patient, the challenges of a recent surgical incision must be considered. Safe access to the peritoneal cavity and ultimate protection of the recent incision are important factors. Finally, unique features of the biliary tract disease during the postpartum period may require special consideration. Any conservative treatment course is hampered by these patients’ strong desire to minimize the number of hospital days, recurrent symptoms, and disability. Physiologically, postpartum patients are still recovering from pregnancy and childbirth. In addition, separation from a newborn, combined with varying degrees of labile emotions related to the postpartum state, serves to accentuate the usual psychological stresses of illness. If early laparoscopy can be applied to this group, the benefits will be even greater than that reported for the general population.

The enlarged uterus did not hamper exposure, even in the first week. At the time of surgery, the uterine fundus was inferior to the umbilicus. This is consistent with subsequent reports of technical success and good exposure in pregnant patients undergoing laparoscopy during the first and second trimesters [135]. There were no adhesions encountered in the Cesarean section group. The course of the procedure and recovery was identical to the remainder of patients.

The final unique consideration in the postpartum patient is the presence of a healing abdominal incision after Cesarean section. There are no published studies on outcomes for recent abdominal incisions subjected to early pneumoperitoneum. Pneumoperitoneum was limited to 10 mmHg pressure in the Cesarean section patients. This may have been beneficial in preventing undue mechanical strain on the healing wound, though we have no controls with the standard (15–16 mmHg pressure) for comparison. It seems prudent to utilize the minimal intra-abdominal pressure necessary for adequate exposure in these patients. Although evidence suggests fascial separation, if present, occurs early, it remains to be seen what long-term status these incisions will achieve. No hernia has developed in these patients with follow-up to 5.5 years [267].

Gallstone-Related Hospitalization During the First Postpartum Year

Gallbladder disease is a leading non-obstetric cause for hospitalization in the first year postpartum. Seventy-six percent were diagnosed with uncomplicated cholelithiasis, 16 % with AP, 9 % with acute cholecystitis, and 8 % with cholangitis. Seventy-three percent of hospitalized women underwent cholecystectomy and 5 % underwent ERCP. On multivariate analysis, independent risk factors for hospitalization included maternal race, age, being overweight or obese prepregnancy, pregnancy weight gain, and estimated gestational age [4].

2.1.8.9 Combined or Consecutive Operations During the Same Pregnancy

As previously reported, one unusual patient required two separate laparoscopic operations during the same pregnancy: cholecystectomy at 6 weeks gestation and later at 20 weeks appendectomy and reduction of an ovarian torsion. Another patient, at term, underwent combined Cesarean delivery (previously planned) and laparoscopic cholecystectomy. The cholecystectomy was performed first, because it was felt that it would be safer to conduct a cholecystectomy in a stable patient prior to any significant bleeding potentially encountered with child birth [268].

2.1.9 Prognosis

2.1.9.1 Fetal Outcome

All of the placental and amniotic complications occurred in patients undergoing cholecystectomy and were all in the laparoscopic group. Additionally, the incidence of placental/amniotic complications was statistically higher in those undergoing cholecystectomy compared with appendectomy [269]. The etiology of this association is not clear. Others state no fetal morbidity or mortality [161]. The incidence of preterm deliveries with conservative management was 3.5 % compared with 6.0 % in patients receiving surgical treatment. Similar figures were found for fetal mortality in conservative group (2.2 %) and operated group (1.2 %) [270].

2.1.9.2 Maternal Outcome

Prognosis after cholecystectomy during pregnancy is excellent. Most authors declare that there is no maternal mortality and complications mostly include wound infections [161]. In six reports of 310 patients comparing conservative with surgical management, all patients were initially treated conservatively. No maternal mortality was reported in either group [270].

2.2 Common Bile Duct Stones, Cholangitis, and Biliary Pancreatitis

2.2.1 Incidence

One in 1,200 pregnancies is complicated by choledocholithiasis [271]. CBD stones have been observed in 10–12.5 % of pregnant women undergoing cholecystectomy [162, 272] and account for 7 % of cases of jaundice in pregnancy [6].

2.2.2 History

Clinical presentation of pregnant patients with CBD stones is the same as in nonpregnant population. Classical symptoms include abdominal pain, jaundice, nausea, vomiting, and itching. Additional diagnostic challenge exists due to specific pathologic states that could be found only in pregnancy and should be included in differential diagnosis. Clinical presentation of biliary AP is the same as every other type of AP and is described in detail in the Chap. 3.

2.2.3 Examination

Physical examination is the same as the examination for cholelithiasis and cholecystitis with special attention on signs of icterus. If painless without elevated body temperature, then CBD stones or periampullary tumor is suspected, or if painful with fever and chills, then acute cholangitis is the most probable diagnosis.

