1. DOI: 10.1111/j.1471-0528.2011.03245.x
Maternal medicine
www.bjog.org
Reference standard for serum bile acids in
pregnancy
N Egan,a A Bartels,a AS Khashan,a DI Broadhurst,a,b C Joyce,c J O’Mullane,c K O’Donoghuea
¨
a
Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork University Maternity Hospital, Cork,
Ireland b Department of Medicine, University of Alberta, Edmonton, Alberta, Canada c Department of Biochemistry, Cork University Hospital,
Cork, Ireland
Correspondence: Dr K O’Donoghue, Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork
University Maternity Hospital, Wilton, Cork, Republic of Ireland. Email k.odonoghue@ucc.ie
Accepted 6 November 2011. Published Online 18 January 2012.
Objective Obstetric cholestasis (OC) is a liver disorder characterised Main outcome measures SBA levels in lmol/l.
by pruritus and elevated serum bile acids (SBA) that affects one in
Results A total of 219 women attending for antenatal care were
200 pregnant women. It is associated with adverse perinatal
recruited, and SBA levels were assayed at 12, 20, 28 and 36 weeks
outcomes such as premature delivery and stillbirth. Mild OC is
of gestation, and up to 72 hours postpartum (n = 44–49 cases at
defined as SBA levels of 10–39 lmol/l, and severe OC is defined by
each stage). The majority were white European women, with a
levels >40 lmol/l. SBA levels in normal pregnancy have not been
median age of 30 years (range 17–46 years) and median BMI of
investigated. We aimed to establish reference values for SBA in
25 (range 18–38). Values of SBA ranged from 0.3 to 9.8 lmol/l in
healthy pregnant women across different trimesters of pregnancy.
216 women, with only three measurements outside this range.
Design Cross-sectional analysis of SBA levels. There were no significant changes throughout pregnancy.
Setting A large tertiary referral university teaching maternity Conclusions SBA values in uncomplicated pregnancies are
hospital. consistent, regardless of gestation, and are not elevated in
pregnancy. The current reference values for the diagnosis of OC
Population Healthy pregnant women with a singleton pregnancy
appear to be appropriate.
and a body mass index (BMI) < 40, excluding women with
significant alcohol intake, history of liver disease, prior Keywords Bile acids, liver function tests, obstetric cholestasis,
cholecystectomy and OC. pregnancy.
Methods Cross-sectional analysis of SBA levels at 12, 20, 28 and
36 weeks of gestation, and on days 1–3 postpartum.
¨
Please cite this paper as: Egan N, Bartels A, Khashan A, Broadhurst D, Joyce C, O’Mullane J, O’Donoghue K. Reference standard for serum bile acids in
pregnancy. BJOG 2012;119:493–498.
Bile acids are produced using two main pathways. The
Introduction classical pathway, which accounts for 90% of the synthesis,
Bile acids play an important role in many physiological occurs in the liver, whereas the alternative pathway occurs
processes. They are the end products of cholesterol catabo- extra-hepatically.3 Following synthesis, bile acids are reab-
lism, with their most recognised function being a detergent sorbed in the terminal ileum, and enter the portal vein for
in the intestines to aid in the digestion and absorption of transport back into the liver. The entero-hepatic circulation
fatty acids, monoacylglcerols and other fatty products. The is highly efficient, and 95% of all bile acids are reabsorbed.
primary bile acids, cholic acid (CA) and chenodeoxycholic They are actively secreted by the liver into bile, and stored in
acid (CDCA) are the final products of hepatic cholesterol the gallbladder, which discharges them into the lumen of the
metabolism, and represent the major route of excretion of intestine after the ingestion of a meal. The average pool of
cholesterol. The recognition of the diverse and important bile acids is roughly 2 g, and because of recycling, hepatic
roles of bile acids has led to an increased interest in these secretion into the duodenum is about 12 g per day.4 In
molecules, and has been the focus of new research in the humans, around 0.5 g of cholesterol is used for bile acid pro-
last decade.1,2 duction daily, and 5% of bile acids are lost in the faeces.5
ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 493

2. Egan et al.
Disorders in the metabolism of bile acids are associated on bile acid values in asymptomatic healthy women with
with various disease states. However, defects in bile acid uncomplicated pregnancies.
