The Journal of Maternal-Fetal & Neonatal Medicine

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Perinatal outcomes associated with intrahepatic

cholestasis of pregnancy

Christina Annette Herrera, Tracy A. Manuck, Gregory J. Stoddard, Michael W.

Varner, Sean Esplin, Erin A. S. Clark, Robert M. Silver & Alexandra G. Eller

To cite this article: Christina Annette Herrera, Tracy A. Manuck, Gregory J. Stoddard, Michael
W. Varner, Sean Esplin, Erin A. S. Clark, Robert M. Silver & Alexandra G. Eller (2017): Perinatal
outcomes associated with intrahepatic cholestasis of pregnancy, The Journal of Maternal-Fetal &
Neonatal Medicine, DOI: 10.1080/14767058.2017.1332036

To link to this article: http://dx.doi.org/10.1080/14767058.2017.1332036

Published online: 05 Jun 2017.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2017
https://doi.org/10.1080/14767058.2017.1332036

ORIGINAL ARTICLE

Perinatal outcomes associated with intrahepatic cholestasis of pregnancy

Christina Annette Herreraa,b, Tracy A. Manucka,b,c, Gregory J. Stoddardd, Michael W. Varnera,b,
Sean Esplina,b, Erin A. S. Clarka,b, Robert M. Silvera,b and Alexandra G. Ellera,b
a
Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA; bIntermountain Healthcare Division of
Maternal Fetal Medicine, Salt Lake City, UT, USA; cDepartment of Obstetrics and Gynecology, University of North Carolina, Chapel Hill,
NC, USA; dDepartment of Internal Medicine, University of Utah, Salt Lake City, UT, USA

ABSTRACT ARTICLE HISTORY

Objective: The objective of this study is to examine perinatal outcomes associated with choles- Received 24 January 2017
tasis of pregnancy according to bile acid level and antenatal testing practice. Revised 30 April 2017
Study design: Retrospective cohort study of women with symptoms and bile acid testing from Accepted 15 May 2017
2005 to 2014. Women were stratified by bile acid level: no cholestasis (<10 lmol/L), mild
(10–39 lmol/L), moderate (40–99 lmol/L), and severe (100 lmol/L). The primary outcome was KEYWORDS
composite neonatal morbidity (hypoxic ischemic encephalopathy, severe intraventricular hemor- Cholestasis; bile acids;
rhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or death). perinatal outcomes;
Results: 785 women were included; 487 had cholestasis (347 mild, 108 moderate, 32 severe) stillbirth
and 298 did not. After controlling for gestational age (GA), severe cholestasis was associated
with the composite neonatal outcome (aRR 5.6, 95% CI 1.3–23.5) and meconium-stained fluid
(aRR 4.82, 95%CI 1.6–14.2). Bile acid levels were not correlated with the frequency of testing
(p ¼ .50). Women who underwent twice weekly testing were delivered earlier (p ¼ .016) than
women tested less frequently, but the difference in GA was 4 d. Abnormal testing prompting
delivery was uncommon. Among women with cholestasis, there were three stillbirths. One of
these women was undergoing antenatal testing, which was normal 1 d prior to the fetal demise.
Conclusion: Severe cholestasis is associated with neonatal morbidity which antenatal testing
may not predict.

Introduction highest risk for adverse perinatal outcomes including

Intrahepatic cholestasis of pregnancy has been associ-
ated with adverse perinatal outcomes but mechanisms
are poorly understood and optimal management is
uncertain [1]. Cholestasis of pregnancy complicates
0.2–2% of pregnancies; the incidence is higher in mul-
tiple gestations and among certain ethnic populations,
particularly Latina women [2]. The disease is multifac-
torial; genetic, hormonal, and environmental factors
may play a role [3]. Cholestasis characteristically
involves maternal pruritus without a rash after
30 weeks gestation and elevated serum bile acid levels
[4]. Although pruritus is medically benign, cholestasis
of pregnancy has been associated with morbid compli-
cations including stillbirth, particularly as gestation
advances [5,6].
Historically, evaluation of maternal serum bile acids
has been used to confirm the diagnosis of intrahepatic
cholestasis of pregnancy and identify women at the
spontaneous preterm birth, meconium-stained amni-
otic fluid, and stillbirth [6]. Furthermore, umbilical cord
levels correlate with maternal serum levels [6].
Elevated bile acids may increase the risk for stillbirth
via sudden cardiac arrhythmia or placental vasospasm;
they may increase the risk of spontaneous preterm
birth via increased oxytocin receptor sensitivity and
expression [6,7]. The impact of severely elevated bile
acids on neonatal outcome is not well defined. One
study attempted to identify predictors of adverse com-
posite neonatal morbidity including total bile acid
level, hepatic transaminase levels, ursodeoxycholic acid
(UDCA) use, gestational age (GA) at diagnosis, and
underlying liver disease. None of these factors were
predictive of composite neonatal morbidity which
included neonatal intensive care unit (NICU) admission,
oxygen by nasal cannula, hypoglycemia, hyperbilirubi-
nemia, respiratory distress syndrome (RDS), mechanical

