Journal of Perinatology (2014) 34, 87–94 & 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp

STATE-OF-THE-ART

Acute pancreatitis during pregnancy: a review G Ducarme1, F Maire2,3, P Chatel4, D Luton4 and P Hammel2,3 This article aims to draw together recent thinking on pregnancy and acute pancreatitis (AP), with a particular emphasis on pregnancy complications, birth outcomes and management of AP during pregnancy contingent on the etiology. AP during pregnancy is a rare but severe disease with a high maternal–fetal mortality, which has recently decreased thanks to earlier diagnosis and some maternal and neonatal intensive care improvement. AP usually occurs during the third trimester or the early postpartum period. The most common causes of AP are gallstones (65 to 100%), alcohol abuse and hypertriglyceridemia. Although the diagnostic criteria for AP are not specific for pregnant patients, Ranson and Balthazar criteria are used to evaluate the severity and treat AP during pregnancy. The fetal risks from AP during pregnancy are threatened preterm labor, prematurity and in utero fetal death. In cases of acute biliary pancreatitis during pregnancy, a consensual strategy could be adopted according to the gestational age, and taking in consideration the high risk of recurrence of AP (70%) with conservative treatment and the specific risks of each treatment. This could include: conservative treatment in first trimester and laparoscopic cholecystectomy in second trimester. During the third trimester, conservative treatment or endoscopic retrograde cholangiopancreatography with biliary endoscopic sphincterotomy, and laparoscopic cholecystectomy in early postpartum period are recommended. A multidisciplinary approach, including gastroenterologists and obstetricians, seems to be the key in making the best choice for the management of AP during pregnancy. Journal of Perinatology (2014) 34, 87–94; doi:10.1038/jp.2013.161; published online 19 December 2013 Keywords: acute pancreatitis; management; pregnancy; review

INTRODUCTION Acute pancreatitis (AP) during pregnancy is a rare disease with an estimated incidence rate of about 1 case per 1000 to 10 000 pregnancies.1–3 The diagnosis of AP is more frequent in multiparous patients (75%).3,4 AP is rare during the first and second trimester of pregnancy (12%), it usually occurs during the third trimester (50%) or the early postpartum period (38%).3–5 AP during pregnancy is a severe disease with a high maternal– fetal mortality rate (37% and 60%, respectively) according to old published series of cases, but this has recently decreased thanks to earlier diagnosis and some maternal and neonatal intensive care improvement.6–8 Latest studies show rare maternal and fetal mortalities, around 0 to 3%.1,5,9,10 Causes of AP occurring during pregnancy can be different, as they are in non-pregnant patients. However, the respective frequency of each cause is different (Table 1). The most common identified causes of AP in pregnancy are gallstones (65 to 100%), alcohol abuse (5 to 10%), idiopathic (15%) and familial hypertriglyceridemia-induced pancreatitis (5%).1,11 Given the current uncertainty regarding incidence, management and outcome of AP in pregnancy, it is important to establish accurate, generalizable information so that patients can be counseled and treated appropriately. This article aims to draw together recent thinking on AP during pregnancy, with a particular emphasis on pregnancy complications, birth outcomes and management of AP during pregnancy contingent on the etiology. We have performed a Pubmed (Medline) search with no

time limit using ‘acute pancreatitis’, ‘pregnancy’, ‘surgery’ or ‘management’ as keywords. DIAGNOSIS OF AP The diagnostic criteria for AP are not specific for pregnant patients. Some standards have been developed in non-pregnant patients and are often used as a guide to diagnose AP during pregnancy. The disease usually appears during the third trimester or in the early postpartum period with the association of symptoms like upper abdominal pain, nausea or vomiting, anorexia, fever and elevated serum amylase or lipase activities.4 The diagnosis of AP during pregnancy can be difficult. Pregnancylinked hematological and biochemical alterations may have an impact on the interpretation of the diagnostic tests (serum amylase and lipase levels) and the assessment of the AP’s severity (physiologic leukocytosis in pregnant women under 16 000 mm–3, alkaline phosphatase can reach to three times normal in normal pregnancy). An increase in serum amylase and lipase activities should be taken into account during pregnancy, as in non-pregnant women, for the diagnosis of AP.12 So, an elevated serum amylase and/or a lipase level higher than three times normal has a good positive predictive value for the diagnosis of AP in pregnant women. The serum lipase level has a better sensitivity (94% vs 83%) and specificity (96% vs 88%) than the serum amylase level to diagnose AP.13 As well as in non-pregnant patients with AP, the etiological investigation based on the assessment data (personal and family

1 Department of Obstetrics and Gynecology, Centre Hospitalier Departemental, La Roche sur Yon, France; 2Poˆle des Maladies de l’Appareil Digestif, Service de Gastroente´rologiePancre´atologie, Hoˆpital Beaujon, AP-HP, Clichy, France; 3Inserm U773-CRB3, Universite´ Paris-Diderot, Clichy, France and 4Department of Obstetrics and Gynecology, Hoˆpital Beaujon, AP-HP, Universite´ Paris-Diderot, Clichy, France. Correspondence: Dr G Ducarme, Department of Obstetrics and Gynecology, Centre Hospitalier Departemental, 85000 La Roche sur Yon, France. E-mail: [email protected] Received 24 May 2013; revised 21 October 2013; accepted 12 November 2013; published online 19 December 2013

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88 Table 1.

