By Aline Andres, PhD
Soy formula has been in use since the 1960s and estimates are that 20 million Americans consumed this food at some point in their development. Currently, approximately 13% of formula-fed infants use soy formula.1 After an extensive review in 2008, the American Academy of Pediatrics concluded that soy formula produces normal growth and development.2 Similarly, in 2010, the U.S. National Toxicology Program (USNTP) concluded that there is minimal concern about the safety of soy formula.3 Nevertheless, soy formula has become controversial because infants are exposed to high levels of isoflavones. To help address this controversy and to answer a call by the USNTP for more data, investigators at the Arkansas Children’s Nutrition Center (ACNC) undertook the “Beginnings Study” in 2002.
Soy formula became controversial when some scientists revisited results of studies from the 1940s in sheep that ate clover which indicated that some chemical components similar to those in soy protein, known as isoflavones, impaired reproduction. Since then reports from several animal studies indicated that purified isoflavones produced adverse effects, including changes in sexual development with estrogen-like effects. It should be noted, however, that results of animal studies at the ACNC using the same soy protein used in soy formula, rather than purified isoflavones used in previous reports, showed no adverse effects. In fact, these results showed potential health benefits and no estrogen-like effects.4-6 These discrepant results sparked the ACNC to initiate the Beginnings Study in children, as well as more mechanistic studies in animals, to compare the side by side growth and development of children fed breast milk, milk formula or soy formula.
In the Beginnings Study, children are followed from the first weeks of life through puberty: 388 children were fed breast milk (BM, n = 138), milk formula (MF, n = 130), or soy formula (SF, n = 120). Developmental landmarks are carefully studied at ages 3, 6, and 9 months and at 1, 2, 3, 4, 5, 6, and 14 years using state of the art methodology. Growth/development, body composition (relative amounts of muscle, fat, and bone), organ development (physical/functional exams, ultrasonography), metabolism (fluid markers, metabolomics), brain development (standardized behavioral testing, EEG, MRI), and bone development/integrity (fluid markers, pQCT) are assessed. To date, data from 376 children have been processed through age 5 years.
This study found growth and development of children in all three groups to be within the reported national and international norms. These data include: growth curves,7organ development8,9 and performance on mental, psychomotor, language,10 and brain development.11-13
While birth weights and body composition do not differ at birth, body composition profiles differed significantly between diet groups over the first year of life. BM-fed infants accrue fat at greater rates than formula-fed infants and SF-fed infants have less fat and more lean body mass than BM-fed infants at 3-6 months. By age 1 year, body composition does not differ between groups.7 Ultrasonography showed the size, shape and structural integrity of primary sex organs (ovary, testes), as well as secondary sex organs (uterus, breast, prostate) were within the normal range at age 4 months (when maximal formula intake/weight occurs) and at age 5 years.8,9 MF-fed infants had significantly larger ovaries compared to BF- or SF-fed children at age 4 months. No other differences were noted at 4 months or 5 years.
The mental development index (MDI) was slightly better in BF compared to formula-fed infants, with no difference between MF and SF infants even after controlling for mother’s IQ, gestational length, education, total income and age, at ages 6 and 12 months. The psychomotor development index was also higher for BF infants compared to SF infants at age 6 months after controlling for socio-economic status, maternal age, maternal IQ, gestational age, child’s race, gender, birth weight, weight, head circumference and diet history. The Preschool Language Scale-3 (which evaluated the expressive communication and auditory comprehension) was lower in MF compared to BF and SF infants at age 3 and 6 months.10
In other studies of infant pigs fed BM, MF or SF, we have replicated many clinical results and showed that the three diet groups have organ specific gene expression profiles; meaning that each diet results in a different and specific pattern in which genes are turned on or off. These studies also showed that SF does not activate the estrogen receptor or display estrogenic properties or gene expression/metabolic profiles, which suggests that SF does not act as an estrogen.14-16
When considered together, these data demonstrate that: 1) early exposure to diet factors can influence the course of normal development; 2) SF-fed children perform as well as MF children, and 3) no evidence was found thus far to support concerns about adverse effects of SF feeding.
The Beginnings Study participants are now being recalled at age 14 years to assess growth, development, bone health, brain function and pubertal onset. Results will inform the long term effect of early infant feeding on overall health.
References
1. Badger TM, Gilchrist JM, Pivik RT, et al. The health implications of soy infant formula. AmJClinNutr. 2009;89(5):1668S-1672S.
2. Bhatia J, Greer F, American Academy of Pediatrics Committee on N. Use of soy protein-based formulas in infant feeding. Pediatrics. 2008;121(5):1062-1068.
3. McCarver G, Bhatia J, Chambers C, et al. NTP-CERHR expert panel report on the developmental toxicity of soy infant formula. Birth Defects Res B Dev Reprod Toxicol. 2011;92(5):421-468.
4. Ronis MJ, Gomez-Acevedo H, Blackburn ML, Cleves MA, Singhal R, Badger TM. Uterine responses to feeding soy protein isolate and treatment with 17beta-estradiol differ in ovariectomized female rats. Toxicol Appl Pharmacol. 2016;297:68-80.
5. Chen JR, Lazarenko OP, Blackburn ML, Badger TM, Ronis MJ. Soy protein isolate inhibits high-fat diet-induced senescence pathways in osteoblasts to maintain bone acquisition in male rats. Endocrinology. 2015;156(2):475-487.
6. Miousse IR, Sharma N, Blackburn M, et al. Feeding soy protein isolate and treatment with estradiol have different effects on mammary gland morphology and gene expression in weanling male and female rats. Physiol Genomics. 2013;45(22):1072-1083.
7. Andres A, Casey PH, Cleves MA, Badger TM. Body fat and bone mineral content of infants fed breast milk, cow's milk formula, or soy formula during the first year of life. J Pediatr. 2013;163(1):49-54.
8. Gilchrist JM, Moore MB, Andres A, Estroff JA, Badger TM. Ultrasonographic patterns of reproductive organs in infants fed soy formula: comparisons to infants fed breast milk and milk formula. JPediatr. 2010;156(2):215-220.
9. Andres A, Moore MB, Linam LE, Casey PH, Cleves MA, Badger TM. Compared with feeding infants breast milk or cow-milk formula, soy formula feeding does not affect subsequent reproductive organ size at 5 years of age. J Nutr. 2015;145(5):871-875.
10. Andres A, Cleves MA, Bellando JB, Pivik RT, Casey PH, Badger TM. Developmental status of 1-year-old infants fed breast milk, cow's milk formula, or soy formula. Pediatrics. 2012;129(6):1134-1140.
11. Pivik RT, Andres A, Bai S, et al. Infant Diet-Related Changes in Syllable Processing Between 4 and 5 Months: Implications for Developing Native Language Sensitivity. Dev Neuropsychol. 2016;41(4):215-230.
12. Pivik RT, Andres A, Tennal KB, Gu Y, Cleves MA, Badger TM. Infant diet, gender and the development of vagal tone stability during the first two years of life. Int J Psychophysiol. 2015;96(2):104-114.
13. Pivik RT, Andres A, Tennal KB, et al. Infant diet, gender and the normative development of vagal tone and heart period during the first two years of life. Int J Psychophysiol. 2013;90(3):311-320.
14. Chen JR, Lazarenko OP, Blackburn ML, Badeaux JV, Badger TM, Ronis MJ. Infant formula promotes bone growth in neonatal piglets by enhancing osteoblastogenesis through bone morphogenic protein signaling. J Nutr. 2009;139(10):1839-1847.
15. Ronis MJ, Chen Y, Shankar K, et al. Formula feeding alters hepatic gene expression signature, iron and cholesterol homeostasis in the neonatal pig. Physiol Genomics. 2011;43(23):1281-1293.
16. Yeruva L, Spencer NE, Saraf MK, et al. Formula diet alters small intestine morphology, microbial abundance and reduces VE-cadherin and IL-10 expression in neonatal porcine model. BMC Gastroenterol. 2016;16:40.
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