Clinical EndocrinologyVolume 85, Issue 3 p. 344-346 Commentary Commentary on the use of thyroglobulin as a biomarker for iodine status in adults† M.L. Mitchell, Corresponding Author M.L. Mitchell New England Newborn Screening Program, University of Massachusetts Medical School, Boston, MA, USACorrespondence: Marvin L. Mitchell, University of Massachusetts Medical School, 305 South Street, Jamaica Plain, Boston, MA 02130, USA. Tel.: 617-983-6300; E-mail: marvin.mitchell@umassmed.eduSearch for more papers by this authorH.W. Hsu, H.W. Hsu New England Newborn Screening Program, University of Massachusetts Medical School, Boston, MA, USASearch for more papers by this author M.L. Mitchell, Corresponding Author M.L. Mitchell New England Newborn Screening Program, University of Massachusetts Medical School, Boston, MA, USACorrespondence: Marvin L. Mitchell, University of Massachusetts Medical School, 305 South Street, Jamaica Plain, Boston, MA 02130, USA. Tel.: 617-983-6300; E-mail: marvin.mitchell@umassmed.eduSearch for more papers by this authorH.W. Hsu, H.W. Hsu New England Newborn Screening Program, University of Massachusetts Medical School, Boston, MA, USASearch for more papers by this author First published: 23 May 2016 https://doi.org/10.1111/cen.13109Citations: 1 †Please see related paper on pages [ 475–482] of this issue. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume85, Issue3September 2016Pages 344-346 RelatedInformation

Summaryobjectives To test the hypothesis that thyroglobulin (Tg) and free T4 (FT4) concentrations more than 2SD from the control mean are not increased in pregnancy in an iodine replete area in the absence of elevated TSH concentrations. The second hypothesis to be tested was that if such abnormalities in FT4 and Tg in the absence of elevated TSH concentrations were to exist they would not be associated with lowered IQs in the progeny.design Cross‐sectional study in New England comparing TSH, Tg, antibodies to Tg and FT4 in volunteer nonpregnant women 20–40 years old with those in hypothyroid mothers and matched euthyroid control mothers. The results are contrasted with those from similar studies reported from iodine deficient areas.subjects Sera obtained at 17 weeks gestation and stored at −20 °C for 8 years were retrieved and analysed from 62 mothers with subclinical hypothyroidism and 124 matched euthyroid mothers. The diagnosis of hypothyroidism was made by finding a TSH concentration > 97·7 percentiile for 25 000 consecutive pregnant women. Sera were also analysed from 53 healthy nonpregnant volunteer women aged 20–40 years.measurements TSH, Tg and Tg antibodies were measured in the sera of the nonpregnant volunteers, and Tg and Tg antibodies in the sera of the pregnant women who had previously been analysed for TSH and FT4. The incidence of FT4 concentrations below the 2·3 percentile of nonpregnant laboratory controls was compared for the euthyroid and hypothyroid mothers and the laboratory normal controls.results Thirty‐one per cent of the 62 hypothyroid mothers had FT4 concentrations below the 2·3 percentile compared with only one (0·8%) of the euthyroid mothers. Mean Tg concentrations did not differ between the nonpregnant controls and the euthyroid pregnant women, 14 ± 10 vs. 16 ± 10 µg/l. Tg concentration in the hypothyroid mothers was 44 ± 61, significantly greater than for either of the euthyroid control groups, P < 0·005. Positive antibodies to Tg were found in 9% and 10% of the control groups and 57% of the hypothyroid mothers, P < 0·0005. When TSH is included as an independent variable in multiple linear and logistic regressions, FT4 and Tg no longer correlate significantly with IQs.conclusions The incidences of FT4 concentrations more than 2SD below the control mean and of Tg > 2SD above the control mean are significantly increased in hypothyroid mothers in iodlne‐sufficient New England. However, in the absence of elevated TSH concentrations, the incidences of such abnormalities in FT4 and TG are negligible. Indeed, concentrations for FT4, Tg and Tg antibodies for nonpregnant and pregnant controls in our iodine‐replete area do not differ significantly from each other or from previously reported normative concentrations with the methods used. Thus, pregnancy in New England neither increases Tg nor lowers FT4 concentrations.

