"RE: DOES THE SIBLING EFFECT HAVE ITS ORIGIN IN UTERO? INVESTIGATING BIRTH ORDER, CORD BLOOD IMMUNOGLOBULIN E CONCENTRATION, AND ALLERGIC SENSITIZATION AT AGE 4 YEARS"

Paulus A. H. van Noord

Department of Oncologic Epidemiology Julius Center, University Medical Center Utrecht 3508 GA Utrecht, The Netherlands

My colleague and I read the report by Karmaus et al. (1) in the November 15, 2001, issue of the Journal with great interest. Apart from the effects of siblings and family size mentioned in the introduction, the authors stated in the Materials and Methods section that they also collected data on the age of the parents, allowing them to calculate the age of the mother at birth. Unfortunately, nowhere in the analysis was maternal age at birth used, either directly or to control for the effects found. We think this was a missed opportunity, as it would have allowed the authors to test a simple alternative interpretation of the so-called sibling effect.

In a 1997 study on determinants of menopause, we observed effects of birth rank for which we had no proper explanation at the time (2). Recently we realized that birth order is highly correlated with the age of the mother at birth. The age of the mother at birth reflects the age of her oocytes, from which the child is conceived. Older oocytes have a higher propensity toward aneuploidy, reflected in higher rates of spontaneous abortion and more trisomies. Having many siblings can be an indicator that one’s mother was older at one’s birth and that one was born from "older" oocytes than one’s older siblings. Having many siblings or a lower birth rank is also a reflection of the fecundity of one’s parents. All of these factors are aspects of heritability and not intrauterine effects. Subsequent analysis of the menopause relation assessing the age of the mother at birth instead of the number of siblings provided a better fit, corroborating our hypothesis on the role of oocyte age as a more likely explanation for the effects detected previously (3).

We wonder whether examining birth order effects from this oocyte-age perspective by the age of the mother at birth could also explain the results presented by Karmaus et al. or explain them even better. Their data allow computation of the ages of the parents at birth and testing of the proposed hypothesis on maternal age at birth. A similar study by Ball et al. (4) lacked the necessary information with which to test the hypothesis.

Age at (first) birth is rising in westernized countries. Thus, this hypothesis would fit equally the observed increase in atopic problems as family size declines, reducing the average number of siblings.

For menopause, we have hypothesized that the intrauterine milieu may not be the relevant factor but that age of the oocyte at conception, reflecting the genetic stability of nuclear and mitochondrial DNA, could be the underlying heritable phenomenon. We hypothesize that this might be an alternative explanation for the results presented by Karmaus et al. (1). If maternal age at birth provided a better fit in the data set of Karmaus et al., this oocyte hypothesis would also predict higher levels of atopic problems among children born through the use of assisted reproductive techniques and among children with trisomies.

REFERENCES

  1. Karmaus W, Arshad J, Mattes J. Does the sibling effect have its origin in utero? Investigating birth order, cord blood immunoglobulin E concentration, and allergic sensitization at age 4 years. Am J Epidemiol 2001;154:909–15.[Abstract/Free Full Text]
  2. van Noord PA, Dubas JS, Dorland M, et al. Age at natural menopause in a population-based screening cohort: the role of menarche, fecundity, and lifestyle factors. Fertil Steril 1997;68:95–102.[ISI][Medline]
  3. van Noord PA, Dubas SJ. Maternal/oocyte age effects on age at natural menopause of daughters: observations in the DOM cohort. (Abstract). Am J Epidemiol 2001;153(suppl):S140.
  4. Ball TM, Castro-Rodriguez JA, Griffith KA, et al. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000;343:538–43.[Abstract/Free Full Text]




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