2.2.4 Differential Diagnosis

There are several entities that should be included in differential diagnosis of CBD stones and cholangitis. Most of them could be easily excluded after abdominal ultrasound or MRCP. The two entities found in pregnancy are presented in more detail for easier determination of definitive diagnosis: intrahepatic cholestasis of pregnancy and acute fatty liver of pregnancy.

2.2.4.1 Intrahepatic Cholestasis of Pregnancy (ICP)

ICP usually occurs during the second or third trimester and disappears spontaneously after delivery. The prevalence of ICP varies widely by country [273, 274]. The highest frequencies have been reported in Bolivia and Chile. In Chile, the prevalence in 1974-1975 was reported to be 15.6 %, ranging 11.8–27.7 % according to ethnic origin [275]. For unknown reasons, the prevalence has more recently appeared to decrease (4.0–6.5 %) [275, 276]. In the United States, the prevalence has been estimated from 0.3 to 5.6 % according to ethnic origin [277, 278]. The prevalence in Europe is about 0.5–1.5 % [274]. Generally, ICP is more common in twin pregnancies [279]. Pruritus, which is the main symptom of ICP, is very uncomfortable and difficult to tolerate. It is often generalized but predominates on the palms and soles. It is more severe at night and disturbs sleep. Pruritus usually disappears within the first few days following delivery [275]. The patient may also be instructed to estimate the intensity of her pruritus on a 100 mm long visual analog scale [280]. These scales for monitoring the intensity of pruritus are particularly useful to evaluate the effect of medical treatment on this subjective symptom. The clinical examination findings are normal except for evidence of scratching. Fever, if present, is usually caused by an associated urinary tract infection. Less than 10 % of patients have jaundice. The greater frequency of jaundice in some studies may be a consequence of concomitant urinary tract infection [281]. ICP with jaundice but without pruritus is rare [282]. Patients do not experience abdominal pain or encephalopathy. Ultrasonographic examination reveals no dilatation of the biliary tract but may show gallstones. Measurement of serum ALT activity is a sensitive test for the diagnosis of ICP. Patients with ICP frequently exhibit very significant increases in serum ALT activity that suggests acute viral hepatitis, which should be ruled out with suitable serologic tests [282]. Liver histology does not reveal necrotic lesions, and the ALT elevations may be secondary to an increase in membrane permeability. The serum GGT activity is normal or only slightly increased [282]. The serum bile acid concentrations are increased and may be the first or only laboratory abnormality [282, 283]. A relationship between maternal serum bile acid levels and fetal distress has been found [284], and evaluation of the serum bile acid concentration has been suggested as a mean of fetal assessment in patients with ICP [280]. At the present time, however, no consensus has been reached concerning the usefulness of evaluating the serum bile acid concentrations in the obstetric management of patients with ICP [285]. Little or no correlation has been found between the serum total bile acid concentrations and other liver test values [282]. The serum bile acid concentration and serum ALT activity decrease rapidly after delivery and, as a rule, normalize in a few weeks. The measurement of serum glutathione S-transferase, a maker of hepatocellular integrity, has been proposed to distinguish ICP from “benign pruritus gravidarum” [286], but its use in routine is limited. The prothrombin time is usually normal. It may become abnormal in severe cholestasis with jaundice or in patients who have been treated with cholestyramine. The abnormality is caused by vitamin K deficiency, which should be anticipated and treated before delivery to prevent hemorrhage. Such therapy contributes to a good maternal prognosis. ICP has been found associated to preeclampsia [287, 288] or acute fatty liver of pregnancy (AFLP) [289]. Liver biopsy is rarely necessary for the diagnosis. Histopathology is characterized by pure cholestasis, sometimes with bile plugs in the hepatocytes and canaliculi, predominantly in zone 3. Inflammation and necrosis are not usually observed, and the portal tracts are unaffected [290].

