Both short and long interpregnancy intervals (IPIs) have recently been associated with increased risk of autism spectrum disorder (ASD). However, this association has not been systematically evaluated.
To examine the relationship between birth spacing and the risk of ASD and other neurodevelopmental disabilities.
Electronic databases from their inception to December 2015, bibliographies, and conference proceedings.
Observational studies with results adjusted for potential confounding factors that reported on the association between IPIs or birth intervals and neurodevelopmental disabilities.
Two reviewers independently extracted data on study characteristics, IPIs/birth intervals, and outcome measures.
Seven studies (1 140 210 children) reported an association between short IPIs and increased risk of ASD, mainly the former subtype autistic disorder. Compared with children born to women with IPIs of ≥36 months, children born to women with IPIs of <12 months had a significantly increased risk of any ASD (pooled adjusted odds ratio [OR] 1.90, 95% confidence interval [CI] 1.16–3.09). This association was stronger for autistic disorder (pooled adjusted OR 2.62, 95% CI 1.53–4.50). Three of these studies also reported a significant association between long IPIs and increased risk of ASD. Short intervals were associated with a significantly increased risk of developmental delay (3 studies; 174 940 children) and cerebral palsy (2 studies; 19 419 children).
Substantial heterogeneity, and few studies assessing neurodevelopmental disabilities other than ASD.
Short IPIs are associated with a significantly increased risk of ASD. Long IPIs also appear to increase the risk of ASD.
Beenstock and colleagues suggest that our finding that short interpregnancy intervals (IPIs) are associated with a significantly increased risk of autism spectrum disorder (ASD)(1) might be a spurious result induced by the failure to specify the birth orders of the index children. This statement is based on the findings of a study performed by the correspondents in which recurrence risk rates were calculated for 4976 younger siblings of children with ASD according to several characteristics. (2) Younger siblings with birth intervals <24 months (which correspond to approximately 15 months IPI) had a significantly increased risk of ASD when compared with younger siblings with birth intervals ≥24 months (OR 1.66, 95% CI 1.25–2.22). Interestingly, the association remained statistically significant in models adjusted for birth order, sex of the index cases and their younger siblings, ethnicity, and parental ages (OR 1.43, 95% CI 1.03–1.96). This finding is in agreement with that of our meta-analysis. The study by Beenstock et al (2) also found that recurrence risk varied inversely with the birth-orders of index cases as well as the birth orders of their younger siblings. The authors concluded that “short birth gaps from the index case increase the risk of ASD among younger siblings”.
The correspondents emphasize that none of the studies included in the meta-analysis controlled for the birth order of the index child, which is not true. In fact, the study by Cheslack-Postava et al,(3) the largest included in our meta-analysis, performed a case-sibling control analysis to compute within-family estimates for the association between birth order (second- versus firstborn) and autism according to IPI. This analysis showed that for short IPIs of <12 months, second-born siblings were at an increased risk of autism relative to their firstborn siblings and the authors concluded that although confounding by family-level factors may be present, it does not entirely account for the association, particularly for IPIs of <12 months. In addition, a nested case-control study included in our meta-analysis carried out a complementary patient–sibling analysis addressing the potential for confounding by family-level factors using pairs of first- and second-born siblings in which one sibling was diagnosed with ASD. (4) For short birth intervals (<21 months), the odds of ASD in the second-born sibling were increased (OR = 1.27; p=0.02), although the difference was not statistically significant after adjustment for covariates (OR = 1.23; p=0.12). Finally, it should be noted that in five of the seven studies included in our meta-analysis the study population was restricted to pairs of first- and second-born siblings to control for birth order effects.
In summary, the results of the study by Beenstock et al2 reaffirm that short IPI are independently associated with a significantly higher risk of ASD.
REFERENCES
1. Conde-Agudelo A, Rosas-Bermudez A, Norton MH. Birth spacing and risk of autism and other neurodevelopmental disabilities: a systematic review. Pediatrics. 2016;137(5):e20153482.
2. Beenstock M, Raz R, Levine H. Birth gap and the recurrence risk of autism spectrum disorders: a population-based cohort study. Res Autism Spectr Disord. 2015;17:86-94.
3. Cheslack-Postava K, Liu K, Bearman PS. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics. 2011;127(2):246–253.
4. Cheslack-Postava K, Suominen A, Jokiranta E, et al. Increased risk of autism spectrum disorders at short and long interpregnancy intervals in Finland. J Am Acad Child Adolesc Psychiatry. 2014;53(10):1074-1081.e4.
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. Pediatrics, 137(5) e20153482.
Heckman JJ, Hotz VJ, Walker JR. (1985) New evidence on the timing and spacing of births. American Economic Review, Papers and Proceedings.