Background An association between maternal subclinical hypothyroidism and low intelligence quotient (IQ) in the offspring has recently been shown. Objective To provide evidence for the causality of the association by testing the hypothesis that severity of maternal hypothyroidism correlates inversely with IQ of the offspring. Methods IQ scores were compared among 8 year old offspring of 124 control mothers whose thyroid stimulating hormone (TSH) concentrations were < 98th percentile of a cohort of 25 000 mothers at 17 weeks gestation, of 28 untreated hypothyroid women whose TSH was between the 98th and 99.85th percentiles, and of 20 untreated women whose TSH concentration was ≥ 99.85th percentile. Results Mean (SD) IQs for each group of children (in ascending order of maternal TSH concentration) were 107 (13), 102 (15), and 97 (14). The difference between the extremes was significant (p = 0.003). The percentage of children with IQs > 1 SD below the control mean was 15, 21, and 50 respectively (p = 0.003). The odds ratio of having an IQ > 1 SD below the control mean, after controlling for socioeconomic status, was 4.7 (p = 0.006) for the third group compared with the controls. Conclusions The inverse correlation between severity of maternal hypothyroidism and IQ of the offspring supports a causal relation and makes the need to screen for and treat pregnant women for hypothyroidism even more compelling.

Objective To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women. Methods TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death. Results Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9–9.5). Other pregnancy complications did not occur more frequently Conclusion From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening.

Results of thyroid screening tests were examined retrospectively on 311,282 infants born in Massachusetts from January 1, 1993 to December 31, 1996. During this period, 118 infants were found to have typical hypothyroidism, characterized by a low thyroxine (T4) and an elevated thyrotropin (TSH) on the initial newborn-screening specimen. Of these, 98 were normal birthweight (NBW, > or = 2,500 g), 9 were low birthweight (LBW, 1,501-2,499 g), and 11 were very low birthweight (VLBW, < or = 1,500 g). Atypical hypothyroidism as defined here is characterized by a low T4 and normal TSH concentration on the initial screening specimen, followed by and elevated TSH level on a repeat blood specimen. This phenomenon occurred in 18 infants, of whom 4 were NBW, 4 were LBW, and 10 were VLBW. The incidence of combined typical and atypical hypothyroidism was: NBW, 1:3051; LBW, 1:1589; VLBW, 1:153, with the highest incidence of atypical hypothyroidism in the VLBW category (48% of cases in this weight category, 56% of all cases of atypical hypothyroidism). In addition, screening programs using a primary TSH screen will miss infants with atypical hypothyroidism. In view of these results, it is suggested that T4 measurements be obtained routinely in all LBW and VLBW infants, with additional routine repeat blood specimens.

Combined maternal and fetal hypothyroidism, due to either endemic iodine deficiency or autoimmune thyroiditis is associated with the fetal neurodevelopmental problems of classic cretinism [1, 2, 3, 4]. The relative contributions of maternal and fetal deficiencies to the CNS developmental problems have not been established. Pharoah et al. [2]reported a correlation of maternal T4 levels, but not of T3, with cognitive and motor adevelopment of the offspring. In cretinism associated with autoimmune disease, central nervous system problems in the offspring have been described only in the rare instances of thyroid deficiency in the mother associated with transient hypothyroidism in the neonate. Such problems have been described in endemic disease when the newborn was not hypothyroid but it is impossible to rule out transient fetal hypothyroidism in either endemic or in autoimmune disease. Treating the transient hypothyroidism in the offspring even from birth does not lessen the CNS problems.Early reports on hypothyroidism in pregnancy commented chiefly on the rarity of its occurence and the poor obstetrical outcomes [5, 6]. Some of the surviving offspring were said to be mentally retarded, but there is no way to distinguish these cases retrospectively from the cases of combined maternal and fetal autoimmune hypothyroidism subsequently recognized [3, 4, 6]. In 1962, Greenman et al. [7]reported a study of 19 pregnant women with confirmed or suspected hypothyroidism. They, too, were more interested in obstetric problems but did follow the surviving offspring for 8–12 months. In this study, no IQ scores were reported presumably because the children were too young. There were 7 women whose hypothyroidism had been diagnosed and whose treatment had begun