- Email: [email protected]
Maternal and fetal outcomes of pancreatitis in pregnancy
Accepted Manuscript Maternal and Fetal Outcomes of Pancreatitis in Pregnancy Francis M. Hacker, MD, Phoebe S. Whalen, MD, Vanessa R. Lee, MD MPH, Aaron B. Caughey, MD PhD PII:
S0002-9378(15)00781-4
DOI:
10.1016/j.ajog.2015.07.031
Reference:
YMOB 10545
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 7 March 2015 Revised Date:
2 June 2015
Accepted Date: 18 July 2015
Please cite this article as: Hacker FM, Whalen PS, Lee VR, Caughey AB, Maternal and Fetal Outcomes of Pancreatitis in Pregnancy, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/ j.ajog.2015.07.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Hacker et al Topic Heading:
Title: Maternal and Fetal Outcomes of Pancreatitis in Pregnancy
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Authors:
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Obstetrics
Francis M Hacker, MD; Phoebe S Whalen, MD; Vanessa R Lee, MD MPH; Aaron B
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Caughey, MD PhD
Affiliations:
Department of Obstetrics & Gynecology; Oregon Health & Science University; Portland,
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OR
Conflict of Interest/Disclosure Statement:
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The authors report no conflicts of interest or disclosures
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Presented as a poster (#641) at the 35th Annual Meeting of the Society for Maternal-Fetal Medicine, San Diego, CA, February 2-7, 2015
Financial Support: no financial support was received
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
1
ACCEPTED MANUSCRIPT Hacker et al Corresponding Author: Francis M Hacker, MD
Department of Obstetrics and Gynecology 3181 SW Sam Jackson Park Rd Portland, OR 97239
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Telephone #: 503-494-2999
Word Count Abstract: 212
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Main Text: 1649
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Fax # 503-494-2391 Email: [email protected]
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Oregon Health & Science University
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
2
ACCEPTED MANUSCRIPT Hacker et al Condensation: Pancreatitis during pregnancy is associated with specific maternal factors and maternal and fetal morbidity and mortality.
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Short Title: Pancreatitis in pregnancy and associated maternal and fetal morbidity and
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mortality
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
3
ACCEPTED MANUSCRIPT Hacker et al ABSTRACT OBJECTIVE: This study examines maternal and neonatal outcomes associated with pancreatitis in pregnancy, in particular preeclampsia.
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METHODS: Retrospective cohort study of all singleton non-anomalous pregnancies in California from 2005-2008 with an identification of all cases of pancreatitis. Outcomes of interest included preeclampsia, intrauterine fetal demise, preterm delivery, and neonatal
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or infant death. Univariate and multivariable analyses were then conducted to examine the association of pancreatitis in pregnancy and maternal characteristics and fetal
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outcomes.
RESULTS: Our cohort of 2,039,870 pregnant women included 342 (0.017%) with pancreatitis. Pancreatitis in pregnancy was not significantly associated with neonatal or infant death. When assessing fetal outcomes, pancreatitis was associated with preterm
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delivery, small for gestational age, jaundice, respiratory distress syndrome, and intrauterine fetal demise (p<0.001). Of note, pregnancy-associated pancreatitis was found to be associated with preeclampsia and severe preeclampsia in both univariate (p<0.001)
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and multivariate analysis after controlling for potential confounders (OR 4.21, 95% CI 2.99-5.93; OR 7.85, 95% CI 5.03-12.24).
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CONCLUSION: We found that pancreatitis in pregnancy was associated with several adverse maternal outcomes; in particular, a strong association existed with preeclampsia, which has its own implications and complications surrounding pregnancy management. Pancreatitis in pregnancy was also associated with increased risk for preterm delivery but not neonatal or infant death, which is consistent with the literature.
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al Key Words: pancreatitis, pregnancy, preeclampsia, preterm delivery, hypertensive
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disorders of pregnancy
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al Introduction: The incidence of pancreatitis in pregnancy is not well established with estimates ranging broadly between 1/1000 – 1/12,000.1-3 Pancreatitis was initially thought to be
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associated with an increased incidence of maternal and fetal death with maternal
mortality rates of 20% and fetal mortality of 50% reported in the literature.4-6 Newer
studies paint a less dismal picture; maternal mortality and fetal mortality rates less than
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1% and 5% respectively are described and may result from earlier recognition and
improved medical management.4,6-9,18 Etiologies of pregnancy-associated pancreatitis are
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similar to those in the non-pregnant patient population and most commonly occur with primary biliary disorders, alcohol abuse, and hyperlipidemia.4,6-9 Of note, recent studies suggest that pancreatitis may have a milder disease course in pregnant patients than the
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general population.7
While rare, it is important to understand the maternal and neonatal outcomes associated with pancreatitis in pregnancy. From this viewpoint, we may better anticipate
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potential complications in those women who develop pancreatitis as well as counsel them about such possibilities. Although, a handful of case reports and small studies point to an
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association between pancreatitis and preeclampsia, the causality and temporal relationships are unclear.9-17. The current study explores the potential association between pregnancy-associated pancreatitis and preeclampsia as well as other maternal and neonatal complications. There are few supported hypotheses in the literature regarding either the association or the temporality of pancreatitis and hypertensive disorders. Perhaps the most likely explanation is that of Badja et al who considered vascular
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al changes to play a primary role.10 We hypothesize that pregnancies complicated by pancreatitis are associated with a higher risk of hypertensive disorders and preterm
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delivery compared to pregnancies without pancreatitis.