synthesis are relatively uncommon (1–2% of cholestatic The aim of this study was to establish pregnancy-specific
disorders in children).5 These display autosomal recessive reference values for SBA in healthy pregnant women across
inheritance with a range of severity from the development different trimesters of pregnancy. We also aimed to investi-
of cholestasis in infancy to advanced cholestasis at birth. At gate whether SBA can be elevated in asymptomatic women.
high concentrations, bile acids are toxic. Elevated intracel-
lular levels are associated with oxidative damage and apop-
Methods
tosis in the adult and fetal liver, and have been proven to
be carcinogenic.6 This was a cross-sectional analysis of SBA in healthy preg-
Obstetric cholestasis (OC) is a liver disorder that occurs nant women attending Cork University Maternity Hospital,
specifically in pregnancy, and affects 0.7% of women in a tertiary referral maternity hospital with around 9000
the UK.7,8 OC is characterised by pruritus, occasionally deliveries per year. The study was approved by the Clinical
jaundice, raised liver enzymes and increased serum bile Research Ethics Committee of the Cork Teaching Hospitals
acids (SBA), with the measurement of SBA considered to (ref. ECM 4 (g) 07/07/09). All women were presented with
be the most important biochemical marker for both the a written copy of the study protocol, and written informed
diagnosis and monitoring of OC. It can be the cause of consent was sought. Two researchers were responsible for
significant maternal morbidity, such as postpartum haem- collecting blood samples and recruiting the study popula-
orrhage, and is associated with adverse fetal outcomes tion.
such as preterm labour, intrapartum fetal distress, and Healthy women attending antenatal care with a singleton
stillbirth.9–12 The aetiology of OC is unclear, although it pregnancy were considered for participation in the study.
is thought to result from the effects of hormones released Women were recruited at five different gestations: 12, 20,
in pregnancy in genetically susceptible women. There is 28 and 36 weeks of gestation, and up to 72 hours postpar-
clear ethnic variation, and the condition is more common tum. The time frame around the gestational weeks allowed
in multiple pregnancy and in women that are over for 1 week on either side of the gestational sampling. For
35 years of age.7,8,13 example, women sampled for the 12 weeks of gestation
There is some variance in the normal reference ranges data included those in gestational weeks 11 and 13. Each
used for SBA in pregnancy. In general, it is accepted that woman was sampled on only one occasion.
levels above 10 lmol/l are abnormal, and levels above Inclusion criteria included a body mass index (BMI) of
40 lmol/l are grossly abnormal.14,15 Although there is evi- <41 and >17 (kg/m2). Weight and height measurements
dence to suggest that OC is associated with adverse fetal were taken from values recorded in antenatal charts at the
outcomes, there is considerable debate about the extent of booking visit (at 10–20 weeks of gestation). Women with a
morbidity, and it has been suggested that the risk of com- previous history of OC or other liver disease, or a history
plications becomes significant only when bile acids reach of gestational pruritus, were excluded from the study.
levels of ‡40 lmol/l.15 It has also been reported that raised Those who had a previous cholecystectomy were also
bile acids (>10 lmol/l) affect about 40% of asymptomatic excluded, along with women who consumed more than 15
pregnant women, and that these women have similar out- units of alcohol per week before or during the pregnancy.
comes to other pregnant women with normal levels14 Finally, women with known hyperlipidaemia or hypercho-
Pregnant women might have slightly elevated bile acid lesterolemia were not eligible for the study and were
values as part of the normal biochemical spectrum of preg- excluded.
nancy, or because of pregnancy-related changes in gallblad- Pregnant women were recruited from low-risk antenatal
der function.14,16 Women treated with progesterone for clinics, the fetal assessment unit, and postnatal wards.
