THE AUTHORS REPLY

Wilfried Karmaus1, Hasan Arshad2 and Jörg Mattes3

1 Department of Epidemiology, College of Human Medicine, Michigan State University, East Lansing, MI 48823.
2 The David Hide Asthma and Allergy Research Centre, St. Mary’s Hospital, Newport, Isle of Wight, PO30 STG, United Kingdom.
3 University Children’s Hospital, Mathildenstrasse 1, D-79106 Freiburg, Germany.

We appreciate the observations of Drs. Maziak (1), Bernsen and van der Wouden (2), and van Noord (3). The innovative character of recent research on asthma etiology is challenging. Mechanistically based hypothesis-driven research, highly respected in the United States, has not stimulated the detection of the sibling effect, since the mechanisms are still unknown and detection is based purely on epidemiologic findings. The world of intuition is less restricted, and there is little chance of being counterintuitive; however, there is a greater likelihood of being countermechanistic when challenging the paradigm of the infection hypothesis.

We thank Wasim Maziak (1) for debating our "counterintuitive" interpretation or, as we would see it, our countermechanistic view. We stated in our paper (4) that the association between infections and asthma might be spurious. Given that the majority of infections in childhood are viral (5, 6), exposure to the same virus may cause an apparent infection in one child (a child with a T helper 1 (Th1) pattern of response at birth) and an upper respiratory tract infection with wheezing in the other (a child with a T helper 2 (Th2) response at birth). The immune systems of children who experience only infection are likely to identify and eliminate the infectious agent. Those children who start out with wheezing are more likely to develop asthma (7, 8). Consequently, it becomes apparent that children with infections may have less asthma, but children with wheezing have more. Given this scenario, infections may not be protective, but the type of infection is a marker of a Th1- or Th2-biased immune response. Accordingly, the alleged protective effect of infections has not been observed consistently in different studies (812). However, we would need other data to address this question.

Roos Bernsen and Johannes van der Wouden (2) emphasize two points: first, the assumption that fetomaternal interactions may underlie the association between birth order and atopy has been hypothesized before; and second, the age of the mother should be controlled for as a confounding factor. With regard to the previously proposed hypothesis, Bernsen and van der Wouden refer to an editorial (13) that addressed a paper cowritten by two of the current authors (J. M. and W. K.) (14). The original paper emphasized prenatal immunologic interactions between the mother and the fetus that may underlie the so-called sibling effect. In support of our earlier hypothesis (14), we were able to present empirical data to address this issue in our recent paper (4).

It is correct that maternal age and the number of offspring are related. However, controlling for maternal age has two aspects, a statistical aspect and a biologic aspect. Statistical considerations include the following. Maternal age at the birth of the child ranged from 16.4 years to 43 years. We grouped the variables into three nearly equidistant groups. Maternal age and the birth order of the offspring were associated (table 1). The information presented in table 1, which corresponds to table 2 in our paper (4), is stratified by maternal age group (16–23 years, 24–33 years, and >=34 years) and shows a nearly identical association between the birth order of the child and cord blood immunoglobulin E level (<0.2, >=0.2–<0.5, and >=0.5 kilounits/liter). For the three age groups, the prevalence of immunoglobulin E levels greater than or equal to 0.5 kilounits/liter is reduced in groups with a higher birth order. Additionally, we included maternal age in the model for immunoglobulin E. Neither the odds ratio for the second child (odds ratio (OR) = 0.80 (95% confidence interval (CI): 0.59, 1.09) and OR = 0.79 (95% CI: 0.57, 1.08) before and after inclusion of maternal age, respectively) nor the odds ratio for the third child (OR = 0.60 (95% CI: 0.42, 0.85) and OR = 0.64 (95% CI: 0.44, 0.93), respectively) changed substantially.


