Reviewer's report 
 Pregnancy weight gain and breast cancer risk: a nested case-control study Title: 
 1  24 April 2004 Version: Date: 
 Bianca L De Stavola Reviewer: 
Reviewer's report: 
The question addressed by the paper is well defined but the measure of exposure available to the 
authors is weak and the statistical methods used are unsatisfactory. Further, the women on whom 
comparisons of pregnancy weight gains could be performed may not be fully representative of the original cohort and the nested case-control design is poor. 
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Major compulsory revision 
Title: incorrect 
Main results refer to a cohort of women who gave birth during 1954-63, for about 2/3 of whom weight 
gain in pregnancy could be estimated. The nested case-control part of the study is only a minor 
component of the results presented. 
Methods: 
Data- 
The women available for analysis may be a biased subset as evidenced by the comparative 
description of women excluded and included (top of page 6). 
Measures of exposure- 
Weight gain during pregnancy is estimated via a piecewise linear model. No details are given on the 
average number of individual observations used to fit this model nor of its goodness of fit. If women 
requiring greater monitoring are those with more measures, their predicted value may be more accurate than for the others. 
Further the range of values reported for weight gains should have been described in terms of 
average and range, possibly by maternal parity (note that the reported top category used in Table 3, >25kg, seems too extreme for singleton births). 
Post- pregnancy weight, as used in the nested case-control study, is potentially too biased to be of 
any value. Firstly weight is known to increase with age, especially after the menopause, so comparisons should be age-standardised. Secondly analyses are restricted to women who either had a diagnosis of breast cancer or a hospital attendance, with weight measured around the time of 
diagnosis (reported median time 0) or at the hospital visit. Those affected by cancer in particular may 
have lost weight because of the cancer; those in hospital for other reasons (which are not 
mentioned) could be again slimmer or heavier than usual because of their illness. 
Statistical analyses- 
1- When analysing data from a cohort, account needs to be taken of both time to the event and time 
to censoring. Thus all t-tests reported when comparing the baseline characteristics of women who 
had or not a diagnosis of breast cancer (Tables 1 and 2) are inappropriate. 
2- The results based on Cox regression are appropriate (although checks of the validity of the 
assumptions should be made). However breast cancer incidence is known to substantially change 
with age: surprisingly age was not included among the potential confounders (the best approach 
would be to use age as the time dimension in the Cox model). 
3- The authors incorrectly refer to risk ratios as being estimated by the Cox regression model: the 
correct term is rate ratios. The fact that they refer to risks indicates misunderstanding of the analyses 
carried out (see point below). 
4- Separate analyses for pre- and post-menopausal women are mentioned. These require 
knowledge of the age at menopause of all women, not just of the cases (or a n appropriate proxy age 
should be sued, e.g. age 50 years). This requirement is not mentioned, nor that the follow-up of all 
women had been split into pre-and post-menopausal women before carrying out the analyses. I 
would like to be re-assured that the authors have not simply analysed the data by simply restricting 
the number of cases to be either pre- or post; this would be a grave error. 
5- The analyses of the case-control part of the study is reported to have been based on Cox 
regression. How was the matching properly taken into account? 
Interpretation 
More emphasis should be given to: 
1- The extent of bias introduced by the lack of weight gain data on about 40% of the cohort 
2- The fact that pregnancy weight gain is only estimated and not observed: by definition the variable 
used is less variable that the actual one. 
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Minor compulsory revision 
Selection of controls- 
These are said to be matched to the cases on age: can the authors specify which age do they refer 
to? The age at diagnosis or the age at birth? 
Survival analysis- 
this should be carried out from end, not beginning- of the pregnancy because women who suffered 
abortions or miscarriages were excluded 
Tables- 
References to weight gain should be stress that it is predicted 
Table 5 is very very confusing 
Appendix- 
Should clarify how line A and B were made to meet at week 15 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Needs some language corrections before being published Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
none