2.2.4.2 Acute Fatty Liver of Pregnancy

AFLP was distinguished as a specific clinical entity unique to pregnancy in 1940 by Sheehan [291]. AFLP is a rare disease. Incidence has been evaluated in range 1/7,000–1/20,000 deliveries [292–295]. As a rule, AFLP is a disease of the third trimester that may occur during any gestation. The frequency of twin gestations is increased among patients with AFLP [293], and 7 % of triplet pregnancies have been reported to be complicated by AFLP [296]. The most frequent initial symptoms are nausea or vomiting, abdominal pain (especially epigastric), anorexia, and jaundice [297]. In the past, jaundice was almost always seen during the course of the disease, but because of earlier diagnosis, prompt delivery, and the diagnosis of milder cases, we now see affected patients without jaundice. The size of the liver is usually normal or small. Patients with AFLP rarely have pruritus. Hypertension and proteinuria which are the main signs of preeclampsia are found in up to half the patients [298, 299]. In severe forms, patients may demonstrate asterixis and encephalopathy, with or without coma. Esophagitis and Mallory-Weiss syndrome related to severe vomiting have been reported, as well as bleeding secondary to these esophageal lesions. Genital bleeding is frequent. These hemorrhages are exacerbated by associated coagulation disorders. Ascites may be present and is partially related to portal hypertension. Polyuria and polydipsia (without diabetes) have been noted in about 5 % of patients with AFLP [298] and are almost pathognomonic symptoms in this setting of liver disease in pregnancy. AP is a rare but a potentially severe complication [300]. The serum aminotransferase levels are raised, but usually the level is not as high as in acute viral hepatitis. The bilirubin level is almost always increased. Patients may demonstrate hypoglycemia, which is uncommon in other liver disease unique to pregnancy. In severe cases, the prothrombin time is increased and the fibrinogen level decreased. These coagulation disorders are caused by hepatic insufficiency, disseminated intravascular coagulation, or both. A low platelet count is usual in AFLP and is not always associated with other signs of disseminated intravascular coagulation. Thrombocytopenia may be the most striking laboratory feature and normalizes spontaneously after delivery. The diagnosis of AFLP should always be considered when thrombocytopenia occurs during late pregnancy and should always prompt the performance of liver function tests. Renal failure (mainly functional) and hyperuricemia are usual. Ultrasonography of the liver may show increased echogenicity. Computed tomography may be useful for the diagnosis, and a liver density that is lower than usual may be demonstrated by Hounsfield unit values in the liver that are equal to or lower than those in the spleen [297]. The findings on imaging studies may be normal; however, a study showed that the findings on computed tomography, which is more sensitive than ultrasonography, were normal in half of patients with AFLP [301]. These complementary examinations should not delay delivery, particularly in severe cases, in which diagnosis can usually be highly suspected on clinical grounds with routine blood tests (serum liver tests, glycemia, creatininemia, electrolytes, uricemia, full blood count including platelets, prothrombin time). Liver biopsy is the best way to confirm the diagnosis of AFLP, but because it is invasive, it is not always performed. Also, we can take advantage of noninvasive procedures to demonstrate fat in the liver and exclude other liver diseases, such as viral hepatitis. Nevertheless, liver biopsy may be useful in atypical cases, especially if the appropriate treatment (delivery) is being delayed. The overall architecture of the liver is not altered. The characteristic picture is a microvesicular fatty infiltration of the hepatocytes, which are swollen. The droplets are minute and surround centrally located nuclei, so that the cytoplasm has a foamy appearance. The microvesicular fatty infiltration is most prominent in the pericentral zones and midzones (zones 2 and 3) and usually spares a rim of periportal cells. The droplets stain with oil red O, which is specific for fat. Electron microscopy confirms the presence of fat droplets and has shown nonspecific changes in mitochondrial size and shape [302]. A stain specific for fat or electron microscopy is useful for pathology confirmation of the diagnosis in patients with ballooning of the cytoplasm but no evident vacuolization [297]. Therefore, whenever AFLP is suspected, a piece of the liver biopsy specimen should be reserved before paraffin embedding and processed appropriately with special stains to confirm the presence of fat in the hepatocytes. The pathologic changes normally reverse rapidly after delivery, and AFLP is not associated with progression to cirrhosis [299].

2.2.5 Diagnosis

2.2.5.1 Transabdominal Ultrasound

Ultrasound is the imaging tool of choice for evaluation of the biliary system and is accurate in diagnosing cholelithiasis in 97 % of cases [29, 109]. Its accuracy, however, is limited in the evaluation of the common bile duct (50 %) and the pancreas (partial visualization in 60 % with unremarkable findings) [115].

2.2.5.2 MRCP

MRCP is the best diagnostic option for definitive diagnosis of biliary diseases in pregnancy if abdominal ultrasound is not diagnostic. MRCP is rarely used due to rarity of the disease and not widespread availability, and only five published case reports of MRCP in pregnant women for stones and cancer are published [115, 218, 303–305]. No maternal or fetal morbidity or mortality was noted in these reports. This imaging method is important because it can differentiate between common bile duct stones and Mirizzi syndrome (Fig. 2.3). Patient diagnosed as having Mirizzi syndrome undergo surgery, and jaundice improves after cholecystectomy without endoscopic sphincterotomy or exploration of the common bile duct. This is especially important in pregnant population because this eliminates radiation exposure during pregnancy. Recent refinements in the technique and the development of 3D MRCP sequences further improved MRCP, allowing the reconstruction of overlapping slices of less than 1 mm [306, 307]. With a reported accuracy close to 100 % in determining the presence and level of biliary obstruction, MRCP has replaced diagnostic ERCP in many institutions, and the utilization of ERCP for diagnostic purposes is steadily decreasing.

2.2.5.3 ERCP

ERCP is both a diagnostic and therapeutic modality, first reported during pregnancy in 1990 by Baillie et al. for the treatment of complicated gallstone disease [308]. There are several important issues for the ERCP use in pregnancy.

