http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–3 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.935325

SHORT REPORT

Does preeclampsia involve the pancreas? A report of original research David B. Nelson1, Sangeetha Duraiswamy2, Donald D. McIntire1, Marlyn J. Mayo2, and Kenneth J. Leveno1 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Washington University Library on 12/29/14 For personal use only.

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Department of Obstetrics and Gynecology and 2Department of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract

Keywords

Objective: To analyze the effect, if any, of pregnancy-related hypertension on the pancreas. Methods: A database of pregnant women with hyperbilirubinemia was reviewed for cases with serum amylase values. These cases were linked to a computerized obstetric database, and women were analyzed according to the diagnosis of preeclampsia. Results: A total of 292 consecutive women with hyperbilirubinemia during pregnancy delivered at our institution between 2005 and 2011. Of these, 52 (18%) were diagnosed with preeclampsia, and in only nine was serum amylase abnormally elevated. Conclusion: Using serum analytes as surrogates for organ injury, it appears preeclampsia infrequently affects the pancreas.

Amylase, pancreatitis, preeclampsia

Introduction Preeclampsia represents more than hypertension and proteinuria complicating pregnancy – it is a syndrome that is unpredictable in onset and progression [1]. Typically, preeclampsia occurs after 20 weeks of gestation, near term, however, timing can vary – with it even presenting in the postpartum period [2,3]. Although the cause of preeclampsia remains unknown, evidence for its manifestation results in pathophysiologic changes that culminate in a clinical spectrum of disease ranging from barely noticeable to multi-organ deterioration [1,4]. These derangements are thought to be a result of vasospasm, endothelial dysfunction, and ischemia with signs and symptoms clinically evident as edema, neurological disturbances, and epigastric pain [2,3]. In fact, recent publication of the ‘‘Hypertension in Pregnancy: Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy’’ has outlined many of these clinical implications as well as advancements in the study of biochemical markers that represent placental ischemia and provoked endothelial activation which provide new insight to the pathophysiology of the disease [2]. Focused investigation into the anatomical effects of the disorder on the brain, kidney, and liver has led to a further understanding of some of the organ-specific consequences [1–4]. However, little is known about the pancreas. The aims of our current study were two-fold: estimate the frequency of elevated serum amylase levels in women with Address for correspondence: David B. Nelson, Maternal-Fetal Medicine Division, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9032, USA. Tel: (214) 648-3113. Fax: (214) 6487262. E-mail: [email protected]

History Received 13 March 2014 Revised 22 May 2014 Accepted 12 June 2014 Published online 17 July 2014

hyperbilirubinemia and preeclampsia as a surrogate for pancreatic involvement, and secondly, to review the literature on the possibility of a pancreatic effect of severe preeclampsia similar to the periportal necrosis seen in the adjoining liver.

Methods This was a secondary analysis of an observational study of jaundice in pregnancy conducted by the Departments of Internal Medicine and Obstetrics and Gynecology at the University of Texas Southwestern Medical Center at Dallas and Parkland Hospital. Parkland Hospital is a countysupported institution serving the medically indigent women of Dallas County. The obstetric and internal medicine services are staffed by faculty, house officers, and fellows under the aegis of the respective departments at the University of Texas Southwestern Medical Center. This study protocol was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center on 8 March 2010. Briefly, the Parkland Hospital laboratory database was queried by members of the Department of Internal Medicine to identify all patients, both men and women, less than 50 years of age with total bilirubin levels greater than 1.2 mg/dL between 18 October 2005 and 17 March 2011 (now referred to as the internal medicine dataset). Women delivering an infant at Parkland Hospital were identified using linkage to an obstetric dataset (see below). The medical record of each pregnant woman was then reviewed by a member of the study team (S.D.). Obstetric and neonatal outcomes for women who deliver at Parkland are entered into a computerized obstetric dataset. Nurses present at delivery complete data sheets that are checked by research nurses for accuracy before electronic

