Accepted Manuscript Predictors of Adverse Neonatal Outcomes in Intrahepatic Cholestasis of Pregnancy Tetsuya Kawakita, MD, Laura I. Parikh, MD, Patrick S. Ramsey, MD, MSPH, ChunChih Huang, PhD, Alexander Zeymo, MS, Miguel Fernandez, MD, Samuel Smith, MD, Sara N. Iqbal, MD PII:

S0002-9378(15)00604-3

DOI:

10.1016/j.ajog.2015.06.021

Reference:

YMOB 10468

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 7 March 2015 Revised Date:

26 April 2015

Accepted Date: 3 June 2015

Please cite this article as: Kawakita T, Parikh LI, Ramsey PS, Huang C-C, Zeymo A, Fernandez M, Smith S, Iqbal SN, Predictors of Adverse Neonatal Outcomes in Intrahepatic Cholestasis of Pregnancy, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.06.021. 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 1 Title: Predictors of Adverse Neonatal Outcomes in Intrahepatic Cholestasis of Pregnancy

Authors: Tetsuya KAWAKITA1, MD; Laura I. PARIKH1, MD; Patrick S. RAMSEY2, MD,

Samuel SMITH5, MD; Sara N. IQBAL1, MD

Department of Obstetrics and Gynecology, Medstar Washington Hospital Center, Washington,

SC

1

DC, United States

Department of Obstetrics and Gynecology, University of Texas Health Science Center at San

M AN U

2

RI PT

MSPH; Chun-Chih HUANG3, PhD; Alexander ZEYMO3, MS; Miguel FERNANDEZ4, MD;

Antonio, San Antonio, Texas, United States 3

Department of Biostatistics and Epidemiology, MedStar Health Research Institute, Hyattsville,

MD, United States

Department of Obstetrics and Gynecology, Virginia Hospital Center, Arlington, VA, United

States 5

TE D

4

Department of Obstetrics and Gynecology, Medstar Franklin Square Medical Center, Baltimore,

EP

MD, United States

AC C

Conflict of interest statement

The authors report no conflicts of interest.

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 2 Acknowledgement This project has been funded in part with Federal funds (Grant # UL1TR000101 previously UL1RR031975) from the National Center for Advancing Translational Sciences (NCATS),

RI PT

National Institutes of Health (NIH), through the Clinical and Translational Science Awards

Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, “Re-Engineering the

SC

Clinical Research Enterprise.

Paper presentation information

Diego, CA (Feb 2-7, 2015).

M AN U

This research was presented at the SMFM 35th Annual Meeting-The pregnancy meeting, San

Corresponding author: Tetsuya Kawakita, MD, Medstar Washington Hospital Center,

TE D

Department of Obstetrics & Gynecology,110 Irving Street, NW, Suite 5B45, Washington, DC 20010; e-mail: [email protected]

AC C

EP

Word count: Abstract 272 words, Main text 2946 words

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 3 Condensation: Total bile acid level ≥ 100 µmol/L is associated with increased risk of

AC C

EP

TE D

M AN U

SC

Short title: Intrahepatic Cholestasis of Pregnancy

RI PT

stillbirth in women with intrahepatic cholestasis of pregnancy.

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 4 Abstract Objective: To determine predictors of adverse neonatal outcomes in women with intrahepatic

RI PT

cholestasis of pregnancy (ICP). Study design:

This study was a multicenter retrospective cohort study of all women diagnosed with

SC

intrahepatic cholestasis of pregnancy across five hospital facilities between January 2009 and December 2014. Obstetric and neonatal complications were evaluated according to

M AN U

total bile acid (TBA) level. Multivariable logistic regression models were developed to evaluate predictors of composite neonatal outcome (neonatal intensive care unit admission, hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, transient tachypnea of the newborn, mechanical ventilation use, oxygen by nasal cannula,

TE D

pneumonia, and stillbirth). Predictors including TBA level, hepatic transaminase level, gestational age at diagnosis, underlying liver disease, and use of ursodeoxycholic acid were evaluated.

EP

Results:

Of 233 women with ICP, 152 women had TBA levels 10-39.9 µmol/L, 55 had TBA 40-

AC C

99.9 µmol/L, and 26 had TBA ≥ 100 µmol/L. There was no difference in maternal age, ethnicity, or pre-pregnancy body mass index according to TBA level. Increasing TBA level was associated with higher hepatic transaminase and total bilirubin level (P40 µmol/L was associated with an increased risk of meconium stained amniotic fluid even after adjusting for confounders.