Radiation

Clinicians may not be well informed of the facts relating to the use of diagnostic radiological studies in pregnancy. Lack of understanding of radiation effects on the fetus causes unnecessary anxiety in pregnant patients exposed to diagnostic radiation and may lead to unnecessary pregnancy termination. A study examining physician perceptions of teratogenic risk associated with undergoing plain radiography and CT during early pregnancy found that six of the 208 family practice physicians would recommend pregnancy termination after first trimester CT and 1 following radiography in the first trimester; 12 % (25/208) of physicians were not sure of the need for pregnancy termination after radiography; and 19 % (39/208) of family practice physicians were not sure about a CT scan examination. The same study reported that 8 % (5/65) of obstetricians included in the study would have recommended pregnancy termination after first trimester CT scan examination [309].

The amount of radiation used during ERCP is 18–310 mrad [310–312], which is lower than the harmful dose of 5–10 rad, which is the dose at which fetal damage occurs. Radiation risk is greatest during the first trimester. Fluoroscopy generally delivers a radiation dose of up to 20 rads/min but varies depending on the X-ray equipment utilized, patient positioning, and patient size. The fetus should be shielded during cholangiography. Other alternatives to fluoroscopy include intraoperative ultrasound and choledochoscopy. Some endoscopists have reported undertaking ERCP without fluoroscopy in pregnant women to minimize radiation risk [313, 314]. Even though the risks to the fetus during the second trimester for radiation exposure are low, it is recommended to protect the uterus with a lead shield.

ERCP Techniques

Eliminating radiation exposure can be accomplished by cannulating the common bile duct with a sphincterotome over a guidewire that can be fixed in place, performing sphincterotomy, exchanging the sphincterotome for an extraction balloon catheter over the guidewire, and sweeping the bile duct without a cholangiogram to extract any stones. The main criticism of this technique is that it provides no real-time information regarding the anatomy of the ductal system and documentation of stone clearance [313]. Axelrad et al. suggested that capturing fluoroscopic images with a videoendoscopy system provides safer ERCP procedure than using spot radiography [49]. But they had to use fluoroscopy for 45 s, 3.4 min, and 2.6 min, respectively, in ERCP applications performed three times at different times in the same patient. Llach et al. carried out sphincterotomy under ultrasound guidance in their first patient and without any imaging technique in the second one [315]. They also stressed that the aspiration of the bile after deep cannulation enabled them to confirm selective common bile duct cannulation and to carry out endoscopic sphincterotomy without radiographic control.

In one modification initial CBD cannulation was done with the help of a double lumen sphincterotome, deep cannulation was achieved, and the bile was aspirated to confirm CBD position. After deep CBD cannulation, the guidewire was passed, and complete biliary sphincterotomy was done over the guidewire. In cases where deep CBD cannulation was not possible, after two attempts, the conventional sphincterotome was removed and patients were subjected to needle-knife sphincterotomy. Once the biliary orifice was identified, a complete biliary sphincterotomy was performed using a conventional double lumen sphincterotome after confirming the location inside CBD. After the biliary sphincterotomy, a Zag guidewire was left in place and a 7Fr double pigtail stent was placed in the CBD. Patients were kept nil orally for 6 h after procedure, and i.v. fluids and i.v. cefotaxime 1 g bid was given for 1 day followed by oral antibiotics for 5–7 days. After delivery all the patients were subjected to definitive ERCP. Biliary stents were removed, and cholangiogram was obtained in all patients. All small stones were removed with Dormia basket, while one patient with a single large stone was subjected to mechanical lithotripsy. Patient with multiple large stones was subjected to surgery [316].

Reports have shown that if certain precautionary measures are taken, therapeutic ERCP can be safely performed during pregnancy [317]. Actually, the American College of Obstetricians and Gynecologists(ACOG) states that risks for fetal anomalies, growth restriction, or abortions are not increased with radiation exposure of less than 5 rad, a level above the range of exposure for diagnostic procedures [318]. Aspiration technique is used to avoid pancreatography, and fluoroscopy time should be as short as possible (<1 min) and spot radiographs avoided if possible [319].

When facing more invasive operative and interventional options – surgery or percutaneous transhepatic cholangiography – ERCP may be the best therapeutic option in the setting of pregnancy. In conclusion, ERCP in pregnancy tends to be safe for both the mother and the fetus, but the procedure should be largely restricted to therapeutic indications with additional intraprocedural safety measures [312].

It should be stressed that due to the ability of amniotic fluid to conduct electrical current to the fetus, the grounding pad should be placed on the patient above the level of the uterus [311].

Sedation

Sedation in pregnancy has always been a challenge to anesthetists. Sedation during ERCP in pregnant patients has important aspects of fetal and maternal monitoring and side effects of the prone position [303, 313, 320]. Following electrocardiography, noninvasive blood pressure measurement, pulse oximetry, and fetal heart rate monitoring devices are applied. Insufflation of oxygen at a flow rate of 6 L/min is maintained throughout the procedure. The patients are placed in a left lateral to prone position. Fetal shielding was accomplished with a lead apron placed between the radiation source and the patient.