before pregnancy. All their 5 surviving infants were considered to be mentally normal. Seven women who were first suspected of being hypothyroid during their pregnancies had the diagnosis verified by low butanol-extractable iodine (BEI) concentrations. Four of their 5 surviving infants were considered to be mentally retarded. Two of of the brain-damaged infants were premature and one had multiple gross congenital anomalies. In retrospect, 2 infants were probably hypothyroid as indicated by low BEI concentrations. The last 6 mothers were suspected of being hypothyroid because each had a goiter, but they all had BEI concentrations in the normal range for pregnancy. They had no obstetric problems and their children were considered to be normal.Man and co-workers [8, 9]first suggested in 1969 that mild maternal hypothyroidism alone was associated with lower IQs in the offspring. They reported that the children of mothers with inadequately treated or untreated hypothyroidism had lower IQs than did the children of either adequately treated hypothyroid or control mothers. Some of the subjects were screened using BEI measurements, and others of women were tested by BEI measurements because of clinical signs suggestive of hypothyroidism.Later investigators reported no increase in mental retardation associated with mild hypothyroidism. They discounted the work of Man because she used the subsequently outdated measurement of BEI for the diagnosis of hypothyroidism. Of more concern is possible selection bias as a result of inappropriate decisions as to adequacy of treatment in Man's studies.In the subsequent studies of later authors, the women were treated during gestation frequently but IQs of offspring were infrequently measured [10, 11, 12, 13]. Again it is likely that many of the mothers had autoimmune hypothyroidism. In one study, that of Liu et al. [12], the 8 mothers were found to be hypothyroid at 5–10 weeks of station and treated at that time. Seven of the 8 had completely normal hormonal values at 13–20 weeks of gestation. The eighth did so at 28 weeks. The 8 children all had normal neonatal screening TSH results and had normal IQs at 4–10 years. Rolland et al. [13]reported results from a questionnaire sent to all females diagnosed with congenital hypothyroidism in their hospital from 1950 to 1980. Eleven of the 22 responders had had 17 pregnancies. Two resulted in spontaneous abortions and 2 liveborn infants died in the first month of life. Treatment of only one of the mothers was discontinued during pregnancy. The 13 surviving infants were reported to have normal psychomotor developmental at 6 months to 21 years of age.The study of Pop et al. [14]is interesting because they reported lower IQs in the children of mothers with antibodies to thyroid peroxidase but normal thyroid hormonal values at 32 weeks gestation. They suggested that the antibodies did not cause the CNS problems but were an epiphenomenon. We presume that the mothers had had earlier gestational hypothyroidism. The possibility remains that the antibodies were associated with temporary, and thus, undiagnosable, fetal autoimmune hypothyroidism as well.Klein et al. [15]reported TSH concentrations in 2,000 blood specimens from women drawn at 17 weeks gestation for alpha-fetoprotein screening. TSH concentrations were ≥6 mU/l in 2.4% and ≥12 mU/l in 0.3%. None was symptomatic, but FT4 concentrations were ≥2 standard deviations below the normal mean in 60% of those with TSH concentrations ≥99.7th percentile. Mean age of the hypothyroid mothers was greater than that of the control mothers, 29.1 vs. 26.9 years (p < 0.02), paralleling the increasing incidence of hypothyroidism with age in the general population. These findings were verified in an unpublished study by the same investigators, of 10,000 women, 2.2% of whom had TSH concentrations ≥6 and 0.3% had concentrations ≥12 mU/l. FT4 concentrations were ≥2 SD below the control mean in 40% of those with TSH concentrations ≥99.7th percentile. Tests for antibodies to TPO were positive in 67% of the mothers with TSH concentrations ≥99.7th percentile. There was an increased incidence of poor obstetric outcomes in this group of hypothyroid mothers with significant increases in spontaneous abortions and intrauterine fetal deaths. There were statistically insignificant increases in overall deaths and premature births as well.A report was presented in Firenze at the 37th meeting of the European Society for Pediatric Endocrinology in 1998 which essentially verified Man's suggestion that children born to mothers with untreated hypothyroidism had lower IQs than children of normal mothers or mothers with adequately treated hypothyroidism [16, 17]. In this last study, 25,000 pregnant women were screened for hypothyroidism retrospectively. TSH concentrations were measured in sera obtained at a mean of 17 weeks of gestation for routine purposes which had been frozen and stored for 8 years. The women were divided into 3 groups comprised of 14 women with a previous clinical diagnosis of hypothyroidism who had been treated before and throughout pregnancy, 48 women whose hypothyroidism was untreated during pregnancy although one had been treated for a year before conception, and 124 matched control mothers whose TSH concentrations were below the 98th percentile. Their children underwent psychometric evaluations at 8 ± 0.5 (SD) years of age.There were no differences among the 124 control, 14 treated, and 48 untreated hypothyroid mothers in maternal and paternal occupations, paternal education, and Hollingshead Indices in addition to the demographic items by which the controls had been matched in the process of selection (maternal education, maternal age, and birthdate and sex of the child).None of the children had either permanent or transient congenital hypothyroidism on neonatal screening or clinically on follow-up at 8 years. One hundred and twenty of the control mothers and 45 of those with untreated hypothyroidism were able to be contacted 10 years following delivery. 58% of the previously untreated hypothyroid mothers and 4% of control mothers had developed sufficient signs and symptoms of hypothyroidism to have been diagnosed clinically at a median time of 5 years postpregnancy. The percentage over the 10 years in the control mothers was what would be expected from the Whickham study [18].Table 1 compares concentrations for TSH, T4, FT4, and for presence of antibodies to TPO in maternal sera at 17 weeks of gestation of the control mothers with those of the treated and of the untreated hypothyroid mothers.Figure 1 depicts the means and 95% confidence intervals for full-scale IQ scores in children of 124 control mothers (cross-hatched rectangle) and 14 treated (clear rectangle) and 48 untreated hypothyroid mothers (dotted rectangle).Table 2 compares the outcomes for children born of control mothers and of treated and untreated hypothyroid mothers for school performance by Fisher's exact test and for 10 psychometric tests using dummy regression analyses.The scores of children of untreated hypothyroid mothers were poorer in all of the 11 outcomes than those of the children of control mothers. The differences were statistically significant for all but the scores for the VMI test.The test scores for the children whose mothers were treated before and during pregnancy were poorer than those of children of control mothers only in the computer test of attention. The children whose mothers were treated did better than did the children of control mothers in the other 9 tests albeit insignificantly. They also did better than the children of untreated hypothyroid mothers. The last differences were statistically significant in only 4 of the tests. The paucity of children of treated mothers and the large variances for their outcomes should be noted. These may have obscured the significance of the differences in some of the comparisons involving children of treated mothers and exaggerated others.Compared with the children of control mothers, twice as many children of untreated hypothyroid mothers had an IQ >1 standard deviation below the control mean, 35 vs. 18%, p = 0.018 and four times as many had IQs >2 standard deviations below the control mean, 13 vs. 4%, p = 0.08 (Fisher's exact tests). The child of one of the 14 treated mothers (7%) had an IQ >1 SD below the control mean and none had an IQ >2 SD below the control mean.Regression analyses of children's IQs and FT4 concentrations of their mothers using treatment status as a covariate were significant at p = 0.025. This supports the hypothesis that severity of maternal hypothyroidism corelates with outcomes in the offspring. There was no correlation of cognitive outcomes with TPO antibodies.There were 46 hypothyroid women, treated and untreated, with TSH concentrations ≥99.7th percentile. Assuming they were representative of the total group of 75 with such TSH concentrations, at least one per thousand of all newborns are at risk of having an IQ >1 SD below the control mean associated with maternal hypothyroidism. This would suggest that if women can be screened before or early enough in pregnancy, the beneficial effects on cognition would be tenfold greater than those provided by neonatal congenital hypothyroidism screening [19].The experience of this study suggests that the increased need for thyroxine in pregnancy is commonly not met.It is clear from Haddow's report that untreated subclinical maternal hypothyroidism is associated with poor cognitive outcomes in the offspring whereas children of previously clinically diagnosed hypothyroid women who had thyroxine replacement therapy before and during pregnancy do