TE D

The optimal cutoff for TBA level was 69 µmol/L with low sensitivity but with relatively high specificity in predicting composite adverse neonatal outcome. Early onset of disease has been reported to be a risk factor of adverse neonatal

EP

outcomes. However, previous research did not adjust for bile acid and liver transaminase levels.14, 20 It is important to adjust for bile acid and transaminase levels, since early onset

AC C

of disease is also reported to be associated with higher level of bile acid and liver enzymes.14 In our study, after adjusting for confounders, early onset of disease was not associated with increased risk of composite neonatal outcome. As previously discussed, meconium stained amniotic fluid occurs more likely at

later compared to earlier gestation21, and it is associated with fetal acidemia.22, 23 Interestingly, in our study, higher rate of meconium stained amniotic fluid was seen in

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 15 women with TBA 40-99.9 and > 100 µmol/L even after controlling for gestational age. The basis for this clinical finding is not completely understood, but may be related to high TBA levels which results in fetal distress and meconium passage at an earlier

RI PT

gestational age.

The major limitation of our study is its retrospective nature. We could not access prenatal data that was not included in the inpatient record. There were 131 women who

SC

were excluded due to lack of TBA results and 57 others who were not included because the TBA documented in their inpatient record was less than 10 µmol/L. There were 33

M AN U

women missing AST level, 34 women missing ALT level, and 78 women with missing total bilirubin level. Due to the large number of missing total bilirubin levels, we could not evaluate aOR of total bilirubin level. Due to our retrospective design, some women had serial bile acid level measurements and some women had only one value reported. As

TE D

a result, we could only evaluate outcomes based on maximum documented bile acid level and not trending bile acid levels over time. Our study was not large enough to evaluate rare outcomes such as neonatal asphyxia, sepsis, and intracranial hemorrhage. Also,

EP

authors did not have access to fetal heart tracings; we relied on the interpretation of the providers. Lastly, our composite neonatal outcomes were based on previous literature

AC C

review and included significant factors that alter neonatal prognosis or prolong neonatal hospital stay.1, 8, 9, 14, 17, 18, 19, 20 The strength of our study is the consideration of a wide variety of predictors and

inclusion of various neonatal outcomes. We used adjusted OR not only for known risk factors such as maternal complications and gestational age at delivery, but also possible predictors such as bile acid level, gestational age at diagnosis, ursodeoxycholic acid use,

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 16 AST, ALT, and pre-existing liver disease when we evaluated composite neonatal outcome. Our results are generalizable as we included multiple centers with diverse ethnicities. To the best of our knowledge, our study is so far the largest multicenter study

RI PT

in the United States to report outcomes in two hundred and thirty three patients with intrahepatic cholestasis of pregnancy.

Bile acid level > 100 µmol/L was associated with an increased risk of stillbirth.

SC

This information may help providers, when they are considering timing of delivery for

gestations complicated by ICP. The optimal cutoff for TBA level was 69 µmol/L for an

M AN U

adverse composite neonatal outcome. In our study, ursodeoxycholic acid was not associated with a reduction in the risk of composite neonatal outcome. Further large prospective trials are required to determine the efficacy of ursodeoxycholic acid and optimal timing of delivery to balance the risks of neonatal prematurity and stillbirth in

AC C

EP

TE D

pregnancies complicated by intrahepatic cholestasis of pregnancy.

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 17 Reference: 1.

Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology.

2.

RI PT

2004;40(2):467-474.

Kenyon AP, Piercy CN, Girling J, Williamson C, Tribe RM, Shennan AH.

Obstetric cholestasis, outcome with active management: a series of 70 cases. Bjog.

3.

SC

2002;109(3):282-288.

Williamson C, Hems LM, Goulis DG, et al. Clinical outcome in a series of cases

2004;111(7):676-681. 4.

M AN U

of obstetric cholestasis identified via a patient support group. Bjog.

Zecca E, De Luca D, Marras M, Caruso A, Bernardini T, Romagnoli C. Intrahepatic cholestasis of pregnancy and neonatal respiratory distress syndrome.

5.

TE D

Pediatrics. 2006;117(5):1669-1672.

Rioseco AJ, Ivankovic MB, Manzur A, et al. Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome. Am J Obstet

6.

EP

Gynecol. 1994;170(3):890-895.

Lo JO, Shaffer BL, Allen AJ, Little SE, Cheng WY, Caughey AB. Intrahepatic

AC C

cholestasis of pregnancy and timing of delivery. J Matern Fetal Neonatal Med.

2014;28:1-5.

7.

Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol.

2014;124(1):120-133.

8.

Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes:

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 18 a prospective population-based case-control study. Hepatology. 2014;59(4):14821491. 9.

Lee RH, Kwok KM, Ingles S, et al. Pregnancy outcomes during an era of

RI PT

aggressive management for intrahepatic cholestasis of pregnancy. Am J Perinatol. 2008;25(6):341-345. 10.

Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. Fetal outcomes

SC

in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort. PLoS One. 2012;7(3):e28343.

Abedin P, Weaver JB, Egginton E. Intrahepatic cholestasis of pregnancy:

M AN U

11.

prevalence and ethnic distribution. Ethn Health 1994;4:35-7. 12.

Puljic A, Kim E, Page J, Esakoff T, Shaffer B, LaCoursiere DY, Caughey AB. The risk of infant and fetal death by each additional week of expectant

TE D

management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol. 2015, doi: 10.1016/j.ajog.2015.02.012. 13.

