Eddy, Jennifer J. MD1; Gideonsen, Mark D. MD1; Song, Jonathan Y. MD2; Grobman, William A. MD, MBA3; O'Halloran, Peggy MPH1
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Pancreatitis in pregnancy is a rare condition estimated to occur in one in 1,000 to one in 12,000 pregnancies.1 There is a wide range of outcomes reported in the literature. Reports through 1980 estimate maternal and perinatal mortality rates at 0–37% and 11–37%,2–6 whereas later, multi-year, single-institution reviews demonstrate better outcomes, with no maternal mortality and perinatal mortality of 0–18%.1,7–12
Generalization from these later reviews is difficult because they span different decades and countries. Some include all cases of pancreatitis,8,9 whereas others report only acute or biliary pancreatitis1,7,10–12; some include only those cases occurring during pregnancy,9–11 whereas others also include postpartum cases.1,7,8 Furthermore, because of the rarity of this condition, the number of cases in these reviews is typically small. Using a Medline search with key words “pancreatitis” and “pregnancy,” we determined that the largest study since 1980 included 43 women.1 Because gallstone pancreatitis accounts for the majority of acute pancreatitis in pregnancy, nongallstone pancreatitis has not been well characterized in these reviews, although it has been associated with poor outcomes in case reports.13–17
Equally uncertain are the actual and the optimal techniques for managing gallstone pancreatitis in pregnancy. Expectant management during pregnancy, once the norm,2,7 has been challenged by case reports and series documenting high recurrence rates among patients receiving conservative management10,19 and, conversely, good outcomes with laparoscopic cholecystectomy,18–24 endoscopic retrograde cholangiopancreatography, and endoscopic sphincterotomy during pregnancy.25–27 Some authors recommend intervening only for worsening or recurrent pancreatitis, others suggest intervening in the second trimester for cases presenting in the first or second trimesters and postpartum for cases presenting in the third trimester,7,9 and still others advocate intervening in all trimesters.10,19
Given the current uncertainty regarding incidence, management, and outcome of pancreatitis in pregnancy, it is important to establish accurate, generalizable information so that patients can be counseled and treated appropriately. To this end, we have analyzed all cases of pancreatitis that occurred in pregnant women at 15 hospitals over 10 years. This study describes the incidence, cause, and complications of both acute and chronic pancreatitis in this population and identifies factors associated with adverse health outcomes.
MATERIALS AND METHODS
Fifteen tertiary care and community hospitals in urban and suburban settings were identified in three Midwestern states and agreed to participate in this study. Institutional review board approval was obtained from the University of Wisconsin and from each of the participating hospitals. We reviewed all charts from 1992–2001 with an International Classification of Disease, 9th Revision, Clinical Modification code for pancreatitis (577.0–577.9) during pregnancy and extracted information on maternal age, gravidity/parity, gestational age at presentation and delivery, cause, and diagnostic testing (eg, amylase/lipase, ultrasonography/magnetic resonance imaging, triglycerides, calcium), interventions (open or laparoscopic cholecystectomy, endoscopic retrograde cholangiopancreatography and/or endoscopic sphinterotomy), and health outcomes. Each hospital provided information on the number of deliveries performed during the study period.
Categorization of the cause of pancreatitis was done based on diagnosis by the managing physician in concert with imaging and laboratory studies. Cases charted as “gallstone pancreatitis” were categorized as gallstone pancreatitis, including four cases in which no ultrasonogram was obtained or referenced. Cases charted as “idiopathic” were analyzed as such, although in half of them a calcium or triglyceride level or both was not checked. All cases involving alcohol abuse were analyzed as alcoholic pancreatitis, including four cases that also had gallstones. Chronic pancreatitis was diagnosed when episodes of pancreatitis occurred over many years accompanied by a diagnosis of chronic pancreatitis or with evidence of pancreatic insufficiency (diabetes) or surgical intervention (Roux-en-Y).
Analysis was performed using SAS 9.1 (SAS Institute, Inc., Cary, NC). Differences between the groups in categorical data were evaluated using χ2, and the Student's t-test was used to discern differences between the groups in continuous data. All tests were two-tailed, and P<.05 were considered significant. The health outcomes of women whose pregnancies resulted in elective abortions were excluded from all analyses except those of maternal age and gestation at presentation, pseudocyst, cause, and management. Gallstone pancreatitis with a second cause (alcohol, tumor, or after endoscopic retrograde cholangiopancreatography) was excluded from the analysis of both simple gallstone pancreatitis and nongallstone pancreatitis.