Causes of AP in pregnant women

Gallstones (65–100%) Alcohol abuse (5–10%) Familial hypertriglyceridemia-induced pancreatitis (5%) Idiopathic (15%) Drugs-induced AP (thiazide diuretics) (cases) Pancreatitis associated with pregnancy-induced hypertension (cases) Acute fatty liver of pregnancy associated with AP (cases) Hyperparathyrodism (cases) Gene mutations (cases) Cationic trypsinogen (PRSS1) CFTR PSTI PPARG Abbreviations: AP, acute pancreatitis; CFTR, cystic fibrosis transmembrane conductance regulator; PPARG, peroxisome proliferator-activated receptor gamma; PSTI, pancreatic secretory trypsin inhibitor.

history, alcohol consumption and drugs), blood tests (white cell count, liver enzyme concentrations guide to the presence of cholelithiasis) and imaging is necessary to orientate, evaluate the severity and treat AP during pregnancy. Abdominal ultrasound is safe and it has higher sensitivity than computerized tomography for detecting gallstones in cases of AP. Magnetic resonance imaging (MRI) is an accurate technique for detecting the cause of acute abdominal and pelvic pain during pregnancy and should be considered for pancreas screening during pregnancy after sonographically indeterminate findings.14 MRI can provide information on AP and its complications (edema, pseudocysts or hemorrhagic pancreatitis), and it can also help to determine whether the main pancreatic duct is clear or not when persistent cholestasis occurs. MRI has also the advantage of not causing any fetal toxicity even when gadolinium contrast media is used, while iodinated contrast medium during computerized tomography could induce fetal hypothyroidism.15–19 Overall, both sensitivity and negative predictive value for the diagnosis of choledocholithiasis are lower than those of endoscopic ultrasonography. However, their non-invasive nature and the absence of general anesthesia lead to prefer them as first choice tests in pregnant patients.20 EVALUATION OF SEVERITY Ranson and Balthazar criteria for the classification of AP’s severity in non-pregnant patients have been developed (Table 2) and are often used as a guide to evaluate the disease’s severity and treat it during pregnancy.21 In addition to abdominal ultrasound, MRI has shown to be as effective as computerized tomography for staging AP using the Balthazar severity index.22 If there is no problem for the differential diagnosis, it is strongly recommended to perform an evaluation using imaging at least 48 h after the beginning of pain (Figure 1), as too early staging may underestimate the severity of an AP.13 In the literature, severe AP (scoreX3) during pregnancy are mainly due to gallstone migration or to hyperglyceridemia.10,23 PRENATAL COMPLICATIONS The fetal risks from AP during pregnancy are threatened preterm labor, prematurity and in utero fetal death. Previously reported high perinatal mortality rates secondary to AP are due to neonatal deaths after preterm delivery. In recent series, perinatal mortality rates were improved, mainly because 74% of the infants were delivered in term.4 A large retrospective study including 101 cases of pancreatitis (89 AP and 12 chronic pancreatitis) affecting among 305 101 deliveries in 10 years showed no maternal death, Journal of Perinatology (2014), 87 – 94

Table 2.

Ranson’s criteria for prognosis of acute pancreatitis

Ranson’s criteria on admission: Age 455 years White blood cell count 416 000 cells mm–3 Blood glucose 411 mmol l–1 Serum AST 4250 IU l–1 Serum LDH 4350 IU l–1 Ranson’s criteria after 48 h of admission: Hypocalcemia (serum calcium o2.0 mmol l–1) Fall in hematocrit by 410% Hypoxemia (PO2 o60 mm Hg) Increase in BUN to 41.98 mmol l–1 after IV fluid hydration Base deficit (negative base excess) 44 mmol l–1 Sequestration of fluids 46 l Interpretation If the score X3, severe pancreatitis likely If the score o3, severe pancreatitis is unlikely Or Score 0–2: 2% mortality Score 3–4: 15% mortality Score 5–6: 40% mortality Score 7–8: 100% mortality Abbreviation: AST, aspartate aminotransferase; BUN, blood urea nitrogen; IV, intravenous; LDH, lactate dehydrogenase.

and the perinatal mortality was 3.6%.1 Patients who developed AP during the first trimester had the lowest percentage of term pregnancy (60%) and the highest risks of fetal loss (20%) and preterm delivery (16%).24 Sun et al.10 compared maternal–fetal risk between 18 pregnancies complicated by severe AP and 51 pregnancies with mild AP. They concluded that miscarriages and preterm infants contributed to fetal loss in the ‘mild’ group, while fetal death and stillbirth contributed in the ‘severe’ group. Cases of acute biliary pancreatitis were associated with better perinatal outcomes than non-biliary causes.1

ACUTE BILIARY PANCREATITIS Epidemiology Elevated progesterone levels induce biliary hypotonia, increasing the pressure of the sphincter of Oddi—which leads to bile stasis— and the impregnation of estrogen changes the composition of bile, which becomes more lithogenic.23 Therefore, the risk of biliary sludge and stones increases throughout pregnancy. The main independent risk factor for gallstones is pre-pregnancy obesity.3,25 high-density lipoprotein cholesterol was also inversely associated with incidental gallbladder lithiasis.25 The incidence of biliary manifestations during pregnancy (colic, acute cholecystitis, cholangitis or biliary AP) is from 0.05 to 8%. During pregnancy, cholelithiasis is the most common cause of AP accounting for 65 to 100% of cases.4,23,26 In a prospective study of over 3000 patients who had ultrasound examination throughout the pregnancy, the authors showed a cumulative incidence of sludge or gallstones in early postpartum in 10.2%, with biliary sludge in 5.1%, stones in 2.8% and gallstones in patients with preexisting sludge in 2.3%.25 A symptomatic biliary complication occurred in 1.2% of the pregnant women. The variability of the reported incidence is related to a center effect and the sensitivity of the techniques used for the lithiasis diagnosis (microlithiasis are frequent during pregnancy and only endoscopic ultrasonography has a high sensitivity for the diagnosis). Treatments The particularity of the acute biliary pancreatitis during pregnancy is its high recurrence rate, around 70% (90% during & 2014 Nature America, Inc.

