Abstract
Dear Editor
In their meta-analysis Conde-Agudelo et al (2016) conclude that short interpregnancy intervals (IPIs) are associated with a significantly increased risk of autism spectrum disorder (ASD). We wish to point out that none of the studies in the meta-analysis controlled for the birth order of the index child. In a recent paper (Beenstock, Levine and Raz 2015) we showed that recurrence risk of ASD varies inversely with birth order, as well as with birth-spacing. Birth order matters because the more parents succeed in having typically developed children, the less likely it is that they have a genetic predisposition to having children with ASD. Therefore, given everything else, if the index child is a firstborn the incidence of ASD is expected to be larger than for index children who are second-borns, and so on for higher birth orders.
If birth-spacing is unrelated to birth order, the omission of birth order effects would not matter for estimates of birth gap effects from linear regressions. Matters are different with nonlinear odds-ratio methods used by Conde-Agudelo et al where the estimated effect of birth-spacing is biased in an unknown direction. If birth-spacing and birth order are positively correlated, the estimated birth-spacing effect is positively biased in linear regression, and it is almost surely positively biased in odds-ratio methods. If birth-spacing and birth order are negatively correlated, the bias is negative, which means that the estimated negative effect of birth-spacing on ASD risk in the meta-analysis might be a spurious result induced by the failure to specify the birth orders of the index children.
If parents have targets for family size, birth-spacing is expected to be negatively correlated with birth order (Heckman, Hotz and Walker 1985). Given everything else, if child 2 was slower to arrive, parents who desire three or more children may try to make up for lost time in producing their third child. Heckman et al used data for Swedish women to establish this negative correlation empirically. Target family size theory inevitably casts doubt on the robustness of the main result in Conde-Agudelo et al (2016).
Using population cohort data for 4976 index children in Israel with ASD, Beenstock et al (2015) found that recurrence risk is 40% larger among younger siblings born within at least two years of their index sibling. Also, if the index is a firstborn and the second child is typically developed, recurrence risk for the third child falls by 0.5% (9.1% in terms of relative risk).
In our study index children have ASD whereas in Conde-Agudelo et al they do not. Therefore, the fact that we found birth spacing is statistically significant after controlling for birth order does not necessarily mean that the same result would be found for the general population. Future research on risk factors of neurodevelopmental disorders should aspire to specify birth-spacing and birth order among the covariates.
Yours sincerely
References:
Beenstock M, Levine H, Raz R (2015) Birth Gap and the Recurrence Risk of Autism Spectrum Disorders: A Population-based Cohort Study. Research in Autism Developmental Disorders, 17: 86-94.
Conde-Agudelo A., Rosas-Bermudez A., Norton MH (2016) Birth spacing and risk of autism and other neurodevelopmental disabilities.
In their meta-analysis Conde-Agudelo et al (2016) conclude that short interpregnancy intervals (IPIs) are associated with a significantly increased risk of autism spectrum disorder (ASD). We wish to point out that none of the studies in the meta-analysis controlled for the birth order of the index child. In a recent paper (Beenstock, Levine and Raz 2015) we showed that recurrence risk of ASD varies inversely with birth order, as well as with birth-spacing. Birth order matters because the more parents succeed in having typically developed children, the less likely it is that they have a genetic predisposition to having children with ASD. Therefore, given everything else, if the index child is a firstborn the incidence of ASD is expected to be larger than for index children who are second-borns, and so on for higher birth orders.
If birth-spacing is unrelated to birth order, the omission of birth order effects would not matter for estimates of birth gap effects from linear regressions. Matters are different with nonlinear odds-ratio methods used by Conde-Agudelo et al where the estimated effect of birth-spacing is biased in an unknown direction. If birth-spacing and birth order are positively correlated, the estimated birth-spacing effect is positively biased in linear regression, and it is almost surely positively biased in odds-ratio methods. If birth-spacing and birth order are negatively correlated, the bias is negative, which means that the estimated negative effect of birth-spacing on ASD risk in the meta-analysis might be a spurious result induced by the failure to specify the birth orders of the index children.
If parents have targets for family size, birth-spacing is expected to be negatively correlated with birth order (Heckman, Hotz and Walker 1985). Given everything else, if child 2 was slower to arrive, parents who desire three or more children may try to make up for lost time in producing their third child. Heckman et al used data for Swedish women to establish this negative correlation empirically. Target family size theory inevitably casts doubt on the robustness of the main result in Conde-Agudelo et al (2016).
Using population cohort data for 4976 index children in Israel with ASD, Beenstock et al (2015) found that recurrence risk is 40% larger among younger siblings born within at least two years of their index sibling. Also, if the index is a firstborn and the second child is typically developed, recurrence risk for the third child falls by 0.5% (9.1% in terms of relative risk).
In our study index children have ASD whereas in Conde-Agudelo et al they do not. Therefore, the fact that we found birth spacing is statistically significant after controlling for birth order does not necessarily mean that the same result would be found for the general population. Future research on risk factors of neurodevelopmental disorders should aspire to specify birth-spacing and birth order among the covariates.
Yours sincerely
References:
Beenstock M, Levine H, Raz R (2015) Birth Gap and the Recurrence Risk of Autism Spectrum Disorders: A Population-based Cohort Study. Research in Autism Developmental Disorders, 17: 86-94.
Conde-Agudelo A., Rosas-Bermudez A., Norton MH (2016) Birth spacing and risk of autism and other neurodevelopmental disabilities.
| Original language | American English |
|---|---|
| Article number | e20153482 |
| Number of pages | 1 |
| Journal | Pediatrics |
| Volume | 137 |
| Issue number | 5 |
| DOIs |
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| State | Published - Aug 2016 |
Bibliographical note
Publisher Copyright:© Copyright 2016 by the American Academy of Pediatrics.