Pancreatitis in pregnancy： etiology， diagnosis，treatment， and outcomes

Padmavathi MaliMarshfield， USA

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Pancreatitis in pregnancy： etiology， diagnosis，treatment， and outcomes

Padmavathi Mali
Marshfield， USA

BACKGROUND： Acute pancreatitis in pregnancy is a rare and dangerous disease. This study aimed to examine the etiology，treatment， and outcomes of pancreatitis in pregnancy.

METHOD： A total of 25 pregnant patients diagnosed with pancreatitis during the period of 1994 and 2014 was analyzed retrospectively.

RESULTS： The pregnant patients were diagnosed with pancreatitis during a period of 21 years. Most （60%） of the patients were diagnosed with pancreatitis in the third trimester. The mean age of the patients at presentation was 25.7 years， with a mean gestational age of 24.4 weeks. Abdominal pain occurred in most patients and vomiting in one patient was associated hyperemesis gravidarum. The common cause of the disease was gallstone-related （56%）， followed by alcohol-related （16%），post-ERCP （4%）， hereditary （4%） and undetermined conditions （20%）. The level of triglycerides was minimally high in three patients. ERCP and wire-guided sphincterotomy were performed in 6 （43%） of 14 patients with gallstone-related pancreatitis and elevated liver enzymes with no complications. Most （84%） of the patients underwent a full-term， vaginal delivery. There was no difference in either maternal or fetal outcomes after ERCP.

CONCLUSIONS： Acute pancreatitis is rare in pregnancy， occurring most commonly in the third trimester， and gallstones are the most common cause. When laparoscopic cholecystectomy is not feasible and a common bile duct stone is highly suspected on imaging， endoscopic sphincterotomy or stenting may help to prevent recurrence and postpone cholecystectomy until after delivery.

（Hepatobiliary Pancreat Dis Int 2016；15：434-438）

pancreatitis；

alcoholic pancreatitis；

pregnancy complications；

diagnostic imaging

Introduction

Pancreatitis in pregnancy is a rare condition estimated to occur in 1 in 1000 to 1 in 12000 pregnancies and can cause serious morbidity for both mother and fetus. Pancreatitis during pregnancy usually occurs as a result of gallstone disease and less often from alcohol or hyperlipidemia. In the past， acute pancreatitis during pregnancy resulted in a high incidence of maternal morbidity and neonatal death after premature birth， but advances in diagnostic imaging and neonatal intensive care have improved prognosis in recent years. Reports［1， 2］suggested that patients with pregnancy-related pancreatitis is most common in the third trimester and postpartum period. The present study was undertaken to examine the causes， treatment， and factors associated with adverse outcomes of acute pancreatitis in pregnancy.

Methods

This study was approved by the institutional review board， with waiver of informed consent. The author retrospectively reviewed pregnant patients diagnosed with pancreatitis during the period of January 1994 to December 2014. The patients with pancreatitis were identified using International Classification of Disease version 9 （ICD-9） codes in the Marshfield Clinic electronic medical record， attempting to exclude tumor-related pancreatitis although nothing was identified. Manual data included age at diagnosis， trimester of pregnancy，demographic characteristics， clinical presentation， causes of pancreatitis （e.g.， gallstones， alcohol consuption， hypertriglyceridemia， and idiopathic factors）， laboratory values （e.g.， serum amylase， lipase， and liver enzymes）. Four parameters were also examined to determine thepresence of systemic inflammatory response syndrome ［i.e. temperature ＞38.3 ℃ or ＜36 ℃， respiratory rate ＞20 breaths per minute， heart rate ＞90 beats per minute，and white blood cell count ＞12 000/μL or ＜4 000/μL or ＞10% immature （band） forms］. If there were ≥2 criteria，severe pancreatitis was considered. Moreover， the following data were collected： ultrasound findings， endoscopic retrograde cholangiopancreatography （ERCP） findings，procedures done during ERCP， treatments given （e.g.，parenteral nutrition）， cholecystectomy （before， during， or after pregnancy）， admission to the intensive care unit， maternal complications （e.g.， preterm delivery， preeclampsia and eclampsia， emergent Cesarean delivery），neonatal complications （e.g.， fetal demise， admission to intensive care unit）， and recurrence of symptoms during pregnancy. Apgar scores of infants at 1 and 5 minutes were collected， and patients who underwent ERCP were compared with those who did not. The data collected from the medical record were retrospectively analyzed. The P values for the Apgar scores were calculated using Wilcoxon's rank-sum test.

