Reviewer's report
Title:Reproductive life disorders in Italian celiac women. A case-control study.
Version: 1Date:11 February 2010
Reviewer: Jonas Ludvigsson
Reviewer's report:
Reviewer: 2
Comments to the Author
Domenico: reproductive life disorders in Italian Celiac women
I would like to thank the editor for asking me to review this paper. This paper
concerns an important paper but could be improved. I have reviewed this paper
for another journal before. Since then it has been improved, but further revisions
are needed. This is especially true regarding the description of the statistics. I
have recalculated some of the ORs and these do not turn out as in the paper.
This worries me and the authors need to explain this.
e.g. main outcome measure amenorrhea: abstract OR is 33. When I calculate it
based on the data 12-50 (cases) and 4-182 (controls) I get 11 (?).
and similarly when I calculate the odds ratio for at least one pregnancy
complication I get 2.5 instead of 4.1.
I cannot rule out that I have misunderstood something but I would be interested
to know how the authors calculcated these ORs. Did the use a matched
approach (they do not state that), or?
I appreciate that the authors have included Ors, confidence intervals and
p-values in their presentation (including in the abstract). Another change of major
importance is that “oats” is not included among the grains containing gluten. I
also urged the authors to define their main outcomes.
ABSTRACT:
Two outcomes are reported with ORs etc in the abstract, “amenorrhea” and “at
least one complication during pregnancy”. However in your methods section in
your abstract you list five main outcome measures. Although I feel five main
outcome measures is a lot, I accept it, but urge you then to present ORs for all
these main outcome measures. Presenting more detailed data (ORs+95%
CI+p-value if you like) will occupy some space and I suggest you skip the list of
all other outcomes.
"in a sample of childbearing age women" is not specific enough, please state the
number of women and their ages (median and range). Was this a matched
case-control study? If so, state that and for what the women with or without CD
were matched (age?, other?) smoking?).
Conclusion. You state that the correlation between CD and reproductive
disorders could explain fertility problems in CD. However, what is very important
is that the largest study until this date (Tata et al) actually found not association
between CD and infertility! Actually we do not know if there is any link between
CD and infertility....
Hence I suggest that you do not refer to infertility in your conclusion.
INTRODUCTION.
The abstract may be shortened by 30-50%, The prevalence on different
continents is not necessary, neither the absolute number of individuals with CD in
the united states.
I suggest skipping the references by Baldassare and Malamut. These were not
original works. If you want a review on the prevalence of CD, try Dube et al 2005.
You cite a paper by Ciacci (reference 17), please note that the shorter
breastfeeding duration in mothers with untreated CD was not statistically
significant (p-value <0.10 but not <0.05). The same was true for the increased
risk of low birth weight that was not stat significantly increased in the Ciacci
paper (p-value above 0.05, but below 0.10).
METHODS
Omit the words about privacy law watchdog
What proportion of women had undergone biopsy, and for women with biopsy did
you require villous atrophy for the diagnosis?
Enrolling women from an Italian association of CD meeting is risky. It is possible
that participants at such a meeting either have: a more severe disease (why else
would you engage in such an organization), or that they are socially more
talented, or less often have children (because than you cannot travel as freely as
if you have children....)?
What were the educational levels of women with and without CD?
I am afraid that the sampling was inappropriate, that you were able to enroll all
participants at the Apulia meeting and then had a 100% response rate is
extraordinary.
compare: 85% of controls accepted to participate,.
Regarding the statistics, it may be that you should have used Fisher's exact test
since the expected number of women in the CD group should have been less
than "5" on several occasions??
Did you use a conditional logistic regression when you evaluated the
case-control study? controls were matched for cases.
A clear description of the statistics is very important.
RESULTS
Please see my comments below “Tables”.
Either the OR or the 95% CI of your data on miscarriages (page 7) is incorrect,
>OR cannot be 1.2 if the 95% CIs are 0.9-4.6 (2.1 ??).