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Figure 1. Non-enhanced abdominal magnetic resonance imaging (MRI) in a woman who presented an acute pancreatitis at 37 weeks gestation. Non-enhanced abdominal MRI showing the extent of necrosis in contact with the tail of the pancreas, around the kidneys and in the parietocolic folds (arrows, a, b), the gallbladder with no parietal thickening and no visible gallstone, and the diffuse enlargement of the pancreas with heterogeneous attenuation of pancreatic parenchyma (arrows, c, d).

hospitalization) vs 20% to 30% in the general population.6,27,28 Management should consider both maternal and fetal risks contingent on the treatment: irradiation during endoscopic retrograde cholangiopancreatography (ERCP) with biliary endoscopic sphincterotomy, general anesthesia and laparoscopy. Surgery? A review included 12 studies, concerning 113 patients with confirmed gallstone-induced AP during pregnancy, comparing conservative with surgical treatment.9 No maternal deaths were reported in either group. Maternal morbidity, fetal morbidity and mortality were low and not significantly different between the two groups. However, in 12 reports about biliary pancreatitis, the authors reported a trend toward higher rate of fetal mortality (8.0% vs 2.6%, P ¼ 0.28) in the conservative group, suggesting the need for earlier cholecystectomy (and biliary tract clearance when necessary) during pregnancy. Recently, Othman et al.29 published a retrospective study in a tertiary-care referral hospital. A total of 112 patients who had complications related to gallstones during pregnancy was reported and classified into three groups: conservative treatment, laparoscopic cholecystectomy and ERCP. The number of emergency department visits, recurrent biliary symptoms and the number of hospitalizations were significantly higher in the conservative treatment group compared with the active intervention group (cholecystectomy and/or ERCP). The authors concluded that ERCP and laparoscopic cholecystectomy can be safe alternative approaches during pregnancy. & 2014 Nature America, Inc.

Open cholecystectomy or laparoscopic cholecystectomy?. The literature review identified 20 studies (197 patients) describing laparoscopic cholecystectomy during pregnancy, excluding small series of o5 patients.9 The procedure was performed more often during the second trimester of pregnancy without any maternal death. Four retrospective studies have compared open cholecystectomy vs laparoscopic cholecystectomy.30–33 These studies did not show any significant difference in maternal and fetal outcome. One fetal death occurred in the laparoscopic cholecystectomy group, compared with two in the open-surgery group (P ¼ 0.41). There were 6 out of 89 (6.74%) preterm deliveries in the laparoscopic cholecystectomy group compared with 2 out of 69 (2.90%) in the open-surgery group (P ¼ 0.27).9 No study has specifically evaluated the fetal risk associated with intraoperative opacification of the biliary tract. This technique should be limited in case of suspected choledocholithiasis, using a preoperative MRI or an intraoperative ultrasound imaging. In addition to the more commonly recognized benefits of laparoscopy, comparing laparotomy (duration of postoperative hospital stay, quicker return transit, lower risk of postoperative venous thrombosis by early mobilization), there is a shorter duration of sedation (responsible for fetal respiratory depression), and a reduced incision size and uterine manipulation, which is the most associated factor with a risk of preterm delivery. Precautions are recommended to avoid high intraperitoneal pressures: to favor Journal of Perinatology (2014), 87 – 94

Acute pancreatitis during pregnancy G Ducarme et al

90 the left lateral decubitus position to minimize aorto-caval compression; to avoid rapid changes in position; and to use electrocoagulation with caution.9,34 Time for surgery?. Another important question is when the best moment for surgery is if the situation allows elective choice in pregnant woman. Laparoscopic cholecystectomy appears to be a safe procedure during all trimesters but it is best carried out during the second trimester because the fetus has completed the organogenesis and the uterus is not too large. Laparoscopic cholecystectomy should be proposed as soon as the technical conditions for surgery are possible without major maternal–fetal morbidity (that is, concomitant cholecystitis).35–37 Role of ERCP. ERCP has become an invaluable diagnostic and therapeutic tool for biliary and pancreatic disorders. The indications for ERCP with biliary endoscopic sphincterotomy are choledocholithiasis associated with AP, and prevention of recurrence of AP during the third trimester of pregnancy. Many studies have reported the results of ERCP during pregnancy and all have shown the absence of serious complications for the mother and the fetus.38–46 The risk of induced AP with ERCP is around 5% without serious form if the procedure is done by an experienced surgeon. The risk of fetal complications related to ERCP has shown to be o5%.47 The main concern about performing ERCP during pregnancy centers on radiation exposure to the fetus during fluoroscopy. Therapeutic ERCP is associated with significantly higher radiation exposure than diagnostic ERCP. Average effective dose was 3.1 mSv for diagnostic and 12.4 mSv for therapeutic ERCP.48,49 Published series on estimated dose exposure to fetus during ERCP have ranged from 0.1 to 3 mSv, which is significantly lower than the threshold dose required for fetal malformation (5 mSv during pregnancy), otherwise known as the deterministic effect.47,50 Studies concerning nonradiation ERCP using wire-guided biliary cannulation and choledochoscopy have been published and the authors have concluded that this technique is a safe and effective treatment for symptomatic choledocholithiasis during pregnancy.43,44 The fetal risks from performing ERCP during pregnancy must therefore be weighed against the risks to the fetus and the patient in the absence of intervention. Therapeutic strategy. No standardized guidelines have been published concerning the most effective management of acute biliary pancreatitis in pregnant women to reduce maternal and neonatal mortality and morbidity. A recent multimodal approach to acute biliary pancreatitis during pregnancy has been published.51 The authors reported seven pregnant women who were managed by using magnetic resonance cholangiopancreatography, ERCP and sphincterotomy followed by laparoscopic cholecystectomy. They concluded that this active management of acute biliary pancreatitis provides definite treatment and seems to put both mother and fetus at lower risk than presumed. Finally, according to the high risk of recurrence of AP (70%) with conservative treatment and the specific risks of each treatment, and although there are no randomized studies, consensual strategy according to the gestational age could be adopted (Table 3): - First trimester: conservative treatment and laparoscopic cholecystectomy during second trimester. - Second trimester: laparoscopic cholecystectomy. - Third trimester: conservative treatment or ERCP with biliary endoscopic sphincterotomy, and laparoscopic cholecystectomy in the early postpartum period. Journal of Perinatology (2014), 87 – 94