Materials and Methods:
This is a retrospective cohort study of all pregnancies recorded in the state of
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California between the years of 2005-2008. The search identified linked datasets of
mother and infants from the California Vital Statistics Birth Certificate Data, California
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Patient Discharge Data, Vital Statistics Death Certificate, and Vital Statistics Fetal Death File. We identified our cohort of women with pancreatitis based on Internal Classification of Diseases, 9th revision (ICD-9) codes 577.0 (acute) and 577.1 (chronic) noted during the delivery admission only. We excluded multiple gestations and pregnancies
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complicated by fetal anomalies. The Institutional Review Boards at Oregon Health & Science University and the State of California approved the study. Informed consent was not required as the linked data sets did not include potential patient identifying
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information.
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Specific maternal characteristics and outcomes of interest were identified. In
particular, maternal age, race/ethnicity (Caucasian, Black, Hispanic, Asian, Other), public insurance, education level (≥12th grade and <12th), diabetes mellitus, and chronic hypertension. Additionally, the development of gestational diabetes mellitus, gestational hypertension, preeclampsia and preeclampsia with severe features were evaluated. Fetal/neonatal outcomes of interest included preterm delivery (<37 weeks), severe
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al preterm delivery (<32 weeks), intrauterine fetal demise, neonatal death, infant death, small for gestational age (birth weight <10th percentile at time of delivery), respiratory
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distress syndrome, grade 3 or 4 intraventricular hemorrhage, and jaundice.
Univariate analyses using chi-squared tests were conducted using Stata v.11
software (College Station, TX) to examine the association of pancreatitis in pregnancy
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with maternal characteristics and maternal and fetal outcomes. Multivariable logistic regression was performed to control for potential confounders including chronic
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hypertension, gestational diabetes mellitus, ethnicity, maternal age, public insurance, and education level. P< 0.01 and 95% confidence intervals were used to determine if the comparisons were statistically significant given the robustness of the sample size
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Results:
Our cohort included 2,039,870 non-anomalous singleton pregnancies. Of these pregnancies, 342 were complicated by pancreatitis, yielding an incidence of pancreatitis
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in pregnancy of 0.017% in our study population. The 342 pregnancies complicated by pancreatitis were then compared with the remaining 2,039,528 control pregnancies. In the
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unadjusted analysis evaluating maternal demographics (Table 1), women with pregnancyassociated pancreatitis were more likely to be African American, followed by Hispanic, then Caucasian and Asian. Additionally, education less than 12th grade, having public insurance, chronic hypertension, and diabetes mellitus were all significantly associated with the development of pancreatitis.
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al Maternal outcomes (Table 2) associated with pancreatitis in pregnancy included the development of gestational diabetes mellitus (12.0% vs. 6.3%; p<0.001) but not gestational hypertension (5.6% vs. 3.2%; p<0.012) using the p-value of <0.01. Of note,
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pancreatitis in pregnancy was found to be associated with both preeclampsia (13.5% vs. 2.9%; p<0.001) and preeclampsia with severe features (6.4% vs. 0.8%; p<0.001).
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The development of pancreatitis during pregnancy was not statistically associated with neonatal (0.6% vs. 0.21%; p<0.124) or infant death (0.29% vs. 0.1%; p<0.265)
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(Table 3). However, pancreatitis was associated with preterm delivery less than 32 weeks (4.68% vs. 1.21%; p<0.001) and preterm delivery less than 37 weeks (30.70% vs. 8.91%; p<0.001), small for gestational age (22.78% vs. 10.70%; p<0.001), jaundice (29.24% vs. 15.26%; p<0.001), respiratory distress syndrome (4.39% vs. 0.86%; p<0.001), and
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intrauterine fetal demise (1.75% vs. 0.33%; p<0.001).
After adjusting for maternal age, ethnicity, type of insurance, education level,
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chronic hypertension, and gestational diabetes, pancreatitis in pregnancy was associated with an increased risk of several adverse perinatal outcomes (Table 4). The odds of
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developing gestational hypertension were not different between groups, but compared to women without pancreatitis, women with pancreatitis had significantly higher odds of developing preeclampsia (OR 4.21, 95% CI 2.99-5.93) and preeclampsia with severe features (OR 7.85, 95% CI 5.03-12.24). Furthermore, women with pancreatitis had higher odds of preterm delivery prior to 32 weeks (OR 3.31, 95% CI 1.93-5.68) and prior to 37 weeks (OR 4.10 95% CI 3.23-5.21).
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al
Pancreatitis in pregnancy conferred significantly higher odds of intrauterine fetal demise (OR 4.35, 95% CI 1.78-10.55). However, the pancreatitis group was not at
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significantly increased risk of neonatal (OR 1.47, 95% CI 0.21-10.46) or infant death (OR 2.80, CI 95% 0.39-19.97) after controlling for key confounders.
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Regarding fetal and neonatal morbidities, pancreatitis in pregnancy was
associated with increased odds of being born small for gestational age (OR 2.26, CI 95%
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1.64-3.11), developing respiratory distress syndrome (OR 4.27, CI 95% 2.44-7.46) and neonatal jaundice (OR 2.22, CI 95% 1.74-2.84).
Comment:
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The incidence of pregnancy-associated pancreatitis in this retrospective study of pregnancies in California during a three-year period was 0.017% or about 1 in 6,000 and falls within the range of proposed incidences found in the literature.1-3 Pregnancy-
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associated pancreatitis was determined to be associated with increased incidence and odds of several maternal characteristics as well as maternal and fetal morbidity and
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mortality. Maternal factors that conferred increased incidence and odds of developing pancreatitis during pregnancy included lower education level, public insurance, AfricanAmerican race, presence of chronic hypertension and diabetes mellitus.
