Association of Severe Intrahepatic Cholestasis of

Pregnancy With Adverse Pregnancy Outcomes: A

Prospective Population-Based Case-Control Study
Victoria Geenes,1 Lucy C. Chappell,2 Paul T. Seed,2 Philip J. Steer,3
Marian Knight,4 and Catherine Williamson1,2

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, charac-

terized by maternal pruritus and raised serum bile acids. Our objectives were to describe
the epidemiology and pregnancy complications associated with severe ICP and to test
the hypothesis that adverse perinatal outcomes are increased in these women. A prospec-
tive population-based case-control study with national coverage was undertaken using
the UK Obstetric Surveillance System (UKOSS). Control data for comparison were
obtained from women with healthy pregnancy outcome through UKOSS (n 5 2,232),
St Mary’s Maternity Information System (n 5 554,319), and Office for National Statis-
tics (n 5 668,195). The main outcome measures investigated were preterm delivery,
stillbirth, and neonatal unit admission. In all, 713 confirmed cases of severe ICP were
identified, giving an estimated incidence of 9.2 per 10,000 maternities. Women with
severe ICP and a singleton pregnancy (n 5 669) had increased risks of preterm delivery
(164/664; 25% versus 144/2200; 6.5%; adjusted odds ratio [OR] 5.39, 95% confidence
interval [CI] 4.17 to 6.98), neonatal unit admission (80/654; 12% versus 123/2192;
5.6%; adjusted OR 2.68, 95% CI 1.97 to 3.65), and stillbirth (10/664; 1.5% versus 11/
2205; 0.5%; adjusted OR 2.58, 95% CI 1.03 to 6.49) compared to controls. Seven of
10 stillbirths in ICP cases were associated with coexisting pregnancy complications.
These differences remained significant against national data. Risks of preterm delivery,
meconium-stained amniotic fluid, and stillbirth rose with increasing maternal serum
bile acid concentrations. Conclusion: In the largest prospective cohort study in severe
ICP to date, we demonstrate significant increased risks of adverse perinatal outcomes,
including stillbirth. Our findings support the case for close antenatal monitoring of
pregnancies affected by severe ICP. (HEPATOLOGY 2013;00:000-000)

I
ntrahepatic cholestasis of pregnancy (ICP) is a labor, meconium staining of the amniotic fluid, low
pregnancy-specific liver disease, characterized by Apgar scores, and sudden intrauterine death, but there
maternal pruritus and raised serum bile acids. It have been concerns over publication bias and case
typically presents in the third trimester with rapid ascertainment when considering the risk against that of
resolution of symptoms and biochemical abnormalities the general pregnant population.1,2
postpartum. Previous retrospective case series have sug- There are accumulating data indicating that the risk
gested that ICP is associated with an increased risk of of fetal complications relates to high levels of circulat-
adverse fetal outcomes, including spontaneous preterm ing bile acids.3-10 One prospective cohort study from

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; ICP, intrahepatic cholestasis of pregnancy;
SMMIS, St Mary’s Maternity Information System; UKOSS, UK Obstetric Surveillance System
From the 1Institute of Reproductive and Developmental Biology, Imperial College London, London, UK; 2Women’s Health Academic Centre, King’s College Lon-
don, London, UK; 3Academic Department of Obstetrics and Gynaecology, Division of Cancer, Imperial College London, Chelsea and Westminster Hospital, Lon-
don, UK; 4National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK.
Received May 3, 2013; accepted July 1, 2013.
Funded by Sands, the stillbirth and neonatal death charity, and Wellbeing of Women Charity. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the article. The research was also supported by the National Institute for Health Research (NIHR) Biomedical
Research Centres based at Imperial College Healthcare NHS Trust, Imperial College London and Kings College London. The views expressed are those of the
author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