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storage. Data on infant outcomes are abstracted from discharge records. During the study period, the definition of preeclampsia was that described in the Report of National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy and Practice Bulletin Number 33 of the American College of Obstetricians and Gynecologists [5,6]. These include: blood pressure of 140/90 mm Hg or greater after 20 weeks’ gestation in a woman not known to be chronically hypertensive and proteinuria of 2+ or greater as measured by dipstick in a catheterized urine specimen. Serum amylase was analyzed on the Cobas 6000 Analyzer (Roche Laboratories). Referent total bilirubin and serum amylase values in the third-trimester of pregnancy were considered within the normal range of 0.1–1.1 mg/dL and 15–81 U/L, respectively [7].

J Matern Fetal Neonatal Med, Early Online: 1–3

with preeclampsia were further analyzed in an attempt to identify the significance of amylase values in relation to symptomatology and severity of disease. Of the 52 women with hyperbilirubinemia, serum amylase measurements, and preeclampsia, only 9 (17%) had amylase values above the normative range for pregnancy (481 U/L) [7]. With the exception of one case that was identified to have cholelithiasis, only eight women with preeclampsia had ‘‘unexplained’’ amylase elevations. The issue of whether these unexplained elevations were due to preeclampsia or some other concomitant clinical diagnosis, such as undiagnosed cholelithiasis, is unclear since these eight women did not undergo evaluation for cholelithiasis. We therefore are unable to resolve this issue given that these women did not all have gallbladder imaging studies.

Discussion Results Between 18 October 2005 and 17 March 2011, a total of 80 857 women were delivered at Parkland Hospital. Within this cohort, hyperbilirubinemia was identified in 397 (0.5%) women. Of these 397 parturients with hyperbilirubinemia, 292 (74%), also had a serum amylase measurement. The distribution of women with amylase values available for analysis is shown in Figure 1 according to their clinical diagnoses. The most common clinical diagnoses in women with amylase measurements was gallstone disease (N ¼ 90 women, 31%). Elevated serum amylase values were relatively uncommon in women with the remaining clinical conditions. Abnormally elevated amylase was seen in only 9 (17%) women with preeclampsia. Within the entire study cohort 80 857 women, a total of 3387 (4.2%) were identified to have preeclampsia. Women

There are several important findings from our study of over 80 000 deliveries. Abnormal elevations of serum bilirubin levels during pregnancy are rare – seen in less than 1% of pregnancies. Moreover, elevations in serum amylase values are even less common – seen in 0.4% of pregnancies in our analysis of pregnant women with hyperbilirubinemia. Importantly, elevations of serum amylase values were infrequent in women with preeclampsia and hyperbilirubinemia. Gallstone-related disease, however, was the most common condition in pregnancies with hyperbilirubinemia, and it was also the most common reason for elevated serum amylase values (Figure 1). The findings from this study provide context for the rarity of pancreatic involvement possibly attributable to preeclampsia. Overall, acute pancreatitis rarely complicates pregnancy with a previously reported incidence of 1 in 3333 pregnancies

Figure 1. Distribution of women delivered during the study period with hyperbilirubinemia and also undergoing serum amylase measurement. Data listed as N (%).

Pancreatitis and preeclampsia

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DOI: 10.3109/14767058.2014.935325