Maternal morbidity associated with pancreatitis specifically included gestational diabetes and preeclampsia. The proposed association of preeclampsia and pregnancy-
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al associated pancreatitis has been a long-standing concept with efforts to confirm it as early as 1969.19 In a study by Sheehan and Lynch, 600 autopsies of pregnancies complicated by hypertension were performed and identified pancreatic lesions in eight women but they
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did not identify a significant relationship.19 Nelson et al reviewed Sheehan’s study and
several others in addition to their own cohort of 43 women who developed pancreatitis in pregnancy and concluded, “preeclampsia is a rare cause of pancreatic injury – if at all”.20
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Although the exact causal and temporal relationship of pancreatitis and preeclampsia has not been established, increasingly, case reports and small studies in the literature have
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attempted to demonstrate an association.10-17 Our findings of an association between hypertensive disease and pancreatitis during pregnancy corroborate these publications. Although the literature is divided regarding the association between preeclampsia and pancreatitis, our study is the largest cohort that we are aware of to date, to find a
direction of causality.
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statistically significant association between the two conditions. What is unclear is the
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Neonates born to women with pancreatitis during pregnancy had increased incidence and odds of being born severely preterm (<32 weeks) and preterm (<37
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weeks), small for gestational age, and developing respiratory distress syndrome or jaundice. Prematurity in the context of pregnancy-associated pancreatitis has been well documented in the literature and much of the resultant fetal mortality and morbidity are likely related to prematurity.13,18,21 Neonates born to mothers afflicted by pancreatitis during pregnancy were not at increased risk for neonatal or subsequent infant death. These findings are consistent with recent publications, which note a decrease in perinatal
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al mortality following preterm delivery, likely a reflection of improved neonatal management.4,6,9
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A strength of this study is that this is one of the largest cohorts describing maternal and fetal morbidity and mortality of pancreatitis in pregnancy. However, the study was not without limitations. For example, these data relied on ICD-9 codes for
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identification of specific diseases and some complications of interest. Thus it relied on
appropriate coding by coders with varying levels of medical proficiency. It is often that
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such methods lead to under identification of cases. However, given the specificity of pancreatitis and the consistency of our rates with previously reported rates it seems likely that the cases we did identify were actual cases, so the associations we identified were likely to have limited misclassification bias. Additionally, this is a retrospective cohort study and thus the temporal relationship between the disease and outcomes is difficult to
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determine. The study included both acute and chronic pancreatitis within the same cohort and did not stratify pancreatitis by etiology. It also was unable to take into account the severity or timing of the development of pancreatitis, for instance there is a small chance
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that a limited number of women developed pancreatitis postpartum prior to discharge.
We characterized a number of maternal risk factors and neonatal and maternal
outcomes in pancreatitis-associated pregnancy. Our findings provide a foundation for counseling patients diagnosed with pancreatitis during pregnancy. The study points to the need for more investigation into the complications of pancreatitis to better understand the pathophysiology as well as potential treatments. Finally, the relationship between
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al pancreatitis and hypertensive disorders of pregnancy requires specific focus in regards to
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pathophysiology and the temporal and causal relationship with pancreatitis.
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ACCEPTED MANUSCRIPT Hacker et al 1. Ramin KD, Ramin SM, Richey SD, Cunningham FG. Acute pancreatitis in pregnancy. Am J Obstet Gynecol 1995;173(1):187–191. 2. Parish FM, Richardson JB. Acute pancreatitis during pregnancy: with report of a
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case. Am J Obstet Gynecol. 1956;72:906-909.
3. Corlett RC, Mishell DR. Pancreatitis in pregnancy. Am J Obstet Gynecol. 1972;113:281-290.
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4. Hernandez A, Petrov MS, Brooks DC, Banks PA, Ashley SW, Tavakkolizadeh A. Acute pancreatitis and pregnancy: a 10 year single center experience. J
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Gastrointestinal Surg 2007;11(12):1623–7.
5. Pitchumoni CS, Yegneswaran B. Acute pancreatitis in pregnancy. World J Gastroenterol 2009;15:5641–6.
6. Ramin KD, Ramsey PS. Disease of the gallbladder and pancreas in pregnancy.
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Obstet Gynecol Clin North Am. 2001;28(3):571-80.
7. Gilbert A, Patenaude V, Abenhaim HA. Acute pancreatitis in pregnancy: a comparison of associated conditions, treatments and complications. J Perinat
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Med. 2014;42(5):565-70.
8. Eddy JJ, Gideonsen MD, Song JY, Grobman WA, O’Halloran P. Pancreatitis in
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pregnancy: a 10 year retrospective of 15 Midwest hospitals. Obstet Gynecol 2008;112:1075–81.
9. Stimac D, Stimac T. Acute pancreatitis during pregnancy. Eur J Gastroenterol Hepatol. 2011;23(10):839-44.
10. Badja N, Troche G, Zazzo J, Benhamou D. Acute pancreatitis and preeclampsiaeclampsia: A case report. Am J Obstet Gynecol 1997;76(3):707-9.
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al 11. Hojo S, Tsukimori K, Hanaoka M, Anami A, Nakanami N, Kotoh K, Nozaki M. Acute pancreatitis and cholecystitis associated with postpartum HELLP syndrome: a case and review. Hypertens Pregnancy 2007;26:23–9.
report. J Obstet Gynaecol Can 2004;26(6):594-5.
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12. Opatrny L, Michon N, Ray E. Preeclampsia as a cause of pancreatitis: a case
13. Papadakis EP, Sarigianni M, Mikhailidis DP, Mamopoulos A, Karagiannis V.
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Acute pancreatitis in pregnancy: an overview. Eur J Obstet Gyn R B 2011;159(2); 261–6.
