S.Nutrients 2013, 5 Figure 3. Forest plot for Tyrphostin AG 490 site effect size (Standard mean difference SMD and 95 confidence interval) of iodine on Win 63843 biological activity mental development of children, cohort prospective studies stratified by maternal iodine status. The studies are heterogeneous (Q = 34.85, df = 12, p < 0.001). The random effects model was therefore more appropriate. Estimated effect size of 0.1 in Oken's study not included as details for computation not reported.Man et al. [66-67] Man et al. [66-67] Pop et al. [68] Pop et al. [68] Smit et al. [69] Smit et al. [69] Smit et al. [69] Li et al. [70] Costeira et al. [71] Costeira et al. [71] Galan et al. [47] Murcia et al. [48] Pop et al. [72] Total (fixed effects) Total (random effects) -1.0 -0.5 0.0 0.5 1.0 1.5 Standardized Mean Difference (SMD) 2.0 2.3.4.4. Observational Cohort Prospective Studies Stratified by Newborn Iodine Status These studies include children with congenital hypothyroidism where the thyroid gland is not functioning at birth, generally defined in terms of high levels of thyroid stimulating hormone (TSH). This is normally detected during screening at birth in high-income regions. The maternal iodine status of the children was not reported in these studies. In high-income countries, children are usually treated immediately upon detection (Table 3). Control or comparison groups of children were iodine-sufficient siblings or mildly deficient children. Thus, the hypothesis of the researchers of these studies was that infants treated with the thyroid hormone after screening and confirmation of congenital hypothyroidism at birth would have a development similar to that of infants without congenital hypothyroidism. Exceptions to this statement include Choudhury et al. [75] from China, Riano Galan et al. [47] and Murcia et al. [48] from Spain, and Oken et al. [49] from the USA where deficient children were not treated. Using cord blood TSH to distinguish iodine-deficient vs. sufficient children (controls), Choudhury and coworkers [75] found that mildly deficient children of 7 months did not differ from controls (Mean 58.9 vs. 59.6; ns, d = 0.19) whereas severely deficient children did differ (Mean 57.5 vs. 59.6; p < 0.05, d = 0.66). At 13 months, using the Bayley, differences were found between controls and the severely deficient children (d = 0.74) [75]. Riano Galan et al. [47] found differences on the McCarthy measure at 40 months, again using neonatal TSH as the main indicator of iodine status (Mean for verbal 49.2 vs. 56.9; p < 0.05, d = 0.81; Mean for perceptual 48.6 vs. 54.2; p < 0.05, d = 0.64). As expected, the overall McCarthy score was also significant. Murcia et al. [48] did not find a difference between children grouped on the basis of their TSH (Mean 96.2 vs. 100.2; ns, d = 0.27).Nutrients 2013,Oken et al. [49] found no difference between groups based on newborn T4 (because only the overall mean was provided, an effect size is estimated at between 0.00 and 0.20 = 0.10). On the basis of these four studies with five comparisons the mean effect size was 0.54 or 8.1 IQ points (Figure 4). Five other studies, whose goal was to examine the efficacy of treatment for congenital hypothyroid children in comparison with normal controls, include Bongers-Schokking et al. [74], Rovet et al. [76,77] and Tillotson et al. [78]. Their findings are described here but the effect sizes were not integrated with the previous four studies. Bongers-Schokking et al. [74] found that severe vs. mild deficiency (d =.S.Nutrients 2013, 5 Figure 3. Forest plot for effect size (Standard mean difference SMD and 95 confidence interval) of iodine on mental development of children, cohort prospective studies stratified by maternal iodine status. The studies are heterogeneous (Q = 34.85, df = 12, p < 0.001). The random effects model was therefore more appropriate. Estimated effect size of 0.1 in Oken's study not included as details for computation not reported.Man et al. [66-67] Man et al. [66-67] Pop et al. [68] Pop et al. [68] Smit et al. [69] Smit et al. [69] Smit et al. [69] Li et al. [70] Costeira et al. [71] Costeira et al. [71] Galan et al. [47] Murcia et al. [48] Pop et al. [72] Total (fixed effects) Total (random effects) -1.0 -0.5 0.0 0.5 1.0 1.5 Standardized Mean Difference (SMD) 2.0 2.3.4.4. Observational Cohort Prospective Studies Stratified by Newborn Iodine Status These studies include children with congenital hypothyroidism where the thyroid gland is not functioning at birth, generally defined in terms of high levels of thyroid stimulating hormone (TSH). This is normally detected during screening at birth in high-income regions. The maternal iodine status of the children was not reported in these studies. In high-income countries, children are usually treated immediately upon detection (Table 3). Control or comparison groups of children were iodine-sufficient siblings or mildly deficient children. Thus, the hypothesis of the researchers of these studies was that infants treated with the thyroid hormone after screening and confirmation of congenital hypothyroidism at birth would have a development similar to that of infants without congenital hypothyroidism. Exceptions to this statement include Choudhury et al. [75] from China, Riano Galan et al. [47] and Murcia et al. [48] from Spain, and Oken et al. [49] from the USA where deficient children were not treated. Using cord blood TSH to distinguish iodine-deficient vs. sufficient children (controls), Choudhury and coworkers [75] found that mildly deficient children of 7 months did not differ from controls (Mean 58.9 vs. 59.6; ns, d = 0.19) whereas severely deficient children did differ (Mean 57.5 vs. 59.6; p < 0.05, d = 0.66). At 13 months, using the Bayley, differences were found between controls and the severely deficient children (d = 0.74) [75]. Riano Galan et al. [47] found differences on the McCarthy measure at 40 months, again using neonatal TSH as the main indicator of iodine status (Mean for verbal 49.2 vs. 56.9; p < 0.05, d = 0.81; Mean for perceptual 48.6 vs. 54.2; p < 0.05, d = 0.64). As expected, the overall McCarthy score was also significant. Murcia et al. [48] did not find a difference between children grouped on the basis of their TSH (Mean 96.2 vs. 100.2; ns, d = 0.27).Nutrients 2013,Oken et al. [49] found no difference between groups based on newborn T4 (because only the overall mean was provided, an effect size is estimated at between 0.00 and 0.20 = 0.10). On the basis of these four studies with five comparisons the mean effect size was 0.54 or 8.1 IQ points (Figure 4). Five other studies, whose goal was to examine the efficacy of treatment for congenital hypothyroid children in comparison with normal controls, include Bongers-Schokking et al. [74], Rovet et al. [76,77] and Tillotson et al. [78]. Their findings are described here but the effect sizes were not integrated with the previous four studies. Bongers-Schokking et al. [74] found that severe vs. mild deficiency (d =.