No anesthetic drug, inhaled anesthetic or local anesthetic, has been proven to be teratogenic in humans [321]. A notable exception is the benzodiazepine group, which has been linked to congenital anomalies [321, 322]. All agents that are administered during pregnancy must be used with caution and vigilance. It is clear that anesthetic effects on placental perfusion and the placental transfer of depressant drugs may influence the fetus [322]. Currently the best options are propofol, midazolam, and fentanyl. Propofol as a short-acting agent is preferred because it can be titrated easily and has a good recovery, with a low incidence of nausea and vomiting. Alternatively midazolam can be used because of its specific amnesic and anxiolytic properties. The analgesic component of this sedation regimen is the opioid. All drugs are given in incremental doses to prevent hemodynamic and respiratory changes in the mother and fetus during the procedure. The most commonly conscious sedation is achieved and maintained with intravenous midazolam 3–5 mg and duodenal hypomobility induced by hyoscine-N-butylbromide 20 mg [47, 316].

Contrast Agents

Among other considerations for ERCP in pregnancy, contrast agents that contain iodine, such as diatrizoate, have the potential to cause hypothyroidism in the baby. Risks may be minimized by using low concentrations of diatrizoate, especially the water-soluble form, thus limiting the number of intraductal injections and avoiding unnecessary pancreatography [323]. Guidelines for the use of contrast media during pregnancy are listed in the Table 2.2.

ERCP in Diabetic Pregnant Patient

There is only one case report of ERCP in diabetic patient on insulin therapy that was euglycemic during the procedure for obstructive jaundice due to residual choledocholithiasis. The patient had ERCP 1 year ago for common bile duct stones with laparoscopic cholecystectomy after 3 months [303].

Complications

In the nonpregnant patient, risk of bleeding and AP is 1.3 and 3.5 %, respectively [324]. The reported rates of complications in pregnancy due to endoscopic biliary interventions range 7–16 %. The complications consist mainly of post-ERCP AP, preterm labor, and post-sphincterotomy bleeding [311, 312, 325–327]. Gupta et al. [325] analyzed 18 pregnant women (first trimester, four; second, six; third, eight) who the women underwent therapeutic ERCP and biliary sphincterotomy for common bile duct (CBD) stones. One woman had a preterm delivery. At follow-up after a median of 6 years, all the babies were healthy. According to the data collected from different centers by Jamidar et al. one AP, two neonatal deaths, and one abortion (3 months following ERCP) occurred in 23 pregnant patients undergoing ERCP applications with a very short period of fluoroscopy [326]. Judging by the data of 45 cases of ERCP interventions during pregnancy, laparoscopic surgery and ERCP during pregnancy appear to be safe and justified. However, ERCP during pregnancy is technically exacting and should be attempted only by experienced biliary endoscopists [47, 162, 312, 319, 325–330]. So ERCP for treatment of choledocholithiasis in pregnancy has been recommended instead of a surgical approach [308, 326, 331]. It should be stressed that there is not any randomized, controlled study comparing ERCP and open (or laparoscopic) surgery in view of the efficacy and safety at present.

2.2.5.4 Endoscopic Ultrasound

Endoscopic ultrasound (EUS), a semi-invasive procedure of the biliary tree, is an accurate modality for detecting common bile duct stones [332]. As solely a diagnostic tool, it has been shown to reduce unnecessary interventions in patients with low or moderate probabilities for choledocholithiasis [333–335]. However, EUS requires expensive equipment, intravenous sedation, and technical expertise. EUS can be considered the best imaging study to evaluate CBD, although not for gallbladder stones. In expert hands small gallstones as well as sludge can be picked up by EUS; however, it is operator dependent. EUS is appropriate prior to the consideration of therapeutic ERCP in patients where noninvasive imaging such as MRCP is not available, contraindicated, or inconclusive. EUS has a high positive predictive value around 100 % in detecting CBD stones, and in many instances EUS is superior to MRCP [333]. EUS entails no radiation exposure and is extremely safe apart from a minimal sedation-related risk. If a common bile duct stone is detected, an ERCP with sphincterotomy can be performed following the EUS study during the same sedation [336].

2.2.6 Therapy

2.2.6.1 Choledochoscopy

Choledochoscopy could be used during CBD exploration (open or laparoscopic) or after sphincterotomy. Recently several reports of successful wire-guided CBD cannulation with sphincterotomy and the removal of biliary stones or sludge were performed without fluoroscopy. Choledochoscopy can then confirm ductal clearance [337, 338]. If choledochoscopy is not available, an alternative approach is to use EUS-guided extraction balloon sweeps to achieve clearance of ductal stones.