CONTACT Christina A. Herrera christina.herrera@hsc.utah.edu University of Utah Department of OBGYN, Division of Maternal Fetal Medicine, 30 N.
Medical Drive, Room 2B200, Salt Lake City, UT 84132, USA

Presentations: This study was presented in part in poster format at the Society of Maternal Fetal Medicine (SMFM) annual Pregnancy Meeting in
February 2016.
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 C. A. HERRERA ET AL.
ventilation use, transient tachypnea of the newborn
(TTN), and stillbirth [8].
Interventions for preventing adverse perinatal out-
comes with intrahepatic cholestasis of pregnancy are
of unproven efficacy. Management schemes differ due
to a lack of high-quality evidence to guide providers.
Fetal non-stress tests are often performed in an effort
to attenuate the risk of adverse perinatal outcomes
including asphyxia and stillbirth. In general, non-stress
tests have a low false-negative rate (less than 1% risk
for stillbirth within 7 d of a reactive (normal) test) [9].
This is appealing given the association between still-
birth and cholestasis of pregnancy. However, non-
stress tests have not been shown to reduce stillbirth in
this population, and fetal death has been documented
within days of a reactive non-stress test in several
cases [8,10–13]. Non-stress tests were introduced as a
means of predicting fetal asphyxia due to chronic
processes such as placental insufficiency [9]. Stillbirth
in the setting of cholestasis of pregnancy is thought
to be a sudden, unpredictable event [7], yet antenatal
testing is commonly used for surveillance.
We sought to examine perinatal outcomes among
women with cholestasis according to bile acid levels
and antenatal fetal testing patterns. We hypothesized
that neonatal morbidity would be positively correlated
with bile acid levels and that antenatal testing would
not prevent adverse outcomes.
Materials and methods
We performed a retrospective cohort study of women
with intrahepatic cholestasis of pregnancy over
10 years (2005–2015) within the Intermountain
Healthcare system, a large healthcare system that
includes 22 hospitals. Administrative and clinical elec-
tronic medical record data are maintained in an
Enterprise Data Warehouse that captures data across
multiple information systems. The Enterprise Data
Warehouse was queried to identify women who deliv-
ered at an Intermountain facility with a diagnosis of
intrahepatic cholestasis of pregnancy, pruritus, or itch-
ing using ICD9 codes (648.93, 576.8, 698.9). Our study
was approved by the Intermountain Institutional
Review Board (IRB#1024616).
Women were included if they met initial ICD9 cod-
ing criteria and had serum bile acid testing performed.
Women were considered to have intrahepatic cholesta-
sis of pregnancy with bile acids 10 lmol/L. Women
with normal bile acids (<10 lmol/L) were categorized
as controls. Women were excluded if they had a major
fetal chromosomal or structural abnormality. In order
to ensure data accuracy, 5% of medical records were
audited (and deemed accurate) by manual physician
review (CAH).
The primary outcome was composite neonatal mor-
bidity which included any of the following: hypoxic
ischemic encephalopathy (HIE), intraventricular hemor-
rhage (IVH) grade 3 or 4, bronchopulmonary dysplasia
(BPD), necrotizing enterocolitis (NEC), or perinatal
death (including stillbirth). These outcomes were
determined by ICD-9 coding. Secondary outcomes
included individual neonatal morbidity and perinatal
outcomes according to antenatal testing frequency.
Perinatal asphyxia was defined as an arterial cord
blood gas with pH less than 7.00 and/or a five minute
Apgar score less than 5 [14]. Delivery GA included all
births (as opposed to only live births). Of note, during
the study epoch, there was no institutional standard
for delivery timing, but delivery at 37 weeks was cus-
tomary. Additionally, there was no protocol for ante-
natal testing scheme, which was provider dependent.
For the primary analysis, women were categorized
into four groups based on maximum serum bile acid
level: no cholestasis (bile acids <10 lmol/L), mild cho-
lestasis (bile acids 10–39 lmol/L), moderate cholestasis
(bile acids 40–99 lmol/L), and severe cholestasis (bile
acids 100 lmol/L). For antenatal testing analysis,
women were grouped by the frequency of non-stress
tests, as determined by billing records: twice weekly or
more, weekly, or less than weekly. Women who did
not have testing at one of our hospitals were excluded
from the analysis as they could have had testing at an
outside clinic (testing records inaccessible to us),
which would bias our results. If women had varying
frequencies of testing during the observation period,
they were categorized by the most frequent testing
received.
In order to appropriately account for multiple gesta-
tions and mothers with more than one pregnancy in
our cohort, we used mixed effects models in all analy-
ses (including patient demographics). We used mixed
effects linear regression for continuous outcomes,
mixed effects gamma regression for severely skewed
continuous outcomes, and mixed effects Poisson
regression for binary outcomes. We performed multi-
variable mixed effects regression models for primary
outcomes to control for potential confounders, begin-
ning with all potential confounders with p values less
than .20, and then eliminating them in a backwards
variable selection fashion. We included multiple gesta-
tions in our analysis as this group is at high risk for
cholestasis. In order to account for possible confound-
ing of neonatal outcomes by including multiple gesta-
tions, we controlled for these pregnancies in our
regression models. There was no adjustment for
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