In the results section you present a large number of absolute data (e.g. 25
women had diarrhea, 11 had vomiting etc. Please write:
(n=25) and not only “(25)” since the latter may be misinterpreted as a reference
even if BMC uses [xx].
DISCUSSION
You suggest that women with menstrual disorders should be screened for CD.
But do we know (and do you show??) that a gluten-free diet will lead to less
menstrual disorders?
Another weakness was that only women that could be reached by phone were
included as controls. You did not report how many could not? This is of some
importance since cases were not reached by phone. It should also be noted that
data from cases and controls were obtained in different ways (or???). Cases
were interviewed at the Apulian meeting while controls were interviewed over the
phone. It cannot be ruled out that phone interviews were shorter, that participants
did not have the time to recall all negative pregnancy outcomes and menstrual
disorders and therefore underreported such events. That will lead to an
overestimation of relative risks among women with celiac disease diagnosis.
Another weakness is that you did not consider smoking status. In most studies,
smoking is negatively associated with CD (although Ludvigsson et al in their
study in Clinical Gastroenterology Hepatology 2005 vol. 3 (9) pp. 869-74 found
no association between CD and smoking in pregnant women). If there is no
association between CD and smoking then lack of smoking data is no problem
(as in the Ludvigsson paper – not the same paper that you have already referred
to, published in Gastroenterology), but if there is a negative association this could
have influenced your risk estimates. Please comment on this.
Finally it should be commented that only 41.9% of the women with CD in this
sstudy had undergone small intestinal biopsy. That is a weakness.
TABLES
Please include the data on at least one pregnancy complication in Table 2, or
better create a new table (third table, see below). These pregnancy
complications should also be defined. Did the interviewed women themselves
define “severe anemia” ? or did you have a certain hemoglobin cut-off? What
was “threatened abortion” – did the women themselves define this? And what is
uterine hyperkinesias? Gestational hypertension. All these concepts should be
defined in the methods section, or you should state that they were self-reported
and not confirmed by patient charts. If so, this should also be listed among the
limitations of this paper, in the discussion section.
Third table. I also suggest that you create a third table for pregnancy
complication.
FIGURES
the figures are really nice. But please define the outcomes of your study, e.g.
threatened abortion?
REFERENCES
Since you wrote your paper, an excellent paper has been published based on
Danish data:
Khashan et al. PMID. 19939833. (at least I believe it is published) Please refer to
that paper.
Several of the references in your manuscript are misspelled. E.g. title of ref 11.
Journal of ref 1 etc.
Please check all the references again.
LANGUAGE
A professional language review of this paper would improve the paper.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:Reproductive life disorders in Italian celiac women. A case-control study.
Version: 1Date:11 February 2010
Reviewer: Jonas Ludvigsson
Reviewer's report:
Reviewer: 2
Comments to the Author
Domenico: reproductive life disorders in Italian Celiac women
I would like to thank the editor for asking me to review this paper. This paper
concerns an important paper but could be improved. I have reviewed this paper
for another journal before. Since then it has been improved, but further revisions
are needed. This is especially true regarding the description of the statistics. I
have recalculated some of the ORs and these do not turn out as in the paper.
This worries me and the authors need to explain this.
e.g. main outcome measure amenorrhea: abstract OR is 33. When I calculate it
based on the data 12-50 (cases) and 4-182 (controls) I get 11 (?).
and similarly when I calculate the odds ratio for at least one pregnancy
complication I get 2.5 instead of 4.1.
I cannot rule out that I have misunderstood something but I would be interested
to know how the authors calculcated these ORs. Did the use a matched
approach (they do not state that), or?
I appreciate that the authors have included Ors, confidence intervals and
p-values in their presentation (including in the abstract). Another change of major
importance is that “oats” is not included among the grains containing gluten. I
also urged the authors to define their main outcomes.