Results

Over the 21-year period from January 1， 1994 through December 31， 2014， there were 25 pregnant patients diagnosed with pancreatitis， of which 5 （20%） were diagnosed in the first trimester， 5 （20%） in the second trimester， and 15 （60%） in the third trimester. Their mean age at presentation was 25.7 ［standard deviation （SD） 5.3］years， ranging from 19 to 39 years. The mean gestational age at occurrence was 24.4 （SD 9.9） weeks， ranging from 6 to 41 weeks. Approximately 76% of the patients were multiparous， and 24% were nulliparous （6 patients were diagnosed during their first pregnancy， 10 during their second， and the rest in their third through sixth pregnancies）. The disease was acute in most （64%） of the patients and acute-on-chronic in 9 （36%）.

Twenty-one of the 25 patients presented with abdominal pain， and twelve were associated with vomiting. Vomiting alone appeared in two patients （hyperemesis gravidarum in one and syncope in one）. Gallstone-related pancreatitis was seen in 14 （56%） patients， alcoholrelated in 4 （16%）， post-ERCP in 1 （4%）， hereditary in 1 （4%）， and undetermined in 5 （20%）. The etiology of pancreatitis and trimesters of the patients at diagnosis are shown in Table 1.

Amylase levels ranged from 18 to 7845 U/L， with an average of 1121 U/L. Lipase levels ranged from 15 to 5325 U/L with an average of 1674 U/L. The level of triglycerides was minimally elevated in 3 patients： two with gallstone-related pancreatitis and one with alcohol-related pancreatitis. One patient with alcohol-related pancreatitis met two criteria positive for systemic inflammatory response syndrome， suggesting severe pancreatitis.

All the patients underwent abdominal ultrasound，and one patient with gallstone-related pancreatitis was subjected to magnetic resonance imaging （MRI） of the abdomen. Of the 14 patients with gallstone-related pancreatitis， 6 （43%） with elevated levels of liver enzymes underwent ERCP and wire-guided endoscopic sphincterotomy without complications （5 patients diagnosed in the third trimester， and 1 in the second trimester）. All patients were treated with intravenous hydration and bowel rest， and only 2 （8%） patients received parenteral nutrition. Symptoms were improved in 21/25 patients within 24-72 hours after treatment with enteral nutrition. One patient was admitted to the intensive care unit for associated anemia requiring transfusions.

Table 1. Etiological diagnosis of pancreatitis by trimesters

Most patients （21/25， 84%） with pancreatitis proceeded to a full-term vaginal delivery （18 began labor spontaneously and 3 were induced）. Of those who did not， Cesarean delivery was performed in two patients with gallstone-related pancreatitis， including one as emergent post-ERCP Cesarean delivery for pancreatitis，and one was done for acute pancreatitis. Of patients who underwent Cesarean delivery， two were in patients with alcohol-related pancreatitis. Recurrent pancreatitis occurred in 3 patients， one with alcohol-related severe pancreatitis and 2 with gallstone-related mild pancreatitis. Maternal outcomes like preterm delivery and Cesarean delivery in the mother and development of complications like preeclampsia and eclampsia were recorded. None of the patients had preeclampsia or eclampsia. Neonatal birth weights were available in 13 patients，ranging from 5 pounds， 12 ounces to 7 pounds， 6 ounces. The average birth weight was 6 pounds， 7 ounces. Apgar scores were available in 10 patients. In 5 patients who had ERCP， the average Apgar score of infants was 8.2 at 1 minute and 9.4 at 5 minutes. In 5 patients who did not undergo ERCP， the scores were 8.2 at 1 minute and 9.0 at 5 minutes. None of the infants were transferred to the neonatal intensive care unit after delivery. Tables 2 and 3illustrate the maternal and neonatal outcomes based on etiology. Table 4 illustrates comparison of neonatal outcomes （Apgar scores） based on ERCP status.

Discussion

Pancreatitis in pregnancy occurs most often in multiparous women in the third trimester of pregnancy. The most common cause of pancreatitis in pregnancy is gallstone-related， accounting for 65%-100% of cases.［1］Cholesterol secretion in the bile increases in the second and third trimesters， leading to formation of supersaturated bile. Emptying of the gallbladder slows due to progesterone-induced increases in gallbladder volume， thus contributing to gallstone formation. The large residual volume of supersaturated bile in the gallbladder predisposes to cholesterol crystals and gallstone formation. An increase in the pressure of sphincter of Oddi also induces bile stasis. This is consistent with the present finding that 14 （56%） of 25 patients with pancreatitis during pregnancy had gallstone disease.

