Short Communication Prenatal and Postnatal Milk Supplementation and Adult Insulin-like Growth Factor I: Long-term Follow-up of a Randomized Controlled Trial Yoav Ben-Shlomo, 1 Jeff Holly, 2 Anne McCarthy, 1 Paul Savage, 2 David Davies, 3 and George Davey Smith 1 1 Department of Social Medicine and 2 Department of Surgery, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom; and 3 Department of Child Health, University College of Wales, Cardiff, United Kingdom Abstract Objective: Insulin-like growth factors (IGF) are increasingly recognized as important determinants of adult health, in particular risk of certain cancers. However, little is known about the determinants of adult IGFs and to what degree they may be programmed by early life influences. Design: Randomized controlled trial of prenatal and post- natal milk supplementation among 951 subjects born in 1972 to 1974 in South Wales. Main outcome measure: Measures of IGF-I, IGF binding protein 3, and the molar ratio. Results: Data on adult IGFs were available from 663 subjects at a mean age of 25 years. Subjects in the intervention arm had lower IGF-I (À8.5 ng/mL; 95% confidence interval, À15.1 to À1.8, P = 0.01) and ratio (À1.20; 95% confidence interval, À2.33 to À0.04, P = 0.04). These differences could not be explained by follow-up bias or confounding factors. Conclusions: These results provide experimental data on the role of early life programming either in the intra- uterine or postnatal period that may have long-term influences on the IGF axis, with potential implications for disease risk. (Cancer Epidemiol Biomarkers Prev 2005; 14(5):1336 – 9) Introduction The insulin-like growth factors (IGF-I and IGF-II) are peptides that have structural and functional homology with insulin. In addition to acute metabolic insulin-like actions, the IGFs mediate many of the effects of growth hormone on embryonic and postnatal childhood growth. The IGFs are present throughout the body, almost entirely bound to a series of six high affinity binding proteins (IGFBP-1 to -6; ref. 1). In the circulation, the majority of IGF-I is bound to IGFBP-3 and an acid labile subunit in a large ternary complex with restricted ability to cross the capillary endothelium. The ratio of IGF-I to IGFBP-3 is considered to reflect the bioavailability of IGF-I to target tissues (1). A number of recent prospective studies have shown that raised levels of IGF-I, low levels of IGFBP-3, and in particular a high molar ratio of IGF-I to IGFBP-3 are associated with increased risk from certain cancers (2, 3). A recent meta- analysis showed positive associations between raised IGF-I levels and premenopausal breast cancer, colorectal cancer, and prostate cancer (4). In contrast, low IGF levels may be associated with an increased risk of insulin resistance and type II diabetes (5), ischaemic heart disease (6), and cognitive decline (7). Given the potential role of IGFs for a wide range of different age-related diseases, it is important to know whether environ- mental determinants may modify adult IGF-I levels. In particular, it has been suggested that adult levels may be influenced or ‘‘programmed’’ by intrauterine or postnatal growth (8). Observational studies that examine early life growth measures are confounded by childhood and adult social circumstances. This makes it hard to distinguish whether associations are related to a genuine critical or sensitive period effect (9). Long-term follow-up of randomized trials provides a unique opportunity to examine whether an early life intervention has a long-term influence, unconfound- ed by other factors. This approach has already been used to test the ‘‘fetal origins’’ hypothesis in relation to high blood pressure, insulin resistance, and markers of atherosclerosis (10-12). The aim of this study was to test whether milk supplementation given to mothers during pregnancy and to their offspring postnatally may have a long-term influence on adult IGF-I, IGFBP-3, and the molar ratio. Materials and Methods The Barry Caerphilly Growth study is the follow-up of an original randomized controlled trial involving pregnant mothers and their offspring, which continued until the age of 5 years. Pregnant mothers, between 1972 and 1974, were recruited through primary care from two towns in Barry and Caerphilly, in South Wales. They were randomized by an independent observer to either a ‘‘supplemented’’ or control group using random number tables. The supplemented group was provided with milk tokens throughout pregnancy and subsequently for their child (index case) until the age of 5 years, which entitled them to additional free milk delivered by their milkman. The women completed a questionnaire during Received 12/15/04; revised 1/10/05; accepted 2/2/05. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: No conflict of interest. YBS had full access to all the data in the study and had final responsibility for the decision to submit for publication. Contributors: DPD was involved in the design and running of the original Barry Caerphilly Growth trial. GDS, YBS, and DPD conceived the follow-up study. YBS, GDS, DPD, and A McC designed and A McC ran the follow-up study with supervision from YBS, GDS, and DPD. JH and PS supervised and undertook the laboratory assays. YBS undertook the statistical analysis and drafted the first version of the article. All authors commented and helped redraft the final version. Requests for reprints: Yoav Ben-Shlomo, Department of Social Medicine, Canynge Hall, University of Bristol, Whiteladies Road, Bristol BS8 2PR, United Kingdom. Phone: 0044-117-928-7206; Fax: 0044-117-928-7325. E-mail: y.ben-shlomo@bristol.ac.uk Copyright D 2005 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 1336 Cancer Epidemiol Biomarkers Prev 2005;14(5). May 2005 on June 20, 2017. © 2005 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from