Transient congenital hypothyroidism (TCH) may occur because of iodine deficiency, iodine overload, transplacental

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1 Transient Neonatal Hypothyroidism is Associated with Elevated Anti-Thyroglobulin Antibody Levels in Newborns and Their Mothers ARASH ORDOOKHANI, MD, PARVIN MIRMIRAN, PHD, PAUL G. WALFISH, CM, MD, AND FEREIDOUN AZIZI, MD Transient congenital hypothyroidism (TCH) was detected in 6 of 35,067 newborns (1:5845 births) screened in Iran. Antithyroglobulin antibodies positivity was present in 4 of 6 (66.7%) of those with TCH and in 6 of 106 (5.7%) of those with transient hyperthyrotropinemia and normal diagnoses (P.0005), but positivity was similar in newborns with transient hyperthyrotropinemia versus normal neonates (P.397). (J Pediatr 2007;150:315-7) Transient congenital hypothyroidism (TCH) may occur because of iodine deficiency, iodine overload, transplacental passage of thyrotropin () receptor-blocking autoantibodies, maternal consumption of goitrogens and/or thyroid affecting medications, neonatal very low birth weight ( 1500 g) and prematurity ( 37 weeks gestation), immaturity of thyroidal iodine organification, and inactivating monoallelic mutations in the THOX2 gene. In some subjects, the etiology remains unknown. 1 This study reports the association of elevated antithyroglobulin antibodies (TgAb) and TCH in two cities of Iran during an iodine sufficiency era. 2 METHODS Screening for congenital hypothyroidism (CH) was initiated in 1998 in seven hospitals in different parts of Tehran and in the general hospital and the rural birth center of Damavand (a city north to Tehran with a population of 66,000) using as the primary screening test. Until August 2002, cord dried blood spot samples were collected in all liveborn neonates and cord 20 miu/l were considered abnormal and were used as the criterion for infant recall. Upon recall, newborns with serum 10 miu/l and total thyroxine (T4) 84 nmol/l or 30 miu/l alone (regardless of T4 levels) were considered to have CH, 1,3,4 and those with normal serum and T4 values were considered to have transient hyperthyrotropinemia (THT). CH-affected neonates and their mothers were immediately recalled again, and neonatal serum, T4, thyrotropin receptor autoantibodies (TRAb) and thyroid peroxidase antibodies (TPOAb), TgAb, and urinary iodine concentration (UIC) of spot urine samples and maternal serum, free thyroxine, TRAb, TPOAb, TgAb, and spot UIC were assessed. Levothyroxine replacement therapy (10-15 g/kg/day) was initiated in hypothyroid neonates. At 3 years of age, Levothyroxine was withheld for 4 to 6 weeks in children in the CH-affected newborn group with orthotopic thyroid (diagnosed by thyroid 99m technetium-pertechnetate scintigraphy and ultrasonography [US]), and normal serum and T4 confirmed TCH. This schedule continued until September TCH diagnoses that were made before 2 years of age were reconfirmed, at least once, by serum and T4 re-testing. Sixty-two mature infants with THT and 44 mature normal (i.e., cord 20 miu/l) newborns were randomly selected as control groups. The study protocol was approved by the appropriate Human Research Committee of Shaheed Beheshti University of Medical Sciences. Where required, informed written consent was obtained from the parents. Laboratory Methods Cord (two-site immunoradiometric assay) was measured by NETRIA kits (RAW/6/003 Project, International Atomic Energy Agency) and serum (immuno- CH T4 TCH TgAb THAb THT Congenital hypothyroidism Total thyroxine Transient congenital hypothyroidism Antithyroglobulin antibodies Thyroid hormone autoantibodies Transient hyperthyrotropinemia TPOAb TRAb