ABSTRACT:
Two outcomes are reported with ORs etc in the abstract, “amenorrhea” and “at
least one complication during pregnancy”. However in your methods section in
your abstract you list five main outcome measures. Although I feel five main
outcome measures is a lot, I accept it, but urge you then to present ORs for all
these main outcome measures. Presenting more detailed data (ORs+95%
CI+p-value if you like) will occupy some space and I suggest you skip the list of
all other outcomes.
"in a sample of childbearing age women" is not specific enough, please state the
number of women and their ages (median and range). Was this a matched
case-control study? If so, state that and for what the women with or without CD
were matched (age?, other?) smoking?).
Conclusion. You state that the correlation between CD and reproductive
disorders could explain fertility problems in CD. However, what is very important
is that the largest study until this date (Tata et al) actually found not association
between CD and infertility! Actually we do not know if there is any link between
CD and infertility....
Hence I suggest that you do not refer to infertility in your conclusion.
INTRODUCTION.
The abstract may be shortened by 30-50%, The prevalence on different
continents is not necessary, neither the absolute number of individuals with CD in
the united states.
I suggest skipping the references by Baldassare and Malamut. These were not
original works. If you want a review on the prevalence of CD, try Dube et al 2005.
You cite a paper by Ciacci (reference 17), please note that the shorter
breastfeeding duration in mothers with untreated CD was not statistically
significant (p-value <0.10 but not <0.05). The same was true for the increased
risk of low birth weight that was not stat significantly increased in the Ciacci
paper (p-value above 0.05, but below 0.10).
METHODS
Omit the words about privacy law watchdog
What proportion of women had undergone biopsy, and for women with biopsy did
you require villous atrophy for the diagnosis?
Enrolling women from an Italian association of CD meeting is risky. It is possible
that participants at such a meeting either have: a more severe disease (why else
would you engage in such an organization), or that they are socially more
talented, or less often have children (because than you cannot travel as freely as
if you have children....)?
What were the educational levels of women with and without CD?
I am afraid that the sampling was inappropriate, that you were able to enroll all
participants at the Apulia meeting and then had a 100% response rate is
extraordinary.
compare: 85% of controls accepted to participate,.
Regarding the statistics, it may be that you should have used Fisher's exact test
since the expected number of women in the CD group should have been less
than "5" on several occasions??
Did you use a conditional logistic regression when you evaluated the
case-control study? controls were matched for cases.
A clear description of the statistics is very important.
RESULTS
Please see my comments below “Tables”.
Either the OR or the 95% CI of your data on miscarriages (page 7) is incorrect,
>OR cannot be 1.2 if the 95% CIs are 0.9-4.6 (2.1 ??).
In the results section you present a large number of absolute data (e.g. 25
women had diarrhea, 11 had vomiting etc. Please write:
(n=25) and not only “(25)” since the latter may be misinterpreted as a reference
even if BMC uses [xx].
DISCUSSION
You suggest that women with menstrual disorders should be screened for CD.
But do we know (and do you show??) that a gluten-free diet will lead to less
menstrual disorders?
Another weakness was that only women that could be reached by phone were
included as controls. You did not report how many could not? This is of some
importance since cases were not reached by phone. It should also be noted that
data from cases and controls were obtained in different ways (or???). Cases
were interviewed at the Apulian meeting while controls were interviewed over the
phone. It cannot be ruled out that phone interviews were shorter, that participants
did not have the time to recall all negative pregnancy outcomes and menstrual
disorders and therefore underreported such events. That will lead to an
overestimation of relative risks among women with celiac disease diagnosis.
Another weakness is that you did not consider smoking status. In most studies,
smoking is negatively associated with CD (although Ludvigsson et al in their
study in Clinical Gastroenterology Hepatology 2005 vol. 3 (9) pp. 869-74 found
no association between CD and smoking in pregnant women). If there is no
association between CD and smoking then lack of smoking data is no problem
(as in the Ludvigsson paper – not the same paper that you have already referred
to, published in Gastroenterology), but if there is a negative association this could
have influenced your risk estimates. Please comment on this.