Over the study period, 305,101 women delivered at the 15 institutions. One hundred one cases of pancreatitis (89 acute and 12 chronic) occurred among this population, for a frequency of one in 3,021 pregnant women (0.033%, 95% confidence interval 0.027–0.040%). The majority (66.3%) of cases of acute pancreatitis was caused by gallstones, and most of these cases were simple gallstone pancreatitis. Of the acute cases, 15 (16.5%) were considered idiopathic and 11 (12.3%) were caused by alcohol. The other causes of acute pancreatitis were varied and are listed in Table 1. The causes of chronic pancreatitis are listed in Table 2. As can be seen, the majority were related to alcohol abuse.
The initial occurrence of pancreatitis was distributed across a range of gestational ages, with significantly more cases presenting later in gestation: 24% presented in the first trimester, 33% presented in the second trimester, and 43% presented in the third trimester. Thirty-seven percent of women were nulliparous, 27% had had one child, 15% had had two children, and 22% had had three or more children. The average maternal age at presentation was 26.2 years and was higher among women with alcoholic (32.1 years, P<.05) and chronic (30.1 years, P<.05) pancreatitis.
Eight patients (8.9% of 90 women who received an ultrasound examination of the right upper quadrant) had documented pseudocysts, with an average length of 5.1 cm. No pseudocyst was drained antenatally, and five women had successful vaginal deliveries despite the pseudocyst, including two in whom the pseudocysts measured more than 6 cm.
Maternal morbidity was determined for 84 women with pancreatitis for whom documentation was available for the entirety of the pregnancy. Parenteral nutrition was required in 20 women (24%) for an average of 20 days (range 3 to 77). Five women required admission to an intensive care unit. Only one of these was directly due to pancreatitis—a case of hyperlipidemic pancreatitis with phlegmon. Two intensive care unit admissions resulted from complications of parenteral nutrition (atrial fibrillation and line sepsis), and the other two were for unrelated medical conditions.
Of the patients with chronic pancreatitis, two had previously undergone Roux-en-Y operations, four had diabetes as a consequence of chronic pancreatitis, and one developed diabetic ketoacidosis during pregnancy but did not require intensive care treatment. Symptoms recurred during the same pregnancy in 36% of cases, more commonly for women with chronic pancreatitis than for those with acute pancreatitis (82% compared with 29%, P<.05). There were no maternal deaths.
With regard to pregnancy outcomes, 27 women (32.1%) delivered a preterm neonate, with 10 (11.9%) delivering before 35 weeks. Of the severely preterm deliveries, four (two with chronic pancreatitis) were by emergent cesarean delivery because of nonreassuring fetal tracing; in two others, labor was induced or augmented because of worsening pancreatitis. In at least four cases, severely premature delivery was due to factors not directly related to pancreatitis, such as placental abruption or chorioamnionitis.
There were three intrauterine deaths (3.6%), including one case of traumatic abruption at 27 weeks secondary to a motor vehicle accident (which caused the patient's pancreatitis), chorioamnionitis and failed cerclage in a twin gestation at 22 weeks occurring 6 weeks after an episode of simple gallstone pancreatitis, and a spontaneous abortion at 15 weeks at initial presentation of acute gallstone pancreatitis. There were also three cases of elective abortion in the first trimester.
Table 3 demonstrates selected patient outcomes stratified by the cause of pancreatitis. In general, biliary pancreatitis had better outcomes than did all-cause pancreatitis. Patients with nongallstone pancreatitis were significantly more likely to have preterm delivery (51.4% compared with 18.6%, P<.05) and pseudocyst (16.2% compared with 0%, P<.05) than were patients with simple gallstone pancreatitis. Patients with alcoholic pancreatitis were more likely to have recurrence of pancreatitis during pregnancy (75.0% compared with 29.2%, P<.05) and preterm delivery (66.7% compared with 26.4%, P<.05) compared with patients in whom alcohol was not a factor. Although the numbers were small, hyperlipidemic pancreatitis had particularly poor outcomes compared with other causes and significantly increased rates of preterm delivery (100% compared with 28.8%, P<.05) and pseudoocyst (50.0% compared with 6.3%, P<.05).