at our hospital [8]. Specifically, Ramin and colleagues reviewed 43 cases at our institution and found that gallbladder disease accounted for almost 70% of cases of pancreatitis [8]. None were associated with preeclampsia [8]. Sheehan and Lynch [9] in their unparalleled textbook on 600 autopsies performed in hypertensive pregnant women recognized that preeclampsia has been implicated to cause pancreatic injury akin to the phenomenon of periportal necrosis seen in the liver of women with preeclampsia. Indeed, they recognized that there were reports from the late nineteenth century where necrosis of the pancreas was observed in women with eclampsia. However, in their series, Sheehan and Lynch found microscopic pancreatic lesions in only 8 women and there was no characteristic pattern to these lesions [9]. Therefore, Sheehan and Lynch concluded that ‘‘occasional obstetric patients with severe pregnancy hypertension have pancreatic lesions, but that there is no obvious relation of these lesions to toxaemia’’ [9]. Haukland and colleagues [10] compared pancreatic function assessed using trypsinogen and amylase in 13 women with severe preeclampsia to 30 women with normal pregnancies. They found that trypsinogen and amylase levels were significantly increased in women with severe preeclampsia – albeit compared to controls early in pregnancy relative to the third-trimester onset of preeclampsia. They hypothesized that the observed increased levels of pancreatic enzymes in the blood of women with preeclampsia was due to hypertension mediated cellular damage in the pancreas as well as hypertension-mediated reduction in renal clearance of these enzymes. They also noted that they could find no reports on the effects of preeclampsia on the pancreas. Hojo and colleagues [11] reported one case of pancreatitis which they attributed to the HELLP syndrome. The most recent report, Swank and colleagues [12] described a woman with HELLP syndrome and necrotizing pancreatitis at autopsy. They concluded that severe preeclampsia may cause wide-spread end-organ damage to include the pancreas. They also noted that they had performed an extensive search of Pubmed and MEDLINE and found only the report by Hojo and colleagues [11] already described above. So, is preeclampsia possibly implicated in damage to the pancreas? Based on this review of the literature and our report of serum amylase levels in 292 pregnant women with

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hyperbilirubinemia with amylase measurement, we are of the view that preeclampsia is a rare cause of pancreatic injury – if at all. We suggest that abnormally increased serum amylase levels that are found in women with preeclampsia should lead to a search for alternative etiologies such as cholelithiasis.

Declaration of interest The authors report no conflicts of interest.

References 1. Lindheimer MD, Roberts JM, Cunningham FG, Chesley L. Introduction, history, controversies, and definitions. In: Lindheimer MD, Roberts JM, Cunningham FG, eds. Chesley’s hypertensive disorders of pregnancy, 3rd ed. New York: Elsevier; 2009:1–23. 2. American College of Obstetricians and Gynecologists. Executive summary: hypertension in pregnancy. Obstet Gynecol 2013;122: 1122–31. 3. Sibai BM. Etiology and management of postpartum hypertensionpreeclampsia. Am J Obstet Gynecol 2012;206:470–5. 4. Cunningham FG, Leveno KJ, Bloom SL, et al. Pregnancy hypertension. In: Cunningham FG, Leveno KJ, Bloom SL, et al., eds. Williams obstetrics. 23rd ed. New York: McGraw-Hill; 2010:706–56. 5. American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia. Practice Bulletin No. 33, January 2002. 6. National High Blood Pressure Education ProgramWorking Group. Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1–22. 7. Abassi-Ghanavati M, Greer LG. Appendix. Reference table of normal laboratory values in uncomplicated pregnancies. In: Cunningham F, Leveno KJ, Bloom SL, et al., eds. Williams obstetrics, 23rd ed. New York: McGraw-Hill; 2010. 8. Ramin KD, Ramin SM, Richey SD, Cunningham FG. Acute pancreatitis in pregnancy. Am J Obstet Gynecol 1995;173:187–91. 9. Sheehan HL, Lynch JB. Pathology of toxaemia of pregnancy. Baltimore: Williams & Wilkins; 1973. 10. Haukland HH, Florholmen J, Oian P, et al. The effect of severe preeclampsia on the pancreas: changes in the serum cationic trypsinogen and pancreatic amylase. BJOG 1987;94:765–7. 11. Hojo S, Tsukimori K, Hanaoka M, et al. Acute pancreatitis and cholecystitis associated with postpartum HELLP syndrome: a case and review. Hypertens Pregnancy 2007;26:23–9. 12. Swank M, Nageotte M, Hatfield T. Necrotizing pancreatitis associated with severe preeclampsia. Obstet Gynecol 2012;120: 453–5.

Does preeclampsia involve the pancreas? A report of original research.

To analyze the effect, if any, of pregnancy-related hypertension on the pancreas...
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