Reviewer ’s report  
 
Title: Fetal death in utero and misc arriage in a patient with Crohn's disease under therapy with 
ustekinumab: case -report and review of the literature  
 
Version: 0 Date: 21 Mar 2017  
 
Reviewer: Jeff McCurdy  
 
Reviewer's report:  
 
Generally a clear case report and a topical issue that will become more common in our everyday 
practice for IBD patients. The case report allo ws the authors to review the current literature and 
discuss potential reasons why ustekinumab may or may not impact fetal loss; but, as the authors 
correctly point out firm conclusions cannot yet be drawn from this case report or the published 
literature.     
 
Major Points  
1) "This led to a rapid clinical improvement and she quickly achieved a complete remission."  
It should be identified if the remission was based on clinical grounds, biochemical remission, 
and/or endoscopically?  Although the authors po int out that the pregnancy was unplanned, recent 
guidelines have recommended objective measures to confirm remission prior to conception to 
reduce the risk of adverse fetal events (Nguyen et al., Gastroenterology 2016;150:734 -757). 
Therefore, this would be  particularly important to know in this case report given that subclinical 
inflammation may have contributed to the pregnancy loss. Similarly at the time of the US which 
detected the in utero death was the patient having clinical symptoms or were their obj ective 
measures of active disease? Moreover, was the patient malnourished from longstanding poorly 
controlled IBD and was their biochemical evidence of nutritional deficiencies (hypoalbuminemia 
and/or folate deficiency etc), any of which may have impacted the pregnancy.   
 
2) The gestational age should be clarified if known for a number of reasons. Spontaneous 
abortions are more common earlier in pregnancy. Conversely, the later the gestational age the 
higher the risk of placental exposure to IgG immunoglobulins from active transport.  
  
Minor Points  
1) Line 39: paradoxical psoriasis: I suggest you refer to this as a "paradoxical psoriaform 
reaction" instead of paradoxical psoriasis.  
2) It should be acknowledged that the true incidence of miscarriage during treatment with  
ustekinumab is unknown, and cannot be determined from the reported cases. The rate of 
miscarriage could be much higher, given that spontaneous abortions often occur without 
knowledge of pregnancy.  
3) For the 64 patients that have been exposed to usteki numab during pregnancy, it would be 
nice to summarize the data in a table including (underlying disease, drug dose, and outcome), 
if the available data from the studies would allow you to do so.  
4) Page 5, lines 14 -17: "As for psoriasis, CD raises by its elf the risk of miscarriage especially 
during flare -ups of the disease." You will need a reference for these statements.  
5) Page 5, lines 8 -15. Risk factors for miscarriage are included. These should be referenced if 
correct. Advanced age is clearly a r isk factor but not multiparity to my knowledge.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comment s to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your commen ts to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
 
Declaration of competing interests  
Please complete a declaration  of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary 
from an  organisation that may in any way gain or lose financially from the 
publication of this  manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of 
the manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financia l competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details be low. 
 
I declare that I have no competing interests' below  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
inclu ding any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Fetal death in utero and misc arriage in a patient with Crohn's disease under therapy with 
ustekinumab: case -report and review of the literature  
 
Version: 0 Date: 21 Mar 2017  
 
Reviewer: Jeff McCurdy  
 
Reviewer's report:  
 
Generally a clear case report and a topical issue that will become more common in our everyday 
practice for IBD patients. The case report allo ws the authors to review the current literature and 
discuss potential reasons why ustekinumab may or may not impact fetal loss; but, as the authors 
correctly point out firm conclusions cannot yet be drawn from this case report or the published 
literature.     
 
Major Points  
1) "This led to a rapid clinical improvement and she quickly achieved a complete remission."  
It should be identified if the remission was based on clinical grounds, biochemical remission, 
and/or endoscopically?  Although the authors po int out that the pregnancy was unplanned, recent 
guidelines have recommended objective measures to confirm remission prior to conception to 
reduce the risk of adverse fetal events (Nguyen et al., Gastroenterology 2016;150:734 -757). 
Therefore, this would be  particularly important to know in this case report given that subclinical 
inflammation may have contributed to the pregnancy loss. Similarly at the time of the US which 
detected the in utero death was the patient having clinical symptoms or were their obj ective 
measures of active disease? Moreover, was the patient malnourished from longstanding poorly 
controlled IBD and was their biochemical evidence of nutritional deficiencies (hypoalbuminemia 
and/or folate deficiency etc), any of which may have impacted the pregnancy.   
 