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TABLE 1. Association between umbilical cord blood immunoglobulin E level and the child’s birth order (n = 857), by maternal age, Isle of Wight, United Kingdom, 1989–1990
 
Regarding biologic considerations, we are not aware of any study indicating that aging explains a reduction in maternal immunoglobulin E levels. However, age is a marker for other biologic processes, and it is preferable to include a potential indicator of the potential biologic process, that is, number of pregnancies, in the model. This is why we did not include age. Regarding pregnancies, it has been suggested that successive pregnancies decrease atopy in the mother and thus reduce the risk of atopy in subsequent offspring (15). Additionally, regarding our speculation of an endocrine effect, there may be several biologic mechanisms involved that increase the tolerance of the mother with an increasing number of pregnancies, including fetomaternal cell trafficking and the possibility of microchimerism (15).

Paulus van Noord also suggested statistical control for maternal age (3). However, the direction of his proposed mechanism—the aging of oocytes until conception and a related increase in adverse effects on the fetus—is the opposite of what we detected. Our results indicated that the incidence of allergic sensitization is higher among firstborns and lower among second- and thirdborn children.

We epidemiologists teach our students to consider epidemiologic explanations (time order, selection bias, the impact of third variables, etc.) first, before biologic mechanisms. Thus, we must first understand the epidemiology of the protective sibling effect (16) before we focus on mechanisms. There are a sufficient number of data sets from different parts of the world to address the most urgent questions and to guide epidemiologists in obtaining additional understanding. Therefore, we suggest that further collaboration and debate is necessary to understand the epidemiology of the so-called sibling effect.

REFERENCES

  1. Maziak W. 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." (Letter). Am J Epidemiol 2002;156:882.[Free Full Text]
  2. Bernsen RM, van der Wouden JC. 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." (Letter). Am J Epidemiol 2002;156:882.[Free Full Text]
  3. van Noord PA. 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." (Letter). Am J Epidemiol 2002;156:882–3.[Free Full Text]
  4. Karmaus W, Arshad H, 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]
  5. Jacobs B, Young NL, Dick PT, et al. Canadian Acute Respiratory Illness and Flu Scale (CARIFS): development of a valid measure for childhood respiratory infections. J Clin Epidemiol 2000;53:793–9.[ISI][Medline]
  6. Illi S, von Mutius E, Lau S, et al. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 2001;322:390–5.[Abstract/Free Full Text]
  7. Weiss ST, Tager IB, Muñoz A, et al. The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. Am Rev Respir Dis 1985;131:573–8.[ISI][Medline]
  8. Nafstad P, Magnus P, Jaakkola JJ. Early respiratory infections and childhood asthma. Pediatrics 2000;106:E38.[Medline]
  9. Nystad W, Skrondal A, Njå F, et al. Recurrent respiratory tract infections during the first 3 years of life and atopy at school age. Allergy 1998;53:1189–94.[ISI][Medline]
  10. Matricardi PM, Franzinelli F, Franco A, et al. Sibship size, birth order, and atopy in 11,371 Italian young men. J Allergy Clin Immunol 1998;101:439–44.[ISI][Medline]
  11. Matricardi PM, Rosmini F, Riondino S, et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 2000;320:412–17.[Abstract/Free Full Text]
  12. Bodner C, Anderson WJ, Reid TS, et al. Childhood exposure to infection and risk of adult onset wheeze and atopy. Thorax 2000;55:383–7.[Abstract/Free Full Text]
  13. von Mutius E. The influence of birth order on the expression of atopy in families: a gene-environment interaction? Clin Exp Allergy 1998;28:1454–6.[ISI][Medline]
  14. Mattes J, Karmaus W, Moseler M, et al. Accumulation of atopic disorders within families: a sibship effect only in the offspring of atopic fathers. Clin Exp Allergy 1998;28:1480–6.[ISI][Medline]
  15. Doull IJ. Does pregnancy prevent atopy? Clin Exp Allergy 2001;31:1335–7.[ISI][Medline]
  16. Karmaus W, Botezan C. Does a higher number of siblings protect against the development of allergy and asthma? J Epidemiol Community Health 2002;56:209–17.[Abstract/Free Full Text]




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