Soy-based formulas and phyto-oestrogens: a safety profile

Phyto-oestrogens are non-steroidal plant-derived compounds that possess oestrogenic activity and act as selective oestrogen receptor modulators (SERMs). Among the dietary oestrogens, the isoflavone class enjoy a wide-spread distribution in most of the members of the Leguminosae family, including such prominent high-content representatives as soybean. Phyto-oestrogen research has grown rapidly in recent years owing to epidemiological studies suggesting that diets rich in soy may be associated with potential health benefits. There is a paucity of data on endocrine effects of soy phytochemicals during infancy, the most sensitive period of life for the induction of toxicity. The safety of isoflavones in infant formulas has been questioned recently owing to reports of possible hormonal effects. Infants fed soy formula receive high levels of phyto-oestrogens in the form of isoflavones (genistein, daidzein and their glycosides). To date, no adverse effects of short- or long-term use of soy proteins have been observed in humans and exposure to soy-based infant formulas does not appear to lead to different reproductive outcomes than exposure to cow milk formulas. Soy formula seems to be a safe feeding option for most infants. Nevertheless, much closer studies in experimental animals and human populations exposed to phyto-oestrogen-containing products, and particularly soy-based infant formulas, are necessary.     

Soy infant formula and phytoestrogens

Soy infant formula contains high levels of the isoflavones, genistein and daidzein, which are commonly referred to as phytoestrogens. These are non-steroidal chemicals with structural similarities to estrogen. Infants consuming soy formula have high levels of circulating isoflavones. These are an order of magnitude greater than the levels of isoflavones which have been shown to produce physiological effects in adult women consuming a high soy diet. There is conflicting evidence about the risks and benefits of soy phytoestrogens, with research presenting a contradictory picture. Some reviewers suggest that early exposure to soy may prevent cancer and heart disease. However, there is very little research on the effects of consumption of soy phytoestrogens by human neonates. Against this generally positive view there is an increasing number of recent reports that suggest that in experimental animals, phytoestrogens have adverse effects with respect to carcinogenesis, reproductive function, immune function, and thyroid disease. Despite the absence of adequate scientific research that quantifies the level of risk to infants, most would argue for a precautionary approach to be taken in situations where there are potential developmental effects from the consumption of pharmacologically active compounds in infancy and childhood.     

Immune status of infants fed soy-based formulas with or without added nucleotides for 1 year: part 1: vaccine responses, and morbidity

BACKGROUND: Immunologic development of soy-fed infants has not been extensively studied. Early studies of soy flour-based formulas showed decreased immunoglobulin production when soy protein intake was limited. However, there were no significant differences in rotavirus vaccine responses between breast-fed and soy protein isolate-based formula-fed infants. Nucleotides added to milk-based formula benefit infant immune status, but reports of the immunologic effects of adding nucleotides to soy-based formula are not available. This study evaluated immune status and morbidity of infants fed soy protein isolate formulas with and without added nucleotides for 1 year. METHODS: Newborn, term infants enrolled in a masked 12-month feeding trial were assigned randomly to groups fed soy formula with or without added nucleotides (n = 94, n = 92). A nonrandomized human milk/formula cohort (n = 81) was concurrently enrolled. Recommended immunizations were administered at 2, 4, and 6 months. Immune status was determined from antibody responses to Haemophilus influenzae type b, tetanus, diphtheria, and poliovirus vaccines at 6, 7, and 12 months. Parents and physicians reported morbidity data. RESULTS: All vaccine responses were within normal ranges. No response differences were observed between infants fed soy formula and those fed nucleotide-supplemented soy. However, antibody to H. influenzae type b at 7 and 12 months was higher in infants fed nucleotide-supplemented soy than in infants fed human milk/formula ( P = 0.007, P = 0.008, respectively). Human milk/formula-fed infants had higher poliovirus neutralizing antibody at 12 months than did soy-fed infants ( P = 0.016). Morbidity analyses showed that only physician-reported diarrhea was different among groups (groups fed human milk/formula had less diarrhea than did soy groups, P = 0.011). CONCLUSIONS: Term infants fed soy protein isolate-based formulas have normal immune development as measured by antibody responses to childhood immunizations.     