In 52 of 59 women with gallstone pancreatitis, management could be determined. Nine of 14 women presenting in the first trimester (64.3%) received antepartum surgical or endoscopic treatment, as did 10 of 16 women presenting in the second trimester (62.5%) and two of 21 women presenting in the third trimester (9.5%). Of women who presented in the first trimester and received intervention, two had cholecystectomy deferred until the second trimester and seven had intervention in the first trimester (four underwent endoscopic retrograde cholangiopancreatography and three had laparoscopic cholecystectomy—two of whom had abortions). Of women who presented in the second trimester and received intervention, all were treated in the second trimester (two with open cholecystectomy, six with laparoscopic cholecystectomy alone, three with endoscopic retrograde cholangiopancreatography alone, and one with endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy). Of the two women receiving intervention who presented in the third trimester, one underwent laparoscopic cholecystectomy and the other had endoscopic retrograde cholangiopancreatography.
Outcomes among the subgroup of women with simple gallstone pancreatitis were stratified according to whether they underwent intervention or conservative management. Forty-six patients had complete information on both management and outcome (Table 4). Excluding two cases of elective abortion, among the 14 women receiving antepartum cholecystectomy or endoscopic retrograde cholangiopancreatography, there was one fetal death (7.1%) at 22 weeks and one preterm delivery (7.1%) at 36 weeks. Among the 30 cases that were conservatively managed, there was one fetal death (3.3%) at 15 weeks and seven preterm deliveries (23.3%). Symptoms of pancreatitis recurred in one (14.3%) woman after laparoscopic cholecystectomy and in eight women managed conservatively (26.7%). Three other cases of pancreatitis were the result of endoscopic retrograde cholangiopancreatography for gallstones, one at 8 weeks and two at 27 weeks, and all three delivered at term without further recurrence.
This large multi-institution review confirms many findings from prior reports of pancreatitis in pregnancy. The incidence of one in 3,428 for acute pancreatitis in pregnancy is comparable with one in 3,333 observed in the largest single-institution study, by Ramin and colleagues.1 Increasing incidence with gestational age has been noted in other studies.1,28,29 The biliary predominance of our cases (58% overall, 65.2% of acute pancreatitis) is similar to 65–100% noted in earlier studies.1,6,7,9 Maternal mortality in this study (less than 1%) is comparable with others' findings for this condition.1,7–12
The overall rate of preterm delivery (32.1%) in this study is significantly higher than the 15–19% observed elsewhere.1,9,10 However, among women with simple gallstone pancreatitis, the frequency of preterm delivery (18.6%) is more consistent with previous data. Despite the higher rate of preterm delivery, the rate of perinatal death (3.6%) in this study is less than the 10.5% found by Ramin et al1 and the 10–20% reported in the literature.28,29 This is surprising because our study includes cases of chronic pancreatitis that presumably should increase the rate of fetal wastage. Our good outcomes most likely reflect the improvements in neonatal intensive and supportive care that have occurred during the past decades in this country, a hypothesis supported by a perinatal death rate of 4.8% in the most recent review by Hernandez.10
No unified approach to the management of gallstone pancreatitis was discernable in this study, perhaps reflecting controversies in management of biliary disease in pregnancy or specialist availability and expertise across a variety of institutions. For women with gallstone pancreatitis not choosing termination (n=50), surgical intervention occurred less frequently in the first (8.3%) and third trimesters (4.5%) compared with the second trimester (47%),7,9 and laparoscopic cholecystectomy occurred more frequently than did open cholecystectomy (11 compared with two). Endoscopic retrograde cholangiopancreatography occurred almost as frequently as surgical intervention (nine compared with 13). Two women with pancreatitits in their first trimester had cholecystectomy deferred until the second trimester; no cases of endoscopic retrograde cholangiopancreatography were deferred until the second trimester. In fact, endoscopic intervention was more common in the first (33.3%) than in the second (23.5%) or third (4.5%) trimesters in this study.
Based on our findings, we are unable determine the optimal management of simple gallstone pancreatitis occurring during pregnancy. Although patients receiving antepartum surgical or endoscopic intervention had lower rates of premature delivery and recurrence than those receiving conservative care, these differences were not statistically significant (P=.2). A sample larger than our 44 cases of simple gallstone pancreatitis would be needed to identify significant differences in outcome based on management, if they exist.
Parenteral nutrition is considered safe in pregnancy and necessary when adequate oral nutrition is not possible, although the frequency of complications from centrally inserted catheters is higher than in nonpregnant patients.30 Almost a quarter of cases in the study received parenteral nutrition, and 9% of those receiving it required intensive care unit admission as a result. Pancreatitis caused by alcohol had much lower rates of parenteral nutrition in this study, which is surprising because malnutrition is a common complication of alcoholism. Lower rates of parenteral nutrition in this population could reflect provider bias or concern about parenteral substance abuse or unreliable follow-up.