1
2 GEENES ET AL. HEPATOLOGY, Month 2013

Sweden examined the relationship between adverse national birth data11-13 as a denominator for the num-
fetal outcomes and maternal serum bile acid levels; ber of maternities during the study period (n 5
there was a 1%-2% increased risk of spontaneous pre- 798,634), less the number of maternities at the four
term delivery, asphyxial events, and meconium-stained nonparticipating units (n 5 21,922). Control data were
amniotic fluid with every 1 lmol/L increase in mater- obtained from three sources. A cohort of women with
nal serum bile acids, but this was not statistically sig- uncomplicated singleton (n 5 2,205) or twin (n 5 27)
nificant until the fasting maternal serum bile acid level pregnancies identified from the UKOSS database of
exceeded 40 lmol/L. However, only 96 women (19%) control women from other studies was used for the
had bile acids exceeding this level.3 Although these majority of the comparisons (https://www.npeu.ox.a-
findings have been partially replicated in other popula- c.uk/ukoss/completed-surveillance). All cases meeting
tions,6-8,10 no studies have been large enough to evalu- the definition are reported to the central data collection
ate the relationship between maternal serum bile acids unit by a clinician without requiring determination of
and stillbirth. Furthermore, there have been no pro- past exposure, while controls were taken from the
spective studies examining the relationship between UKOSS database, in order to minimize information
maternal nonfasting serum bile acid levels and perina- bias. Outcomes were restricted to those that could be
tal outcomes. reported without subjective interpretation to minimize
We hypothesized that the risks of adverse perinatal interviewer bias. Response bias should also be mini-
outcomes, including stillbirth, are increased in women mized by the use of a national survey tool (UKOSS),
with nonfasting serum bile acid levels 40 lmol/L, and with 98% of maternity units contributing data. As the
that the extent of the rise in bile acid level can be used UKOSS control database does not have information
to predict the likelihood of specific adverse outcomes. about meconium-stained amniotic fluid, the St Mary’s
Maternity Information System (SMMIS) was used; rou-
tine maternity data were collected prospectively from all
Materials and Methods pregnancies (585,291) booked at 15 maternity units in
A prospective population-based cohort study was car- North West London, from 1988 to 2000.14,15 National
ried out over 12 months (June 2010 to May 2011). data were obtained from the Office of National Statis-
Cases of severe ICP were identified through the UK tics, England, for 2010-2011 (n 5 668,195).16 Ethnic-
Obstetric Surveillance System (UKOSS). UKOSS is a ity was categorized into groups as defined by the Office
national system that allows collection of information for National Statistics (UK).
about specific uncommon disorders of pregnancy (i.e., The perinatal outcomes studied were gestational age
conditions that affect no more than 1 in 2,000 births) at delivery, iatrogenic and spontaneous preterm deliv-
from all hospitals with consultant-led maternity units in ery, stillbirth, mode of delivery, birthweight and birth-
the UK; 209 of 213 eligible units reported cases for this weight centile, 5-minute Apgar score 7, neonatal
study. Severe ICP was defined as serum bile acid levels unit admission, and meconium-stained amniotic fluid.
40 lmol/L at any time during pregnancy. Exclusion Data on maternal demographics, obstetric, and medi-
criteria included women with pruritus but no elevation cal history were collected for all women; data on
in serum bile acids, and pregnancies ending before 24 serum biochemistry, management, and monitoring
weeks’ gestation. Biochemical, management and out- were collected for the ICP cases. Data missing due to
come data were collected (www.npeu. incomplete reporting are indicated in the footnotes of
ox.ac.uk/ukoss/dcf). Data were anonymized and the relevant tables.
double-entered into a customized database. The overall The study number of 700 cases was prespecified in
incidence with 95% confidence intervals (CIs) of severe the protocol as being of sufficient size to enable esti-
ICP was calculated using the most recently available mation of uncommon adverse perinatal outcomes

Address reprint requests to: Professor Catherine Williamson, Women’s Health Academic Centre, 10th floor North Wing, St Thomas’ Hospital, London SE1 7EH,
UK. E-mail: catherine.williamson@kcl.ac.uk
Copyright VC 2013 The Authors. HEPATOLOGY published by Wiley on behalf of the American Association for the Study of Liver Diseases. This is an open access article

under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original
work is properly cited, the use is noncommercial and no modifications or adaptations are made.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.26617
Potential conflict of interest: Nothing to report.
Additional Supporting Information may be found in the online version of this article.
HEPATOLOGY, Vol. 00, No. 00, 2013 GEENES ET AL. 3

(with intrauterine death estimated at 0.5% to 3%).