2) The gestational age should be clarified if known for a number of reasons. Spontaneous 
abortions are more common earlier in pregnancy. Conversely, the later the gestational age the 
higher the risk of placental exposure to IgG immunoglobulins from active transport.  
  
Minor Points  
1) Line 39: paradoxical psoriasis: I suggest you refer to this as a "paradoxical psoriaform 
reaction" instead of paradoxical psoriasis.  
2) It should be acknowledged that the true incidence of miscarriage during treatment with  
ustekinumab is unknown, and cannot be determined from the reported cases. The rate of 
miscarriage could be much higher, given that spontaneous abortions often occur without 
knowledge of pregnancy.  
3) For the 64 patients that have been exposed to usteki numab during pregnancy, it would be 
nice to summarize the data in a table including (underlying disease, drug dose, and outcome), 
if the available data from the studies would allow you to do so.  
4) Page 5, lines 14 -17: "As for psoriasis, CD raises by its elf the risk of miscarriage especially 
during flare -ups of the disease." You will need a reference for these statements.  
5) Page 5, lines 8 -15. Risk factors for miscarriage are included. These should be referenced if 
correct. Advanced age is clearly a r isk factor but not multiparity to my knowledge.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comment s to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your commen ts to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
 
Declaration of competing interests  
Please complete a declaration  of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary 
from an  organisation that may in any way gain or lose financially from the 
publication of this  manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of 
the manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financia l competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details be low. 
 
I declare that I have no competing interests' below  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
inclu ding any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Fetal death in utero and misc arriage in a patient with Crohn's disease under therapy with 
ustekinumab: case -report and review of the literature  
 
Version: 0 Date: 21 Mar 2017  
 
Reviewer: Jeff McCurdy  
 
Reviewer's report:  
 
Generally a clear case report and a topical issue that will become more common in our everyday 
practice for IBD patients. The case report allo ws the authors to review the current literature and 
discuss potential reasons why ustekinumab may or may not impact fetal loss; but, as the authors 
correctly point out firm conclusions cannot yet be drawn from this case report or the published 
literature.     
 
Major Points  
1) "This led to a rapid clinical improvement and she quickly achieved a complete remission."  
It should be identified if the remission was based on clinical grounds, biochemical remission, 
and/or endoscopically?  Although the authors po int out that the pregnancy was unplanned, recent 
guidelines have recommended objective measures to confirm remission prior to conception to 
reduce the risk of adverse fetal events (Nguyen et al., Gastroenterology 2016;150:734 -757). 
Therefore, this would be  particularly important to know in this case report given that subclinical 
inflammation may have contributed to the pregnancy loss. Similarly at the time of the US which 
detected the in utero death was the patient having clinical symptoms or were their obj ective 
measures of active disease? Moreover, was the patient malnourished from longstanding poorly 
controlled IBD and was their biochemical evidence of nutritional deficiencies (hypoalbuminemia 
and/or folate deficiency etc), any of which may have impacted the pregnancy.   
 
2) The gestational age should be clarified if known for a number of reasons. Spontaneous 
abortions are more common earlier in pregnancy. Conversely, the later the gestational age the 
higher the risk of placental exposure to IgG immunoglobulins from active transport.  
  
Minor Points  
1) Line 39: paradoxical psoriasis: I suggest you refer to this as a "paradoxical psoriaform 
reaction" instead of paradoxical psoriasis.  
2) It should be acknowledged that the true incidence of miscarriage during treatment with  
ustekinumab is unknown, and cannot be determined from the reported cases. The rate of 
miscarriage could be much higher, given that spontaneous abortions often occur without 
knowledge of pregnancy.  
3) For the 64 patients that have been exposed to usteki numab during pregnancy, it would be 
nice to summarize the data in a table including (underlying disease, drug dose, and outcome), 
if the available data from the studies would allow you to do so.  
4) Page 5, lines 14 -17: "As for psoriasis, CD raises by its elf the risk of miscarriage especially 
during flare -ups of the disease." You will need a reference for these statements.  
5) Page 5, lines 8 -15. Risk factors for miscarriage are included. These should be referenced if 
correct. Advanced age is clearly a r isk factor but not multiparity to my knowledge.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comment s to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your commen ts to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
 
Declaration of competing interests  
Please complete a declaration  of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary 
from an  organisation that may in any way gain or lose financially from the 
publication of this  manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of 
the manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financia l competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details be low. 
 
I declare that I have no competing interests' below  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
inclu ding any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant