A recently published antioxidant vitamin and mineral supplement study was so understated, that the significance of what the researchers were doing and found was largely missed. But it could provide parents of babies with Down syndrome information to help protect them from questionable, costly and potentially harmful products promoted with promises that far exceed the science. There’s a valuable take-home message in this story for all of us, too.
Children with Down syndrome — a genetic condition also known as Trisomy 21 for the extra copy of the 21st chromosome — have a multitude of special medical issues and developmental needs, making thoughtful, compassionate and scientifically-sound guidance essential for parents and families. Understandably, parents are interested in interventions that promise to improve outcomes for their children. This can leave them especially vulnerable to alternative modalities that appear to offer help that mainstream medicine cannot. Special nutritional supplements are one of the most heavily promoted alternative modalities, according to Dr. William I. Cohen, M.D., writing for the Down Syndrome Medical Interest Group charity. These products typically claim to “improve intellectual function, alter physical or facial appearance, decrease infections and generally improve the well-being of the child.” And much more. Back in the 1960s, Dr. Henry Turkel, M .D., introduced a mixture of 48 ingredients he said would improve the intellect and physical features of Down’s syndrome children. Even forty years later, no double-blind trial has ever tested his formula. But in 1978, Dr. Ruth Harrell, M.D., and colleagues published, in the Proceedings of the National Academy of Sciences, a study of a complex vitamin and mineral combination in 16 children with Down syndrome. They suggested the genetotrophic disease hypothesis — “diseases in which the genetic pattern of the afflicted individual requires an augmented supply of one or more nutrients such that when these nutrients are adequately supplied the disease is ameliorated.” Their study made the extraordinary claim that in just four months the five children who’d received supplements “increased their average IQ by 5-9.6 points, depending on the investigator, whereas the 11 subjects given placebos showed negligible change.” These statements would lead to the marketing of popular supplements for children and adults with Down syndrome, which have been publicized on television, the internet and through parent groups. MSB Plus, made by a Canadian company Nutri-Chem Labs, and the more widely-known NuTriVene-D, marketed by International Nutrition, Inc. in Middle River, Maryland are similar formulas of vitamins, minerals and anti-oxidants, along with digestive enzymes and amino acids. International Nutrition refers to NuTriVene-D as “Targeted Nutrition Intervention.” Two doctors: a naturopath, Robert Thiel, Ph.D., and Dr. Lawrence Leichtman, M.D., are associated with International Nutrition and have put forth the medical theories behind their supplement. It contains 18 vitamins; 9 minerals; and 17 amino acids, flavonoids, and digestive enzymes. Dr. Thiel suggested in a 2005 issue of Medical Hypotheses, that oxidative stress causes brain damage and cognitive deterioration in Down’s syndrome which leads to dementia at younger ages compared to people without Down syndrome. Based on in vitro and rodent tests, he speculated that antioxidant “essential nutrients such as folate, vitamin B6, vitamin C, vitamin E, selenium, and zinc, as well as alpha-lipoic acid and carnosine may possibly be partially preventive” and if supplements are begun in early infancy or prenatally, the onset of dementia could be prevented or delayed. He specifically noted, however, that alpha-lipoic acid (which NuTriVene-D contains) may not be safe to use in those with Down syndrome as it depletes vitamin B6, raising risks for seizures and neuropathies. In a letter to physicians on the principles behind the use of TNI and therapeutic guidelines, Dr. Leichtman stated: “First of all, it isn’t snake oil. The TNI formulation, NuTriVene-D, was designed originally... based on the work of Henry Turkel, M.D., carried out from the 1940s to the 1970s, in which he used a formulation based on some educated guesses.” Since then, he said, more about the genetics of Trisomy 21 has been learned and why antioxidant vitamins are needed to prevent, delay or even reverse cognitive decline: The zinc/copper enzyme Super Oxide Dismutase (SOD) is well known to be over-functioning in Trisomy 21. It normally is the first step in metabolic conversion of superoxide. Superoxide is a free radical that may cause problems to both the cell membrane and the cell nucleus. SOD produces hydrogen peroxide which two other (not on chromosome 21) gene products, catalase and glutathione peroxidase, convert to nontoxic products. Neither catalase nor glutathione peroxidase are sufficiently upregulated to handle the excess hydrogen peroxide. Hydrogen peroxide is a potent oxidizer which on the cell surface produces lipid peroxidation and compromises the cell membrane, particularly in the presence of excess iron (Fenton reaction). At the organelle and nuclear level, hydrogen peroxide causes damage and stimulates apoptosis (“programmed" death) of the cell. In a study by de Haan et al in Human Molecular Genetics, it was found that the ratio of SOD to glutathione peroxidase led to increased hydrogen peroxide in the cells and cellular senescence. In a study from Nature (1995), Busciglio and Yankner demonstrated that fetal neuronal cells from non-DS and DS [Down syndrome] fetuses grew differently. The non-DS cells grew in culture in an orderly fashion but the DS cells grew for only 72 hours and began dying. When a second DS culture was incubated with powerful antioxidants these cells began growing normally. While not direct evidence of the role of reactive oxygen species in the production of symptomotology of DS it certainly provides useful information and a starting place for future studies. This is the logic behind using additional antioxidants in DS. Supplement promoters commonly claim that ‘infants with Down syndrome become retarded largely because of the overexpression of’ superoxide dismutase, and that supplements can compensate for this....The theory claims that antioxidant supplements may prevent and even reverse damage by peroxidation. However, no evidence of this oxidative damage has been found in living humans with Down syndrome, and the possibility of adverse effects from long-term use of large amounts of antioxidants has received little attention. While these nutritional supplements are marketed as being specifically designed for people with Down syndrome, he said, there is no published research proving that children with Down syndrome have any consistent nutrient deficiencies to correct. Nor does TNI recommend testing for vitamin and nutrient levels before using the supplements, said Dr. Leshin. A long bibliography of studies appears at the end of Dr. Leightman’s article, seeming to support his paper — except few turn out to be studies related to nutritional supplements. Of nine papers that examined supplements in Down syndrome children, one is the Harrell study, which was not double-blind. The remaining randomized, double-blind, placebo-controlled clinical trials had attempted, unsuccessfully, to replicate Harrell's findings, and concluded that vitamin supplements, even at high doses, is ineffective: Pediatrics (1983) — A double-blind, case-control study of 20 children with Down syndrome (5-13 years) randomly assigned to vitamin and mineral supplementation or placebo. After 8 months, they reported: “No significant group differences or suggestive trends were found in any tested area of development or behavior, including intelligence (IQ), school achievement, speech and language, and neuromotor function. No group differences in appearance, growth, or health were seen.” Am J Ment Defic (1983) — A double-blind clinical trial of megadose multi-vitamin/mineral supplement in 24 children with Down syndrome (6-17 years) with a matching control group of 23 who received a placebo. After 4 months, they concluded no differences were found in any measures as a result of supplementation (IQ using Stanford-Binet Intelligence Scale, vision, visual-motor integration (using Beery-Buktenica Developmental Form Sequence) and weekly checks of behavioral changes. Journal of Pediatrics (1984) — A double-blind clinical trial of megadoses of vitamins and minerals in 56 school-age children with Down syndrome evaluated after 4 and 8 months with a battery of psychological tests, physical examinations and blood tests. They found no significant difference in intelligence and other test scores between the children that received the vitamins and the placebo. J Ment Defic Res (1985) — A double-blind, placebo-controlled clinical trial of vitamin B6 among 19 babies with Down syndrome, beginning at 8 weeks of age until 3 years of age. It concluded: “ no statistically significant differences were found between the two groups in mental age, height, weight, cranial circumference or tongue protrusion” Nutr Research (1988) — A randomized, placebo-controlled trial of 50 children with Down syndrome (5-16 years) using megadoses of vitamins and minerals in half and placebo in remaining half. Blood was analyzed for Zn, Cu, folate, vitamin A, carotene, B6, retinol binding protein, and RBC transketolase and glutathione reductase and serum proteins at 4 and 8 months. No malnutrition was evident in the mean values for either group when they enrolled, and “no change in mental status was detected between the two groups at the end of the study.” Dev Med Child Neurol (1989) — A randomized, placebo-controlled high-dosage multivitamin and mineral supplement trial on 15 children with Down syndrome (ages 7.5 to 63 months) concluded: “Active treatment was associated with decreased developmental progress, and various side-effects were reported by the parents. The only suggestions of benefit were parents' observations of improvement in general appearance and skin freshness.” Journal Nutr Sci Vitaminol (1989) — Doctors at the University of Nebraska Medical Center in Omaha documented their efforts to replicate Harrell’s research. They found no significant differences between active treatment groups and control groups at the end of the study. Also included in Dr. Leichtman’s bibliography is a 1989 review in Exceptional Children that concluded “subsequent studies [since Harrell], focusing exclusively on children with Down syndrome and using less flawed research designs, have demonstrated that vitamin therapy is not useful for members of this population.” Dr. Leshin did a similar examination of the lengthy bibliographies appended to many articles promoting TNI, and found “many of the articles have little to do with nutritional supplementation, and of those that do, the vast majority actually conclude that supplementation is not beneficial. Such lists can be very misleading to the parent with no medical background or a physician who lacks the time to investigate the actual articles or even read the abstracts.” He also wrote a succinct review of the claims and science of nutritional supplements for Down Syndrome for Quackwatch. Despite the lack of clinical evidence to support antioxidant vitamin and nutrient supplements in children with Down syndrome, he said, claims of benefits have reached the extreme — even promising normalization of cognition, muscle tone, sleep habits, speech, visual acuity and facial features. One clinic on the internet even claimed the supplements “turns the Down syndrome patient into a normal, healthy individual,” he said. Most of the public would never imagine the intensity of some of the promises and testimonials parents encounter. The passionate anecdotal reports from other parents, who strongly believe in the supplements, are especially prolific online. The pressures on parents to buy supplements “tends to prey mostly on the parents of infants and young children with Down syndrome, who are most vulnerable to the suggestion that they might be bad or neglectful parents if they don’t give their chidren these products,” Dr. Leshin wrote. Down’s is typically misrepresented, leaving parents to believe that it’s a progressive degenerative disease that if left untreated leads to poor health, mental retardation and ultimately premature death, he said. “The outlook for people with Down syndrome is not bleak, and each generation has had a healthier, longer lifespan. There is no evidence that any nutritional supplement enhances the prognosis.” In 2001, the American Academy of Pediatrics Committee on Genetics issued its guidelines for pediatricians caring for children with Down syndrome and recommended cautioning parents about alternative nutritional modalities. The National Down Syndrome Society also advises parents: The administration of the vitamin related therapies — e.g. the vitamin/mineral/amino acid/hormone/enzyme combination, has not been shown to be of benefit in a controlled trial, that the rationale advanced for these therapies is unproven, and that the previous use of these therapies has not produced any scientifically validated significant results. Moreover, the long term effects of chronic administration of many of the ingredients in these preparations are unknown. Despite the large sums of money which concerned parents have spent for such treatments in the hope that the conditions of their child with Down syndrome would be bettered, there is no evidence that any such benefit has been produced. This background helps to understand why these pediatricians, biochemists, pediatric epidemiologists and researchers were inspired to do this new study, and why they designed it as they did. They said that anti-oxidant vitamin and mineral supplements continue to be widely used in children with Downs syndrome the United States and Europe “as a result of vitamin marketing that claims substantial benefits for these children.” Since no randomized, double-blind, placebo-controlled clinical trial of antioxidant vitamins and mineral supplementation in children with Down syndrome has yet to find any effect on cognitive function or development, they did a carefully conducted and designed study to try and answer any lingering questions for parents. Their trial is the largest to date and had sufficient numbers of participants to be able to detect clinically important differences on these cognitive and developmental measures, they said. They specifically studied the antioxidant vitamins and folinic acid that form the basis of the claims that these supplements offer cognitive benefits. Between May 2002 and February 2004, 156 babies with Down’s syndrome, all under the age of 7 months, were enrolled in this clinical