Reviewer ’s report  
Title: Intrahepatic cholestasis of pregnancy and associated cause s of death: a cohort study with 
follow -up of 27 -46 years  
 
Version: 1 Date: 11 Sep 2017  
 
Reviewer: Hanns -Ulrich Marschall  
 
Reviewer's report:  
The auth ors investigated the causes of deaths of women with intrahepatic cholestasis of 
pregnancy (ICP) that were seen at Tampere University Hospital between 1969 and 1988, in 
comparison to twice as many apparently non -ICP controls that were seen before or after t he ICP 
index patients. They found an overrepresentation of gastrointestinal death causes in women with 
ICP. 
 
COMMENTS:  
This is an interesting approach to further define the future risk of women with ICP. However, 
there are some serious concerns as to relia bility and validity of methods that ultimately bear the 
risk of substantially misleading conclusions.  
 
MAJOR COMMENTS  
a) It says, that only women with ICD diagnosed between 1969 and 1988 when ICD -8 and ICD -
9 were in use were followed up. This reviewer suspects a typing error for 1988 as ICD -9 
actually was used in Finland until 1996. However, if true, why was the investiga tion 
truncated at 1988?  
b) It is appreciated that written diagnoses were checked, however, definitions of ICP at that 
time of ICD -8 and ICD -9 were less precise than today. Although, definition of ICP by 
laboratory tests as presented is quite unique. Most s tudies would not consider one of the 
following ASAT >35 U/l, ALAT >40 U/l, or bile acids 6 > μmol/l as diagnostic for ICP. 
Both issues need to be addressed.  
c) As ICP in a very large population -based study was found to be highly associated with later 
hepat obiliary malignancy that may have a quite rapid progress, investigation of women 
diagnosed from 1999 on when ICD -10 (probably) was introduced would have been feasible. 
It is hard to understand why this was not done, in particular, as underlying causes of d eath 
were screened from Statistics Finland from 1971 on, i.e. two years after the first potential 
case with ICP was investigated. Inclusion of ICD -10 (and completion of the ICD -9 years 
1989 -1998) might have provided information as the risk of hepatobiliary  malignancies even 
in this single centre study.  
d) 5/6 deaths within the group of digestive were attributed to hepatobiliary diseases. It is 
unclear whether hepatobiliary malignancies, if ever found, were added to neoplasms or 
diseases of the digestive sy stem or both. These few diagnoses should be listed individually.  
e) 95% confidence intervals for all results are lacking.  
f) Ranges in Table 1 are missing! And in particular, for different disease groups. Indeed, as 
suggested above, death to hepatobiliary diseases and malignancies might have occurred 
much earlier  
 
MINOR COMMENTS  
 
a) The conclusion that the overrepresentation of death from gastrointestinal diseases in ICP is 
reflected by the women's genetic background is not substantiated. The reference give n is an 
opinion paper that not specifically addresses the genetic background of ICP. Rather, a 
number of excellent papers have been published in recent years about the genetic 
background of ICP that would not support the author's conclusion.  
b) Although it  is understandable that own work is cited as done in references 4 and 12, the 
authors should not neglect that much larger studies have addressed the respective issues of 
these references. It is unfair not to cite them as it gives the reader the impression that 
references 4 and 12 are the only relevant ones.  
 
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: 
Accept able 
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