Phytoestrogens: a review of recent findings

Phytoestrogens have been investigated at the epidemiological, clinical and molecular levels to determine their potential health benefits. The two major groups of phytoestrogens, isoflavones and lignans, are abundant in soy products and flax respectively, but are also present in a variety of other foods. It is thought that these estrogen-like compounds may protect against chronic diseases, such as hormone-dependent cancers, cardiovascular disease and osteoporosis. Furthermore, phytoestrogens are used as a natural alternative to hormone replacement therapy and to reduce menopausal symptoms. Phytoestrogens have been shown to induce both estrogenic and anti-estrogenic effects but their biological relevance and potency have not been well characterized. In children, consumption of soy-based formulas and soy milk can lead to high levels of exposure to phytoestrogens with only limited data available concerning potential benefits or adverse effects. Phytoestrogens are considered good candidates for use in natural therapies and as chemopreventive agents in adults. Safe and efficacious levels have yet to be established.     

Use of soy protein-based formulas in infant feeding

Soy protein-based formulas have been available for almost 100 years. Since the first use of soy formula as a milk substitute for an infant unable to tolerate a cow milk protein-based formula, the formulation has changed to the current soy protein isolate. Despite very limited indications for its use, soy protein-based formulas in the United States may account for nearly 25% of the formula market. This report reviews the limited indications and contraindications of soy formulas. It will also review the potential harmful effects of soy protein-based formulas and the phytoestrogens contained in these formulas.     

Soy as an endocrine disruptor: cause for caution?

Endocrine disrupting compounds (EDCs) alter the function of the endocrine system and consequently cause adverse health effects. Phytoestrogens, natural plant compounds abundantly found in soy and soy products, behave as weak estrogen mimics or as antiestrogens. They are considered to be EDCs, and have some beneficial effects on health, including reducing the risk of breast cancer and improving metabolic parameters. However, the supporting evidence that consumption of phytoestrogens is beneficial is indirect and inconsistent. Lifetime exposure to estrogenic substances, especially during critical periods of development, has been associated with formation of malignancies and several anomalies of the reproductive systems. Phytoestrogen consumption in infants, through soy-based formulas, is of particular concern. Prospective epidemiological studies for the evaluation of the effect of phytoestrogens alone, and in combination with other estrogenic chemicals, are lacking, yet possible adverse effects should not be taken lightly.     

Immune status of infants fed soy-based formulas with or without added nucleotides for 1 year: part 2: immune cell populations

BACKGROUND: Infants fed a soy protein isolate-based formula have immunization responses similar to breast-fed infants. However, cellular aspects of the immunologic development of soy-fed infants have not been studied extensively. Nucleotides added to milk-based formula benefit infant immune status, but reports of the immunologic effects of adding nucleotides to soy-based formula are not available. This study examines immune cell populations of infants fed soy protein isolate formulas with and without added nucleotides for 1 year. METHODS: Newborn, term infants studied in a masked 12-month feeding trial were assigned randomly to soy formula groups with and without added nucleotides (n = 94, n = 92). A nonrandomized human milk/formula-fed cohort (n = 81), was concurrently enrolled. Blood samples were collected at 6, 7, and 12 months. Thirty-two immune cell populations were characterized using three-color flow cytometry. Cellular markers were chosen to assess general pediatric immune status, emphasizing maturation and activation of B, T, and NK lymphocytes. RESULTS: All cell populations, number and percentages, were within age-related normal ranges. The only significant difference found between soy formula and human milk/formula-fed infants was the percentage of CD57 + NK T cells at 12 months (human milk/formula > soy formula, P = 0.034). There were significant differences at some time points between human milk/formula-fed and nucleotide-supplemented soy formula-fed infants in populations of lymphocytes, eosinophils, total T, helper T, naive helper, memory/effector helper, CD57 - T, and CD11b + CD8 + NK cells. None of the cell populations differed between infants fed soy formula versus soy plus nucleotides. CONCLUSIONS: Infants fed this commercial soy formula demonstrated immune cell status similar to human milk/formula-fed infants, consistent with normal immune system development. The addition of nucleotides to soy formula did not significantly change specific individual immune cell populations but tended to increase numbers and percentages of T cells and decreased numbers and percentages of NK cells.     

