There is a great body of evidence that siblings have a protective effect against atopic manifestations such as hay fever, atopic eczema, allergic sensitization, or asthma. Factors that may explain this association remain largely unknown. One hypothesis is that siblings promote early infections in childhood, and repeated infections protect against atopic disorders. Another hypothesis, the potential in utero programming, has been neglected. The authors investigated if cord blood immunoglobulin E (IgE) is dependent upon birth order and if both are associated with an increased incidence of allergic sensitization (skin prick test) at the age of 4 years in a cohort of 981 newborns recruited between January 1989 and February 1990 on the Isle of Wight, England. The authors found that IgE is reduced with increasing birth order (first child: odds ratio (OR) = 1; second child: OR = 0.78, 95% confidence interval (CI): 0.57, 1.05; third child: OR = 0.59, 95% CI: 0.41, 0.83). Cord IgE, but not birth order, is a significant predictor of skin prick test positivity at age 4 (IgE below detection limit: OR = 1; IgE of 0.2-<0.5 kilounits/liter: OR = 1.11, 95% CI: 0.73, 1.68; IgE of >or=0.5 kilounits/liter: OR = 2.63, 95% CI: 1.62, 4.29). The findings suggest that cord IgE is reduced in pregnancies with higher order, indicating that the sibling effect may have its origin in utero.