HYPERTRIGLYCERIDEMIA Epidemiology Hypertriglyceridemia in pregnant patients can occur on preexisting dyslipidemia, associated with others diseases (hypertension, diabetes and alcoholism), or without any predisposing factor. Triglycerides concentration rises gradually, 2.5-fold over prepregnancy levels, reaching a peak during the third trimester to as high as almost twice the non-pregnant values. That’s why the AP occurs more often during the third trimester of pregnancy. Lipids decrease gradually during postpartum to regain prepregnancy level in 6 weeks.52,53 These changes are related to an increasing hepatic synthesis of very low-density lipoproteins and a reduction in the activity of lipoprotein lipase in relation to the high levels of estrogen.53 Factors favoring dyslipidemia disturbances are excessive weight gain, diabetes, alcohol consumption, drugs (steroids, diuretics and beta-blockers) and latent genetic abnormalities (lipoprotein lipase, apoC2 or apoE). Experimental models of isolated dog pancreas have shown direct toxicity of triglycerides.54 Pregnancy, especially in the third trimester, can deregulate controlled lipid levels in women with familial hypertriglyceridemia and it may lead to AP and significant morbidity in both mother and fetus. Familial severe hypertriglyceridemia (levels 410 g l–1) is a known cause of AP during pregnancy. The incidence of familial hypertriglyceridemia-induced pancreatitis is estimated at 1/25 000 pregnancies.55,56 Treatment A history of familial hypertriglyceridemia requires biological monitoring for pregnancy-related hypertriglyceridemia in those patients with a pre-pregnancy fasting triglyceride level 44 mmol l–1. A serum triglyceridemia level over 10 g l–1 is an identifiable risk factor for complications.57,58 The mainstay treatment, including dietary restriction of fat and lipid-lowering agents when triglyceride level increases to 410 g l–1, effectively prevents further episodes of hypertriglyceridemia-induced AP during pregnancy.59 In the non-pregnant population, plasma exchange is proven to be a safe and useful management method in cases of severe hypertriglyceridemia where conventional drug treatment has failed.60,61 It can quickly clear triglycerides from plasma, both by lipid epuration and by compensation using fresh frozen plasma and lipoprotein lipase adjunction.62 There are very few data on the efficacy of plasma exchange in pregnant patients, based on clinical cases or short series.52,56,63 A short series reported a mean removal rate during a single plasma exchange for triglyceride of around 66 and 83% after the second in 17 nonpregnant patients with hypertriglyceridema-induced pancreatitis.62 Technical variants are numerous and involve centrifugation or filtration supplemented or not by immunoadsorption (Ac anti-apoB), precipitation (heparin-induced extracorporeal low-density lipoprotein precipitation) or by adsorption on dextran. They all share a high production cost and require high technology. Other treatment options including combined heparin and insulin infusions have been described in the context of hypertriglyceridemia-induced AP.64–67 The clinical data of these publications have shown pain relief and a reduction of triglycerides below 10 g l–1 in 24 to 48 h. These results were comparable to those obtained with plasma exchange. In conclusion, no standardized guidelines have been published concerning the most effective management of hypertriglyceridemia-induced AP during pregnancy. Therapy should include a multidisciplinary team to address dietary fat restriction, appropriate nutritional supplements and possible medications when needed. Therapeutic plasma exchange and/or other treatment options including combined parenteral heparin and insulin & 2014 Nature America, Inc.

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91 Table 3.

Algorithm of treatment in acute biliary pancreatitis in pregnant women

infusions in severe cases are effective approaches to treat gestational hypertriglyceridemia-induced AP. Termination of pregnancy (induction of labor or cesarean section) would be discussed according to the term and the severity of the AP. The early application of treatments in parturient women with hypertriglyceridemia-induced AP may improve the clinical course.57,58

ALCOHOL Chronic alcoholic consumption is a rare cause of AP during pregnancy, estimated at 5 to 10%. Alcohol and chronic alcoholic pancreatitis before pregnancy were associated with increased rates of recurrence of AP and preterm delivery (66.7% vs 18.6% in case of simple gallstone pancreatitis).1,68 No standardized guidelines have been published concerning the most effective management of chronic alcoholic pancreatitis during pregnancy. Therapeutic strategy should include a multidisciplinary team to address appropriate nutritional supplements, & 2014 Nature America, Inc.

and possible medications when needed. Termination of pregnancy would be discussed according to the term and the severity of the recurrence of AP. The early application of treatments in parturient women with chronic alcoholic pancreatitis may improve the clinical course.

DRUGS-INDUCED AP As in non-pregnant patients, drug-induced AP may occur and it should be systematically explored in the examination. In the literature, thiazide diuretics are the most common drugs implicated in the occurrence of AP during pregnancy.69

PANCREATITIS ASSOCIATED WITH PREGNANCY-INDUCED HYPERTENSION Pancreatitis associated with pregnancy-induced hypertension is exceptional. Severe preeclampsia may cause widespread end-organ damage with abnormalities of the microcirculation Journal of Perinatology (2014), 87 – 94

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92 involving brain, liver, kidney and circulatory systems, and it may affect the gastrointestinal system, resulting in a concomitant pancreatic ischemia and severe necrotizing AP.70–72 Haukland et al.73 showed in 13 patients with severe preeclampsia that mean serum concentration of amylase was statistically significantly higher than the corresponding mean serum concentrations in 30 normal pregnancies (1.6 vs 1.1 mmol l–1). ACUTE FATTY LIVER OF PREGNANCY ASSOCIATED WITH AP Acute fatty liver of pregnancy is a rare condition occurring in the third trimester of pregnancy, characterized by nausea, vomiting, abnormal and moderate hyperbilirubinemia. It may be complicated by renal and acute liver failure, respiratory distress, coagulopathy and rarely pancreatitis. Twelve cases of acute fatty liver of pregnancy associated with AP have been reported with a high maternal mortality rate (17%).74 GENETIC CAUSE Very rare cases of gene mutations (cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator, pancreatic secretory trypsin inhibitor or peroxisome proliferator-activated receptor gamma) have been reported in pregnant women with AP.75–77 ADDITIONAL TREATMENT IN PREGNANT PATIENTS WITH AP Management of AP in pregnant patients is often guided by management of AP in non-pregnant patients: fasting, analgesics, nutritional support and various complications. A particular attention should be paid to the nutrition of pregnant women with severe AP, based on the American Society for Parenteral and Enteral Nutrition standards.78 Early enteral nutrition for a very short period in a pregnant woman to avoid denutrition has a significant impact because such therapy modulates the stress response, promotes more rapid resolution of the disease process, also decreases the risk of bacterial translocation and infection of tissue necrosis, and results in better outcome.79 In cases of pregnancy complicated by AP, the main risks of maternal mortality are those usually associated with necrotizing AP, necrosis infection and multi-organ failure. No prophylactic antibiotic is recommended in agreement with the meta-analysis comparing antibiotics with placebo, which concluded that prophylactic intravenous antibiotics cannot reduce infected pancreatic necrosis and mortality in patients with acute necrotizing pancreatitis.80 No standardized guidelines have been published concerning the most effective way for delivery in women with AP during the third trimester of pregnancy to reduce maternal and neonatal mortality and morbidity. The decision depends on the gestational age and the severity of AP. When vaginal delivery is possible, it is preferable to limit the risk of superinfection necrosis associated with laparotomy used for cesarean sections. A multidisciplinary approach involving gastroenterologists, surgeons and obstetricians is desirable.37,81 Pancreatic pseudocysts complicate 5% of the cases of pancreatitis (fewer than 1 in 60 000 deliveries) and are most frequently associated with alcoholic pancreatitis. The management of this rare condition is not standardized. If a pseudocyst of the pancreas is formed, the recommended management is to observe asymptomatic pseudocysts and those present for o6 weeks, as these have a 30% to 40% rate of spontaneous resolution. Although in some cases laparoscopic or percutaneous or endoscopic drainage of pseudocysts was performed antepartum, most patients were conservatively managed before delivery.82–84 Journal of Perinatology (2014), 87 – 94

CONCLUSION AP during pregnancy is a rare but severe disease. There is no consensus in the literature regarding the management of AP during pregnancy. Traditionally conservative, the treatment of biliary lithiasis depends on the symptoms. A multidisciplinary approach, including gastroenterology and obstetric care, seems to be a key in making the best choice for management of AP during pregnancy. CONFLICT OF INTEREST The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS GD, FM and PC were the main contributors to the conception, manuscript design and preparation of the manuscript. DL and PH advised on the original design and reviewed the manuscript.