Flavor experiences during formula feeding are related to preferences during childhood

As part of a program of research designed to investigate the long-term effects of early feeding experiences, the present study exploited the substantial flavor variation inherent in three classes of commercially available infant formulas and determined whether flavor preferences during childhood differed as a function of the class of formula (i.e., milk, soy, hydrolysate) that 4- to 5-year-old children were fed during their infancy. Age appropriate, game-like tasks that were fun for children and minimized the impact of language development were used to examine their preferences for a wide range of food-related odor qualities including infant formulas, as well as the flavor of milk-based and hydrolysate formulas and plain, sour- and bitter-flavored apple juices. Formula type influenced children's flavor preferences when tested several years after their last exposure to the formula. When compared to children who were fed milk-based formulas (n=27), children fed protein hydrolysate formulas (n=50) were more likely to prefer sour-flavored juices, as well as the odor and flavor of formulas, and less likely to make negative facial expressions during the taste tests. Those fed soy formulas (n=27) preferred the bitter-flavored apple juice. That the effects of differential formula feeding also modified children's food preferences is suggested by mothers' reports that children fed hydrolysate or soy formulas were significantly more likely to prefer broccoli than were those fed milk formulas. These data are consistent with the hypothesis that flavor experiences influence subsequent flavor preferences even several years following the early experience.     

Human lactoferrin supplementation of infant formulas increases thymidine incorporation into the DNA of rat crypt cells

Lactoferrin has been identified as the factor in human colostrum that accounts for the increased incorporation of thymidine into DNA in a rat crypt enterocyte bioassay. Commercially available infant formulas used in the refeeding of infants who have severe dietary intolerance associated with mucosal atrophy were tested in this bioassay. In contrast to human milk, no stimulation was observed with these formulas in the assay. All formulas inhibited basal thymidine incorporation. The degree of inhibition of the basal assay progressed from 14% with cow's-milk formula to 30% with soy-based formulas to 45% with hydrolyzed casein formulas. When the formulas were supplemented with lactoferrin to match the level of that in human milk, the result was a 35% relative increase in thymidine incorporation into DNA. The quantitative level of response was primarily influenced by the baseline inhibitions associated with the specific formulas. The most profound effect was observed with the hydrolyzed casein formula, when lactoferrin supplementation reversed the baseline inhibition but did not result in a response greater than that seen in control basal bioassays. The supplementation of infant formulas with lactoferrin improved the thymidine incorporation in rat crypt enterocytes; a response equivalent to that of human milk, however, would require a redesign of other formula components to reduce basal inhibition.     

Soy infant formula: is it that bad?

The objective of this study is to review the indications of soy infant formula (SIF). Structured review of publications is made available through standard search engines (Pubmed,…). The medical indications for SIF are limited to galactosaemia and hereditary lactase deficiency. In the treatment of cow’s milk allergy, SIF is used for economic reasons, as extensive hydrolysates are expensive. SIF is dissuaded mainly because of its phytooestrogen content. Isoflavone serum levels are much higher in SIF‐fed infants than in breastfed or cow milk formula–fed infants. Administration of pure isoflavones to animals causes decreased fertility, but clinically relevant adverse effects of SIF in infants are not reported. Conclusion: Soy infant formula remains an option for feeding of term born infants if breastfeeding is not possible and if standard infant formula is not tolerated.     

Widespread use of soy-based formula without clinical indications

OBJECTIVES: In view of reports of the growing popularity of soy-based formula for infants, we examined soy consumption and its possible overuse during early infancy in central Israel. METHODS: Mothers of 1,803 infants aged 2, 4, 6 and 12 months attending well-baby clinics participated in a telephone survey covering background data, rate, duration, and pattern of soy-based formula use and the reasons for its initiation. The reasons were grouped into those based on the recommendations of the medical personnel and those based on mothers' initiative, and evaluated according to infants' age at soy-based formula initiation (0 to 1, 2 to 4 and 5 to 12 months). The symptoms that prompted soy-based formula use were assessed quantitatively. RESULTS: The rate of soy-based formula use was 10.4% at 2 months and 31.5% at 12 months (P<0.001); 70.6%+/- 2.7% of the infants were given soy for>6 months. Regardless of infants' age, the role of the mothers in the decision to use soy-based formula was greater than that of the medical personnel, and increased significantly with age (chi for trend=0.018). A suspicion of cow's milk allergy was responsible for only 10.9% (7/64) of all soy initiations in infants aged 5 to 12 months. In all ages, occasional symptoms, mainly diarrhea (33.3%) and colic (19.8%), were the leading cause for recommending soy-based formula by medical personnel, whereas the personal preference without clinical justification was the leading cause among mothers. CONCLUSIONS: The use of soy-based formula in central Israel is extensive and continues for long periods, with rates far beyond clinical indications. Mothers play a greater role than medical personnel in the decision to initiate soy-based formula.     