Table 2. Maternal and neonatal outcomes based on etiology

Table 4. Comparison of Apgar scores in infants whose mothers underwent ERCP with those who did not

Hyperlipidemia is reported to be the second most common cause of acute pancreatitis in pregnancy.［1］Plasma triglyceride level is increased by 2 to 3 times during pregnancy， especially in the third trimester because of increased triglyceride-rich lipoprotein formation and decreased lipoprotein lipase activity.［3］A triglyceride level greater than 1000 mg/dL is a risk factor for pancreatitis，but a reduction to 100 mg/dL reduces the likelihood of further episodes. Only three patients in the present study had elevated levels of triglycerides in the range of 100-200 mg/dL， and all had other risk factors for pancreatitis， including gallstones in two patients and alcohol use in one， suggesting that the elevated level of triglycerides is not a causative factor. Other causes of pancreatitis reported in the literature are consistent with the present findings and they include alcohol use and medications such as diuretics， anti-hypertensive agents， and antibiotics although many cases are idiopathic.

Acute pancreatitis during pregnancy is diagnosed by laboratory testing and diagnostic imaging. The former comprises tests for complete blood count， amylase， lipase，triglycerides， and liver function which could detect the presence of cholelithiasis. Combined elevated amylase and lipase testing increases the sensitivity of diagnosis to 94%， while amylase testing alone has a sensitivity of 81%. In pregnancy， alkaline phosphatase levels can increase up to 3 times the normal level. Serum amylase and lipase levels higher than 3 times the normal level are of positive predictive value for diagnosis.［4］

Abdominal ultrasound is ideal for diagnosing acute pancreatitis in pregnancy as it does not have a radiation risk， however， it is not sensitive enough to detect common bile duct stones or sludge. Computed tomography has a radiation risk and， as such， is not recommended as a diagnostic modality during pregnancy.［5］Magnetic resonance cholangiopancreatography （MRCP） and endoscopic ultrasound （EUS） are useful to diagnose acute pancreatitis with biliary etiology. MRI provides information on acute pancreatitis and its complications such as edema， pseudocysts， and hemorrhagic pancreatitis without fetal toxicity because of the use of gadolinium instead of iodinated contrast. It is neither invasive nor does it require anesthetic. EUS has a better predictive value and is more sensitive for the diagnosis of choledocholithiasis than MRI.［6］It has no risk of radiation exposure， but does require intravenous sedation and expertise. None of the patients in this study underwent EUS， and only one patient underwent MRI.

If a common bile duct stone is detected， ERCP with sphincterotomy can be performed immediately after EUS without the need to repeat sedation. Persistent bili-ary obstruction increases the severity of acute pancreatitis and predisposes to bacterial cholangitis. ERCP with sphincterotomy helps to drain infected bile and extract impacted stones in patients with acute pancreatitis. Reports［7， 8］suggest that ERCP is safe during pregnancy so long as fluoroscopy time is minimized and the fetus and pelvis are shielded with lead to reduce fetal radiation to the maximum permissible dose. MRCP or EUS helps to identify patients who require therapeutic ERCP， thus reducing the number of ERCP procedures performed. In the study， ERCP was performed in slightly less than half of the patients with gallstone-related pancreatitis， and there was no obvious difference in outcomes of patients who underwent ERCP or not. For most patients with acute pancreatitis during pregnancy， conservative treatment including bowel rest and intravenous fluid is sufficient.

There are several treatment options for gallstonerelated pancreatitis during pregnancy， which are largely dependent on the trimester of pregnancy， severity of pancreatitis， presence of cholangitis， and dilatation of the common bile duct. The options include surgery［9］with either an open or laparoscopic approach［10-14］and ERCP with biliary sphincterotomy；［15-20］however， no comprehensive guidelines are available for the treatment of biliary pancreatitis in pregnancy. When acute pancreatitis occurs as a result of hypertriglyceridemia， dietary fat restriction， nutritional supplements， and medications can be used as needed. In severe cases， therapeutic plasma exchange and/or combined heparin and insulin infusions to increase lipoprotein lipase activity are effective.［21-23］In severe acute hypertriglyceridemic pancreatitis， treatment with dietary fat restriction and lipid lowering drugs might be inadequate. A meta-analysis［21］showed improvement clinically and in laboratory testing； however，a definitive conclusion could not be reached because of lack of control group. Plasmapharesis has been used，but not without risk of a transfusion or allergic reaction. The American Society for Apheresis （ASFA） guidelines list apheresis as category 3 （specific role not determined）because of limited data and conflicting reports. The 2010 ASFA guidelines list urgent plasma exchange as the treatment for acute pancreatitis due to hyperglyceridemia，but it is a category 3 and grade 1b recommendation.［24］In this study， most patients underwent ERCP， and none had cholecystectomy during pregnancy.