Statistical analysis was performed using Stata v. 11.2
(StataCorp, College Station, TX). Unadjusted and
adjusted odds ratios or mean differences and 95% CIs
were calculated. Perinatal outcome data were adjusted
for maternal age, body mass index (BMI), occupation,
ethnicity, and parity. Data were available on >99% of
cases for all demographic variables except BMI
(91.7%) and occupational group (83%). As BMI was
missing in 247 (24 cases and 223 controls) of 2,963
women, multiple imputation (50 repeats) and proxy
indicator analysis were used to estimate the association
between ICP and perinatal outcomes, based on birth-
weight, delivery mode, ethnic group, and parity. Only
data from the multiple imputation model are pre-
sented here, as the results from both methods were
very similar. No imputation was used for occupational
group. The numbers of values for biochemical tests are
provided. Logistic regression (LR) was used to establish
a relationship between adverse perinatal outcomes and Fig. 1. Flow diagram showing the case ascertainment and com-
pleteness of reporting.
maternal biochemical parameters (peak level of serum
bile acids, alanine transaminase [ALT], aspartate demographic and clinical characteristics of ICP twin,
transaminase [AST], bilirubin, and gamma glutamyl ICP singleton, and control twin pregnancies are given
transferase [GGT]). Correlations between different in Supporting Tables 1 and 2 and Supporting Fig. 1.
maternal biochemical parameters were examined using Of the remaining 669 singleton pregnancies, 4.9%
Spearman’s correlation. (33 women) had a history of gallstones and 1.2% (8
women) had known coexistent hepatitis B infection.
Results There was one woman with documented hepatitis C
infection and one woman reported hepatic impairment
Incidence and Maternal Characteristics. During following use of the oral contraceptive pill. Of the 349
the study period there were 713 confirmed cases of multiparous women, 42% (145 women) had a history
severe ICP (Fig. 1) in an estimated 776,712 deliveries, of ICP and 9.7% (34 women) had previous pree-
giving an estimated incidence of 9.2 per 10,000 mater- clampsia or HELLP (hemolysis, elevated liver enzymes,
nities (95% CI 8.5-9.9 per 10,000). low platelets) syndrome.
For singleton pregnancies, the mean gestation was The maternal serum biochemistry from ICP cases is
32 6 4 weeks (SD 5.3 days) for onset of symptoms shown in Table 2 and Supporting Table 3. There were
and 33 6 4 weeks (SD 5.2 days) for diagnosis. Three no significant correlations between markers of liver
percent (23 cases) were diagnosed before 20 weeks’ function (ALT, AST, bilirubin, and GGT) and mater-
gestation. The mean gestation for both onset of symp- nal serum bile acids (data not shown).
toms and diagnosis were earlier in twin pregnancies Management of Severe ICP. Ursodeoxycholic acid
(31 6 0 and 31 6 6, weeks respectively; SD 4.7 and treatment was given to 72% (481 women) of the cases
6.1 days). (Table 3); the starting doses used ranged from 150 mg
The demographic and obstetric characteristics of to 2 g per day. The second most common drug used
women with severe ICP are shown in Table 1. Women was vitamin K, given to 55% (368 women) of cases.
with ICP were more likely to be Asian (OR 1.93, Rifampicin was used in seven cases for symptoms or
95% CI 1.50 to 2.49) and there were more twin preg- worsening biochemical markers despite treatment with
nancies (6.2%, 44 women) than the control popula- UDCA. Further details of antenatal fetal monitoring,
tion (1.2%, 27 women). Given that the rates of the pharmacological and nonpharmacological management
perinatal outcomes of interest were likely to be higher of ICP are shown in Table 3.
in twin pregnancies, we included only data from Pregnancy Outcomes in Severe ICP. Women with
singleton pregnancies in all subsequent analyses (ICP severe ICP delivered earlier than controls (mean differ-
n 5 669, control n 5 2,205). Data comparing ence in gestational age 22.12 weeks; 95% CI 21.98
4 GEENES ET AL. HEPATOLOGY, Month 2013

Table 1. Sociodemographic and Obstetric Histories of Women With Severe ICP

and Healthy Controls With Singleton Pregnancies
ICP Population n (%) UKOSS Controls n (%) Comparison*
† ‡
Total 669 2,205
Sociodemographic features
Maternal age (mean 1 SD) 29.6 (6.3) 29.0 (6.1) MD 0.55 (0.0 to 1.09)
Ethnicity
White 524 (78%) 1771 (80%) —
Black 14 (2.1%) 130 (5.9%) OR 0.36 (0.21 to 0.64)
Asian 111 (17%) 194 (8.8%) OR 1.93 (1.50 to 2.49)
Other 20 (3.0%) 110 (5.0%) OR 0.61 (0.38 to 1.00)
Body mass index (mean 1 SD) 25.1 (4.9) 25.7 (5.5) MD 20.54 (20.09 to 20.99)
< 18.5 15 (2.2%) 56 (2.5%) OR 0.80 (0.45 to 1.43)
18.5 - 25 353 (52.7%) 1050 (47.6%) —
25 - 30 184 (27.5%) 537 (24.4%) OR 1.02 (0.83 to 1.25)
30 - 35 63 (9.4%) 227 (10.3%) OR 0.83 (0.61 to 1.12)
> 35 30 (4.5%) 139 (6.3%) OR 0.64 (0.42 to 0.97)
Occupation
Managerial 173 (25.9%) 556 (25.2%) OR 1.26 (0.97 to 1.65)
Intermediate 140 (20.9%) 468 (21.2%) OR 1.21 (0.92 to 1.60)
Manual and unskilled 202 (30.2%) 591 (26.8%) OR 1.39 (1.07 to 1.79)
Unemployed 32 (4.8%) 113 (5.1%) OR 1.15 (0.74 to 1.79)
Student 7 (1.0%) 11 (0.5%) OR 2.58 (0.98 to 6.80)
Obstetric history
Parity
0 317 (47.3%) 968 (43.9%) —
1 201 (30%) 716 (32.5%) OR 0.86 (0.70 to 1.05)
>2 148 (22%) 517 (23.4%) OR 0.87 (0.70 to 1.09)
Twin pregnancy 44 (6.2%) 27 (1.2%)
Current pregnancy complications
Preeclampsia 44 (6.6%) n/a N/a
Gestational diabetes 41 (6.1%) n/a N/a