Antigenicity of infant formulas: role of immature intestine on protein permeability

Preliminary studies of 25 infants fed casein hydrolysate, soy-based or milk-based formulas were undertaken to determine the importance of age with respect to the relative antigenicity of formula proteins. Infants fed casein hydrolysate for the first three months had lower antibody titers (hemagglutinins) to subsequent milk-based or soy-based proteins than those given these formulas since birth. The clinical implications with regard to atopy and gastrointestinal protein intolerance are discussed. Soy protein is at least as antigenic as milk protein and should be used with caution in prophylaxis against possible dietary antigen/antibody-related disease.     

Population-based study of the developmental outcome of children exposed to chloride-deficient infant formula

In 1978 and 1979 a large number of US children were fed chloride-deficient soy-based infant formula. A representative sample of such children was identified in a southern county through a mailing to the homes of 3639 first- and second-grade children in the public schools. Of the 2329 (64%) who responded, 56 reported use of deficient formula and were invited to have developmental testing by one of four study psychologists at their school. Of the 310 users of other soy formulas, 112 were selected for testing as matched controls on the basis of their sex, feeding history, age, birth weight, and socioeconomic status (as indicated by school attended). After exclusions and refusals, 42 children who used deficient formula and 66 control children were tested using the McCarthy Scales of Children's Abilities. Examiners were unaware of the child's history of formula use. The mean General Cognitive Index was 102.8 in those using deficient formula and 105.4 in controls. After adjustment for demographic differences the children who used chloride-deficient formula were found to average 4.9 points less than the controls (P = .04, 1-tailed). The largest difference was in the Quantitative subscale (P = .005). These data show a statistically significant although small effect of chloride-deficient formula on the long-term developmental outcome of exposed children; however, further study of these results is needed for full confirmation.     

The absorption of iron as supplements in infant cereal and infant formulas.

The absorption of iron was measured from isotopically tagged salts used in supplementing infant cereals and as the iron supplement in cow's milk and soy-based formulas. Iron as sodium iron pryophosphate and ferric orthophosphate were poorly absorbed from infant cereal (mean, smaller than 1.0%) and thus are not dependable sources of iron to meet the nutritional needs of infants. Reduced iron of very small particle size and ferrous sulfate when added to cereal was absorbed to a greater extent (mean, 4.0% and 2.7% respectively). For technical reasons, these two forms of iron had not been added to commercial cereal products because of discoloration, distribution problems of the iron in the product, and shortened shelf life. Therefore, at the present time, iron supplementation of infant cereals with sodium iron pyrophosphate, ferric orthophosphate, and reduced iron of large particle size does not provide a predictable and available source of iron to meet the needs of infants. Supplemental iron as ferrous sulfate in milk- and soy-based formulas gave a mean absorption of 3.4% and 5.4%. The iron supplements in these formulas can essentially meet the needs for dietary iron of healthy infants.     

Cow's milk versus soy-based formula in mild and moderate diarrhea: a randomized, controlled trial