threatened preterm labour have been shown to have an Those who met the study inclusion criteria answered a
increased risk of developing cholestasis,10 whereas estrogens short lifestyle questionnaire and volunteered for a blood
can increase the total SBA concentration.17 test. Information was obtained from each participant
There are no pregnancy-specific reference ranges for regarding alcohol intake prior to and during pregnancy,
SBA. The range of values used in most biochemical labora- and smoking, as well as recreational, over-the-counter and
tories to assess pregnant women is the same as that used prescription medications. A detailed medical and family
in the non-pregnant population, and normal ranges of history was also recorded. In the postnatal group, details
0–10 lmol/l are most commonly used.8 Bile acid levels are including time and mode of delivery, weight and sex of the
not routinely checked in pregnancy unless a pregnant baby were recorded.
woman is symptomatic or there is a clinical suspicion of Approximately 6 ml of venous blood was withdrawn
OC. In the published literature there is a paucity of data and sent to the Cork University Hospital biochemistry
494 ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG

3. Serum bile acids are not elevated in normal pregnancy
laboratory. Samples were analysed for total SBA and liver
function tests were also performed. Biochemical analysis Results
was performed on an Olympus AU640 analyser using the A total of 219 women attending for antenatal care in Cork
Randox Total Bile Acids Assay. This is an enzymatic col- University Maternity Hospital participated in the study
orimetric assay for the quantitative determination of bile between July 2009 and February 2010. All had an uncom-
acids in human serum. Two reactions are combined in plicated medical history, and were carrying a singleton
this kinetic enzyme cycling method. In the first reaction, pregnancy. These women were separated into five different
bile acids are oxidised by 3a-hydroxysteroid dehydro- gestational groups: 12 weeks (n = 48); 20 weeks (n = 49);
genase (3a-HSD) in the presence of thionicotinamide- 28 weeks (n = 32); 36 weeks (n = 44); and postpartum
adenine dinucleotide (Thio-NAD). The reaction is revers- days 1–3 (n = 46). A further 30 women were approached
ible and 3a-HSD can also convert 3-keto steroids and but declined to participate. The majority of women (94%)
Thio-NADH to bile acids and Thio-NAD. In the second were white Europeans, whereas the remaining minority
reaction, in the presence of NADH, 3-keto steroids are were African, Indian, and Pakistani. The median maternal
immediately reduced back to bile acids, which are again age was 30 years (range 16–46 years). The majority of
re-oxidised and re-reduced. This creates a kinetic oxida- women were multifarious (57.5%; 126/219), with parity
tion–reduction cycle, which leads to the accumulation of ranging from one to six. The maternal BMIs ranged from
high levels of Thio-NADH in the sample. In the presence 18 to 40, with a mean BMI of 25.9 (Table 1). Maternal
of an excess of co-factors Thio-NAD and NADH, the demographics are similar to the general antenatal booking
rate of formation of Thio-NADH is directly proportional population. These parameters were not significantly differ-
to the level of bile acids present in the sample. This is ent across the time points of sampling, with the exception
calculated by measuring the change in absorbance at that none of the postnatal measurements were made on
405 nm. primiparous women (Table 1).
The assay manufacturer (Randox Laboratories) states a Thirty-six women were smokers (16.4%; 36/219), with
sensitivity of 1 lmol/l, and gives coefficients of variation of an average of eight cigarettes smoked per day. Alcohol
5% for levels of 8 lmol/l. The minimum required sample intake prior to pregnancy was disclosed by 135 women
size was estimated based on the assay precision standard (61.6%), with an average of 3.9 units per week. During
deviation of 1.5 lmol/l for each data value and an expected pregnancy, 14 (6.3%) women disclosed an alcohol intake
measured population standard deviation of 2 lmol/l (based ranging from 1 to 6 units, with an average intake of 1.5
on preliminary data). For a 95% confidence interval units per week. The time of food intake prior to blood
of ± 0.5 lmol/l on the sample means at each time point, sampling ranged from 0 to 12 hours, with an average inter-
the central limit theorem indicates that the sample size val of 3.4 hours. Thirty (13.7%; 30/219) women were fast-
should be 36. ing (>9 hours since they had last eaten). Of the non-fasting
Data were recorded on a Microsoft excel spreadsheet. women, the majority had consumed a light meal: typically
The null hypothesis that the sample populations from each breakfast cereal and toast, as most samples were collected
gestational period had equal median values was tested mid-morning.