multiple comparisons and no imputation was made
for missing data. All p values were derived from a two-
sided comparison. Statistical analyses were performed
using STATA software (v14.1, College Station, TX).
Results
Seven hundred and eight-five pregnancies from 759
mothers including 843 neonates (731 singletons, 50
twins, and four triplets) met inclusion criteria. Two
hundred and ninty-eight had no laboratory evidence
of cholestasis of pregnancy, 347 had mild cholestasis
of pregnancy, 108 had moderate cholestasis of preg-
nancy, and 32 had severe cholestasis of pregnancy.
Maternal demographics and pregnancy characteristics
are shown in Table 1. Women with severe intrahepatic
cholestasis of pregnancy were more likely to be
Hispanic (p ¼ .047) and have a higher pre-pregnancy
BMI (p ¼ .042). Women with moderate intrahepatic
cholestasis of pregnancy were more likely to have mul-
tiple gestations (p ¼ .037). Women without intrahepatic
cholestasis of pregnancy were more likely to have
hypertensive disorders (p ¼ .030).
Neonatal outcomes adjusted for GA according to
maternal bile acid level are presented in Table 2.
Women with severe cholestasis of pregnancy were
more likely to have the composite neonatal morbidity
(p ¼ .004) and meconium-stained amniotic fluid
(p ¼ .014), while women with moderate cholestasis of
pregnancy were more likely to have longer NICU stay
(p ¼ .052). After controlling for potential confounders
(Tables 3(a) and 3(b)) including Hispanic ethnicity, pre-
pregnancy BMI, hypertensive disorder, cesarean deliv-
ery and delivery GA, severe intrahepatic cholestasis of
pregnancy remained associated with the composite
neonatal morbidity (p ¼ .019) and meconium stained
amniotic fluid (p ¼ .004). However, NICU stay was only
related to delivery GA (p ¼ .065, Table 3c). These find-
ings persisted after controlling for multiple gestations.
Figure 1 shows the incidence of neonatal morbidity
and delivery GA according to bile acid level.
Women with severe cholestasis of pregnancy were
delivered earlier in gestation (mean 36.5 weeks,
p ¼ .002, Table 4). There was no difference in the inci-
dence of spontaneous preterm birth between groups
(p ¼ .729). Of the 34 neonates (from 22 pregnancies)
with composite morbidity, 11 were singletons, 20 were
twins, and three were triplets. Among those pregnan-
cies with neonatal morbidity, seven had no antenatal
testing, 14 had some form of antenatal testing which
was normal prior to delivery, and one was delivered
due to a non-reactive non-stress test in the setting of
comorbidities (subject 1 of Table 6).
Perinatal outcomes according to antenatal testing
frequency are shown in Table 5. Of patients under-
going antenatal testing, 150 women had non-stress
tests twice weekly or more, 43 had weekly testing, and
53 were tested less than once per week. Bile acid lev-
els did not differ between groups according to testing
frequency (p ¼ .50, Table 5). Women receiving twice
weekly or more testing were delivered earlier in gesta-
tion (mean 36.6 weeks, p ¼ .016), but the difference in
GA was 4 d. Women with antenatal testing less than
once per week were diagnosed at a later GA than
women with higher testing frequencies (p < .001).
Four women had abnormal antenatal testing
prompting delivery with no evidence of perinatal
asphyxia in these neonates. These pregnancies are