SpyGlass Direct Visualization System (Boston Scientific, Natick, MA, USA) is presented. A 4.4 Fr sphincterotome was angled in the biliary orientation, and a hydrophilic 0.35″ guidewire was gently advanced into the major papilla resulting in bile flow around the guidewire. The sphincterotome was advanced over the wire, and aspiration of 10 ml of clear yellow bile confirmed the location within the bile duct. A biliary sphincterotomy was performed. Sweep with a 9 mm extraction balloon easily removed a single 8 mm stone from the bile duct. The SpyGlass SpyScope was exchanged over the guidewire, and cholangioscopy directly visualized the common bile duct, common hepatic duct, and left and right intrahepatic ducts. Saline lavage through the cholangioscope flushed debris and two 2 mm residual stones from the bile duct into the duodenum. No fluoroscope was used during the entire procedure. To date, seven pregnant patients undergoing SpyGlass cholangioscopy-assisted ERCP have been reported [337–339]. It is important to note that the use of non-fluoroscopy interventions may actually prolong the overall duration of the procedure due to learning curves and technical experiences of endoscopists and hence increases the risk, especially in difficult cases. Furthermore, in daily practice, non-fluoroscopy modalities are not often used. Therefore, one should not hesitate to use fluoroscopy if required with the knowledge that limited radiation exposure is safe during pregnancy [312].

2.2.6.2 Laparoscopic Cholecystectomy After ERCP

There is no consensus if the laparoscopic cholecystectomy should be performed after successful ERCP with stone extraction. There are several options.

Selective Approach (Wait-and-See Approach)

In the study by Sungler et al. selective approach was used. Five patients underwent ERCP due to common bile duct stones (three patients had jaundice and two had AP). The remainder of the pregnancy was uneventful in three of the patients. One patient had persistent colic; therefore, laparoscopic cholecystectomy was performed 2 weeks later, in the 32nd gestational week. Another patient with severe AP, cholangitis, and cholecystitis was released symptom-free after successful ERCP on day 7, but she was readmitted for recurrent severe cholecystitis 2 weeks later [47]. It is not known which patient developed complications (with obstructive jaundice or AP). All of them had healthy babies at term with vaginal delivery.

In nonpregnant patients, prospective randomized trial by Boerma et al. demonstrated a conversion rate of 55 % in patients who were allocated to a wait-and-see policy after ERCP and a 23 % conversion rate in the elective LC group. This result implies that LC after ERCP is mandatory. The fact that there is high conversion rate in both groups is partly due to the fact that LC is undertaken in a specific subgroup of patients, having complicated gallstone disease [340].

Mandatory Cholecystectomy

The prospective randomized trial in nonpregnant patients compared selective approach and mandatory cholecystectomy and showed such a high rate of recurrent biliary events in the wait-and-see group that an elective laparoscopic cholecystectomy after ERCP seems justified [340]. In practice, some strongly advocate a cholecystectomy within 6 weeks of the initial biliary event.

In pregnant population, Simmons et al. during the 2-year interval, reported a successful ERCP in six pregnant women between 6 and 30 weeks of gestation with symptomatic acute cholangitis or AP, without radiation exposure or major maternal complications [313]. No post-ERCP complications occurred. Two patients required cholecystectomy later, one in the postpartum period, and the other 5 weeks post-ERCP. Two infants were born at term without complications. Two infants were born prematurely at 35 weeks, one with significant growth restriction and pulmonary complications, and one without developmental problems or complications.

Interval Between ERCP and Laparoscopic Cholecystectomy

There are no such studies in pregnant population. In nonpregnant population, the results suggest that there is an increased risk of conversion of an LC to an open procedure 2–6 weeks after ERCP. An important explanation for a higher conversion rate could be that ERCP leads to an inflammation around the gallbladder, including the hepatoduodenal ligament, making a laparoscopic procedure more demanding [340, 341]. Adhesions, operation time, and bile duct damage did not significantly differ between the groups, but significantly higher conversion rate due to adhesions 2–6 weeks after ERCP suggests that these adhesions are less friendly and potentially dangerous compared to the adhesions encountered at surgery within 2 weeks of ERCP [342].

Others claim that time interval is of no importance. These authors found that male gender, bilirubin levels during ERCP, severe adhesions during LC, and pre-LC CRP levels were associated with an adverse outcome for an LC after ERCP. From the previous studies and studies by Alimoglu et al. and Lai et al. the recommendations in pregnant as in nonpregnant patients is that LC should be performed 24–48 h after ERCP to shorten the hospitalization, to avoid another hospitalization, and to reduce the possibility of recurrent biliary events [156, 343].