trial in Britain. They were randomized to receive daily antioxidants (selenium, zinc, vitamin A, vitamin E, and vitamin C), or folinic acid (an active metabolite of folic acid), both, or a placebo. The doses were 100% of the recommended daily allowance for vitamin E, zinc and selenium and 200% the FDA for vitamin C and folinic acid, all in excess of what they received in their regular diets. The doses were increased at one year of age as the babies grew. The researchers said they hesitated to use higher doses on babies because data on safety of higher doses for young children were lacking and high doses of antioxidants like vitamin C can have pro-oxidant properties. Compliance was good and the investigators monitored and verified doses given with phone calls and office visits, as well as laboratory vitamin E blood and urine level measurements at one year of age. Seventeen babies didn’t complete the study (three died, three developed leukemia and four moved out of the country). The results of this study were published in the online edition of the British Medical Journal. It “found no evidence that either the antioxidants or the folinic acid supplements used in this trial had any effect on psychomotor development or language acquisition in children with Down’s syndrome.” There were no statistically significant differences between those receiving the supplements and the placebo in any of the measures. The measures all showed insignificant (all within random error or chance) differences on either side of null. To see if the supplements might be having a subclinical effect that might suggest higher doses could be beneficial, they examined biomarkers of oxidative stress in blood and urine (blood glutathione peroxidase and superoxide dismutase and urinary isoprostane) in accordance with the principles behind the use of antioxidants according to the supplement companies, but found no affect on oxidative stress among any of the groups. Besides the cost of commercial nutritional supplements and the increase in vomiting seen in infants taking the antioxidants, they wrote, the long-term safety of antioxidant vitamins has come into question in recent studies which suggest they may increase mortality in a range of conditions. To date there is no evidence to support the use of antioxidant or folinic acid supplements in children with Down syndrome, they concluded. “Parents who choose to give supplements to their children need to weigh their hope of unproved benefits against potential adverse effects from high dose, prolonged supplementation,” they said. As Dr. Leshin cautioned parents: “No matter how alluring the theories are, or how convincing the anecdotal evidence may seem, it’s important to remember that these theories have not been proven, past experience with similar claims have been proven unhelpful, and the currently promoted formulas have not been scientifically proven safe or effective.”
Background
Dr. Len Leshin, M.D., a pediatrician and member of the Down Syndrome Medical Interest Group, as well as the father of a boy with Down syndrome, put it more simply: 
The costs of these supplements are not insignificant, either, especially for young parents already faced with considerable medical expenses. According to its website, NuTriVene-D costs $74 for 150-grams of power and $78 for a single bottle of capsules that are a one-month supply for children. The company also recommends a protocol regimen of additional supplements that includes ginkgo biloba, probiotics and other controversial substances. The total number of pills parents are urged to give their child each day, and the costs for parents, are considerable.
The babies’ mental developments were assessed 18 months after enrollment by trained assessors using the Griffiths mental developmental scale. Parents also recorded major motor development milestones, such as sitting without support and walking. Language development was examined using the MacArthur communicative development inventory questionnaire. The study remained blinded throughout and most of the parents didn’t feel able to even guess at what their babies had been receiving and the few that ventured a guess did no better than chance.
Findings
© 2008 Sandy Szwarc
For parents, caring for the medical issues of babies and children with Down syndrome can feel overwhelming, but there are numerous resources and many things that can help ensure their little ones have the best outcomes. The Down Syndrome Medical Interest Group, an international nonprofit group of clinicians caring for children with Down syndrome, developed a medical check list for each child’s age and medical issue, based on the best science to date, that can be used by doctors, geneticists, nurses and other care givers, physical therapists, speech-language pathologists, audiologists and parents. The National Down Syndrome Society, for example, also has free healthcare guidelines and a New and Expectant Parent Guide.