Table 1. Maternal demographics and pregnancy characteristics stratified by maximum serum bile acid level.
No ICP, bile acids Mild ICP, bile acids Moderate ICP, bile acids Severe ICP, bile acids
<10 lmol/L 10–39 lmol/L 40–99 lmol/L 100 lmol/L
(n ¼ 298) (n ¼ 347) (n ¼ 108) (n ¼ 32) p Value
Maternal age (years), mean ± SD 27.9 ± 5.7 28.0 ± 5.1 28.1 ± 5.0 29.7 ± 6.2 .496
Nulliparous 128 (43.0) 126 (36.3) 40 (37.0) 8 (25.0) .129
White race 242 (81.8) 266 (77.3) 79 (73.8) 19 (59.4) .530
Hispanic ethnicity 41 (13.9) 57 (16.6) 22 (20.6) 11 (34.4) .047
Multiple gestations
Twins 16 (5.4) 20 (5.8) 12 (11.1) 2 (6.3) .037
Triplets 0 (0) 2 (0.6) 2 (1.9) 0 (0)
Pre-pregnancy BMI, kg/m2, mean ± SD 26.0 ± 6.0 25.2 ± 5.7 24.2 ± 5.6 26.7 ± 6.3 .042
Current smoker 6 (2.0) 11 (3.2) 1 (0.9) 0 (0) .597
Hypertensive disorder 25 (8.4) 10 (2.9) 5 (4.6) 1 (3.1) .030
Diabetes 28 (9.4) 23 (6.6) 4 (3.7) 3 (9.4) .156
Treated with UDCA NA 131 (37.8) 52 (48.1) 14 (43.8) .148
GA at cholestasis diagnosis, mean ± SD NA 34.4 ± 3.7 33.9 ± 3.8 33.2 ± 5.0 .113
Maximum bile acid result, lmol/L, median (IQR) NA 19 (14, 26) 55 (45, 76) 122 (112.5, 159) NA
Maximum AST result (U/L), median (IQR) NA 49 (33, 81) 72 (44, 148) 68 (46, 125) NA
Maximum ALT result (U/L), median (IQR) NA 63 (34, 129) 89 (250, 50) 86.5 (237, 60) NA
Cesarean delivery 89 (29.9) 73 (21.0) 33 (30.6) 7 (21.9) .109
Data are N (%) unless otherwise specified. NA: not applicable. Statistical comparison not of interest, groups differ as defined. IQR: interquartile range
(25th, 75th percentiles). ICP: intrahepatic cholestasis of pregnancy; BMI: body mass index; UDCA: ursodeoxycholic acid; GA: gestational age; AST: aspartate
aminotransferase; ALT: alanine transaminase.
4 C. A. HERRERA ET AL.

Table 2. Adjusteda relative risks of composite and individual neonatal morbidity.

No ICP, bile acids Mild ICP, bile acids Moderate ICP, bile acids Severe ICP, bile acids
<10 lmol/L (n ¼ 298) 10–39 lmol/L (n ¼ 347) 40–99 lmol/L (n ¼ 108) 100 lmol/L (n ¼ 32)
Composite neonatal morbidityb Referent 0.94 (0.32–2.82, 0.917) 1.61 (0.53–4.87, 0.399) 5.39 (1.70–17.11, 0.004)
HIE, n 0 0 0 0
IVH 3 or 4, n 0 0 0 0
NEC, n 2 1 1 1
BPD, n 3 7 7 5
Death, n 0 1 1 1
Unadjusted incidence, n (%) 5 (1.6) 9 (2.4) 9 (7.3) 7 (20.6)
Perinatal asphyxia Referent 1.02 (0.17–6.24, 0.983) 0.89 (0.11–7.60, 0.917) 5.76 (0.76–43.88, 0.091)
Meconium-stained fluid Referent 1.55 (0.79–3.02, 0.201) 1.60 (0.66–3.91, 0.300) 3.74 (1.31–10.68, 0.014)
SGA Referent 1.45 (0.80–2.63, 0.225) 1.37 (0.63–2.99, 0.429) 2.19 (0.79–6.05, 0.132)
NICU admission Referent 0.86 (0.62–1.19, 0.359) 0.90 (0.60–1.35, 0.610) 0.91 (0.48–1.74, 0.781)
NICU length of stay Referent 0.89 (0.71–1.11, 0.293) 1.33 (1.00–1.77, 0.052) 1.52 (0.97–2.38, 0.068)
Hyperbilirubinemia Referent 0.99 (0.80–1.22, 0.900) 1.02 (0.77–1.36, 0.886) 0.79 (0.46–1.35, 0.386)
RDS Referent 0.91 (0.52–1.59, 0.747) 0.80 (0.41–1.59, 0.808) 1.130 (0.42–3.03, 0.808)
Data are RR (95% CI, p values). ICP: intrahepatic cholestasis of pregnancy; SGA: small for gestational age; NICU: neonatal intensive care unit; RDS: respira-
tory distress syndrome.
a
Adjusted for delivery gestational age.
b
Composite includes: hypoxic ischemic encephalopathy, intraventricular hemorrhage (grade 3 or 4), necrotizing enterocolitis, bronchopulmonary dysplasia,
or perinatal death.