2.2.6.3 Common Bile Duct Exploration

Six cases of laparoscopic [136, 305, 344–346] and 20 cases of open [5, 15, 133, 135, 164] CBD exploration were described in the literature. There was no maternal or fetal morbidity or mortality. Multiple studies have demonstrated safe and effective management of CBD stones in pregnancy with ERCP and sphincterotomy with subsequent LC [15, 47, 308, 319, 347, 348]. Therefore, indications for laparoscopic CBD exploration in pregnant patients, following an episode of gallstone pancreatitis, are yet to be clearly defined. Some authors use 1 mg of glucagon intravenously for sphincter of Oddi relaxation.

Transcystic Approach

In general, laparoscopic clearance of duct calculi by means of the cystic duct approach is achieved in approximately 80-90 % of attempts, appearing to be a viable alternative to postoperative ERCP [349]. This approach seems valuable when one considers the potential teratogenic effects of radiation exposure when ERCP is performed in the first trimester and the inability to appropriately shield the fetus from radiation during the third trimester [326]. However, such recommendations for laparoscopic management of biliopancreatic disease to include laparoscopic CBD exploration in pregnancy, as stated previously, are yet to be precisely defined.

The location of the bile duct stones, size, number, as well as the anatomy should be considered when choosing between a transcystic approach and choledochotomy. Guidelines for a laparoscopic transcystic approach include [350]:

· Small (<0.8 cm) stones in the CBD

· Limited number of CBD stones (≤5)

· Absence of stones in the common hepatic duct

· Cystic duct joining the CBD on its lateral or posterior (not medial) aspect

Choledochotomy

Choledochotomy is indicated when [351]:

· Transcystic approach fails or is contraindicated.

· Biliary lithotripsy needed.

· CBD is dilated more than 7 mm.

The number of case reports describing LCBDE in pregnant women is limited, but they appear to advocate this procedure as a safe alternative to ERCP [345].

Intraoperative Cholangiography

Since Mirizzi first described intraoperative cholangiography (IOC) in 1934 [352], the technique has developed from static views to dynamic real-time fluoroscopic cholangiography, and recently to three-dimensional dynamic cholangiography [353]. However, so far this latter method has only been used experimentally in liver surgery.

In nonpregnant patients dynamic real-time intraoperative fluoroscopic cholangiogram is achieved with the help of mobile C-arm X-ray equipment (Ziehm exposcop CB7-D), using 10–40 ml Iohexol (Omnipaque, GE Healthcare, UK), 200 mg/ml as contrast medium, and 1 ml glucagon (Glucagon^®, Novo Nordisk A/S, Bagsvaerd, Denmark; 1 mg/ml) intravenously to release any papillary spasm, or in cases of diabetes mellitus, 1–2 ml (20 mg/ml) intravenous butylscopolamine (Buscopan^®, Boehringer Ingelheim, Ingelheim am Rheine, Germany).

IOC with LC were described in eight reports [5, 7, 9, 15, 133, 216, 354, 355]. IOC was used frequently, along with cholecystectomy, until the early 1990s. However, recent literature recommends the use of IOC only in the presence of choledocholithiasis and during exploration of CBD [216]. Radiation exposure during cholangiography is estimated to be less than 0.5 rad. Fluoroscopy generally delivers a radiation dose of up to 20 rads/min but varies depending on the X-ray equipment utilized, patient positioning, and patient size. If the IOC is performed, the use of a shield to cover the fetus is recommended in all trimesters [9, 15]. From these reports, it is clear that there was no maternal morbidity or mortality. However, 1 spontaneous abortion was reported [354].

With the advent of ERCP and MRCP, the need for IOC is minimal, although specialized units use it routinely for demonstrating the anatomy of the biliary tree. There have been no reports investigating the safety of IOC during pregnancy. In the absence of clear evidence, potential risks should be discussed with the patient.

2.2.6.4 Postpartum Presentation

The lack of initial appreciation for the higher rate of choledocholithiasis in this group led the authors to initially (patients 1 through 24) apply selective criteria for cholangiography. In the latter part of the series, routine cholangiography was applied to the postpartum patients and led to the diagnosis of two patients with common duct stones and none of the traditional risk factors. Three patients (8.8 %) had missed common duct stones. The rate in total patient series, including the patients in this report, is 0.6 % (7/1,068) and 0.4 % (4/1,034) in the non-postpartum group (unpublished data, Diettrich and Kaplan). The high incidence of choledocholithiasis, often silent, suggests that routine cholangiography should be the norm in the postpartum patient with biliary tract disease.

Intraoperative Ultrasound

Glasgow et al. did not use IOC but described the use of laparoscopic ultrasound in six patients to exclude retained CBD stones [136].

2.2.7 Prognosis

2.2.7.1 Fetal Outcome

Prognosis after common bile duct surgery during pregnancy is excellent. Six cases of laparoscopic and 20 cases of open CBD exploration were described in the literature. There was no fetal morbidity or mortality [270].

2.2.7.2 Maternal Outcome

As for fetal outcome, maternal outcome is also excellent. In all six cases of laparoscopic and 20 cases of open CBD exploration described in the literature, there was maternal morbidity or mortality [270].