REFERENCES 1 Eddy JJ, Gideonsen MD, Song JY, Grobman WA, O’Halloran P. Pancreatitis in pregnancy. Obstet Gynecol 2008; 112: 1075–1081. 2 Pitchumoni CS, Yegneswaran B. Acute pancreatitis in pregnancy. World J Gastroenterol 2009; 15: 5641–5646. 3 Igbinosa O, Poddar S, Pitchumoni C. Pregnancy associated pancreatitis revisited. Clin Res Hepatol Gastroenterol 2013; 37: 177–181. 4 Ramin KD, Ramin SM, Richey SD, Cunningham FG. Acute pancreatitis in pregnancy. Am J Obstet Gynecol 1995; 173: 187–191. 5 Geng Y, Li W, Sun L, Tong Z, Li N, Li J. Severe acute pancreatitis during pregnancy: eleven years experience from a surgical intensive care unit. Dig Dis Sci 2011; 56: 3672–3677. 6 Wilkinson EJ. Acute pancreatitis in pregnancy: a review of 98 cases and a report of 8 new cases. Obstet Gynecol Surv 1973; 28: 281–303. 7 Augustin G, Majerovic M. Non-obstetrical acute abdomen during pregnancy. Eur J Obstet Gynecol Reprod Biol 2007; 131: 4–12. 8 Hernandez A, Petrov MS, Brooks DC, Banks PA, Ashley SW, Tavakkolizadeh A. Acute pancreatitis and pregnancy: a 10-year single center experience. J Gastrointest Surg 2007; 11: 1623–1627. 9 Date RS, Kaushal M, Ramesh A. A review of the management of gallstone disease and its complications in pregnancy. Am J Surg 2008; 196: 599–608. 10 Sun L, Li W, Geng Y, Shen B, Li J. Acute pancreatitis in pregnancy. Acta Obstet Gynecol Scand 2011; 90: 671–676. 11 Papadakis EP, Sarigianni M, Mikhailidis DP, Mamopoulos A, Karagiannis V. Acute pancreatitis in pregnancy: an overview. Eur J Obstet Gynecol Reprod Biol 2011; 159: 261–266. 12 Karsenti D, Bacq Y, Bre´chot JF, Mariotte N, Vol S, Tichet J. Serum amylase and lipase activities in normal pregnancy: a prospective case-control study. Am J Gastroenterol 2001; 96: 697–699. 13 Socie´te´ Nationale Franc¸aise de Gastro-Ente´rologie. [Consensus conference: acute pancreatitis]. Gastroenterol Clin Biol 2001; 25: 177–192. 14 Masselli G, Brunelli R, Casciani E, Polettini E, Bertini L, Laghi F et al. Acute abdominal and pelvic pain in pregnancy: MR imaging as a valuable adjunct to ultrasound? Abdom Imaging 2011; 36: 596–603. 15 Webb JA, Thomsen HS, Morcos SK. Members of Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur Radiol 2005; 15: 1234–1240. 16 Tuech JJ, Binelli C, Aube C, Pessaux P, Fauvet R, Descamps P et al. Management of choledocholithiasis during pregnancy by magnetic resonance cholangiography and laparoscopic common bile duct stone extraction. Surg Laparosc Endosc Percutan Tech 2000; 10: 323–325. 17 Jabbour N, Brenner M, Gagandeep S, Lin A, Genyk Y, Selby R et al. Major hepatobiliary surgery during pregnancy: safety and timing. Am Surg 2005; 71: 354–358. 18 Birchard KR, Brown MA, Hyslop WB, Firat Z, Semelka RC. MRI of acute abdominal and pelvic pain in pregnant patients. AJR Am J Roentgenol 2005; 184: 452–458. 19 ACOG Committee on Obstetric Practice. ACOG Committee Opinion. Number 299, September 2004 (replaces No. 158, September 1995). Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 2004; 104: 647–651. 20 Roumieu F, Ponchon T, Audra P, Gaucherand P. Acute pancreatitis in pregnancy: place of the different explorations (magnetic resonance cholangiopancreatography, endoscopic ultrasonography) and their therapeutic consequences. Eur J Obstet Gynecol Reprod Biol 2008; 140: 141–142.

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Acute pancreatitis during pregnancy G Ducarme et al