Finally it should be commented that only 41.9% of the women with CD in this
sstudy had undergone small intestinal biopsy. That is a weakness.
TABLES
Please include the data on at least one pregnancy complication in Table 2, or
better create a new table (third table, see below). These pregnancy
complications should also be defined. Did the interviewed women themselves
define “severe anemia” ? or did you have a certain hemoglobin cut-off? What
was “threatened abortion” – did the women themselves define this? And what is
uterine hyperkinesias? Gestational hypertension. All these concepts should be
defined in the methods section, or you should state that they were self-reported
and not confirmed by patient charts. If so, this should also be listed among the
limitations of this paper, in the discussion section.
Third table. I also suggest that you create a third table for pregnancy
complication.
FIGURES
the figures are really nice. But please define the outcomes of your study, e.g.
threatened abortion?
REFERENCES
Since you wrote your paper, an excellent paper has been published based on
Danish data:
Khashan et al. PMID. 19939833. (at least I believe it is published) Please refer to
that paper.
Several of the references in your manuscript are misspelled. E.g. title of ref 11.
Journal of ref 1 etc.
Please check all the references again.
LANGUAGE
A professional language review of this paper would improve the paper.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:Reproductive life disorders in Italian celiac women. A case-control study.
Version: 1Date:11 February 2010
Reviewer: Jonas Ludvigsson
Reviewer's report:
Reviewer: 2
Comments to the Author
Domenico: reproductive life disorders in Italian Celiac women
I would like to thank the editor for asking me to review this paper. This paper
concerns an important paper but could be improved. I have reviewed this paper
for another journal before. Since then it has been improved, but further revisions
are needed. This is especially true regarding the description of the statistics. I
have recalculated some of the ORs and these do not turn out as in the paper.
This worries me and the authors need to explain this.
e.g. main outcome measure amenorrhea: abstract OR is 33. When I calculate it
based on the data 12-50 (cases) and 4-182 (controls) I get 11 (?).
and similarly when I calculate the odds ratio for at least one pregnancy
complication I get 2.5 instead of 4.1.
I cannot rule out that I have misunderstood something but I would be interested
to know how the authors calculcated these ORs. Did the use a matched
approach (they do not state that), or?
I appreciate that the authors have included Ors, confidence intervals and
p-values in their presentation (including in the abstract). Another change of major
importance is that “oats” is not included among the grains containing gluten. I
also urged the authors to define their main outcomes.
ABSTRACT:
Two outcomes are reported with ORs etc in the abstract, “amenorrhea” and “at
least one complication during pregnancy”. However in your methods section in
your abstract you list five main outcome measures. Although I feel five main
outcome measures is a lot, I accept it, but urge you then to present ORs for all
these main outcome measures. Presenting more detailed data (ORs+95%
CI+p-value if you like) will occupy some space and I suggest you skip the list of
all other outcomes.
"in a sample of childbearing age women" is not specific enough, please state the
number of women and their ages (median and range). Was this a matched
case-control study? If so, state that and for what the women with or without CD
were matched (age?, other?) smoking?).
Conclusion. You state that the correlation between CD and reproductive
disorders could explain fertility problems in CD. However, what is very important
is that the largest study until this date (Tata et al) actually found not association
between CD and infertility! Actually we do not know if there is any link between
CD and infertility....
Hence I suggest that you do not refer to infertility in your conclusion.
INTRODUCTION.
The abstract may be shortened by 30-50%, The prevalence on different
continents is not necessary, neither the absolute number of individuals with CD in
the united states.
I suggest skipping the references by Baldassare and Malamut. These were not
original works. If you want a review on the prevalence of CD, try Dube et al 2005.
You cite a paper by Ciacci (reference 17), please note that the shorter
breastfeeding duration in mothers with untreated CD was not statistically
significant (p-value <0.10 but not <0.05). The same was true for the increased
risk of low birth weight that was not stat significantly increased in the Ciacci
paper (p-value above 0.05, but below 0.10).