2.3 Symptomatic Choledochal Cysts

2.3.1 History

Since Vater first described the condition in general population in 1723, many cases of choledochus cyst have been recorded in the literature. Rupture of the cyst is a rare complication, only six cases having been documented by 1956 [356]; one of these, published by Friend in 1958, occurred 2 weeks after a normal delivery. The first rupture of the choledochal cyst during pregnancy was published by Saunders and Jackson in 1969 [357].

2.3.2 Incidence

Choledochal cyst is a rare congenital abnormality of the biliary tract, occurring in approximately 1/2,000,000 live births [358]. Usually diagnosed during childhood, choledochal cysts present for the first time during adulthood in 25 % of patients but rarely during pregnancy with only several case reports published [359–364].

2.3.3 Clinical Presentation

Clinical manifestations are nonspecific and variable. The classical characteristic triad (abdominal pain, jaundice, and right hypochondrial mass) occurs mostly in childhood [365] and are seldom seen in adults [366]. With all anatomic changes during pregnancy, the cyst is not easily detected in pregnant women [367]. If silent, it can be unnoticed during pregnancy. Reported complications of choledochal cyst during pregnancy include pain in the upper right quadrant due to enlarged mass or palpable mass [364], cholangitis, jaundice, AP, cystic rupture, and malignancy [367]. The pain and jaundice caused by choledochal cyst in pregnancy may be due to hormonal effect, compression of the bile duct lumen and cyst by the gravid uterus, and increase in intra-abdominal pressure during pregnancy [361]. The symptoms are sometimes similar to the symptoms of CBD stones (see “Common Bile Duct Stones, Choledocholithiasis, and Cholangitis”).

2.3.4 Diagnosis

Pregnancy makes diagnosis of this disease more difficult because similar symptoms are often encountered during a normal pregnancy, and radiographic study is limited by fetal exposure. Abdominal ultrasonography is commonly used as the initial screening examination in the evaluation of acute abdomen or hepatobiliary conditions. However, difficulties may arise due to distortion of the normal abdominal anatomy and gravid uterus during pregnancy. The cyst may be misdiagnosed as an ovarian tumor or mucocele [360]. ERCP or computed tomography (CT) may provide more accurate information, but ionizing radiation should probably be avoided in pregnancy [368]. Magnetic resonance imaging (MRI) is suggested as the preferred examination due to high resolution of the biliary tree without the problems associated with exposing the mother and the fetus to ionizing radiation [366]. MRI can even define the type of choledochal cyst preoperatively (Figs. 2.6 and 2.7).

Fig. 2.6

MR of the abdomen showing pregnant patient with gallbladder calculi and choledochal cyst (white arrow) also filled with calculi [359]

Fig. 2.7

A 17-year-old female at 27 weeks gestation who had obstructive jaundice. Coronal T2-weighted single-shot fast spin-echo image demonstrates a significantly dilated common bile duct (arrow) and intrahepatic biliary tree (arrowheads), consistent with a type IVA choledochal cyst [115]

2.3.5 Therapy

The therapeutic principles depend on the type of symptomatology (elective or emergent presentation) and the type of the cyst according to the Todani classification as in nonpregnant patients [369].

2.3.5.1 Asymptomatic Patients

If presented as asymptomatic palpable or painful mass, the patient should be checked regularly and definitive treatment postponed after labor and puerperium as elective operation. In elective settings current recommendations in nonpregnant as in a pregnant woman are complete excision of the extrahepatic duct, cholecystectomy, and Roux-en-Y hepaticojejunostomy because the risk of malignant degeneration has been reported to be as high as 30 % [370]. Sometimes, if the cyst is large, even bilateral Roux-en-Y hepaticojejunostomy should be performed [360].

2.3.5.2 Cholangitis

Complication in the form of acute cholangitis can be treated first with percutaneous cystic decompression under US, CT, or MRCP guidance and after labor and possibly puerperium definitive surgical excision of the cyst and a Roux-en-Y reconstruction [115].

If the patient is in late pregnancy, elective Cesarean section followed by percutaneous decompression after 6 weeks is recommended [364].

2.3.5.3 Cholangitis with Biliary Obstruction or Acute Pancreatitis

However, symptoms from complications such as AP, biliary obstruction, and cholangitis require a more urgent approach. Some authors recommend, in order to avoid complications during pregnancy, definitive surgical management of the choledochal cyst should be delayed until the patient’s general physiological condition becomes normal after elective Cesarean section [364].

2.3.5.4 Postpartum Presentation

The same principles as in pregnancy are recommended. If the patient presents with an emergency diagnosis, the emergency operation should follow. Otherwise the patient should be operated electively after the puerperium or even better after the termination of breastfeeding to minimize possible complications or surgery or medication therapy related to the newborn.

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