Authors' reply

We agree with Downs & Jonas that it is important to establish whether the association between inter-pregnancy interval and schizophrenia is indeed causal, and that residual confounding is a potential explanation for our findings.

Residual confounding is, of course, a potential explanation for any association in observational epidemiological studies, as we discuss in our paper. ¹ However, we believe that one of the strengths of our study is that we compare the relationship between the pre-birth inter-pregnancy interval and risk of schizophrenia with that of the post-birth inter-pregnancy interval and risk of this disorder. If the association between pre-birth inter-pregnancy interval and risk of schizophrenia is due to confounding, we would expect to observe a similar relationship for the post-birth interval, but we did not find this in our study. Although it is possible that there are confounders that are associated with pre-birth, but not post-birth inter-pregnancy intervals, this seems rather unlikely for most potential confounders.

For example, Downs & Jonas suggest that one such possible confounder is ethnicity, whereby individuals born to families from specific ethnic groups may be more likely to be conceived following a shorter pre-birth inter-pregnancy interval, as well as to have an increased risk of schizophrenia. However, if this were true then we would expect to see the same (confounded) relationship between post-birth inter-pregnancy interval and risk of schizophrenia. Comparing results for pre-birth and post-birth intervals allows us to be slightly more confident (although by no means certain) that unmeasured confounders do not provide an adequate explanation for our findings, and that the increased risk of schizophrenia following a shorter pre-birth inter-pregnancy interval might be causal. What it is about a shorter pre-birth inter-pregnancy interval that leads to an increased risk of schizophrenia is, as yet, unknown, ¹ although arguments that this acts as a proxy for fetal undernutrition or exposure to stress have received the greatest support in the literature to date. ^2-5

Downs & Jonas also argue that short inter-pregnancy intervals favour male offspring and that, given the gender variation in age-specific incidence of schizophrenia, this could lead to an overestimation of the effect of a shorter inter-pregnancy interval. However, if male gender was indeed on the causal pathway between inter-pregnancy interval and schizophrenia, this would not, of itself, lead to a biased estimate of association between inter-pregnancy interval and schizophrenia. Furthermore, if male gender was indeed on the causal pathway, then adjusting for gender should lead to an attenuation of the association between inter-pregnancy interval and schizophrenia; however, adjusting for gender made no difference to our results, ¹ indicating that gender is unlikely to be an adequate explanation as a mechanism for the association with shorter inter-pregnancy interval.