UIC US Thyroid peroxidase antibodies Thyrotropin receptor autoantibodies Thyrotropin Urinary iodine concentration Ultrasonography From the Endocrine Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran (A.O., P.M., F.A.); and the Endocrine Division, Department of Medicine, Mount Sinai Hospital, University of Toronto Medical School, Toronto, Ontario, Canada (P.G.W.). This study was supported partly by grant no. 115 NRCI of the National Research Council of the I.R. Iran and partly by a grant from the Endocrine Research Center, Shaheed Beheshti University of Medical Sciences. Submitted for publication Feb 23, 2006; last revision received Oct 5, 2006; accepted Nov 8, Reprint requests: Dr Arash Ordookhani, Endocrine Research Center, Taleghani Hospital, Evin Avenue, Tehran, Iran. P.O. Box: arash_ordookhani@ yahoo.com; ordookhani@erc.ac.ir /$ - see front matter Copyright 2007 Mosby Inc. All rights reserved /j.jpeds

2 Table I. Frequency distribution of thyroid autoantibodies in newborns with TCH and THT, and in normal newborns Diagnosis TPOAb TgAb Positive (>100 IU/mL) Negative (<100 IU/mL) Positive* (>150 IU/mL) Negative* (<150 IU/mL) TCH 0 (0) 6 (100) 4 (66.7) 2 (33.3) THT 8 (12.9) 54 (87.1) 5 (8.1) 57 (91.9) Normal 3 (6.8) 41 (93.2) 1 (2.3) 43 (97.7) Total 11 (9.8) 101 (90.2) 10 (8.9) 102 (91.1) P value Odds ratio (95%CI OR ) 33.3 ( ) *Odds ratio (95%CI OR ) in TCH vs. THT was 22.8 ( ; P.002) and in TCH vs. normal newborns was 86 ( ; P.0003). TgAb positivity was similar in THT vs. normal neonates (P.397). Values in parentheses show percentage. Five newborns had both positive TPOAb and TgAb and three had only positive TPOAb. TCH vs. THT and normal newborns. radiometric assay) and T4 (radioimmunoassay) by Spectria kits (Orion Diagnostica, Finland). free thyroxine and TRAb (DRG Diagnostics, Marburg, Germany) and TPOAb and TgAb (RADIM, Italy) were assayed by the enzymelinked immunosorbent assay method. TgAb was assayed using sera incubated in the polystyrene wells coated with purified human Tg. The absorbance of calibrators, controls, and samples were measured using a plate reader with wavelength set at 450 nm. Minimum detectable value was 11 IU/mL. Intraassay coefficient of variation at concentrations of 98.5 IU/mL, 307 IU/mL, and 976 IU/mL were 8.5%, 4.9%, and 4.4%, and interassay coefficient of variation at concentrations of 97 IU/mL, 296 IU/mL, and 962 IU/mL were 14.3%, 11.8%, and 13.4%, respectively. UIC was measured by Sandell-Kolthoff digestion method. Abnormal (positive) TPOAb and TgAb were 100 IU/mL and 150 IU/mL, respectively. Mann-Whitney and Kruskal-Wallis tests were used for quantitative and Fisher s exact test was used for categorical variables. Correlation between neonatal TPOAb and TgAb was assessed by Spearman s rank correlation test. Statistical analyses were performed using the Statistical Package for the Social Sciences, version 9.05 software package (SPSS, Inc., Chicago, Ill). Significance was established at P.05. RESULTS A total of 35,067 newborns (32,397 [92.4%] from Tehran and 2670 [7.6%] from Damavand) were screened by August Six (1:5845 births) neonates had TCH who were mature ( 37 weeks gestation) and weighed between 2510 and 3950 g at birth. Positive TPOAb and/or TgAb were present in 16 (14.3%) of 112 (6 TCH, 62 THT, and 44 normal) newborns. Positive TgAb frequency was significantly higher in TCH than in THT and normal neonates, whereas positive TPOAb frequency was similar among groups (Table I). A box-and-whisker plot of TgAb in newborns with TCH and THT, and in normal newborns is shown in the Figure. Follow-up of newborns with TCH showed serum TgAb was 20 to 64 IU/mL, 23 to 40 IU/mL, and 14 to 25 IU/mL