Alcoholic pancreatitis was more prevalent in this study than in other reviews of pancreatitis in pregnancy (17.8% overall; 12.3% of 89 acute pancreatitis cases compared with 7% or less in other studies of acute pancreatitis)7,9,10 because of our inclusion of chronic pancreatitis and perhaps also because of our selection of Midwestern states with a high prevalence of alcohol use.31 Alcohol was responsible for more than half of cases of chronic pancreatitis, and chronic pancreatitis complicated more than a third of all cases where alcohol was involved. Alcoholic pancreatitis was associated with significantly higher rates of preterm delivery and recurrence than all-cause pancreatitis in this study.
Nongallstone pancreatitis as a whole had worse outcomes than simple gallstone pancreatitis in this study. Traumatic, hyperlipidemic, and alcohol-induced pancreatitis had particularly poor outcomes. Pseudocysts were almost exclusively associated with nongallstone pancreatitis, which has been reported elsewhere.32
Symptomatic hyperparathyroidism in pregnancy is rare and most often due to parathyroid adenoma.33 Pancreatitis occurs as a result of hypercalcemia, which also can cause hyperemesis gravidarum, nephrolithiasis, muscle weakness, mental status changes, and even hypercalcemic crisis (calcium greater than 14 mg/dL), which may progress to uremia, coma, and death.33 Fetal complications include postpartum neonatal hypocalcemia, intrauterine growth restriction, low birth weight, preterm delivery, and fetal death. Prompt diagnosis and treatment has been shown to improve outcomes. Our single case of hyperparathyroidism-induced pancreatitis was diagnosed with parathyroid adenoma, and the patient underwent parathyroidectomy in the second trimester without complication and delivered uneventfully at term.
Plasma triglycerides increase twofold to fourfold in pregnancy,34 principally in the third trimester,35 because of increased triglyceride-rich lipoprotein production and decreased lipoprotein lipase activity.36 In women with abnormal lipoprotein metabolism, this can lead to severe hypertriglyceridemia and chylomicronemic syndrome, precipitating pancreatitis.35 Delivery, which causes an abrupt drop in triglycerides, may be necessary to optimize maternal health in some cases.36 Published reports estimate that hyperlipidemic pancreatitis accounts for 4–6% of acute pancreatitis in pregnancy and is associated with particularly poor outcomes.13,34 Our findings confirm this characterization: four patients (4.4% of acute pancreatitis cases) with hyperlipidemic pancreatitis presented at a mean gestational age of 32 weeks (range 30–34 weeks) and an average triglyceride level of 5,000 mg/dL; all delivered prematurely, one at less than 35 weeks. Half of these patients had pseudocysts, half required parenteral nutrition, and one required intensive care because of worsening pancreatitis with phlegmon.
The worse outcomes observed for nongallstone pancreatitis emphasize the importance of evaluating women with pancreatitis for evidence of hyperparathyroidism, hyperlipidemia, or alcohol abuse by obtaining calcium and triglyceride levels and by questioning them about their alcohol use.
Even with appropriate screening, the cause of pancreatitis may be elusive. Patients may be reluctant to reveal a history of alcohol use during pregnancy given the potential for stigmatization; in one case report, an elevated gamma-glumatyl transpeptidase level prompted further questioning by a patient's physician before the history of alcohol use, and the correct diagnosis, was obtained.37 Triglyceride levels higher than 1,000 mg/dL are necessary to cause pancreatitis34 but have been reported to decline with bowel rest and hydration. The hypercalcemia of hyperparathyroidism may be suppressed by magnesium tocolysis16 or factitiously lowered by hypoalbuminemia. Our findings demonstrate that a comprehensive search for cause is not always undertaken, even when the cause of pancreatitis is obscure.
This large, multi-institution review confirms prior reports regarding the incidence, biliary predominance, and overall good outcomes for pancreatitis in pregnancy. Despite the large number of cases, however, no single management strategy for gallstone pancreatitis was observed in this study nor can one be recommended as a result of its findings. Because of the rarity of pancreatitis in pregnancy (fewer than one in 3,000 pregnancies), any geographic or ethnic variation would be expected to significantly affect its characterization. Our study of Midwestern patients found higher rates of alcohol-associated pancreatitis than did prior reports. This review adds substantially to our understanding of pancreatitis in pregnancy, in particular affirming the increased risks for mother and fetus associated with chronic and nonbiliary pancreatitis (particularly from alcohol and hypertriglyceridemia) and thus the importance of identifying nonbiliary causes.
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