using the Wilcoxian rank sum tests (the nonparametric A first-degree relative with hypercholesterolemia was
version of the classical parametric Student’s t-test), after reported by 32.4% (71/219). Four women developed gesta-
rejecting, at the 5% significance level, the null hypothesis tional diabetes mellitus, but only one was recruited to the
of sample normality at each time point (Lilliefors test). All study before diagnosis. Although medication was taken by
statistical analyses were carried out using the matlab 43.4% (95/219) of women, this largely consisted of simple
scripting language (http://www.mathworks.com). analgesia, folic acid and iron supplements. Of the 47
Table 1. Maternal demographics
Gestation (weeks) Number of women (n) Age (range) BMI Non-white European, % Primparous, % Smoking, %
12 (11–13) 48 29 (27–34) 24 (22–27) 2 40 15
20 (19–21) 49 30 (27–34) 25 (23–29) 6 60 18
28 (27–29) 32 32 (31–34) 27 (24–30) 3 45 13
36 (35–37) 44 29 (24–32) 26 (22–29) 5 54 15
Postnatal (days 1–3) 46 32 (26–35) 25 (24–29) 2 0 20
ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 495

4. Egan et al.
Table 2. Total serum bile acid values at different gestations
Gestation (weeks) Number of Mean Median Standard Range 5th 95th
patients (n) (lmol/l) (lmol/l) deviation (lmol/l) percentile percentile
12 (11–13) 48 4.0 3.5 1.90 1.2–9.8 1.68 9.05
20 (19–21) 49 3.4 3.2 1.73 0.3–8.7 1.29 6.72
28 (27–29) 32 3.8 2.9 3.36 1.2–16.7 1.32 8.69
36 (35–37) 44 3.9 3.3 2.06 1.3–12.0 1.80 8.22
Postnatal (days 1–3) 46 3.1 2.6 2.10 0.3–11.6 0.95 7.24
women recruited postnatally, 38 had a vaginal delivery and 10
nine were delivered by caesarean section; the average infant
birthweight was 3658 g.
Total SBA levels ranged from 0.3 to 16.7 lmol/l across 8
the entire study population. A total of 98% of the values
fell under 10 lmol, which is the upper limit of normal.
SBA levels ranged from 0.3 to 9.8 lmol/l in 216 women, 6
Bile acids
with only three measurements outside this range (16.7,
12.0 and 11.6 lmol/l). These were across three different
time points (28 and 36 weeks of gestation, and postnatal). 4
Liver function tests were performed in all women at the
time of SBA sampling, and were within the normal ranges
2
established for pregnancy.
The calculated mean, median, standard deviation and
range of SBA levels is displayed in Table 2. Figure 1 shows
0
the sample distribution around the median according to
each gestational period, with the three outlying observa-
12 weeks 20 weeks 28 weeks 36 weeks Postnatal
tions mentioned above removed. Pairwise significance test-
Gestation
ing showed that during pregnancy there was no significant
difference between the medians of each of the observed Figure 1. Distribution of serum bile acid values around the median at
different gestations. A box–whisker plot showing the distribution of
gestational sample populations (a = 0.05; Bonforonni cor-
serum bile acid values around the median at different gestations. The
rected for multiple comparisons, a/n = 0.005). However, tops and bottoms of each ‘box’ are the 25th and 75th percentiles of
there was a significant difference between women sampled the samples, respectively. The line in the middle of each box is the
at 11–13 weeks of gestation compared with women sam- sample median. Whiskers extend to the most extreme data points that
pled postnatally (P = 0.003). Also when comparing the cal- are not considered to be outliers, and outliers are plotted individually.