93 21 Ranson JH. Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol 1982; 7: 633–638. 22 Arvanitakis M, Koustiani G, Gantzarou A, Grollios G, Tsitouridis I, HaritandiKouridou A et al. Staging of severity and prognosis of acute pancreatitis by computed tomography and magnetic resonance imaging-a comparative study. Dig Liver Dis 2007; 39: 473–482. 23 Robertson KW, Stewart IS, Imrie CW. Severe acute pancreatitis and pregnancy. Pancreatology 2006; 6: 309–315. 24 Tang SJ, Rodriguez-Frias E, Singh S, Mayo MJ, Jazrawi SF, Sreenarasimhaiah J et al. Acute pancreatitis during pregnancy. Clin Gastroenterol Hepatol 2010; 8: 85–90. 25 Ko CW, Beresford SA, Schulte SJ, Matsumoto AM, Lee SP. Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology 2005; 41: 359–365. 26 Maringhini A, Ciambra M, Baccelliere P, Raimondo M, Orlando A, Tine` F et al. Biliary sludge and gallstones in pregnancy: incidence, risk factors and natural history. Ann Intern Med 1993; 119: 116–120. 27 Swisher SG, Hunt KK, Schmit PJ, Hiyama DT, Bennion RS, Thompson JE. Management of pancreatitis complicating pregnancy. Am Surg 1994; 60: 759–762. 28 Debette-Gratien M, Yahchouchy E. Management of acute biliary pancreatitis. Gastroenterol Clin Biol 2001; 25(Suppl): 1S225–240. 29 Othman MO, Stone E, Hashimi M, Parasher G. Conservative management of cholelithiasis and its complications in pregnancy is associated with recurrent symptoms and more emergency department visits. Gastrointest Endosc 2012; 76: 564–569. 30 Curet MJ, Allen D, Josloff RK, Pitcher DE, Curet LB, Miscall BG et al. Laparoscopy during pregnancy. Arch Surg 1996; 31: 546–551. 31 Barone JE, Bears S, Chen S, Tsai J, Russell JC. Outcome study of cholecystectomy during pregnancy. Am J Surg 1999; 177: 232–236. 32 Cosenza CA, Saffari B, Jabbour N, Stain SC, Garry D, Parekh D et al. Surgical management of biliary gallstone disease during pregnancy. Am J Surg 1999; 178: 545–548. 33 Affleck DG, Handrahan DL, Egger MJ, Price RR. The laparoscopic management of appendicitis and cholelithiasis during pregnancy. Am J Surg 1999; 178: 523–529. 34 Society of American Gastrointestinal Endoscopic Surgeons (SAGES). Guidelines for laparoscopic surgery during pregnancy. Surg Endosc 1998; 12: 189–190. 35 Uhl W, Warshaw A, Imrie C, Bassi C, McKay CJ, Lankisch PG et al. International Association of Pancreatology. IAP Guidelines for the Surgical Management of Acute Pancreatitis. Pancreatology 2002; 2: 565–573. 36 Nealon WH, Bawduniak J, Walser EM. Appropriate timing of cholecystectomy in patients who present with moderate to severe gallstone-associated acute pancreatitis with peripancreatic fluid collections. Ann Surg 2004; 239: 741–749. 37 Pandey R, Jacob A, Brooks H. Acute pancreatitis in pregnancy: review of three cases and anaesthetic management. Int J Obstet Anesth 2012; 21: 360–363. 38 Jamidar PA, Beck GJ, Hoffman BJ, Lehman GA, Hawes RH, Agrawal RM et al. Endoscopic retrograde cholangiopancreatography in pregnancy. Am J Gastroenterol 1995; 90: 1263–1267. 39 Farca A, Aguilar ME, Rodriguez G, de la Mora G, Arango L. Biliary stents as temporary treatment for choledocholithiasis in pregnant patients. Gastrointest Endosc 1997; 46: 99–101. 40 Howden JK, Baillie J. Preoperative versus postoperative endoscopic retrograde cholangiopancreatography in mild to moderate pancreatitis: a prospective randomized trial. Gastrointest Endosc 2001; 53: 834–836. 41 Tham TC, Vandervoort J, Wong RC, Montes H, Roston AD, Slivka A et al. Safety of ERCP during pregnancy. Am J Gastroenterol 2003; 98: 308–311. 42 Kahaleh M, Hartwell GD, Arseneau KO, Pajewski TN, Mullick T, Isin G et al. Safety and efficacy of ERCP in pregnancy. Gastrointest Endosc 2004; 60: 287–292. 43 Simmons DC, Tarnasky PR, Rivera-Alsina ME, Lopez JF, Edman CD. Endoscopic retrograde cholangiopancreatography (ERCP) in pregnancy without the use of radiation. Am J Obstet Gynecol 2004; 190: 1467–1469. 44 Shelton J, Linder JD, Rivera-Alsina ME, Tarnasky PR. Commitment, confirmation, and clearance: new techniques for nonradiation ERCP during pregnancy (with videos). Gastrointest Endosc 2008; 67: 364–368. 45 Tang SJ, Mayo MJ, Rodriguez-Frias E, Armstrong L, Tang L, Sreenarasimhaiah J et al. Safety and utility of ERCP during pregnancy. Gastrointest Endosc 2009; 69: 453–461. 46 Chong VH, Jalihal A. Endoscopic management of biliary disorders during pregnancy. Hepatobiliary Pancreat Dis Int 2010; 9: 180–185. 47 Chan CH, Enns RA. ERCP in the management of choledocholithiasis in pregnancy. Curr Gastroenterol Rep 2012; 14: 504–510. 48 Larkin CJ, Workman A, Wright RE, Tham TC. Radiation doses to patients during ERCP. Gastrointest Endosc 2001; 53: 161–164. 49 Boix J, Lorenzo-Zu´n˜iga V. Radiation dose to patients during endoscopic retrograde cholangiopancreatography. World J Gastrointest Endosc 2011; 3: 140–144.