2004;5(2):101-104.
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14. Parmer MS. Pancreatic Necrosis Associated with Preeclampsia-Eclampsia. JOP
15. Swank M, Nageotte M, Hatfield T. Necrotizing pancreatitis associated with
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severe preeclampsia. Obstet Gynecol 2012;120(2 Pt 2):453-5. 16. Chen CP1, Wang KG, Su TH, Yang YC. Acute pancreatitis in pregnancy. Acta Obstet Gynecol Scand. 1995;74(8):607-10.
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17. Haukland HH, Oian P, Maltau JM, Florholmen J, Burhol P. The effect of severe pre-eclampsia on the pancreas: changes in the serum cationic trypsinogen and
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pancreatic amylase. BJOG. 1987;94:765-767. 18. Juneja SK, Gupta S, Virk SS, Tandon, P, Bindal V. Acute pancreatitis in pregnancy: A treatment paradigm based on our hospital experience. Int J Appl Basic Med Res 2013; 3(2): 122–125.
19. Sheehan H, Lynch J. (1973). Pathology of toxemia of pregnancy. Edinburgh: Churchill Livingstone. 20. Nelson DB, Duraiswamy S, McIntire DD, Mayo MJ, Leveno1 KJ. Does
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ACCEPTED MANUSCRIPT Hacker et al preeclampsia involve the pancreas? A report of original research. J Matern Fetal Neonatal Med 2014 Jul 17:1-3. Epub ahead of print. 21. Institute of Medicine (US) Committee on Understanding Premature Birth and
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Assuring Healthy Outcomes; Behrman RE, Butler AS, editors. Preterm Birth:
Causes, Consequences, and Prevention. Washington (DC): National Academies
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Press (US); 2007.
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ACCEPTED MANUSCRIPT Hacker et al
Table 1: Maternal Demographics of Pregnancy-Associated Pancreatitis vs. the Control Population Pancreatitis
No Pancreatitis
% (n)
% (n)
0.829
≥35
16.4% (56)
16.9% (343,784)
83.6% (285)
83.1%
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<35
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Maternal age, y
P-value
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Variable
(1,695,272)
Race
<0.001
8.2% (28)
5.1% (103,327)
Caucasian
22.2% (76)
26.8%
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African American
60.8% (208)
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Hispanic
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Asian/Pacific Islander
Other
5.8% (20)
(545,661) 54.7%
(1,113,699) 11.5% (235,152)
2.9% (10)
1.9% (38,883)
Education, grade <12th
0.001 64.5% (213)
55.7% (1,101,967)
≥12th
35.5% (117)
44.3%
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al (875,910) Insurance
0.026 54.7% (187)
48.7% (992,248)
Private
45.3% (155)
51.3% (1,047,280)
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Public
3.5% (12)
1.1% (12,947)
<0.001
Diabetes mellitus
3.2% (11)
0.7% (14,863)
<0.001
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Chronic Hypertension
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al
Table 2: Unadjusted Incidence of Maternal Outcomes of PregnancyAssociated Pancreatitis vs. the Control Population
Gestational
Pancreatitis
No Pancreatitis
% (n)
% (n)
5.6% (19)
3.2% (64,781)
12.0% (41)
6.3% (128,546)
mellitus
<0.001
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Gestational diabetes
0.012
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hypertension
P-value
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Variable
13.5% (46)
2.9% (296)
<0.001
Severe preeclampsia
6.4% (22)
0.8% (16,051)
<0.001
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Preeclampsia
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al
Table 3: Unadjusted Incidence of Fetal Outcomes of PregnancyAssociated Pancreatitis vs. the Control Population No Pancreatitis
% (n)
% (n)
4.7% (16)
1.2 % (24,779)
30.7% (105)
8.9% (181,778)
weeks Preterm delivery <37
Intrauterine fetal demise
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weeks
P-value
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Preterm delivery <32
Pancreatitis
<0.001
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Variable
<0.001
1.8% (6)
0.3% (6,766)
<0.001
Small for Gestational Age
22.8% (54)
10.7% (198,615)
<0.001
Respiratory distress
4.4% (15)
0.9% (17,624)
<0.001
0.3% (1)
0.0% (197)
<0.001
29.2% (100)
15.3% (311,237)
<0.001
0.60% (2)
0.20% (4,281)
0.124
0.30% (1)
0.10% (2,057)
0.265
Intraventricular
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syndrome
Jaundice Neonatal death
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Infant death
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Hemorrhage (grade 3 or 4)
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ACCEPTED MANUSCRIPT Hacker et al
Table 4: Adjusted Odds ratios for Outcomes of PregnancyAssociated Pancreatitis vs. the Control Population* Odds Ratio
95% Confidence Interval
1.18
0.67-2.06
Preeclampsia
4.21
2.99-5.93
Severe preeclampsia
7.85
5.03-12.24
Preterm delivery <32 weeks
3.31
1.93-5.56
Preterm delivery <37 weeks
4.10
3.23-5.21
Intrauterine fetal demise
4.35
1.80-10.55
Small for Gestational Age
2.26
1.64-3.11
Respiratory distress
4.27
2.44-7.46
Neonatal death
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2.22
1.74-2.84
1.47
0.21-10.46
2.8
0.39-19.97
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Infant death
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Jaundice
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syndrome
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Gestational hypertension
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Outcome
*Adjusted for chronic hypertension, gestational diabetes, maternal ethnicity, maternal age (≥35 or <35), insurance (public vs private), education level (≥12th grade or <12th grade)
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
21
S0002-9378(15)00781-4
DOI:
10.1016/j.ajog.2015.07.031
Reference:
YMOB 10545
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 7 March 2015 Revised Date:
2 June 2015
Accepted Date: 18 July 2015
Please cite this article as: Hacker FM, Whalen PS, Lee VR, Caughey AB, Maternal and Fetal Outcomes of Pancreatitis in Pregnancy, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/ j.ajog.2015.07.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Hacker et al Topic Heading:
Title: Maternal and Fetal Outcomes of Pancreatitis in Pregnancy
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Authors:
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Obstetrics
Francis M Hacker, MD; Phoebe S Whalen, MD; Vanessa R Lee, MD MPH; Aaron B
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Caughey, MD PhD
Affiliations:
Department of Obstetrics & Gynecology; Oregon Health & Science University; Portland,
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OR
Conflict of Interest/Disclosure Statement:
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The authors report no conflicts of interest or disclosures
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Presented as a poster (#641) at the 35th Annual Meeting of the Society for Maternal-Fetal Medicine, San Diego, CA, February 2-7, 2015
Financial Support: no financial support was received
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
1
ACCEPTED MANUSCRIPT Hacker et al Corresponding Author: Francis M Hacker, MD
Department of Obstetrics and Gynecology 3181 SW Sam Jackson Park Rd Portland, OR 97239
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Telephone #: 503-494-2999
Word Count Abstract: 212
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Main Text: 1649
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Fax # 503-494-2391 Email: [email protected]
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Oregon Health & Science University
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
2
ACCEPTED MANUSCRIPT Hacker et al Condensation: Pancreatitis during pregnancy is associated with specific maternal factors and maternal and fetal morbidity and mortality.