We determined the efficacy of a soy-based formula compared with a cow's milk formula in infant re-feeding after acute diarrhea in a randomized controlled double-blind clinical trial. Infants 2–12 months of age with diarrhea of less than one week's duration and mild or moderate dehydration admitted to a pediatric hospital or in the practice of a participating primary care pediatrician were investigated. Seventy-six patients were enrolled and 73 completed the study; 39 infants received a soy-based formula (Isomil) and 34 received a cow's milk formula (SMA). Hospitalized patients were rehydrated with an oral glucose-electrolyte solution or an iv dextrose-sodium solution. Outpatients received oral glucose-electrolyte solution. In all patients, the study formula was commenced ad libitum during the first 24 h as determined by the attending pediatrician. The primary outcome measure was duration of diarrhea, defined as time to first normal stool, when subsequent stools were normal for a 24-h period. In addition, a predetermined secondary outcome was proportion of treatment failures, defined as the need to reinstitute clear fluids because of emesis, refusal to accept study formula, need for iv fluids due to negative fluid balance or diarrhea persisting beyond 7 days after enrollment. Total duration of diarrhea was significantly longer ( p = 0.03) in those receiving cow's milk (mean±SD 6.6 ± 4.2 days) than in those receiving soy-based formula (4.5 ± 3.6 days). Volume of formula intake and weight gain at 14 days were not different in the two groups. There were 18 treatment failures in the cow's milk formula recipients and 13 failures in the soy formula recipients ( p = 0.08). Soy-based formula significantly shortened the duaration of acute diarrhea in well nourished infants compared with cow's milk formula.     

Bone mineral metabolism in full-term infants fed human milk, cow milk-based, and soy-based formulas.

OBJECTIVE--To study the hypothesis that ingestion of a modified soy-based formula with an improved mineral suspension system may result in bone mineral content similar to that observed in infants fed human milk or cow milk-based formulas. DESIGN--Prospective, self-selected group of infants fed human milk randomized between the two formula-fed groups. SETTING--University-based hospital nursery and follow-up. PARTICIPANTS--Fifty-six normal, healthy, full-term infants, free of major malformations or disorders, including 17 infants fed human milk, 19 infants fed a cow milk-based formula, and 20 infants fed a soy protein formula were followed up to 6 months' postnatal age. The soy-based formula studied was modified to improve the suspendability of the minerals. INTERVENTIONS--Infants were fed human milk or the study formula for the first 4 months, at which time beikost was permitted. Infants fed human milk received vitamin supplementation to provide 400 IU of vitamin D per day. MEASUREMENTS--Anthropometric variables, serum calcium, magnesium, phosphorus, alkaline phosphatase, and parathyroid hormone levels were measured at enrollment, and at 8, 16, and 24 to 26 weeks' postnatal age. Bone mineral content at the distal third radius site was measured with single photon absorptiometry at these times. Growth in the infants did not differ significantly among the groups. There was no significant difference in serum calcium, magnesium, alkaline phosphatase, or parathyroid hormone concentrations among the infants during the study. Serum phosphorus was significantly lower at 8 weeks in the group fed human milk than in that fed the cow milk-based formula. Bone mineral content at 16 and 24 to 26 weeks was higher in the group fed the soy-based formula than in that fed human milk, and bone width was also higher at 16 weeks in the infants fed the soy-based formula. CONCLUSIONS--Improving the suspendability of the mineral system in the soy formula results in bone mineralization in infants fed the soy-based formula similar to that measured in infants fed human milk and cow milk-based formula. We suggest that the suspendability of the minerals used is an important variable in the interpretation of the effect of feedings on the bone mineral status of infants.     

Calcium and zinc retention from protein hydrolysate formulas in suckling rhesus monkeys.

OBJECTIVE--To determine calcium and zinc retention from infant formulas based on protein hydrolysates. DESIGN--Randomized, crossover. SETTING--Newborn nursery at the California Primate Research Center, Davis. PARTICIPANTS--Suckling infant rhesus monkeys (N = 7), aged 6 weeks at the beginning of the study. Each infant received seven different formulas. INTERVENTIONS--Fasted infant monkeys were fed diets radiolabeled with calcium 47 and zinc 65. Retention was determined by counting whole body radioactivity immediately after dosing and 7 days after dosing. MEASUREMENTS AND RESULTS--Retention of 47Ca was a mean (+/- SEM) of 79% +/- 4% from casein hydrolysate and 72% +/- 6% from the whey protein hydrolysate formula. Calcium 47 retention from hydrolysates based on whey protein/casein mixtures (a ratio of 60:40 or 50:50) was similar despite differences in protein sources and calcium content. Calcium 47 retention from two types of soy/collagen hydrolysate formula was found to be 68% +/- 6% and 59% +/- 4%, respectively, which is significantly lower than retention from casein hydrolysate. Considering the different calcium content of these formulas, total calcium retention from milk protein hydrolysates was higher than from soy/collagen products. Retention of 65Zn from milk protein hydrolysates ranged from 18% +/- 3% to 29% +/- 4% and was higher than that from soy/collagen formulas with a mean retention of 7% +/- 3% and 10% +/- 4%, respectively. Despite these differences in 65Zn retention, total zinc retention from all soy/collagen formulas was similar due to their higher zinc content. CONCLUSIONS--Calcium and zinc bioavailability was high from formulas based on milk protein hydrolysate, but was considerably lower from soy hydrolysates. Higher levels of calcium and zinc provided in soy hydrolysate formula compensated for the lower bioavailability and resulted in similar amounts of calcium and zinc retained.     

