Reviewer ’s report  
Title: Intrahepatic cholestasis of pregnancy and associated cause s of death: a cohort stu dy with 
follow -up of 27 -46 years  
 
Version: 1 Date: 23 Dec 2017  
 
Reviewe r: William Bill Hague  
 
Reviewer's report:  
This is an intriguing study, with a good underlying philosophy to examine the long term 
mortality of women who have experienced ICP.  The case control design within a population 
seems appropriate and an appropriately  long follow -up period has been possible.  
 
I am concerned, however, that the study population may be diluted by a proportion of normal 
pregnant women, given the diagnostic criteria employed: a serum BA concentration of 6 umol/L 
is very low to diagnose ICP.   Some of the control population may have had serum BA of this 
degree.  I would suggest reanalysing the data and only including women with pruritus associated 
with a (non -fasting) serum BA of >10 umol/L as the study population. Women have also been 
include d with raised transaminase concentrations, but these are not essential to the diagnosis, and 
may reflect other disorders including a recent viral illness, pre -eclampsia, hyperemesis and 
steatohepatitis, while there may be other disorders (eg, iron deficien cy, hypothyroidism, 
dermatitis) which may contribute to the pruritus.  It is not clear from the manuscript at what stage 
a increased transaminase concentration may have been measured to suggest the diagnosis.  
 
If these data are to be reanalysed, it would b e of interest to see if there is a dose dependent effect 
of BA concentration, such as has been shown in the Swedish study to relate to perinatal outcome 
(>40 umol/L).  
 
There have been recent data showing the association of ICP with both pre -eclampsia and 
gestational diabetes, each of which is associated with long term morbidity (hypertension and type 
2 diabetes respectively).  Are there any data from this population to support these associations 
and might there be long term mortality implications which coul d be addressed?  
 
A few other points:  
Introduction para 1 line 4 -5: while meconium staining of amniotic fluid is well recognised as 
being associated with perinatal complications, it is a surrogate.  Preterm birth is a far more 
important complication which s hould be mentioned.  
Methods para 3 line 1: I am not sure whether the authors mean "all the underlying causes of 
death of the cohort" or "the underlying causes of death of the whole cohort".  
Discussion para 6 line 2: I suspect the authors mean "hepatobiliar y disorders are more common 
among mothers who experience ICP", but this could also bear expansion.  
Discussion para 7 line 3: I don't understand what the authors mean here by "respectively".  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
No 
Does the work include the necessary controls?  
If not, please specify  which controls are required in your comments to the authors.  
Yes 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
No 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I am able to assess the statistics  
Quality of written English  
Please indicate the quality of language in the manuscri pt: 
Needs some language corrections before being published  
 
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