An ‘outlier’ is defined as a value that is more than 1.5 times the
culated median, 5th and 95th percentile bile acid levels
interquartile range away from the top or bottom of the box. Three
across all time periods, the postnatal group was consistently outlying cases were excluded from analysis, and are not represented
the lowest. Although the time frame around the gestational here (SBA levels measured >10 lmol/l). The width of a notch is
weeks allowed for 1 week on either side of the gestational computed so that box plots in which notches do not overlap have
sampling, this range was exceeded in five cases. When these different medians at the 5% significance level.
cases were excluded from the data analysis, the results were
similar.
the different gestational groups within pregnancy, but a
significant drop in SBA levels postnatally. Almost all of
Discussion
the values recorded (98%) were under 10 lmol/l, which is
This study investigated the values of total SBA in healthy the upper limit of the normal range of SBA. Pregnancy, in
pregnant women to determine the reference standard for this population, did not cause an increase in SBA.
bile acids in pregnant women. We also aimed to show The performance characteristics and reference ranges for
whether bile acid levels were incidentally elevated during bile acids and liver function tests have been thoroughly
pregnancy, and if there was any difference across trimesters. reviewed and established in the non-pregnant population.18
We found no significant difference in SBA levels between The normal range is the mean value within ± 2 SD in the
496 ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG

5. Serum bile acids are not elevated in normal pregnancy
reference non-pregnant population. An abnormal level is women over the age of 35 years,27 which is above the average
usually defined as a value exceeding the upper reference age of our study population, and only 18% (40/219) were
limit, as there is no known clinical significance of low lev- aged 36 and over. However, the mean BMI of our study pop-
els of SBA. In our laboratory, the normal range of bile ulation was 25.9, which is classified as overweight. Although
acids in the general population lies between 0 and the sample displayed an above average mean BMI, the litera-
10 lmol/l, established by the manufacturer of the bile acid ture has not yet shown a link between obesity and OC.
assay used. The universal range can vary according to local A minority of the study population engaged in smoking and
policies, but generally the upper limit of normal is alcohol consumption during pregnancy: 16% said they
reported to lie between 10 and 14 lmol/l.8 Among our smoked during pregnancy, whereas 6% disclosed alcohol
entire study population of 219 women, there was only one intake. These percentages may be conservative estimates of
value recorded that was >14 lmol/l, and only three values nicotine and alcohol intake, because of the negative percep-
were >10 lmol/l. tions associated with reporting smoking and drinking
Our study is the first cross-sectional study to examine in pregnancy. Nevertheless, neither of these are known risk
levels of SBA in healthy women with uncomplicated preg- factors for the development of OC.
nancies using a statistically reliable sample size. In this A limitation in our study design is the cross-sectional
study population, pregnancy did not affect SBA levels and analysis of total SBA: comparing different population
there was no significant difference between the gestational groups at a single point of time. A longitudinal study
groups during pregnancy in this study population. Whereas design, where the same women are followed-up at five time
the postnatal measurements were different, they were con- points of gestational age, would have been more appropri-
sistently lower. Therefore, the current reference ranges used ate. However, we anticipated that such a design would have
to distinguish ‘normal’ and ‘abnormal’ appear to be appro- been very challenging, as patients are less likely to volunteer
priate. From this finding one can further deduce that raised for five blood tests, and may have resulted in substantial
levels are indeed abnormal, and that levels of >10 lmol/l missing data. Although we were able to recruit a large
indicate a pathological change is in process. number of women to participate in the study, the number
Although reproductive hormones have been implicated of participants in each gestational age group was relatively
in the aetiology of cholestasis, and OC usually presents in small, and ranged from 32 to 46. It would have been pref-
the third trimester of pregnancy, studies have to date erable to have a larger sample size, but this is always
reported conflicting results. A longitudinal study of 56 difficult in any pregnant population because of loss to
women showed a minimal rise in SBA levels with increas- follow-up, unavailability for extra hospital visits, or the
ing gestation.19 When individual primary bile acids were unpredictable complications of pregnancy.