Growth of newborn, term infants fed soy formulas for 1 year.

Few studies have measured long-term growth in infants fed soy protein-based formulas. The effect of nucleotide (NT) supplementation of soy protein-based infant formulas on growth is unknown. Growth was therefore evaluated in healthy term infants fed a soy protein-based formula (SOY; n = 73), SOY with added NT (72 mg added NT/L) at human milk (HM) levels (SOYN, n = 73), or mixed feeding (MF, n = 67) in a randomized, masked, parallel 1-year feeding study. The MF group (a nonrandomized reference group) was fed HM exclusively from birth to 2 months of age followed by HM and/or a standard milk-based formula (Similac with Iron with no supplemental NTs) to 1 year of age. Results indicated that growth (weight, length, and head circumference) was normal and comparable among the three groups. All three groups had similar plasma albumin (at 2 months of age) and hemoglobin levels (at 12 months of age). Thus, this study demonstrated similar growth in the first year of life among infants fed MF feeding or soy formula with or without supplemental NTs.     

Rice protein-based infant formula: current status and future development

Rice is the world's leading staple cereal food and is the major source of protein for many parts of the world. Rice is among the first solid foods fed to infants in many cultures, in part because of its hypoallergenicity from lack of gluten. Nutritional quality of rice protein compares favorably with other cereal proteins including wheat, oat and barley. It is rich in methionine and cystine, although as is the case for other cereals, it is an incomplete protein source for human infants with lysine and threonine being the primary limiting amino acids. Fortification of rice proteins with these two limiting amino acids improves its protein quality. Rice protein-based infant formulas (RPF) were initially based on high protein rice flours, but more recently are based on rice protein concentrates, isolates or hydrolysates, fortified with lysine and threonine. Hypoallergenicity efficacy, particularly for hydrolyzed rice protein-based formulas, has been reported, and limited data indicated that rice protein based infant formula may provide potentially adequate alternative if standard milk- or soy protein-based formulas are not tolerated. Unlike the rice-protein based infant formula, rice beverage formulas made from rice flour are nutritionally inadequate for infants. Reports have indicated stunted growth in infants/children fed rice beverage formulas. Future development for the RPF include those based on genetically improved rice with high lysine and threonine content, supplementation with appropriate mineral and fat blend, and long-term clinical studies in infants to confirm its efficacy and safety.     

Role of a soy-based lactose-free formula in the outpatient management of diarrhea

The introduction of a soy-based, lactose-free formula during the acute phase of diarrheal illness in infants has been shown to reduce stool output and duration of diarrhea in hospitalized patients. In the United States, most infants with acute diarrhea are treated as outpatients. In the present study, infants with diarrhea who were treated as outpatients were randomly assigned to receive either a soy-based, lactose-free formula alternating with oral rehydration solution from the beginning of therapy ("early feeding") or oral rehydration solution alone for the first 24 hours of therapy, followed by a soy-based, lactose-free formula alternating with oral rehydration solution (control group). Twenty-nine infants were randomly assigned to the early-feeding group and 27 to the control group. Twenty-one (72%) of 29 in the early-feeding group resolved their diarrhea at the end of 48 hours of therapy compared with 12 (44%) of 27 in the group fed oral rehydration solution only (P = .02). It is concluded that the introduction of a soy-based, lactose-free formula from the beginning of therapy for acute diarrhea in children treated as outpatients is safe and may shorten duration of diarrhea while maintaining adequate caloric intake.