Table 3a. Multivariable mixed effects Poisson regression Table 3c. Multivariable mixed effects Poisson regression
model with neonatal composite morbiditya. model with NICU length of staya.
RR (95% CI) p Value RRb (95% CI) p Value
Delivery GA 0.56 (0.45–0.69) <.001 Delivery GA 0.74 (0.72–0.77) <.001
Bile acid levels Bile acid levels
No ICP Referent No ICP Referent
Mild ICP 1.01 (0.30–3.37) .987 Mild ICP 9.8 (8.1–11.5) .261
Moderate ICP 2.03 (0.58–7.13) .272 Moderate ICP 20.9 (15.4–26.2) .065
Severe ICP 5.59 (1.33–23.53) .019 Severe ICP 21.3 (10.9–31.7) .157
Bile acid levels – controlling for multiple gestations Bile acid levels – controlling for multiple gestations
No ICP Referent No ICP Referent
Mild ICP 0.90 (0.30–2.69) .846 Mild ICP 10.3 (9.0–11.7) .249
Moderate ICP 1.38 (0.44–4.30) .577 Moderate ICP 14.4 (11.8–17.1) .075
Severe ICP 5.21 (1.63–16.61) .005 Severe ICP 15.0 (9.8–20.1) .972
a
Potential confounders dropped from the final model (p > .20) included RR: relative risk; GA: gestational age; ICP: intrahepatic cholestasis of
Hispanic ethnicity, pre-pregnancy BMI, hypertensive disorder, and cesar- pregnancy.
ean delivery. a
Potential confounders dropped from the final model (p > .20) included
Hispanic ethnicity, pre-pregnancy BMI, hypertensive disorder, and cesar-
ean delivery.
b
Table 3b. Multivariable mixed effects Poisson regression Reported in days. Counts of days are modeled so RR represents the ratio
of mean days in NICU.
model with meconium-stained amniotic fluida.
RR (95% CI) p Value
Delivery GA 1.24 (1.03–1.50) .026
Bile acid levels
No ICP Referent One stillbirth (subject 1, Table 7) may have been
Mild ICP 1.80 (0.90–3.59) .094 related to cholestasis of pregnancy since it was other-
Moderate ICP 2.04 (0.81–5.11) .129
Severe ICP 4.82 (1.64–14.18) .004 wise unexplained. This patient had a reactive non-
Bile acid levels – controlling for multiple gestations stress test one day prior to the fetal demise. The
No ICP Referent other two had causes of stillbirth unrelated to choles-
Mild ICP 1.79 (0.89–3.58) .100
Moderate ICP 2.03 (0.81–5.09) .132 tasis of pregnancy.
Severe ICP 4.75 (1.60–14.13) .005 The observed sample sizes for the four bile acid
a
Potential confounders dropped from the final model (p > .20) included level (cholestasis) groups were no (n ¼ 314), mild
Hispanic ethnicity, pre-pregnancy BMI, hypertensive disorder, and cesar-
ean delivery. (n ¼ 317), moderate (n ¼ 124), and severe (n ¼ 34).
Relative to the observed incidence for the primary
outcome of neonatal morbidity in the no cholestasis
summarized in Table 6. Two of these cases had a con- group (1.6%), these sample sizes provided 80%
current comorbidity for which testing was already indi- power, using a two-sided alpha 0.05 comparison,
cated, which may have also impacted the decision to to detect a difference between the no cholestasis
deliver. There were three stillbirths in the cohort. group and the following incidences for the three cho-
Details are summarized in Table 7. INCODE classifica- lestasis groups: mild (5.6%), moderate (7.3%), and
tions were used to categorize the cause of death [15]. severe (11.9%).
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

Figure 1. Shown are adjusted means and proportions using marginal estimation [25] following the appropriate mixed effects
regression model, controlling for gestational age in composite morbidity, and perinatal asphyxia.

Table 4. Pregnancy and delivery characteristics stratified by bile acid level.

Mild ICP, bile acids Moderate ICP, bile acids Severe ICP, bile acids
10–39 lmol/L (n ¼ 347) 40–99 lmol/L (n ¼ 108) 100 lmol/L (n ¼ 32) p Value
Delivery GA, mean ± SD 37.3 ± 1.5 36.9 ± 1.6 36.5 ± 1.9 .002
Stillbirth 1 (0.3) 1 (0.8) 1 (2.9) NA
Spontaneous preterm birth 21 (6.1) 8 (7.4) 3 (9.4) .729
Number of non-stress tests, median (IQR) 4.1 (3.3, 6.2) 3.9 (3.2, 5.5) 4.2 (3.4, 7.4) .253
Number of BPPs, median (IQR) 1 (1, 2) 1 (1, 2) 1 (1, 1) NA
Data are N (%) unless otherwise specified. NA: not applicable. Outcome too rare to fit a model without over-fitting. IQR: interquartile range (25th, 75th
percentiles). ICP: intrahepatic cholestasis of pregnancy; GA: gestational age; NST: non-stress test; BPP: biophysical profile.

