Corresponding author
Di Tommaso Mariarosaria, MD, PhD.
Department of Health Sciences, Obstetrics and Gynecology Unit,
University of Florence.
Largo Brambilla, 3, 50134, Florence, Italy, Email:
mariarosaria.ditommaso@unifi.it.
Tel 0039-335332709
We welcome the updated guidelines from the Royal College of Obstetrics
and Gynaecology for Intrahepatic Cholestasis of Pregnancy (ICP)
diagnosis and management (Green-top Guideline No. 43 June 2022)[1].
We believe that the new recommendations, based on a recent body of
evidence, will positively impact patients’ care and the management of
ICP.
The correlation with a potentially increased risk of stillbirth makes
ICP a difficult obstetrics pathology to manage. Since it is strongly
associated with maternal anxiety and active management, the diagnosis of
ICP has serious implication, and therefore a correct diagnosis is
essential.
While the previous edition of the guidelines (April 2011) recommended to
apply the upper limit of pregnancy-specific ranges of total serum bile
acids (TSBA) for diagnosis, an important innovation in the current
guidelines is the accurate definition of the diagnostic threshold
[2]. The new edition, based on a recent study by Mitchell et al
[1], establishes for the first time the upper limit of 19 μmol/L for
random measurement of TSBA. Mitchell et al, by retrospective analysis of
non-fasting serum samples from a local database, determined the upper
reference limit of TSBA in three ethnic groups. The authors proposed
using the upper limit of the black ethnicity population, in order to
avoid overdiagnosis and since no adverse events were associated with
TSBA concentration below that threshold [3].
We regret that the new guidelines were published shortly after the
publication of our cross-sectional study in which we aimed to establish
reference standards for TSBA in pregnancy, and thereby could not include
our paper. Our study used a prospective design and was based on the
largest pregnant population so far (612 patients). Interestingly, a very
similar upper reference limit (20 μmol/l) of the postprandial TSBA
measurement was found in the whole population that has been examined
[4]. We believe that pregnancy-specific reference ranges should be
used to identify patients with altered TSBA concentration within the
pregnant population, and to better distinguish patients with mild ICP
from those with moderate or severe ICP.
Having two independent studies that arrive at such a similar threshold
may reinforce the new proposed diagnostic criteria and increase the
level of evidence of the recommendation.
In the new edition of the Guidelines, the first key recommendation
refers to TSBA random measurement for diagnosis of ICP. The authors then
specify that bile acid measurements “should be taken at a convenient
time, and do not need to be performed fasting”. We would like to
briefly comment the decision to use a random threshold for the
diagnosis.
To understand ICP, we believe it is important to understand the
relationship between fasting TSBA and postprandial TSBA in pregnant
women. Following a meal, TSBA concentrations increase only slightly in
healthy non-pregnant patients. However in the pregnant population, with
and without ICP, TSBA concentrations significantly increase in response
to food intake [3][4][5][6]. Postprandial TSBA
measurements correspond to the peak concentration and are more likely to
identify women with TSBA ≥ 100 μmol/l, therefore at an increased risk of
stillbirth [7].
Conversely, a random measurement may not correspond to the peak
concentration, as TSBA peak at 60-90 minutes and then return to fasting
levels [8]. For example, a random concentration of 18 μmol/l could
be a peak value in a patient with gestational pruritus according to the
new guidelines, but it could also be closer to the fasting
concentration, and thereby a potential diagnosis of ICP would be missed.
Our study suggests that two different reference ranges should be used,
one for each timepoint (fasting ≥ 14 μmol/l, postprandial ≥ 20 μmol/l).
The physician should consider at which timepoint the measurement was
taken in order to interpret the results correctly. By prescribing a
random measurement, the patient is usually requested to perform the
blood sample at any moment during the day: which can be 5 hours
postprandialy, shortly after a meal, or in cases of inadequate
communication, together with other blood test that requested fasting.
It is important to specify that the postprandial sample should be
drowned 2-3 hours after a meal. Just like the glucose challenge test
should be performed in a very specific timeline, since a random
glycaemic stick would diagnose gestational diabetes with difficulty. We
believe that the measurement of TSBA should be standardized too, based
on the current literature.
We agree that the peak measurement is more clinically relevant, and
essential for the diagnosis and severity assessment of ICP. We believe,
however, that at least one measurement of fasting TSBA, together with
postprandial assessment, should be performed in the initial workup for
ICP. High fasting concentrations are more specific for ICP, as suggested
previously [5][6][9]. Fasting measurement are also more
predictable, have less variability, and correlate better with certain
risk factors. The postprandial peak measurement should be repeated for
risk stratification and for the follow-up of patients diagnosed with
ICP, to guide the management of the pregnancy and the timing of
delivery.
We are happy to see the attention that this topic has recently received
and the continuation of this important debate regarding the diagnostic
criteria, that have important implication for maternal, fetal and
neonatal health. We congratulate the RCOG on their important new
recommendations that will benefit pregnant patients worldwide.
Keywords: Intrahepatic cholestasis of pregnancy; Total serum
bile acids; Diagnostic thresholds; Guidelines.