measured, deoxycholic acid (DCA) displayed no change as Another negative aspect of our study is that the SBA val-
gestation advanced, whereas CDCA showed a doubling at ues were not all from fasting blood samples. Only 14%
term.20 In addition, some studies showed that CA signifi- (n = 30) of the 219 women in our study were fasting
cantly increased in the third trimester when compared with (>9 hours). It was very difficult to organise and encourage
the first,21,22 whereas other work showed no difference.23 women to fast for their routine antenatal visits or to fast
Raised SBA in the absence of symptoms of cholestasis have after delivery. There was no difference in mean SBA values
been reported, and labelled as asymptomatic hypercholo- when the fasting group was compared with the non-fasting
anaemia (AHP),24 reportedly affecting up to 10% of the group. However, there is no agreement whether SBA
pregnant population.8,14 should be measured in the fasting or postprandial state.8 It
Bile acid abnormalities have demonstrated a geographic has been shown for OC that the consumption of a test
and ethnic variation, with countries such as Finland and meal causes a more dramatic postprandial rise (<2 hours)
Chile showing an increased incidence of OC.25,26 The in SBA than in controls,20 yet it is unclear whether this is
majority of our study population were white Europeans relevant to normal pregnancy.
(94%), mainly Irish or Polish, and other ethnic groups
included African, Indian, and Pakistani women. The preva-
Conclusion
lence of OC in the UK is 0.7%, as opposed to 2.4% in
Chile.7 Comparatively, the Irish population from which In conclusion, this study found that pregnancy did not
our study was recruited has a much lower incidence. cause a significant increase of total SBA. The current refer-
In addition, there is seasonal variation of OC, with more ence ranges used for total SBA appear to be appropriate for
cases presenting in the winter.26 Ireland, with a temperate use in pregnancy. An elevated level can therefore be consid-
climate, should be relatively stable in this regard. ered to be abnormal, signifying a pathological process. The
All participants were healthy women with an average age currently accepted levels of SBA for the diagnosis of OC
of 30 years. There is an increased risk of cholestasis in appear to be correct.
ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 497

6. Egan et al.
Disclosure of interests 10 Bacq Y, Myara A, Brechot MC, Hamon C, Studer E, Trivin F, et al.
Serum conjugated bile acid profile during intrahepatic cholestasis of
The authors have no conflicts of interest to disclose.
pregnancy. J Hepatol 1995;22:165–9.
11 Alsulyman OM, Ouzountain JG, Ames-Castro M, Goodwin TM. Intra-
Contribution to authorship hepatic cholestasis of pregnancy; perinatal outcome associated with
KOD conceived the idea for the study. KOD, NE, CJ, and expectant management. Am J Obstet Gynaecol 1996;175:957–60.
JOM designed the study. NE and AB recruited women to 12 Fisk NM, Storey GN. Fetal outcome in obstetric cholestasis. BJOG
1988;95:1137–43.
the study and collected the data. CJ and JOM contributed
13 Gonzalez MC, Reyes H, Arrese M, Figueroa D, Lorca B, Andresen M,
laboratory tools and reagents. AK, DB and NE analysed the et al. Intrahepatic cholestasis of pregnancy in twin pregnancies.
data and performed the statistical analysis. NE, AB and J Hepatol 1989;9:84–90.
KOD wrote the paper. All authors reviewed the article and ˜
14 Castano G, Lucangioli S, Sookonian S, Masquida M, Lemberg A, Di
approved the final draft for submission. Scala M, et al. Bile acid profiles by capillary electrophoresis in intra-
hepatic cholestasis of pregnancy. Clin Sci (Lond) 2006;110:459–65.
15 Glantz A, Marschall HU, Mattson LA. Intrahepatic cholestasis of
Details of ethics approval pregnancy: relationships between bile acid levels and fetal complica-
The study was approved by the Clinical Research Ethics tion rates. Hepatology 2004;40:467–74.
Committee of the Cork Teaching Hospitals on 29 May 16 Everson GT. Gastrointestinal motility in pregnancy. Gastroenterol
2009 (ECM 4 (g) 07/07/09). Clin North Am 1992;21:751–76.