Figure. Box-and-whisker plot, showing 2.5, 25, 50, 75, and 97.5 cumulative relative frequencies (centiles) of TgAb in newborns with TCH (n 6) and THT (n 57), and in normal (n 44) newborns (excluding 5 neonates with THT whose TgAb values were lower than the detection limit of the kit). indicates Outliers. Median (range) TgAb values in newborns with TCH and THT, and in normal newborns were 274 (40-851) IU/mL, 30 (11-200) IU/mL, and 21.1 ( ) IU/mL (Kruskal- Wallis test; P.0001), respectively. Median TgAb was significantly different in TCH versus THT (P.0002), in TCH versus normal (P.0001), and in THT versus normal neonates (P.007) using Mann- Whitney test. Excluding positives, median (range) TgAb in newborns with THT (n 52) was 27.5 (11-133) IU/mL and in normal newborns (n 43) was 20.8 ( ) IU/mL (Mann-Whitney test; P 0.021). TCH, transient congenital hypothyroidism; THT, transient hyperthyrotropinemia. between 3 and 5, 6 and 8, and 11 and 14 months of age, respectively. Correlation between paired TPOAb and TgAb in 57 THT (r 0.66, P.0001) decreased when calculated for 63 neonates with TCH and THT (r 0.29, P.020). The correlation was also significant in 43 normal neonates (r 0.53; P.0003). TRAb values ranged 0.7 and 2.7 IU/L and 0.8 and 1.3 IU/L in neonates with TCH and mothers, respectively 316 Ordookhani et al The Journal of Pediatrics March 2007

3 (normal: 3 IU/L). Characteristics of newborns with TCH and their mothers are shown in detail in Table II (available at History of maternal consumption of goitrogens and thyroid-affecting medications was negative, and TCH was not associated with low and excessive neonatal UIC. DISCUSSION Our study indicates that TCH is attributable to maternal autoimmune thyroid disease in an iodine-replete area. However, TRAb (although not bioassayed) did not seem to produce TCH because none of newborns had high TRAb levels. TPOAb and TgAb apparently have no pathogenetic effect on fetal and neonatal hypothyroidism. 5,6 Antimicrosomal antibodies were assessed in primary CH 7 and in a significant number of (n 78) neonates with TCH. 8 Positive TPOAb were present in 17.5% of 40 newborns with TCH in Italy. 9 Studies on TgAb and CH are less frequent. Lack of association between CH (not specifically TCH) and TgAb have been reported previously. 10 The association between elevated TgAb and TCH occurrence in our population may be considered as new evidence in favor of the pathogenetic role of TgAb. Salt iodization in Iran may cause the 14.3% prevalence of positive TPOAb and/or TgAb, but this would not explain the difference in frequency of TgAb positivity among groups. Positive levels of thyroid hormone autoantibodies (THAb) coexist with positive TgAb values in 50% of cases. 11 High concentrations of THAb might cause hypothyroidism in a patient with no thyroid reserve, and THAb probably represents a subset of TgAb that interact with Tg epitopes containing the iodothyronines. 12 TgAb or a subset of TgAb (e.g., THAb) may contribute to TCH in some neonates with little thyroid hormone reserve. Further studies on TgAb (and THAb) in newborns and infants with TCH are warranted. The authors are indebted to the parents of the children for making the study possible. We are thankful to the staff of the laboratory of Endocrine Research Center, Shaheed Beheshti University of Medical Sciences. REFERENCES 1. Fisher DA. Disorders of the thyroid in the newborn and infant. In: Sperling MA, ed. Pediatric Endocrinology. 