*OR: odds ratios and 95% confidence intervals; MD: mean difference and standard deviation.
— 5 the reference group to which the comparisons are made.
n/a 5 data not available for comparison.
†
Variable denominator numbers were a consequence of incomplete reporting and were as follows: BMI n 5 645, parity n 5 666 and occupational group n 5 664.
‡
Variable denominator numbers were a consequence of incomplete reporting and were as follows: BMI n 5 2,009, parity n 5 2,201, and occupational group
n 5 2,009.

to 22.27) (Table 4). There was a significant increase iatrogenic, with 17% (114 women) in the ICP popula-
in the number of spontaneous and iatrogenic preterm tion compared to 2.7% (60 women) in the controls
deliveries. The majority of preterm deliveries were (unadjusted OR 7.39; 95% CI 5.33 to 10.25) being

Table 2. Maternal Serum Biochemistry; All Results Are Given as Median (IQR)
Gestation Gestation Gestation
Level at time of (weeks1days) (weeks1days) at Level at time (weeks1days) Typical reference
diagnosis at measurement Peak level measurement of delivery at measurement range for pregnancy*

Serum bile acids (lmol/L) 47 3414 72.5 3516 46 3711 < 14 lmol/L
(27 to 75) (3114 to 3614) (53 to 109) (3410 to 3711) (21 to 75) (3612 to 3810)
Alanine transaminase 92 3414 151 3514 80 3712 6 - 32
(IU/L) (41 to 202) (3114 to 3614) (63 to 281) (3313 to 3712) (29 to 180) (3612 to 3810)
Aspartate transaminase 82.5 3414 110 3515 79 3712 11 - 30
(IU/L) (44 to 180) (3114 to 3614) (59 to 226) (3315 to 3712) (37 to 174) (3612 to 3810)
Bilirubin (lmol/L) 10 3414 12 3515 9 3712 3- 14
(7 to 14) (3114 to 3614) (8 to 17) (3313 to 3712) (7 to 14) (3612 to 3810)
Gamma glutamyl 26 3414 28 3511 22 3711 3 - 41
transferase (16 to 41) (3114 to 3614) (18 to 46) (3310 to 3710) (12 to 40) (3612 to 3716)
(IU/L)

*Please note that some hospitals use different reference ranges and it is recommended that the upper limit of normal for liver transaminases, bilirubin and
gamma glutamyl transferase is reduced by 20% in pregnancy.
HEPATOLOGY, Vol. 00, No. 00, 2013 GEENES ET AL. 5

Table 3. Pharmacological and Antenatal Management of for potential confounding factors (maternal age, BMI,
Severe ICP occupation, ethnicity, and parity).
Drug Therapy n (%) In our unadjusted analysis, there were significantly
Ursodeoxycholic acid 481 (72%) higher rates of stillbirth in the ICP population (1.5%,
Ursodeoxycholic acid and rifampicin 7 (1%) 10/664 versus 0.5%, 11/2,205) (OR 3.05; 95% CI
Vitamin K 368 (55%) 1.29 to 7.21) (Table 4). There was also an increased
Cholestryamine 3 (0.5%)
S-adenosyl methionine 0 (0)
risk of admission to the neonatal unit (OR 2.34; 95%
Guar gum 0 (0) CI 1.74 to 3.15). These differences remained signifi-
Dexamethasone / betamethasone 33 (4.9%) cant following adjustment for potential confounding
Antihistamines 271 (41%)
Antenatal fetal monitoring
factors, and when compared to national data. The
Cardiotocography 581 (87%) main reasons given for admission to the neonatal unit
Fetal movement charts 29 (4.3%) were preterm delivery (45%, 36 babies) and respiratory
Ultrasound scan for fetal growth 437 (65%)
problems (30%, 24 babies). There were no cases of
Doppler ultrasound scan 315 (47%)
Imaging meconium aspiration syndrome. The median duration
Liver ultrasound scan 288 (43%) of stay on the neonatal unit was 7 days (IQR 2.25 to
13.75). Meconium-stained amniotic fluid was observed
in 16% (106 women) of ICP cases, and occurred at
induced or delivered electively (Fig. 2; Supporting lower gestational weeks than in the control population
Table 4). The differences in rates of preterm delivery (Fig. 3). The odds ratio for meconium staining of the
remained significant following correction of the data amniotic fluid in women with severe ICP compared to