17 Barth A, Klinger G, Rost M. Influence of ethinyloestradiol propa-
nolsulphonate on serum bile acids in healthy volunteers. Exp Toxicol
Funding Pathol 2003;54:381–6.
None. 18 Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide
for clinicians. CMAJ 2005;172:367–77.
Acknowledgements 19 Carter J. Serum bile acids in normal pregnancy. Br J Obstet Gynaecol
1991;98:540–3.
None. j
20 Heikkinen J. Effect of a standard test meal on serum bile acid
levels in healthy non-pregnant and pregnant women and in patients
with intrahepatic cholestasis of pregnancy. Ann Clin Res
References 1983;15:183–8.
1 Babu P, Sangeetha NM, Maitra U. Supramolecular chemistry of bile 21 Lunzer M, Barnes P, Byth K, O’Halloran M. Serum bile acid concen-
acid derivatives: formation of gels. Macromol Symp 2006;241:60–7. trations during pregnancy and their relationship to obstetric chole-
2 Hoffman AF. The continuing importance of bile acids in liver and stasis. Gastroenterology 1986;91:825–9.
intestinal disease. Arch Intern Med 1999;159:2647–58. 22 Fulton IC, Douglas JG, Hutchon DJ, Beckett GJ. Is normal pregnancy
3 Fuchs M. Bile Acid Regulation of Hepatic Physiology. III. Regulation cholestatic? Clin Chim Acta 1983;130:171–6.
of bile acid synthesis: past progress and future challenges. Am J 23 Heikkinen J, Maentausta O, Ylostalo P, Janne O. Changes in serum
Physiol Gastroint Liver Physiol 2003;284:G551–7. bile acid concentrations during normal pregnancy and in patients
4 Hoffman AF, Roda A. Physicochemical properties of bile acids and with intrahepatic cholestasis of pregnancy and in pregnant women
their relationship to biological properties: an overview of the prob- with itching. BJOG 1981;88:240–5.
lem. J Lipid Res 1984;25:1477–89. 24 Sinakos E, Lindor K. Bile Acid Profiles in intrahepatic cholestasis of
5 Monte MJ, Marin JG, Antelo A, Vazquez-Tato J. Bile acids: chemis- pregnancy; Is this the solution to the enigma of Intrahepatic Chole-
try, physiology, and pathophysiology. World J Gastroenterol stasis of Pregnancy? Am J Gastroenterol 2010;105:596–8.
2009;15:804–16. 25 Brites D, Rodrigues CM, Van–Zeller H, Brito A, Silva R. Relevance of
6 Debruyne PR, Bruyneel EA, li X, Zimber A, Gespach C, Mareel MM. serum bile acid profile in the diagnosis of intrahepatic cholestasis of
The role of bile acids in carcinogenesis. Mutat Res 2001;480– pregnancy in a high incidence area:Portugal. Eur J Obstet Gynecol
481:359–69. Reprod Biol 1998;80:31–8.
7 Kenyon AP, Tribe RM, Nelson-Piercy C, Girling JC, Williamson C, 26 Berg B, Helm G, Petersohn L, Tryding N. Cholestasis of pregnancy
Seed PT, et al. Pruritus in Pregnancy: a study of anatomical distribu- Clinical and Laboratory studies. Acta Obstet Gynaecol Scand
tion and prevalence in relation to the development of obstetric cho- 1986;65:107–13.
lestasis. Obstetric Med 2010;3:5. 27 Jiang ZH, Qiu ZD, Lu WW, Liu YH, Wang QN, Miao HZ, et al.
8 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. Intrahepatic cholestasis of pregnancy and its complications Analysis
World J Gastroenterol 2009;15:2049–66. of 100 cases in Chongquing area. Chin Med J (Engl) 1986;99:
9 Reid R, Ivey KJ, Rencoret RH. Fetal complications of obstetric chole- 957–60.
stasis. Br Med J 1976;1:870–2.
498 ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG