Reports

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85th Annual Meeting of the Canadian Paediatric Society

Victoria, British Columbia / June 24-28, 2008

Neurodevelopmental Outcomes and IDA

Dr. Patricia Parkin, Associate Professor of Paediatrics, University of Toronto, Ontario, reviewed current research on the status of IDA. She examined evidence for the neurodevelopmental consequences of IDA, synthesized in two systematic reviews (J Nutr 2001;131:649S, Cochrane Database of Systematic Reviews 2001). One approach to this question is the use of longitudinal studies. In seven studies of children under 2 years old at entry and evaluated at age 4 to 14, global assessment techniques such as IQ tests and developmental assessment all indicated that children with IDA were at a developmental disadvantage at follow-up. However, Dr. Parkin questioned whether covariates such as socioeconomic variables were adequately controlled for in these studies. Short-term trials in which children were given supplementary iron have been conducted. There were five such randomized, controlled trials (RCTs) of five to 11 days duration in a total of 180 children, none of which demonstrated any treatment benefit. The short period of these trials may not have been adequate to demonstrate an effect on development, she noted. Of two longer-term RCTs, one did show a benefit using the Bayley screen. The question in this case is whether infant developmental assessments are sufficiently sensitive to predict outcomes, remarked Dr. Parkin. Six of eight studies that treated children older than 2 years of age for four to 16 weeks, then followed their development, showed a treatment benefit. Anemic children had poorer school achievement and cognition. They tended to catch up in cognition with treatment, although not in school achievement.

Another approach to the question of the relationship between IDA and neurodevelopmental outcomes is preventive treatment of healthy infants. However, in three RCTs comparing untreated healthy children and supplemented healthy children aged 2 to 18 months, with a treatment duration of six to 18 months, the treated infants enjoyed only small, transient benefits, reported Dr. Parkin. Data published since the systematic reviews, however, have demonstrated a benefit from this approach. Lozoff (Pediatrics 2003;112:846-54) examined the effect of iron supplementation in a study of over 1600 healthy infants in Chile. At 12 months, IDA was seen in 3.1% of supplemented children compared to 22.6% of those without supplementation. Although no differences were seen in global test scores, unsupplemented children processed information more slowly, and were less likely to show positive affect, interact socially or check their caregivers’ reactions. “I think this is one of the strongest studies to date,” Dr. Parkin commented.

It has been suggested that there is an association between IDA and stroke. In an attempt to quantify this link, Dr. Parkin’s group conducted a study comparing 15 children aged 12 to 38 months who had suffered a stroke in the absence of known risk factors, with 143 controls. After controlling for platelet count, the odds ratio between groups was 10 (95% CI, 3-33). “We concluded that previously healthy children with strokes are 10 times more likely to have IDA than healthy children without strokes,” she said. “Children with IDA accounted for more than half of all stroke cases of children without an underlying illness.” Dr. Parkin also presented new data showing that microcytic anemia is strongly associated with stroke when other known risk factors are absent (Pediatics 2007;120:1053-7). Overall, she concluded that the evidence for a link between IDA, neurodevelopmental delay and stroke is “very supportive, but not conclusive.”

Definition and Measurement of IDA

The National Health and Nutrition Examination Surveys (NHANES) have traditionally used the ferritin model (two of three abnormal values of ferritin, transferrin saturation and erythrocyte protoporphyrin). They have recently introduced the Body Store model, or R/F ratio, which is the ratio of serum transferrin receptor to ferritin. However, Dr. Parkin commented that the validity of this test is controversial, and there is doubt about whether physicians would be willing to use this test. A paper by Guyatt (J Gen Intern Med 1992;7:145-53), although conducted on adults, clearly shows the superiority of serum ferritin at predicting iron deficiency, with very good sensitivity and specificity. With the caveat that results should be interpreted differently for patients with inflammatory or liver disease, the researchers concluded that serum ferritin is the only blood test that should be used for diagnosis of IDA. The likelihood ratio for this test at a serum level of <u><</u>15 µg/L was 51.85 (95% CI, 41.53-62.27). Dr. Parkin recommended that the values for a diagnosis of clinically significant IDA should be Hb <110 g/L, ferritin <10 µ/L, mean cell volume <70 femtolitres (fL).

A meta-analysis of the diagnostic value of clinical pallor (conjunctival, palmar and nail bed) in anemia found that the rate of false positives and negatives was unacceptably high (BMC Pediatrics 2005;5:46). Dr. Parkin did not suggest that clinicians entirely discard this tool, but cautioned that they should be aware of its limitations.

Clinical predictors of IDA and iron deficiency include toddlers who are overweight and not in daycare and bottle-feeding in second and third years of life. Dr. Parkin’s group found that beyond 16 months, there was a steady increase in iron depletion risk among bottle-feeders, and a steady decline in risk among cup-feeders. Bottle-feeders also consumed more milk per day.

Screening

Dr. Parkin introduced NutriSTEP, a new validated screening tool developed at the University of Guelph, Ontario, for pre-schoolers. “This tool may prove to be an important screening tool to identify children at high risk for nutritional disorders,” she told listeners. Yet screening has not yet proved effective for detection of iron deficiency. One of the problems, according to Dr. Parkin, is timing. “The risk factors in the first year of life may be very different from the risk factors in the second and third years of life, and so trying to identify a good time for screening may in fact be quite challenging.” There have been no controlled studies of screening, but cross-sectional studies have revealed difficulties. A study of 1358 children aged between 9 and 36 months concluded that routine screening was “problematic” because of a high rate of anemia, poor follow-up rates, and a high spontaneous resolution rate (Arch Pediatr Adolesc Med 2001;155:366-71). Most organizations do not recommend routine screening, although some recommend selective screening for high-risk individuals. For example, the Joint Working Group: Canadian Paediatric Society, Dietitians of Canada and Health Canada (2005) suggest that if parents do not follow their nutrition guidelines, screening for anemia, followed by supplementation if necessary, should be carried out at 6 to 8 months of age.

Modifiable Risk Factors

Primary prevention is an important strategy, Dr. Parkin stated. Her group is currently conducting a controlled study of educational intervention focused on diet in the second and third year of life. Specific topics include optimal milk intake and potential hazards of prolonged bottle-feeding. Bottle-weaning at or before 15 months will be recommended, and a sip cup will be provided. Primary outcome will be iron depletion as indicated by ferritin <10 µg/L.

Dr. Stanley H. Zlotkin, Professor of Pediatrics, Nutritional Sciences and Public Health Sciences, University of Toronto, agreed. “The one thing that every pediatrician should know is that variety is certainly the key to the prevention of any nutrient deficiencies.” However, dietary variety is typically limited in the first two years of life. In the absence of dietary diversification, possible remedies include fortification, as in infant cereals and breakfast cereals, and supplementation, e.g. iron drops or syrups. He noted that in Canada, the incidence of anemia is low (about 5% in Toronto) compared to rural areas, where it may be as high as 40%, and Third World regions, with rates in the 60% to 70% range. Most of these differences, he added, are due to fortification.

Conditions affecting iron status include intrauterine growth restriction, premature birth and early cord clamping, all of which may result in low initial stores of iron. Depletion of iron stores may result from exclusive breast-feeding prolonged beyond six months, and from inappropriate use of whole cow’s milk, as mammalian milk generally has low concentrations of iron. Furthermore, consumption of cow’s milk can lead to some enteric blood loss. Inappropriate timing of introduction and/or type of complementary foods, e.g. home-prepared non-fortified foods, may reduce the availability of iron. Frequent infections may also lead to poor iron status due to anorexia, decreased erythropoiesis or enteric bleeding, in the case of some parasitic infections.

Babies are born with sufficient iron stores for the first four to six months of life, noted Dr. Zlotkin. Accordingly, exclusive breast-feeding or the use of an iron-fortified formula is sufficient initially. However, dietary sources of iron become critical to support the rapid rate of erythropoiesis by 6 months of age. The WHO and the Canadian Paediatric Society recommend the introduction of iron-rich complementary foods by this age, as well as foods containing ascorbic acid, to enhance iron absorption. In reality, the average age at which supplementary formula is introduced in Canada is a little over 2 months.

Fortified cereals are by far the richest sources of iron in the Canadian infant’s diet. Few common unfortified foods contain sufficient iron to easily maintain the recommended daily allowances of 11 mg/day at 7 to 12 months and 7 mg/day at 1 to 3 years. Dr. Zlotkin confirmed that fortified foods are the best choice for maintaining iron in infants; should treatment for anemia be necessary, the entire recommended daily dose can be given once a day, rather than the standard thrice-daily dosing.

Summarizing, Dr. Zlotkin recommended exclusive breast-feeding for the first six months. “When not breast-feeding, use iron-fortified formulas until 9 to 12 months of age.” Iron deficiency can be prevented by providing iron-containing or iron-fortified foods, such as meat and fortified cereals. Milk intake should be limited. Once-daily ferrous sulphate or fumarate can be given to treat anemia.