Table 5. Pregnancy and neonatal outcomes stratified by testing frequency among patientsa with intrahepatic cholestasis of
pregnancy.
Twice weekly or more Once weekly Less than weekly
(n ¼ 150) (n ¼ 43) (n ¼ 53) p Value
Delivery GA, mean ± SD 36.6 ± 1.3 37.2 ± 1.4 37.1 ± 1.2 .016
<37 weeks 24 (16.0) 10 (23.3) 13 (24.5) .380
<36 weeks 23 (15.3) 3 (7.0) 4 (7.6) .107
<34 weeks 9 (6.0) 2 (4.7) 1 (1.9) .590
<32 weeks 1 (0.7) 0 (0) 0 (0) NA
<28 weeks 0 (0) 0 (0) 0 (0) NA
Delivery GA singletons, mean ± SD 36.9 ± 1.2 37.5 ± 1.1 37.2 ± 1.0 .013
Composite neonatal morbidity 9 (5.2) 4 (8.2) 1 (1.8) .537
Perinatal asphyxia 4 (2.3) 0 (0) 0 (0) NA
GA at ICP diagnosis, mean ± SD 32.4 ± 3.6 32.4 ± 3.8 34.6 ± 3.6 <.001
Maximum bile acid result (lmol/L), median (IQR) 25.5 (16, 44) 26 (19, 39) 24 (17, 45) .496
Maximum bile acids >40 42 (28.0) 10 (23.3) 15 (28.3) .682
Multiple gestations
Twins 18 (12.0) 6 (14.0) 2 (3.8) .149
Triplets 3 (2.0) 0 (0) 0 (0)
One or more BPPs performed 27 (18.0) 5 (11.6) 5 (9.4) .289
Abnormal NST prompting delivery 2 (1.5) 2 (4.7) 0 (0) >.99
Number of admissions not resulting in delivery, median (IQR) 1 (0,2) 1 (0,2) 1 (0,1) NA
Data are N (%) unless otherwise specified. NA: not applicable. Outcome too rare to fit a model without over-fitting. IQR: interquartile range (25th, 75th
percentiles). ICP: intrahepatic cholestasis of pregnancy; GA: gestational age; NST: non-stress test; BPP: biophysical profile.
a
These data include only those women who underwent testing at one of our clinical sites.
6 C. A. HERRERA ET AL.

Table 6. Summary of intrahepatic cholestasis of pregnancy cases with abnormal testing prompting delivery.
Delivery
Testing gestational Max bile Delivery Arterial cord
Subject frequency NST result agea acids type Apgars gas (pH, BE) Additional maternal comorbidities or history
1 Weekly Non-reactive 30 30 Cesarean 6, 7 7.3, 2.2 Lupus, antiphospholipid syndrome, pre-eclampsia,
history of 2 prior stillbirths
2 Twice weekly Non-reactive 34 16 Vaginal 8, 8 7.3, 3.6 Depression on Quetiapine and Clonazepam
3 Twice weekly Non-reactive 36 24 Vaginal 8, 9 NA None
4 Weekly 1 Late deceleration 39 14 Vaginal 8, 9 NA None
NA: not available; GA: gestational age; NST: non-stress test; BE: base excess.

Table 7. Summary of intrahepatic cholestasis of pregnancy cases complicated by stillbirth.

Gestational Autopsy and Max bile Other complica-
age at placental acids tions or
Subject stillbirth Testing Clinical presentation pathology (lmol/L) comorbidities INCODE
1 35 Weekly Decreased fetal move- Acute hypoxemia, placen- 47 None Unexplained; may be
ment after reactive tal infarction, wavy car- related to intrahepatic
NST one day prior diac myocytes cholestasis of
pregnancy
2 23 None Decreased fetal Short umbilical cord with 31 None Possible cause (cord
movement tight nuchal, acute accident)
asphyxia
3 25 None Monochorionic twin Necrotic umbilical cord 118 Twin twin transfu- Probable cause (twin twin
pregnancy with and extensive placental sion syndrome, transfusion syndrome)
known twin trans- infarction preeclampsia
fusion syndrome,
demise of twin A