METHODS
Omit the words about privacy law watchdog
What proportion of women had undergone biopsy, and for women with biopsy did
you require villous atrophy for the diagnosis?
Enrolling women from an Italian association of CD meeting is risky. It is possible
that participants at such a meeting either have: a more severe disease (why else
would you engage in such an organization), or that they are socially more
talented, or less often have children (because than you cannot travel as freely as
if you have children....)?
What were the educational levels of women with and without CD?
I am afraid that the sampling was inappropriate, that you were able to enroll all
participants at the Apulia meeting and then had a 100% response rate is
extraordinary.
compare: 85% of controls accepted to participate,.
Regarding the statistics, it may be that you should have used Fisher's exact test
since the expected number of women in the CD group should have been less
than "5" on several occasions??
Did you use a conditional logistic regression when you evaluated the
case-control study? controls were matched for cases.
A clear description of the statistics is very important.
RESULTS
Please see my comments below “Tables”.
Either the OR or the 95% CI of your data on miscarriages (page 7) is incorrect,
>OR cannot be 1.2 if the 95% CIs are 0.9-4.6 (2.1 ??).
In the results section you present a large number of absolute data (e.g. 25
women had diarrhea, 11 had vomiting etc. Please write:
(n=25) and not only “(25)” since the latter may be misinterpreted as a reference
even if BMC uses [xx].
DISCUSSION
You suggest that women with menstrual disorders should be screened for CD.
But do we know (and do you show??) that a gluten-free diet will lead to less
menstrual disorders?
Another weakness was that only women that could be reached by phone were
included as controls. You did not report how many could not? This is of some
importance since cases were not reached by phone. It should also be noted that
data from cases and controls were obtained in different ways (or???). Cases
were interviewed at the Apulian meeting while controls were interviewed over the
phone. It cannot be ruled out that phone interviews were shorter, that participants
did not have the time to recall all negative pregnancy outcomes and menstrual
disorders and therefore underreported such events. That will lead to an
overestimation of relative risks among women with celiac disease diagnosis.
Another weakness is that you did not consider smoking status. In most studies,
smoking is negatively associated with CD (although Ludvigsson et al in their
study in Clinical Gastroenterology Hepatology 2005 vol. 3 (9) pp. 869-74 found
no association between CD and smoking in pregnant women). If there is no
association between CD and smoking then lack of smoking data is no problem
(as in the Ludvigsson paper – not the same paper that you have already referred
to, published in Gastroenterology), but if there is a negative association this could
have influenced your risk estimates. Please comment on this.
Finally it should be commented that only 41.9% of the women with CD in this
sstudy had undergone small intestinal biopsy. That is a weakness.
TABLES
Please include the data on at least one pregnancy complication in Table 2, or
better create a new table (third table, see below). These pregnancy
complications should also be defined. Did the interviewed women themselves
define “severe anemia” ? or did you have a certain hemoglobin cut-off? What
was “threatened abortion” – did the women themselves define this? And what is
uterine hyperkinesias? Gestational hypertension. All these concepts should be
defined in the methods section, or you should state that they were self-reported
and not confirmed by patient charts. If so, this should also be listed among the
limitations of this paper, in the discussion section.
Third table. I also suggest that you create a third table for pregnancy
complication.
FIGURES
the figures are really nice. But please define the outcomes of your study, e.g.
threatened abortion?
REFERENCES
Since you wrote your paper, an excellent paper has been published based on
Danish data:
Khashan et al. PMID. 19939833. (at least I believe it is published) Please refer to
that paper.
Several of the references in your manuscript are misspelled. E.g. title of ref 11.
Journal of ref 1 etc.
Please check all the references again.
LANGUAGE
A professional language review of this paper would improve the paper.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
I declare that I have no competing interests
assistant