Table 4. Maternal and Perinatal Outcomes of Severe ICP and Healthy Pregnancies
UKOSS National ONS
ICP n (%) Controls n (%) Controls n (%)
Unadjusted Adjusted Unadjusted
N 5 669y N 5 2,205z Comparison* P Value Comparison* P Value N 5 668,195 Comparison* P Value

Mean (SD) gestational age 37.5 39.6 MD 22.12 <0.001 MD 22.21 <0.001 n/a n/a n/a
at delivery (weeks) (1.6) (1.9) (21.98 to 22.27) (22.05 to 22.37)
Preterm delivery 164 144 OR 4.68 <0.001 OR 5.39 <0.001 47657 OR 3.39 <0.001
(25%) (6.5%) (3.67 to 5.98) (4.17 to 6.98) (8.9%) (2.84 to 4.04)
Spontaneous < 37 weeks 50 84 OR 2.05 <0.001 OR 2.25 <0.001 28444 OR 1.46 0.009
(7.5%) (3.8%) (1.43 to 2.94) (1.54 to 3.27) (5.3%) (1.10 to 1.95)
Iatrogenic < 37 weeks 114 60 OR 7.39 <0.001 OR 8.75 <0.001 19213 OR 5.38 <0.001
(17%) (2.7%) (5.33 to 10.25) (6.19 to 12.37) (3.6%) (4.40 to 6.58)
Mode of delivery
Cesarean section 164 508 OR 1.09 0.39 n/a n/a 162512 1.09 0.29
(25%) (23%) (0.89 to 1.34) (24.3%) (0.93 to 1.29)
Birthweight (g) 3049.5 3357.5 MD 2308 <0.001 MD 2309 <0.001 n/a n/a n/a
(2262 to 2353) (2263 to 2355)
Mean (SD) customized 47.6 40.8 MD 6.7 <0.001 MD 6.2 <0.001 n/a n/a n/a
birthweight centile (28.8) (28.3) (4.0 to 9.5) (3.4 to 8.9)
> 90th Centile 54 82 RR 1.21 0.26 RR 1.14 0.44 n/a n/a n/a
(8.5%) (7.0%) (0.87 to 1.68) (0.82 to 1.59)
< 10th Centile 70 193 RR 0.67 0.002 RR 0.70 0.007 n/a n/a n/a
(11%) (16%) (0.52 to 0.86) (0.54 to 0.91)
Adverse outcomes
Stillbirth 10 11 OR 3.05 0.011 OR 2.58 0.044 2626 OR 3.05 <0.001
(1.5%) (0.5%) (1.29 to 7.21) (1.03 to 6.49) (0.44%) (1.65 to 5.63)
5 min Apgar  7 18 14 OR 1.81 0.101 OR 1.92 0.081 n/a n/a n/a
(2.8%) (1.6%) (0.89 to 3.66) (0.92 to 3.99)
Neonatal unit admission 80 123 OR 2.34 <0.001 OR 2.68 <0.001 n/a n/a n/a
(12%) (5.6%) (1.74 to 3.15) (1.97 to 3.65)

*OR: odds ratios and 95% confidence intervals; MD: mean difference and standard deviation. Adjusted risk ratios are calculated with correction for potential
confounding factors (maternal age, ethnicity, parity, body mass index and occupation).
n/a 5 data not available.
†
Variable denominator numbers were a consequence of incomplete reporting and were as follows: preterm delivery and stillbirth n 5 664, caesarean section
n 5 665, Apgar score n 5 643, neonatal unit admission n 5 654.
‡
Variable denominator numbers were a consequence of incomplete reporting and were as follows: preterm delivery n 5 2190, caesarean section n 5 2183,
stillbirth n 5 2,187, Apgar score n 5 892, neonatal unit admission n 5 2,185.
6 GEENES ET AL. HEPATOLOGY, Month 2013

respectively. The median gestational age at delivery in the

ICP stillbirth cases was 36 6 2 (IQR 35 6 4 to 38 6 1
days), compared with 30 6 5 (IQR 28 6 4 to 38 6 0
days) in the controls with a stillbirth. Six of the 10 ICP
stillbirths occurred before 37 weeks’ gestation. Of the
women with stillbirth, 50% of those with ICP were
white, whereas the predominant ethnic group affected in
the control population with stillbirths was Asian (55%).
Seven of 10 ICP cases had coexistent pregnancy compli-
cations, including two cases with preeclampsia, three
with gestational diabetes, and two with nonspecified
complications. Spontaneous preterm delivery was
observed in three ICP stillbirth cases and one control.
There were no small for gestational age babies in the ICP
Fig. 2. Timing of spontaneous and iatrogenic deliveries of singleton
pregnancies in women with severe ICP and controls. TD, term delivery stillbirth cases, but there were three large for gestational
(37 weeks gestation); PTD, preterm delivery (<37 weeks gestation). age babies; none of these mothers had coexistent gesta-
tional diabetes diagnosed prior or subsequent to the loss.
published controls14 was significantly greater at each Peak bile acid levels were significantly higher in the still-
week of gestational age up to and including 38 weeks’ birth cases (median 137 lmol/L; IQR 104 to 159) than
gestation. Of those who had a cord blood sample in the live births from the ICP cases (median 72 lmol/L;
taken, cord artery pH  7.1 was present in 8.5% (24/ IQR 53 to 107; P 5 0.0021). There was one neonatal
283) and pH  7.0 in 3.5% (10/283). For the pur- death among the women with ICP, after term delivery
poses of this study a reassuring cord artery pH was with meconium-stained amniotic fluid and normal
considered to be >7.1, as decreasing cord arterial pH birthweight.
levels below 7.1 and particularly below 7.0 are associ-
ated with worsening perinatal and long-term infant Discussion
outcomes.17 Cardiotocography abnormalities were
This is the largest prospective study of perinatal out-
recorded in 28% (163 cases). The most common
comes in women with severe ICP, demonstrating its
abnormalities reported were variable decelerations/prel-
association with significantly increased risks of sponta-
abor decelerations (80 cases, 49.1%), early decelera-
neous and iatrogenic preterm delivery, neonatal unit
tions (14 cases, 10.3%), bradycardia (<110 beats per
admission, and stillbirth. The incidence of severe ICP
minute; 14 cases, 8.6%), and tachycardia (>160 beats
was 1 case per 1,000 deliveries. The overall incidence
per minute; 11 cases, 6.7%) (Supporting Table 5).
Relationship Between Bile Acids and Fetal Com-
plications. Significant relationships were found
between the maternal serum bile acid level and pre-
term delivery, spontaneous preterm delivery, stillbirth,
and meconium-stained amniotic fluid (Fig. 4; Support-
ing Fig. 2). Logistic regression analysis demonstrated
that a doubling in the level of serum bile acids
increased the risk of all preterm delivery by 68%,
spontaneous preterm delivery by 66%, meconium
staining of the amniotic fluid by 55%, and stillbirth
by 200%. A weaker but still significant relationship
was also found between serum ALT and preterm deliv-
ery, but not with any other adverse outcomes (Sup-
porting Figs. 3, 4). None of the other biochemical
parameters had a significant relationship with any peri-
natal complications.
Characteristics of Stillbirth Cases. There were 10 Fig. 3. The incidence of meconium staining of the amniotic fluid by
gestational age in 669 women with severe ICP compared with
stillbirths in the ICP population and 11 in the control 514,635 controls with a gestational age from 24 to 44 weeks gesta-
population, giving an incidence of 1.5% and 0.5%, tion. Gestation was calculated as described.14
HEPATOLOGY, Vol. 00, No. 00, 2013 GEENES ET AL. 7

Fig. 4. The estimated probability and 95% CIs of preterm delivery (A), spontaneous preterm delivery (B), stillbirth (C), and meconium-stained
amniotic fluid (D) in relation to the maternal serum bile acid level, based on simple logistic regression.

of ICP in the UK has been estimated at 0.7%,1,18 and Use of the UKOSS national data collection system
severe ICP accounts for 15% of all ICP in the UK. adds considerable weight to the findings, given the
Significant positive correlations between maternal extensive coverage of UK maternity units by this sur-
serum bile acid levels and adverse fetal outcomes, veillance method (https://www.npeu.ox.ac.uk/ukoss/
including preterm delivery, spontaneous preterm deliv- annual-reports), which has been informative previously
ery, meconium staining of the amniotic fluid, and still- for similar cohort studies.21,22 This also enabled
birth were demonstrated. ALT also has a significant, recruitment of a prospective cohort of ICP cases with
albeit weaker, positive correlation with preterm deliv- serum bile acids 40 lmol/L that is more than seven
ery. A relatively large proportion (17%) of women times larger than the number of severe ICP cases in
with severe ICP were delivered prior to 37 weeks’ ges- the only previous cohort3 that aimed to establish the
tation. This may reflect concerns with regard to the relationship between maternal serum bile acid levels
risk of fetal death or adverse outcome in pregnancies and adverse pregnancy outcome. Furthermore, the
complicated by high maternal serum bile acids, and wide coverage of maternity units provided by UKOSS
therefore the clinicians managing these pregnancies obviates the publication bias associated with previous
may have preferred a management strategy of induc- case series in which selected ascertainment and report-
tion of labor prior to 37 weeks despite emerging con- ing has led to uncertainty over the estimation of
cerns about special education needs19 and poorer adverse perinatal outcomes. It is therefore likely that
school performance20 in babies born late preterm. This these findings are generalizable to maternity units in
is the first study of severe ICP to show a significant the UK, and to other similar populations.
association with stillbirth. It should be noted that a A further strength of our study is examination of
large proportion (7 of 10) of the women with stillbirth the relationship between nonfasting maternal serum
also had other pregnancy complications. Importantly, bile acid levels and perinatal complications, demon-
this may indicate that women with severe ICP and strating that the previously described association
other coexisting conditions require closer monitoring observed with fasting bile acid levels3 remains when
than those with ICP alone, as the etiology of fetal postprandial samples are used. As most women are not
death in these cases may be multifactorial. fasting when they attend for antenatal care, this means
8 GEENES ET AL. HEPATOLOGY, Month 2013

that the results presented here are directly applicable high levels of bile acids in the fetal compartment.
to all UK maternity units and to other populations in Spontaneous preterm labor may be explained by a
which nonfasted serum bile acid levels are used for dose-dependent bile acid effect on myometrial contrac-
monitoring ICP. A limitation is the lack of directly tility, as has been demonstrated in rodents.25 Further-
comparable control data for some secondary outcomes, more, myometrial cells from women with ICP are
such as meconium-stained amniotic fluid. Although it more responsive to oxytocin, and cells from normal
is likely that this would not change the conclusions of women demonstrate an increased response to oxytocin
the study, future research should aim to capture com- in the presence of bile acids.26,27 Meconium-stained
plete data on cases and controls. amniotic fluid may be explained by an increase in
A limitation of using the UKOSS system to acquire colonic motility secondary to bile acids; 100% of preg-
the data for this study was the inability to obtain pro- nant sheep infused with cholic acid have meconium-
spective data from ICP pregnancies with bile acid lev- stained amniotic fluid but no other signs of fetal dis-
els of 10-39 lmol/L. The criteria for inclusion of a tress.28 Evidence for the involvement of bile acids in
study in the UKOSS program state that the condition the etiology of neonatal respiratory distress comes
is an uncommon disorder of pregnancy affecting no from studies of rabbits undergoing intratracheal injec-
more than 1 in 2,000 births per year in the UK tion of bile acids,29 which results in atelectasis, eosino-
(https://www.npeu.ox.ac.uk/ukoss/survey-applications). philic infiltration, and the formation of hyaline
When we initiated the study we anticipated that ICP membrane, all of which can be reversed by the admin-
affected 1 in 2,000 pregnant women in the UK. istration of surfactant. Interestingly, a recent series of
Therefore, we were unable to use this system to study infants with unexpected respiratory distress in associa-
ICP with lower bile acid levels as the incidence in the tion with ICP reported an improvement in condition
UK is 0.7%.18 However, the published literature following treatment with intratracheal surfactant ther-
regarding perinatal outcomes in women with ICP and apy.30 The mechanisms causing stillbirth in ICP are
lower levels of bile acids are generally reassuring,3 but poorly understood. At autopsy the babies have no
further studies are required to fully establish the risk signs of chronic uteroplacental insufficiency, but do
in this subpopulation. have evidence of acute anoxia.31 Histological changes
Our findings of increased risks of adverse perinatal described in the placentas of women with ICP support
outcomes in ICP are consistent with previous smaller the hypothesis of a sudden acute event leading to fetal
studies that reported preterm delivery, fetal asphyxia, death.32 A possible mechanism would be fetal cardiac
and meconium staining in white-European and Latina arrhythmia and there are case reports of this in the lit-
populations.4-8,23 Previous work has led to uncertainty erature.33 Further evidence for this hypothesis comes
over the risks of stillbirth; early studies suggested an from studies of cultured rat neonatal cardiomyocytes,
increased risk but were considered subject to case which have a decreased rate of contraction when
ascertainment bias, while later reports suggested lower exposed to bile acids and also develop arrhythmogenic
rates of stillbirth, largely attributed to policies of active activity.34,35
management, with increased antenatal fetal monitoring The implications of this study are that women with
and elective delivery at around 37 weeks’ gestation. severe ICP warrant increased surveillance for adverse
Interestingly, the most recent study of fetal outcomes perinatal outcomes. Clinicians need to make a difficult
in ICP showed no significant increase in the number and individualized judgment as to whether the risks of
of stillbirths in an actively managed ICP population early delivery are greater than the risks associated with
compared to controls during the study period (1997- the disease. A previous feasibility trial compared early
2009).24 However, this epidemiological study based on delivery against expectant management in women with
registry data, in common with many others, was not ICP,18 but the study did not have sufficient power to
able to consider the extent of the rise in serum bile provide a definitive answer on best management. The
acids when evaluating the stillbirth risk in ICP. Fur- finding that the infants of women with severe ICP had
thermore, the data presented here demonstrate that normal birthweight centiles and were not growth
despite high rates of iatrogenic preterm delivery restricted suggests that management strategies involving
(17%), suggesting the use of policies of active manage- ultrasound assessment of fetal growth for identification
ment, severe ICP remains associated with a signifi- of placental dysfunction will not be of use in identify-
cantly increased risk of stillbirth in the UK. ing babies at risk. However, the risk of adverse perina-
The mechanisms underlying the fetal complications tal outcome is associated with increased serum bile
in ICP are unclear, but appear to relate to the effect of acids, suggesting that bile acids should be routinely
HEPATOLOGY, Vol. 00, No. 00, 2013 GEENES ET AL. 9

used for surveillance, contrary to the most recent 10. Lee RH, Kwok KM, Ingles S, Wilson ML, Mullin P, Incerpi M, et al.
Pregnancy outcomes during an era of aggressive management for intra-
national guidelines on management of the disease.2 Our hepatic cholestasis of pregnancy. Am J Perinatol 2008;25:341-345.
finding of increased stillbirth in women with ICP and 11. Office for National Statistics. Birth summary tables, England and Wales
serum bile acids 40 lmol/L provides the first evidence 2010. Newport: Office for National Statistics; 2011.
12. General Register Office for Scotland. Vital Events Reference Tables
base on which to offer delivery from 37 weeks’ gesta-
2010. Edinburgh: General Register Office for Scotland; 2011.
tion, as the benefits of intervention are likely to out- 13. Northern Ireland Statistics and Research Agency. Registrar General
weigh the risks of preterm delivery for the fetus. Annual Report 2010. Belfast: Northern Ireland Statistics and Research
Future research now needs to focus on improving Agency; 2011.
14. Balchin I, Whittaker JC, Lamont RF, Steer PJ. Maternal and fetal char-
prediction and treatment of severe ICP. Women with acteristics associated with meconium-stained amniotic fluid. Obstet
genetic variants in biliary transporters36,37 and recep- Gynecol 2011;117:828-835.
tors38 have increased susceptibility to ICP. New bio- 15. Steer PJ, Little MP, Kold-Jensen T, Chapple J, Elliott P. Maternal blood
pressure in pregnancy, birth weight, and perinatal mortality in first
markers may also be useful in identifying women with births: prospective study. BMJ 2004;329:1312.
ICP at greatest risk of subsequent adverse outcomes. 16. Centre TNI.Hospital Episode Statistics - NHS Maternity Statistics. 2011.
Specific compounds of interest are sulfated progester- 17. Malin GL, Morris RK, Khan KS. Strength of association between
one metabolites.39-41 Ursodeoxycholic acid has been umbilical cord pH and perinatal and long term outcomes: systematic
review and meta-analysis. BMJ 2010;340:c1471.
shown to improve pruritus in women with ICP9,18,40 18. Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton
but definitive proof of its protective effect on the fetus JG. Ursodeoxycholic acid versus placebo, and early term delivery versus
remains elusive until larger trials are undertaken. expectant management, in women with intrahepatic cholestasis of preg-
nancy: semifactorial randomised clinical trial. BMJ 2012;344:e3799.
In summary, severe ICP in the UK affects 0.1% of 19. MacKay DF, Smith GC, Dobbie R, Pell JP. Gestational age at delivery
pregnant women and is associated with an increased and special educational need: retrospective cohort study of 407,503
risk of preterm delivery, neonatal unit admission, and schoolchildren. PLoS Med 2010;7:e1000289.
20. Quigley MA, Poulsen G, Boyle E, Wolke D, Field D, Alfirevic Z, et al.
stillbirth. The risk of these perinatal complications Early term and late preterm birth are associated with poorer school per-
increases with increasing levels of maternal serum bile formance at age 5 years: a cohort study. Arch Dis Child Fetal Neonatal
acids. These findings support the current practice of Ed 2012;97:F167-173.
21. Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M. Perinatal
close antenatal monitoring and indicate the need for a
outcomes after maternal 2009/H1N1 infection: national cohort study.
randomized controlled trial to assess the benefit of BMJ 2011;342:d3214.
treatment at reducing these risks. 22. Fitzpatrick KE, Kurinczuk JJ, Alfirevic Z, Spark P, Brocklehurst P,
Knight M. Uterine rupture by intended mode of delivery in the UK: a
national case-control study. PLoS Med 2012;9:e1001184.
Acknowledgment: The authors thank the UKOSS
23. Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of
team and reporting clinicians. We also thank Bernard intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles
North for advice regarding statistical analysis. population. J Perinatol 2006;26:527-532.
24. Wikstrom Shemer E, Marschall HU, Ludvigsson J, Stephansson O.
Intrahepatic cholestasis of pregnancy and associated adverse pregnancy
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