Discussion levels or the proportion of women with bile acids

Severe bile acid elevation was associated with com-
posite neonatal morbidity, even after controlling for
potential confounders (including GA and multiple ges-
tations). Notably, our composite was driven predomin-
ately by BPD, which is not surprising, given the GA at
delivery of the cohort (mostly late preterm or early
term). The incidence of BPD increases with decreasing
GA [16] and birth weight [17]. While little is known
about the association between cholestasis and BPD,
antenatal infection and inflammation have been asso-
ciated with cholestasis, which in turn increase the risk
of BPD [18]. Additionally, delivery in higher altitude
settings, such as the State of Utah, where this cohort
was derived, is a risk factor for BPD [19].
More frequent antenatal testing (twice weekly or
more) was associated with earlier GA at delivery,
although the difference was probably not clinically sig-
nificant (4 d). However, 15.3% of women tested twice
weekly were delivered at <36 weeks compared to only
7.3% of women with lower testing frequencies. While
the difference did not reach statistical significance, this
finding warrants further investigation. Testing fre-
quency was inversely correlated to GA at diagnosis –
the earlier the diagnosis was made, the more testing
the patient received. Of course, more frequent testing
may reflect provider perception of disease severity
which may have also impacted delivery timing; how-
ever, there was no difference in maximum bile acid
>40 lmol/L among testing groups. Testing results
prompted delivery in four patients (2%), none of
whom had evidence of perinatal asphyxia. A larger
sample size and trial design could better assess the
relevance of testing and timing of delivery in women
with cholestasis.
There were three stillbirths (0.6%) in the cohort
with cholestasis, two of whom had possible or prob-
able causes of death unrelated to cholestasis of preg-
nancy. Stillbirth was rare in our cohort, but our sample
size precludes us from making definitive conclusions
about the role of antenatal testing in preventing still-
birth among women with cholestasis.
Our current knowledge regarding interventions for
intrahepatic cholestasis of pregnancy remains limited.
UDCA improves pruritus, but has not been shown to
reduce the rates of abnormal fetal testing or asphyxial
events [1,20]. The risk of stillbirth may be directly cor-
related with the severity of bile acid elevation,
although a variety of thresholds have been used to
define “severe” elevation (>40 lmol/L, >100 lmol/L)
[6,21]. Severely elevated bile acids may increase the
risk of stillbirth at a threshold of 100 lmol/L [8].
Timing of delivery remains controversial [22,23]. Early-
term delivery (e.g. 37 weeks gestation) is a common
approach for women with moderate to severe disease
(bile acids 40 lmol/L), while other experts advocate
for later term delivery (e.g. 38–39 weeks gestation) for

women with mild disease (bile acids <40 lmol/L)
[22,24]. While antenatal testing may provide reassur-
ance for the patient and/or provider, the benefit of
testing remains unproven in women with cholestasis
of pregnancy.
Our study has several strengths. First, we used
rigorous case ascertainment of a large cohort of
women with intrahepatic cholestasis of pregnancy via
ICD9 coding and bile acid criteria. Second, accuracy of
the database was vetted by medical record audit of
5% of cases, including all cases with composite mor-
bidity, abnormal testing prompting delivery, or still-
birth. Third, we included a control group with
documented normal bile acids for comparison.
The study also has several limitations. First, we used
a retrospective design, due to the rarity of the disease.
Second, our population was predominately Caucasian,
reducing generalizability. Third, although large for
studies of intrahepatic cholestasis of pregnancy, our
sample size limited our ability to perform subset analy-
ses and make definitive conclusions about rare, but
important outcomes, such as stillbirth. Fourth, our con-
trol group, chosen because of the documentation of
normal bile acid levels, were likely tested due to sus-
pected cholestasis based on the presence of pruritus.
While this control group was chosen for their normal
objective criteria (normal bile acids), they may repre-
sent a biased group in that they were symptomatic
which prompted testing. The inclusion of multiple ges-
tations may also introduce bias as they have a higher
a priori risk of adverse outcomes. We attempted to
reduce bias by controlling for multiples in our regres-
sion models. Fifth, many of our patients were treated
with UDCA, delivered early, and/or underwent ante-
natal testing and thus, any conclusions we have made
must be interpreted with caution in this context.
Lastly, our study may have been subject to type II
error in that active management of cholestasis could
have resulted in a decreased frequency adverse
outcomes.
In summary, severe bile acid elevation is associ-
ated with increased neonatal morbidity. More fre-
quent testing may not reduce the risk of adverse
outcomes. While our study design does not allow us
to make specific recommendations regarding ante-
natal testing or timing of delivery among women
with intrahepatic cholestasis of pregnancy, our data
raise questions about the utility of non-stress tests in
this population. Factors such as cost, time commit-
ment, the potential for both false-positive and false-
negative results, and patient/provider goals should all
be considered when developing an individualized
antenatal testing plan.
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 7
Acknowledgements
Authors thank Vickie Baer, RN: Research support nurse who
performed data abstraction.
Disclosure statement
The authors report no conflicts of interest.
References
[1] Gurung V, Middleton P, Milan SJ, et al. Interventions
for treating cholestasis in pregnancy. Cochrane
Database Syst Rev. 2013;6:CD000493.
[2] Puljic A, Kim E, Page J, et al. The risk of infant and
fetal death by each additional week of expectant
management in intrahepatic cholestasis of pregnancy
by gestational age. Am J Obstet Gynecol. 2015;212:
667.e1–5.
[3] Reyes H. What have we learned about intrahepatic
cholestasis of pregnancy? Hepatology. 2016;63:4–8.
[4] Kenyon AP, Piercy CN, Girling J, et al. Obstetric choles-
tasis, outcome with active management: a series of 70
cases. BJOG. 2002;109:282–288.
[5] Williamson C, Hems LM, Goulis DG, et al. Clinical out-
come in a series of cases of obstetric cholestasis iden-
tified via a patient support group. BJOG. 2004;111:
676–681.
[6] Brouwers L, Koster MPH, Page-Christiaens GCML, et al.
Intrahepatic cholestasis of pregnancy: maternal and
fetal outcomes associated with elevated bile acid lev-
els. Am J Obstet Gynecol. 2015;212:100.e1–7.
[7] Williamson C, Geenes V. Intrahepatic cholestasis of
pregnancy. Obstet Gynecol. 2014;124:120–133.
[8] Kawakita T, Parikh LI, Ramsey PS, et al. Predictors of
adverse neonatal outcomes in intrahepatic cholestasis
of pregnancy. Am J Obstet Gynecol. 2015;213:
570.e1–8.
[9] NA. Practice bulletin no. 145: antepartum fetal surveil-
lance. Obstet Gynecol. 2014;124:182–192.
[10] Alsulyman OM, Ouzounian JG, Ames-Castro M, et al.
Intrahepatic cholestasis of pregnancy: perinatal out-
come associated with expectant management. Am J
Obstet Gynecol. 1996;175:957–960.
[11] Laatikainen T, Tulenheimo A. Maternal serum bile acid
levels and fetal distress in cholestasis of pregnancy.
Int J Gynaecol Obstet. 1984;22:91–94.
[12] Sentilhes L, Verspyck E, Pia P, et al. Fetal death in a
patient with intrahepatic cholestasis of pregnancy.
Obstet Gynecol. 2006;107:458–460.
[13] Lee RH, Incerpi MH, Miller DA, et al. Sudden fetal
death in intrahepatic cholestasis of pregnancy. Obstet
Gynecol. 2009;113:528–531.
[14] NA. Executive summary: Neonatal encephalopathy
and neurologic outcome, second edition. Report of
the American College of Obstetricians and
Gynecologists' Task Force on Neonatal
Encephalopathy. Obstet Gynecol. 2014;123:896–901.
[15] Stillbirth Collaborative Research Network Writing
Group. Causes of death among stillbirths. Jama.
2011;306:2459–2468.
8 C. A. HERRERA ET AL.
[16] Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of
extremely preterm infants from the NICHD Neonatal
Research Network. Pediatrics. 2010;126:443–456.
[17] Walsh MC, Szefler S, Davis J, et al. Summary proceed-
ings from the bronchopulmonary dysplasia group.
Pediatrics. 2006;117:S52–S56.
[18] Wright CJ, Kirpalani H. Targeting inflammation to
prevent bronchopulmonary dysplasia: can new
insights be translated into therapies? Pediatrics.
2011;128:111–126.
[19] Fernandez CLA, Fajardo CA, Favareto MV, et al.
Oxygen dependency as equivalent to bronchopulmo-
nary dysplasia at different altitudes in newborns
1500 g at birth from the SIBEN network. J Perinatol.
2014;34:538–542.
[20] Chappell LC, Gurung V, Seed PT, et al. Ursodeoxycholic
acid versus placebo, and early term delivery versus
expectant management, in women with intrahepatic
cholestasis of pregnancy: semifactorial randomised
clinical trial. BMJ. 2012;344:e3799.
[21] Geenes V, Chappell LC, Seed PT, et al. Association of
severe intrahepatic cholestasis of pregnancy with
adverse pregnancy outcomes: a prospective popula-
tion-based case–control study. Hepatology.
2014;59:1482–1491.
[22] Henderson CE, Shah RR, Gottimukkala S, et al. Primum
non nocere: how active management became modus
operandi for intrahepatic cholestasis of pregnancy.
Am J Obstet Gynecol. 2014;211:189–196.
[23] Jain R, Suri V, Chopra S, et al. Obstetric cholestasis:
outcome with active management. J Obstet Gynaecol
Res. 2013;39:953–959.
[24] Glantz A, Marschall H-U, Mattsson L-A. Intrahepatic
cholestasis of pregnancy: relationships between bile
acid levels and fetal complication rates. Hepatology.
2004;40:467–474.
[25] Muller CJ, MacLehose RF. Estimating predicted proba-
bilities from logistic regression: different methods cor-
respond to different target populations. Int J
Epidemiol. 2014;43:962–970.