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Short Title: Pancreatitis in pregnancy and associated maternal and fetal morbidity and
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mortality
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
3
ACCEPTED MANUSCRIPT Hacker et al ABSTRACT OBJECTIVE: This study examines maternal and neonatal outcomes associated with pancreatitis in pregnancy, in particular preeclampsia.
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METHODS: Retrospective cohort study of all singleton non-anomalous pregnancies in California from 2005-2008 with an identification of all cases of pancreatitis. Outcomes of interest included preeclampsia, intrauterine fetal demise, preterm delivery, and neonatal
SC
or infant death. Univariate and multivariable analyses were then conducted to examine the association of pancreatitis in pregnancy and maternal characteristics and fetal
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outcomes.
RESULTS: Our cohort of 2,039,870 pregnant women included 342 (0.017%) with pancreatitis. Pancreatitis in pregnancy was not significantly associated with neonatal or infant death. When assessing fetal outcomes, pancreatitis was associated with preterm
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delivery, small for gestational age, jaundice, respiratory distress syndrome, and intrauterine fetal demise (p<0.001). Of note, pregnancy-associated pancreatitis was found to be associated with preeclampsia and severe preeclampsia in both univariate (p<0.001)
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and multivariate analysis after controlling for potential confounders (OR 4.21, 95% CI 2.99-5.93; OR 7.85, 95% CI 5.03-12.24).
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CONCLUSION: We found that pancreatitis in pregnancy was associated with several adverse maternal outcomes; in particular, a strong association existed with preeclampsia, which has its own implications and complications surrounding pregnancy management. Pancreatitis in pregnancy was also associated with increased risk for preterm delivery but not neonatal or infant death, which is consistent with the literature.
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
4
ACCEPTED MANUSCRIPT Hacker et al Key Words: pancreatitis, pregnancy, preeclampsia, preterm delivery, hypertensive
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disorders of pregnancy
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al Introduction: The incidence of pancreatitis in pregnancy is not well established with estimates ranging broadly between 1/1000 – 1/12,000.1-3 Pancreatitis was initially thought to be
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associated with an increased incidence of maternal and fetal death with maternal
mortality rates of 20% and fetal mortality of 50% reported in the literature.4-6 Newer
studies paint a less dismal picture; maternal mortality and fetal mortality rates less than
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1% and 5% respectively are described and may result from earlier recognition and
improved medical management.4,6-9,18 Etiologies of pregnancy-associated pancreatitis are
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similar to those in the non-pregnant patient population and most commonly occur with primary biliary disorders, alcohol abuse, and hyperlipidemia.4,6-9 Of note, recent studies suggest that pancreatitis may have a milder disease course in pregnant patients than the
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general population.7
While rare, it is important to understand the maternal and neonatal outcomes associated with pancreatitis in pregnancy. From this viewpoint, we may better anticipate
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potential complications in those women who develop pancreatitis as well as counsel them about such possibilities. Although, a handful of case reports and small studies point to an
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association between pancreatitis and preeclampsia, the causality and temporal relationships are unclear.9-17. The current study explores the potential association between pregnancy-associated pancreatitis and preeclampsia as well as other maternal and neonatal complications. There are few supported hypotheses in the literature regarding either the association or the temporality of pancreatitis and hypertensive disorders. Perhaps the most likely explanation is that of Badja et al who considered vascular
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al changes to play a primary role.10 We hypothesize that pregnancies complicated by pancreatitis are associated with a higher risk of hypertensive disorders and preterm
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delivery compared to pregnancies without pancreatitis.
Materials and Methods:
This is a retrospective cohort study of all pregnancies recorded in the state of
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California between the years of 2005-2008. The search identified linked datasets of
mother and infants from the California Vital Statistics Birth Certificate Data, California
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Patient Discharge Data, Vital Statistics Death Certificate, and Vital Statistics Fetal Death File. We identified our cohort of women with pancreatitis based on Internal Classification of Diseases, 9th revision (ICD-9) codes 577.0 (acute) and 577.1 (chronic) noted during the delivery admission only. We excluded multiple gestations and pregnancies
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complicated by fetal anomalies. The Institutional Review Boards at Oregon Health & Science University and the State of California approved the study. Informed consent was not required as the linked data sets did not include potential patient identifying
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information.
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Specific maternal characteristics and outcomes of interest were identified. In
particular, maternal age, race/ethnicity (Caucasian, Black, Hispanic, Asian, Other), public insurance, education level (≥12th grade and <12th), diabetes mellitus, and chronic hypertension. Additionally, the development of gestational diabetes mellitus, gestational hypertension, preeclampsia and preeclampsia with severe features were evaluated. Fetal/neonatal outcomes of interest included preterm delivery (<37 weeks), severe
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al preterm delivery (<32 weeks), intrauterine fetal demise, neonatal death, infant death, small for gestational age (birth weight <10th percentile at time of delivery), respiratory
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distress syndrome, grade 3 or 4 intraventricular hemorrhage, and jaundice.
Univariate analyses using chi-squared tests were conducted using Stata v.11
software (College Station, TX) to examine the association of pancreatitis in pregnancy
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with maternal characteristics and maternal and fetal outcomes. Multivariable logistic regression was performed to control for potential confounders including chronic
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hypertension, gestational diabetes mellitus, ethnicity, maternal age, public insurance, and education level. P< 0.01 and 95% confidence intervals were used to determine if the comparisons were statistically significant given the robustness of the sample size
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Results:
Our cohort included 2,039,870 non-anomalous singleton pregnancies. Of these pregnancies, 342 were complicated by pancreatitis, yielding an incidence of pancreatitis
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in pregnancy of 0.017% in our study population. The 342 pregnancies complicated by pancreatitis were then compared with the remaining 2,039,528 control pregnancies. In the
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unadjusted analysis evaluating maternal demographics (Table 1), women with pregnancyassociated pancreatitis were more likely to be African American, followed by Hispanic, then Caucasian and Asian. Additionally, education less than 12th grade, having public insurance, chronic hypertension, and diabetes mellitus were all significantly associated with the development of pancreatitis.
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al Maternal outcomes (Table 2) associated with pancreatitis in pregnancy included the development of gestational diabetes mellitus (12.0% vs. 6.3%; p<0.001) but not gestational hypertension (5.6% vs. 3.2%; p<0.012) using the p-value of <0.01. Of note,
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pancreatitis in pregnancy was found to be associated with both preeclampsia (13.5% vs. 2.9%; p<0.001) and preeclampsia with severe features (6.4% vs. 0.8%; p<0.001).
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The development of pancreatitis during pregnancy was not statistically associated with neonatal (0.6% vs. 0.21%; p<0.124) or infant death (0.29% vs. 0.1%; p<0.265)
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(Table 3). However, pancreatitis was associated with preterm delivery less than 32 weeks (4.68% vs. 1.21%; p<0.001) and preterm delivery less than 37 weeks (30.70% vs. 8.91%; p<0.001), small for gestational age (22.78% vs. 10.70%; p<0.001), jaundice (29.24% vs. 15.26%; p<0.001), respiratory distress syndrome (4.39% vs. 0.86%; p<0.001), and
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intrauterine fetal demise (1.75% vs. 0.33%; p<0.001).
After adjusting for maternal age, ethnicity, type of insurance, education level,
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chronic hypertension, and gestational diabetes, pancreatitis in pregnancy was associated with an increased risk of several adverse perinatal outcomes (Table 4). The odds of
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developing gestational hypertension were not different between groups, but compared to women without pancreatitis, women with pancreatitis had significantly higher odds of developing preeclampsia (OR 4.21, 95% CI 2.99-5.93) and preeclampsia with severe features (OR 7.85, 95% CI 5.03-12.24). Furthermore, women with pancreatitis had higher odds of preterm delivery prior to 32 weeks (OR 3.31, 95% CI 1.93-5.68) and prior to 37 weeks (OR 4.10 95% CI 3.23-5.21).
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ACCEPTED MANUSCRIPT Hacker et al
Pancreatitis in pregnancy conferred significantly higher odds of intrauterine fetal demise (OR 4.35, 95% CI 1.78-10.55). However, the pancreatitis group was not at
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significantly increased risk of neonatal (OR 1.47, 95% CI 0.21-10.46) or infant death (OR 2.80, CI 95% 0.39-19.97) after controlling for key confounders.
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Regarding fetal and neonatal morbidities, pancreatitis in pregnancy was
associated with increased odds of being born small for gestational age (OR 2.26, CI 95%
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1.64-3.11), developing respiratory distress syndrome (OR 4.27, CI 95% 2.44-7.46) and neonatal jaundice (OR 2.22, CI 95% 1.74-2.84).
Comment:
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The incidence of pregnancy-associated pancreatitis in this retrospective study of pregnancies in California during a three-year period was 0.017% or about 1 in 6,000 and falls within the range of proposed incidences found in the literature.1-3 Pregnancy-
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associated pancreatitis was determined to be associated with increased incidence and odds of several maternal characteristics as well as maternal and fetal morbidity and
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mortality. Maternal factors that conferred increased incidence and odds of developing pancreatitis during pregnancy included lower education level, public insurance, AfricanAmerican race, presence of chronic hypertension and diabetes mellitus.
Maternal morbidity associated with pancreatitis specifically included gestational diabetes and preeclampsia. The proposed association of preeclampsia and pregnancy-
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al associated pancreatitis has been a long-standing concept with efforts to confirm it as early as 1969.19 In a study by Sheehan and Lynch, 600 autopsies of pregnancies complicated by hypertension were performed and identified pancreatic lesions in eight women but they
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did not identify a significant relationship.19 Nelson et al reviewed Sheehan’s study and
several others in addition to their own cohort of 43 women who developed pancreatitis in pregnancy and concluded, “preeclampsia is a rare cause of pancreatic injury – if at all”.20
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Although the exact causal and temporal relationship of pancreatitis and preeclampsia has not been established, increasingly, case reports and small studies in the literature have
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attempted to demonstrate an association.10-17 Our findings of an association between hypertensive disease and pancreatitis during pregnancy corroborate these publications. Although the literature is divided regarding the association between preeclampsia and pancreatitis, our study is the largest cohort that we are aware of to date, to find a
direction of causality.
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statistically significant association between the two conditions. What is unclear is the
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Neonates born to women with pancreatitis during pregnancy had increased incidence and odds of being born severely preterm (<32 weeks) and preterm (<37
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weeks), small for gestational age, and developing respiratory distress syndrome or jaundice. Prematurity in the context of pregnancy-associated pancreatitis has been well documented in the literature and much of the resultant fetal mortality and morbidity are likely related to prematurity.13,18,21 Neonates born to mothers afflicted by pancreatitis during pregnancy were not at increased risk for neonatal or subsequent infant death. These findings are consistent with recent publications, which note a decrease in perinatal
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al mortality following preterm delivery, likely a reflection of improved neonatal management.4,6,9
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A strength of this study is that this is one of the largest cohorts describing maternal and fetal morbidity and mortality of pancreatitis in pregnancy. However, the study was not without limitations. For example, these data relied on ICD-9 codes for
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identification of specific diseases and some complications of interest. Thus it relied on
appropriate coding by coders with varying levels of medical proficiency. It is often that
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such methods lead to under identification of cases. However, given the specificity of pancreatitis and the consistency of our rates with previously reported rates it seems likely that the cases we did identify were actual cases, so the associations we identified were likely to have limited misclassification bias. Additionally, this is a retrospective cohort study and thus the temporal relationship between the disease and outcomes is difficult to
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determine. The study included both acute and chronic pancreatitis within the same cohort and did not stratify pancreatitis by etiology. It also was unable to take into account the severity or timing of the development of pancreatitis, for instance there is a small chance
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that a limited number of women developed pancreatitis postpartum prior to discharge.
We characterized a number of maternal risk factors and neonatal and maternal
outcomes in pancreatitis-associated pregnancy. Our findings provide a foundation for counseling patients diagnosed with pancreatitis during pregnancy. The study points to the need for more investigation into the complications of pancreatitis to better understand the pathophysiology as well as potential treatments. Finally, the relationship between
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al pancreatitis and hypertensive disorders of pregnancy requires specific focus in regards to
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pathophysiology and the temporal and causal relationship with pancreatitis.
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ACCEPTED MANUSCRIPT Hacker et al 1. Ramin KD, Ramin SM, Richey SD, Cunningham FG. Acute pancreatitis in pregnancy. Am J Obstet Gynecol 1995;173(1):187–191. 2. Parish FM, Richardson JB. Acute pancreatitis during pregnancy: with report of a
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case. Am J Obstet Gynecol. 1956;72:906-909.
3. Corlett RC, Mishell DR. Pancreatitis in pregnancy. Am J Obstet Gynecol. 1972;113:281-290.
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4. Hernandez A, Petrov MS, Brooks DC, Banks PA, Ashley SW, Tavakkolizadeh A. Acute pancreatitis and pregnancy: a 10 year single center experience. J
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Gastrointestinal Surg 2007;11(12):1623–7.
5. Pitchumoni CS, Yegneswaran B. Acute pancreatitis in pregnancy. World J Gastroenterol 2009;15:5641–6.
6. Ramin KD, Ramsey PS. Disease of the gallbladder and pancreas in pregnancy.
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Obstet Gynecol Clin North Am. 2001;28(3):571-80.
7. Gilbert A, Patenaude V, Abenhaim HA. Acute pancreatitis in pregnancy: a comparison of associated conditions, treatments and complications. J Perinat
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Med. 2014;42(5):565-70.
8. Eddy JJ, Gideonsen MD, Song JY, Grobman WA, O’Halloran P. Pancreatitis in
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pregnancy: a 10 year retrospective of 15 Midwest hospitals. Obstet Gynecol 2008;112:1075–81.
9. Stimac D, Stimac T. Acute pancreatitis during pregnancy. Eur J Gastroenterol Hepatol. 2011;23(10):839-44.
10. Badja N, Troche G, Zazzo J, Benhamou D. Acute pancreatitis and preeclampsiaeclampsia: A case report. Am J Obstet Gynecol 1997;76(3):707-9.
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ACCEPTED MANUSCRIPT Hacker et al 11. Hojo S, Tsukimori K, Hanaoka M, Anami A, Nakanami N, Kotoh K, Nozaki M. Acute pancreatitis and cholecystitis associated with postpartum HELLP syndrome: a case and review. Hypertens Pregnancy 2007;26:23–9.
report. J Obstet Gynaecol Can 2004;26(6):594-5.
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12. Opatrny L, Michon N, Ray E. Preeclampsia as a cause of pancreatitis: a case
13. Papadakis EP, Sarigianni M, Mikhailidis DP, Mamopoulos A, Karagiannis V.
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Acute pancreatitis in pregnancy: an overview. Eur J Obstet Gyn R B 2011;159(2); 261–6.
2004;5(2):101-104.