Conservative treatment is usually given in the first trimester， laparoscopic cholecystectomy in the second trimester， and conservative treatment or ERCP with sphincterotomy or cholecystectomy in the early postpartum period for patients presenting in the third trimester. ERCP with sphincterotomy is indicated for patients with choledocholithiasis associated with acute pancreatitis，cholangitis， and those who are poor candidates for surgery in the first and third trimesters.［6］The effectiveness of endoscopic sphincterotomy is demonstrated in highrisk patients as an alternative to cholecystectomy in preventing further episodes of biliary pancreatitis.［15， 18， 20］The fetal risk of ERCP must be weighed against the risk to the fetus and mother in the absence of intervention，and there is no evidence that ERCP is required in all patients with biliary sludge in pregnancy.

In the present study， patients diagnosed in the first trimester were treated conservatively and those diagnosed in the second trimester underwent ERCP. In those diagnosed in the third trimester， 50% had ERCP， and all underwent postpartum cholecystectomy if ERCP was not done during pregnancy. There are currently no standardized guidelines concerning the most effective method of delivery for women with acute pancreatitis in the third trimester to reduce maternal and neonatal mortality and morbidity， and decision-making is dependent on gestational age and severity of the disease.

In the past， acute pancreatitis in pregnancy was associated with 20%-50% maternal deaths and fetal loss. A recent study［25］has shown a mortality of less than 5% due to earlier diagnosis， better treatment options， and availability of high-quality intensive care. However， there are still some fetal risks related to acute pancreatitis during pregnancy， including preterm labor， prematurity，and in utero fetal death.［26］Another study［27］showed that pancreatitis in pregnancy was not associated with neonatal or infant deaths， but with preterm delivery， short gestational age， jaundice， respiratory distress syndrome，intrauterine fetal death， and even with preeclampsia and severe preeclampsia.

In the present study， preterm deliveries occurred in 4 patients （Table 3）. Cesarean delivery was performed in 2 patients with gallstone-related pancreatitis and 2 with alcohol-related pancreatitis. Other maternal outcomes like preeclampsia and eclampsia were monitored and none of the patients suffered from these diseases. Neonatal outcomes were measured by Apgar scores. The scores at 1 and 5 minutes were not different in patients who underwent ERCP from those who did not. None of them had infant death or infants being admitted to the neonatal intensive care unit. The major limitation of the present study is the small number of patients.

In conclusion， acute pancreatitis presents a challenge during pregnancy. Gallstones are the most common cause of the diesease. Abdominal ultrasound， MRCP，and EUS in conjunction with laboratory testing can be used for the diagnosis of acute pancreatitis. Treatment is primarily supportive with hospitalization， bowel rest，intravenous fluid administration， analgesia and later enteral nutrition. Laparoscopic cholecystectomy can be performed safely in the second trimester. If it is not feasible， and a common bile duct stone is highly suspected on imaging， endoscopic sphincterotomy or stenting may help to prevent recurrence and postpone cholecystectomy until after delivery.

Contributors： MP wrote the whole manuscript， and is the guarantor. Funding： None.

Ethical approval： This study was approved by the institutional review board， with waiver of informed consent.

Competing interest： No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Accepted after revision January 4， 2016

Author Affiliations： Department of Internal Medicine， Marshfield Clinic，1000 N Oak Ave， Marshfield， WI 54449， USA （Mali P）

Padmavathi Mali， MD， Department of Internal Medicine， Marshfield Clinic， 1000 N Oak Ave， Marshfield， WI 54449， USA （Tel： +1-715-389-5127； Email： mali.padmavathi@marshfieldclinic.org）
? 2016， Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872（16）60075-9
Published online February 24， 2016.

July 19， 2015