Brouwers L, Koster M, Kemperman H, Boon J, Evers IM, Bogte A, Oudijk M.

EP

Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol. 2015;212:100.e1-7 Jin J, Pan SL, Huang LP, Yu YH, Zhong M, Zhang GW. Risk factors for adverse

AC C

14.

fetal outcomes among women with early- versus late-onset intrahepatic cholestasis of pregnancy. Int J Gynaecol Obstet. 2015;128(3):236-40

15.

Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL, Glasinovic JC.

Bile acids increase response and expression of human myometrial oxtocin receptor. Am J Obstet Gynecol.2003;189:577-582

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 19 16.

Isarel EJ, Guzman ML, Campos GA. Maximal response to oxytocin of the isolated myometrium from pregnant patients with intrahepatic cholestasis. Acta Obstet Gynecol Scand 1986;65:581-2 Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG, et al.

RI PT

17.

Ursodeoxycholic acid versus placebo, and early term delivery versus expectant

randomised clinical trial. BMJ 2012;344:e3799 18.

SC

management, in women with intrahepatic cholestasis of pregnancy: semifactorial

Bacq Y, Sentilhes L, Reyes H, Glantz A, Kondrackiene J, Binder T, et al.

M AN U

Efficacy of ursodeoxycholic aci in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012;143:1492-501 19.

Gurung V, Middleton P, Milan SJ, Hague W, Thornton JG. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev. 2013 Jun

20.

TE D

24;6:CD000493.

Madazli R, Yuksel MA, Oncul M, Tuten A, Guralp O, Aydin B. Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of

EP

pregnancy. J Obstet Gynaecol. 2014;10:1-4

AC C

21.Matthews TG, Warshaw JB. Relevance of the gestational age distribution of meconium passage in utero. Pediatrics 1979; 64:30.

22. Greenwood C, Lalchandani S, MacQuillan K, Sheil O, Murphy J, Impey L. Meconium passed in labor: how reassuring is clear amniotic fluid? Obstet Gynecol. 2003 Jul;102(1):89-93.

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT 20 23. Yeomans ER, Gilstrap LC 3rd, Leveno KJ, Burris JS. Meconium in the amniotic fluid

AC C

EP

TE D

M AN U

SC

RI PT

and fetal acid-base status. Obstet Gynecol. 1989 Feb;73(2):175-8.

Intrahepatic Cholestasis of Pregnancy

ACCEPTED MANUSCRIPT Table 1. Demographic data and pregnancy comorbidities of patients with intrahepatic cholestasis of pregnancy by bile acid level. TBAa 10-39.9 n=152

TBAa 40-99.9 n=55

TBAa> 100 n=26

P-Value

Mean maternal age (yr), mean ±(SD)

29.7 ± 6.0

30.4 ± 5.6

30.2 ± 7.4

.73

Nulliparous

66 (43.4)

28 (50.9)

12 (46.2)

.63

White

52 (34.2)

23 (41.8)

11 (42.3)

African American

37 (24.3)

5 (9.1)

Hispanic

39 (25.7)

14 (25.5)

Asian

16 (10.5)

7 (12.7)

Other

8 (5.3)

6 (10.9)

116 (88.6)

40 (88.9)

.22

b

2

Prepregnancy BMI (kg/m )

7 (26.9)

3 (11.5)

2 (7.7)

3 (11.5)

21 (91.3)

SC

Induction of labor

RI PT

Race/ethnicity

1 .41

83 (54.6)

37 (67.3)

14 (53.9)

Overweight

36(23.7)

12 (21.8)

7 (26.9)

Obese

33 (21.7)

6 (10.9)

5 (19.2)

13 (8.6)

10 (18.2)

1(3.9)

.09

1 (1.8)

0 (0)

1

9 (16.4)

1 (3.9)

.11

16 (10.5)

5 (9.1)

0 (0)

.23

Chronic hypertension

5(3.3)

0 (0)

0 (0)

.48

Preeclampsia

11 (7.2)

4 (7.3)

0 (0)

.47

Gestational hypertension

4 (2.6)

c

Any Diabetes

Preexisting diabetes

2 (1.3)

Gestational diabetes

11 (7.2)

ICPe in prior pregnancy History of liver or biliary diseasef Maternal Hepatitic B infection Maternal Hepatitic C infection Ursodiol use Improvement of pruritus

0 (0)

.83

10 (37.0)

4 (26.7)

.54

16 (10.5)

4 (7.3)

5 (19.2)

.24

1 (0.7)

0 (0)

0 (0)

1

7 (4.6)

2 (3.6)

2 (7.7)

.79

9 (6.0)

0 (0)

0 (0)

.14

67 (44.1)

35 (63.6)

16 (61.54)

.02

49 (43.0)

14 (32.6)

8 (34.78)

.44

EP

Smoking

2 (3.6)

22 (25.9)

TE D

Any hypertensive disease

d

M AN U

Underweight/Normal weight

34.2 ± 3.9

33.6 ± 4.3

30.6 ± 5.8