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50 Smith I, Gaidhane M, Goode A, Kahaleh M. Safety of endoscopic retrograde cholangiopancreatography in pregnancy: fluoroscopy time and fetal exposure, does it matter? World J Gastrointest Endosc 2013; 5: 148–153. 51 Polydorou A, Karapanos K, Vezakis A, Melemeni A, Koutoulidis V, Polymeneas G et al. A multimodal approach to acute biliary pancreatitis during pregnancy: a case series. Surg Laparosc Endosc Percutan Tech 2012; 22: 429–432. 52 Klingel R, Go¨hlen B, Schwarting A, Himmelsbach F, Straube R. Differential indication of lipoprotein apheresis during pregnancy. Ther Apher Dial 2003; 7: 359–364. 53 Knopp RH, Warth MR, Charles D, Childs M, Li JR, Mabuchi H et al. Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biol Neonate 1986; 50: 297–317. 54 Saharia P, Margolis S, Zuidema GD, Cameron JL. Acute pancreatitis with hyperlipemia: studies with an isolated perfused canine pancreas. Surgery 1977; 82: 60–67. 55 Crisan LS, Steidl ET, Rivera-Alsina ME. Acute hyperlipidemic pancreatitis in pregnancy. Am J Obstet Gynecol 2008; 198: 57–59. 56 Safi F, Toumeh A, Abuissa Qadan MA, Karaz R, Alakdar B, Assaly R. Management of familial hypertriglyceridemia-induced pancreatitis during pregnancy with therapeutic plasma exchange: a case report and review of literature. Am J Ther 2012, e-pub ahead of print 23 August 2012. 57 Goldberg AS, Hegele RA. Severe hypertriglyceridemia in pregnancy. J Clin Endocrinol Metab 2012; 97: 2589–2596. 58 Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A. Hypertriglyceridemic pancreatitis: presentation and management. Am J Gastroenterol 2009; 104: 984–991. 59 Athyros VG, Giouleme OI, Nikolaidis NL, Vasiliadis TV, Bouloukos VI, Kontopoulos AG et al. Long-term follow-up of patients with acute hypertriglyceridemiainduced pancreatitis. J Clin Gastroenterol 2002; 34: 472–475. 60 Stefanutti C, Di Giacomo S, Vivenzio A et al. Therapeutic plasma exchange in patients with severe hypertriglyceridemia: a multicenter study. Artif Organs 2009; 33: 1096–1102. 61 Ewald N, Kloer HU. Severe hypertriglyceridemia. An indication for apheresis? Atheroscler Suppl 2009; 10: 49–52. 62 Yeh JH, Chen JH, Chiu HC. Plasmapheresis for hyperlipidemic pancreatitis. J Clin Apher 2003; 18: 181–185. 63 Altun D, Eren G, Cukurova Z, Hergu¨nsel O, Yasar L. An alternative treatment in hypertriglyceridemia-induced acute pancreatitis in pregnancy: plasmapheresis. J Anaesthesiol Clin Pharmacol 2012; 28: 252–254. 64 Exbrayat V, Morel J, De Filippis JP, Tourne G, Jospe R, Auboyer C. Hypertriglyceridemia-induced pancreatitis in pregnancy. A case report. Ann Fr Anesth Reanim 2007; 26: 677–679. 65 Sleth JC, Lafforgue E, Servais R, Saizy C, Pluskwa F, Huet D et al. A case of hypertriglycideremia-induced pancreatitis in pregnancy: value of heparin. Ann Fr Anesth Reanim 2004; 23: 835–837. 66 Gu¨rsoy A, Kulaksizoglu M, Sahin M, Ertugrul DT, Ozer F, Tutuncu NB et al. Severe hypertriglyceridemia-induced pancreatitis during pregnancy. J Natl Med Assoc 2006; 98: 655–657. 67 Ewald N, Hardt PD, Kloer HU. Severe hypertriglyceridemia and pancreatitis: presentation and management. Curr Opin Lipidol 2009; 20: 497–504. 68 Stimac D, Stimac T. Acute pancreatitis during pregnancy. Eur J Gastroenterol Hepatol 2011; 23: 839–844. 69 Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J Clin Gastroenterol 2005; 39: 709–716. 70 Parmar MS. Pancreatic necrosis associated with preeclampsia-eclampsia. JOP 2004; 5: 101–104. 71 Hojo S, Tsukimori K, Hanaoka M, Anami A, Nakanami N, Kotoh K et al. Acute pancreatitis and cholecystitis associated with postpartum HELLP syndrome: a case and review. Hypertens Pregnancy 2007; 26: 23–29. 72 Swank M, Nageotte M, Hatfield T. Necrotizing pancreatitis associated with severe preeclampsia. Obstet Gynecol 2012; 120: 453–455. 73 Haukland HH, Florholmen J, Oian P, Maltau JM, Burhol PG. The effect of severe pre-eclampsia on the pancreas: changes in the serum cationic trypsinogen and pancreatic amylase. Br J Obstet Gynaecol 1987; 94: 765–767. 74 Moldenhauer JS, O’brien JM, Barton JR, Sibai B. Acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication. Am J Obstet Gynecol 2004; 190: 502–505. 75 Virgilis D, Rivkin L, Samueloff A, Picard E, Goldberg S, Faber J et al. Cystic fibrosis, pregnancy, and recurrent, acute pancreatitis. J Pediatr Gastroenterol Nutr 2003; 36: 486–488. 76 Inoue N, Ito T, Akashi T, Kawabe K, Oono T, Gibo J et al. Acute pancreatitis in the early stages of pregnancy associated with a PSTI gene mutation. Pancreas 2004; 29: 242–243. 77 Madhra M, Noh RM, Zammitt NN, Patrick AW, Love CD. A complicated pregnancy in a patient with lipodystrophic diabetes attributable to a peroxisome proliferatoractivated receptor gamma (PPARG) mutation. Diabet Med 2012; 29: e398–e401.

Journal of Perinatology (2014), 87 – 94

Acute pancreatitis during pregnancy G Ducarme et al

94 78 Kochevar M, Guenter P, Holcombe B, Malone A, Mirtallo J. ASPEN Board of Directors and Task Force on Parenteral Nutrition Standardization. ASPEN statement on parenteral nutrition standardization. J Parenter Enteral Nutr 2007; 31: 441–448. 79 McClave SA. Nutrition support in acute pancreatitis. Gastroenterol Clin North Am 2007; 36: 65–74. 80 Bai Y, Gao J, Zou DW, Li ZS. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled trials. Am J Gastroenterol 2008; 103: 104–110.

Journal of Perinatology (2014), 87 – 94

81 Ducarme G, Chaˆtel P, Alves A, Hammel P, Luton D. Management of necrotizing pancreatitis in the third trimester of pregnancy. Arch Gynecol Obstet 2009; 279: 561–563. 82 Bansal VK, Misra MC, Goswami A, Garg P, Yonjen T, Kilambi R. Laparoscopic management of pseudocyst of the pancreas in a pregnant patient. Surg Laparosc Endosc Percutan Tech 2012; 22: e37–e38. 83 Eddy JJ, Lynch GE, Treacy DE. Pancreatic pseudocysts in pregnancy: a case report and review of the literature. J Perinatol 2003; 23: 69–72. 84 Gyokeres T. Successful endoscopic resolution of pancreatic pseudocyst in pregnancy. J Perinatol 2004; 24: 270.

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