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14. Parmer MS. Pancreatic Necrosis Associated with Preeclampsia-Eclampsia. JOP
15. Swank M, Nageotte M, Hatfield T. Necrotizing pancreatitis associated with
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severe preeclampsia. Obstet Gynecol 2012;120(2 Pt 2):453-5. 16. Chen CP1, Wang KG, Su TH, Yang YC. Acute pancreatitis in pregnancy. Acta Obstet Gynecol Scand. 1995;74(8):607-10.
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17. Haukland HH, Oian P, Maltau JM, Florholmen J, Burhol P. The effect of severe pre-eclampsia on the pancreas: changes in the serum cationic trypsinogen and
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pancreatic amylase. BJOG. 1987;94:765-767. 18. Juneja SK, Gupta S, Virk SS, Tandon, P, Bindal V. Acute pancreatitis in pregnancy: A treatment paradigm based on our hospital experience. Int J Appl Basic Med Res 2013; 3(2): 122–125.
19. Sheehan H, Lynch J. (1973). Pathology of toxemia of pregnancy. Edinburgh: Churchill Livingstone. 20. Nelson DB, Duraiswamy S, McIntire DD, Mayo MJ, Leveno1 KJ. Does
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ACCEPTED MANUSCRIPT Hacker et al preeclampsia involve the pancreas? A report of original research. J Matern Fetal Neonatal Med 2014 Jul 17:1-3. Epub ahead of print. 21. Institute of Medicine (US) Committee on Understanding Premature Birth and
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Assuring Healthy Outcomes; Behrman RE, Butler AS, editors. Preterm Birth:
Causes, Consequences, and Prevention. Washington (DC): National Academies
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Press (US); 2007.
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ACCEPTED MANUSCRIPT Hacker et al
Table 1: Maternal Demographics of Pregnancy-Associated Pancreatitis vs. the Control Population Pancreatitis
No Pancreatitis
% (n)
% (n)
0.829
≥35
16.4% (56)
16.9% (343,784)
83.6% (285)
83.1%
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<35
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Maternal age, y
P-value
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Variable
(1,695,272)
Race
<0.001
8.2% (28)
5.1% (103,327)
Caucasian
22.2% (76)
26.8%
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African American
60.8% (208)
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Hispanic
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Asian/Pacific Islander
Other
5.8% (20)
(545,661) 54.7%
(1,113,699) 11.5% (235,152)
2.9% (10)
1.9% (38,883)
Education, grade <12th
0.001 64.5% (213)
55.7% (1,101,967)
≥12th
35.5% (117)
44.3%
Pancreatitis in pregnancy and associated maternal and fetal morbidity and mortality
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ACCEPTED MANUSCRIPT Hacker et al (875,910) Insurance
0.026 54.7% (187)
48.7% (992,248)
Private
45.3% (155)
51.3% (1,047,280)
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Public
3.5% (12)
1.1% (12,947)
<0.001
Diabetes mellitus
3.2% (11)
0.7% (14,863)
<0.001
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Chronic Hypertension
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ACCEPTED MANUSCRIPT Hacker et al
Table 2: Unadjusted Incidence of Maternal Outcomes of PregnancyAssociated Pancreatitis vs. the Control Population
Gestational
Pancreatitis
No Pancreatitis
% (n)
% (n)
5.6% (19)
3.2% (64,781)
12.0% (41)
6.3% (128,546)
mellitus
<0.001
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Gestational diabetes
0.012
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hypertension
P-value
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Variable
13.5% (46)
2.9% (296)
<0.001
Severe preeclampsia
6.4% (22)
0.8% (16,051)
<0.001
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Preeclampsia
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ACCEPTED MANUSCRIPT Hacker et al
Table 3: Unadjusted Incidence of Fetal Outcomes of PregnancyAssociated Pancreatitis vs. the Control Population No Pancreatitis
% (n)
% (n)
4.7% (16)
1.2 % (24,779)
30.7% (105)
8.9% (181,778)
weeks Preterm delivery <37
Intrauterine fetal demise
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weeks
P-value
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Preterm delivery <32
Pancreatitis
<0.001
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Variable
<0.001
1.8% (6)
0.3% (6,766)
<0.001
Small for Gestational Age
22.8% (54)
10.7% (198,615)
<0.001
Respiratory distress
4.4% (15)
0.9% (17,624)
<0.001
0.3% (1)
0.0% (197)
<0.001
29.2% (100)
15.3% (311,237)
<0.001
0.60% (2)
0.20% (4,281)
0.124
0.30% (1)
0.10% (2,057)
0.265
Intraventricular
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syndrome
Jaundice Neonatal death
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Infant death
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Hemorrhage (grade 3 or 4)
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ACCEPTED MANUSCRIPT Hacker et al
Table 4: Adjusted Odds ratios for Outcomes of PregnancyAssociated Pancreatitis vs. the Control Population* Odds Ratio
95% Confidence Interval
1.18
0.67-2.06
Preeclampsia
4.21
2.99-5.93
Severe preeclampsia
7.85
5.03-12.24
Preterm delivery <32 weeks
3.31
1.93-5.56
Preterm delivery <37 weeks
4.10
3.23-5.21
Intrauterine fetal demise
4.35
1.80-10.55
Small for Gestational Age
2.26
1.64-3.11
Respiratory distress
4.27
2.44-7.46
Neonatal death
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2.22
1.74-2.84
1.47
0.21-10.46
2.8
0.39-19.97
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Infant death
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Jaundice
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syndrome
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Gestational hypertension
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Outcome
*Adjusted for chronic hypertension, gestational diabetes, maternal ethnicity, maternal age (≥35 or <35), insurance (public vs private), education level (≥12th grade or <12th grade)
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