1st ed. Philadelphia: W. B. Saunders Company; 1996: Azizi F, Sheikholeslam R, Hedayati M, Mirmiran P, Malekafzali H, Kimiagar M, et al. Sustainable control of iodine deficiency in Iran: beneficial results of the implementation of mandatory law on salt iodization. J Endocrinol Invest 2002;25: Ordookhani A, Mirmiran P, Moharamzadeh M, Hedayati M, Azizi F. High prevalence of consanguineous and severe congenital hypothyroidism in an Iranian population. J Pediatr Endocrinol Metab 2004;17: Fisher DA. Physiological variations in thyroid hormones: physiological and pathophysiological considerations. Clin Chem 1996;42: Fisher DA. Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 1997;40: Bech K, Hertel J, Rasmussen NG, Hegedus L, Hornnes PJ, Feldt-Rasmussen U, et al. Effect of maternal thyroid autoantibodies and post-partum thyroiditis on the fetus and neonate. Acta Endocrinol (Copenh) 1991;125: Dussault JH, Letarte J, Guyda H, Laberge C. Lack of influence of thyroid antibodies on thyroid function in the newborn infant and on a mass screening program for congenital hypothyroidism. J Pediatr 1980;96(3 Pt 1): Dussault JH, Fisher DA. Thyroid function in mothers of hypothyroid newborns. Obstet Gynecol 1999;93: Weber G, Vigone MC, Rapa A, Bona G, Chiumello G. Neonatal transient hypothyroidism: aetiological study. Italian Collaborative Study on Transient Hypothyroidism. Arch Dis Child Fetal Neonatal Ed 1998;79:F70-F Ilicki A, Larsson A, Karlsson FA. Circulating thyroid antibodies in congenital hypothyroidism. Acta Paediatr Scand 1991;80: Benvenga S, Bartolone L, Squadrito S, Trimarchi F. Thyroid hormone autoantibodies elicited by diagnostic fine needle biopsy. J Clin Endocrinol Metab 1997;82: Marcocci C, Marino M. Thyroid-directed antibodies. In: Braverman LE, Utiger RD, eds. Werner and Ingbar s The Thyroid. A Fundamental and Clinical Text. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2005.p Transient Neonatal Hypothyroidism is Associated with Elevated Anti-Thyroglobulin Antibody Levels in Newborns and Their Mothers 317

4 Table II. Characteristics of neonates with TCH and their mothers, * No. Neonatal (vs. maternal) values between 7 and 38 days of age Cord DBS T4 TPOAb TgAb TRAb (miu/l) (miu/l) (nmol/l) (IU/mL) (IU/mL) (IU/L) Thyroid 99m Tc (US) (1.8) 72 (18) 19 (15) 40 (35) 0.9 (0.9) NG ( ) (1.2) 36 (12) 17 (18) 50 (47) 1.2 (1.2) G ( ) (48) 81 (15) 4.0 ( 4.0) 228 (773) 2.2 (1.3) NG ( ) (2.0) 168 (27) 5.0 (4.0) 337 (521) 2.1 (0.8) NG ( ) (32) 124 (3.9) 5.0 (5.0) 320 (275) 0.7 (1.0) (NG) ( ) 86 ( ) 4.0 ( ) 851 ( ) 2.7 ( ) ( ) n.v ( ) (10-26) DBS, dried blood spot; G, goitrous; NG, non-goitrous;, not done; n.v., normal value; off-therapy, discontinuation of levothyroxine replacement therapy; 99m Tc, Technetium pertechnetate thyroid scan; US, ultrasonography. *All the values presented in the parentheses in the table display maternal values. Values are total T4 (nmol/l) of neonates and those in parentheses are free T4 (pmol/l) of their mothers. values of 30th day of life are shown. values of 38th day of life are shown. No blood samples were obtained from the mother of newborn 6 because of her severe injection phobia. In infants and children 1-12 months and 1-5 years of age, normal serum values are miu/l and miu/l and T4 values are nmol/l and nmol/l, respectively e1 Ordookhani et al The Journal of Pediatrics March 2007

5 Table II. Continued Values in TCH subjects (vs. mothers) after 4-6 weeks of off-therapy Follow-up of TCH subjects T4 TPOAb TgAb Age Duration of off-therapy T4 (miu/l) (nmol/l) (IU/mL) (IU/mL) (months) (months) (miu/l) (nmol/l) 1.4 (1.8) 89 (13) 8.2 (29) 24 (32) (1.1) 120 (10) 7.3 (7.3) 25 (23) (1.4) 151 (13) 4.0 ( 4.0) 40 (774) (4.4) 102 (12) 4.0 ( 4.0) 22 (131) (0.6) 111 (12) 4.0 (21) 46 (33) ( ) 143 ( ) ( ) ( ) ( ) (10-26) Transient Neonatal Hypothyroidism is Associated with Elevated Anti-Thyroglobulin Antibody Levels in Newborns and Their Mothers 317.e2