as well as children of control mothers. The obvious possibility that hypothyroidism is the cause of the cognitive deficits and that thyroxine therapy prevents this is the most likely explanation. Maternal hypothyroidism could act directly by causing fetal hypothyroidism or indirectly by affecting placental function, for instance. There is, however, a question about the relation of maternal treatment to childhood outcomes. The treated mothers' mean hormonal values at 17 weeks of gestation were no better than those of untreated women. The present authors hypothesize that maternal thyroid function was normal in the treated mothers at a critically earlier time before the required maternal T4 replacement dose increased pari passu with the increasing concentrations of TBG [20]. Maternal hormonal levels are expected to become irrelevant sometime after 10–12 weeks of gestation if the fetal thyroid produces the normal increasing amounts of thyroxine absent autoimmune or congenital fetal hypothyroidism [4, 21].The data suggest that the damage to the fetal CNS most likely occurred early in pregnancy presumably before fetal thyroxine production was significant. In sporadic congenital hypothyroidism, measurable brain damage occurs only when the child is no longer protected by maternal thyroid hormone since early and adequate postnatal treatment is associated with normal IQs in the progeny [22]. In cretinism of either etiology, the damage must come earlier since treatment of the neonate from the first day of life does not prevent it. Treatment of the mother with autoimmune hypothyroidism throughout pregnancy will prevent fetal brain damage, however [4]. Most authors suggest that fetal brain damage in cretinism occurs at least as early as the first trimester [23, 24]. However, Cao et al. [25]have suggested that the damage can be prevented in endemic disease by treating the mother with iodine as late as the second trimester. The problem with this is that a fourth of the mothers who were treated in the second trimester in that study had also had iodized oil treatments within 6 months of the pregnancy and their infants' IQs are not identified separately in Cao's report.We believe that the literature reviewed indicates that: (1) Maternal hypothyroidism, even if subclinical, interferes with normal fetal brain development. The incidence of cognitive deficiency in all newborns from maternal hypothyroidism is much greater than that due to sporadic congenital hypothyroidism before the advent of neonatal hypothyroidism screening. (2) This fetal CNS damage is preventable by maternal thyroxine therapy. It therefore follows that mothers should be screened for hypothyroidism and treated before or as early as possible during pregnancy.

BACKGROUND When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

BACKGROUND AND OBJECTIVE Screening for congenital adrenal hyperplasia (CAH) in newborns has become a routine part of many programmes by measuring levels of 17 alpha-hydroxyprogesterone (17-OHP) in the newborn filter-paper blood specimen, Unfortunately, raised levels of 17-OHP, which are largely the consequence of cross-reacting metabolites, are also found in low birth weight, premature and ill neonates. We speculated that differences in concentrations of cortisol in the newborn screening specimen would aid in distinguishing between CAH positive and CAH negative infants among those with raised levels of 17-OHP,DESIGN Comparison of cortisol concentrations was made between newborns with CAH and those without but with raised 17-OHP levels.PATIENTS Newborn filter-paper blood specimens from 31 infants with transient 17-OHP elevations and 16 infants with confirmed CAH were analysed for cortisol. In addition, assay performance was validated by comparing cortisol Values obtained from dried whole blood on filter-paper with the corresponding plasma from 31 adults and six neonates.MEASUREMENTS Cortisol in filter-paper blood specimens was determined by adapting a commercial radioimmunoassay kit that had been designed for the determination of cortisol in serum.RESULTS The mean cortisol revel in the CAH negative group was significantly higher than the mean value in the group with documented CAH (means 1190 +/- 795 nmol/l vs 627 +/- 210 nmol/l; P<0.01). However, approximately half of the CAH negative infants had cortisol values that overlapped those from the CAH positive group. There was no relationship between the magnitude of the 17-OHP elevation and cortisol concentrations,CONCLUSION The measurements of cortisol in dried blood on filter-paper using a commercial radioimmunoassay kit has been shown to be reliable and simple to carry out. The level of cortisol in newborn blood specimens can be used to exclude some infants with elevated 17 alpha-hydroxyprogesterone levels from further testing for CAH, However, overlapping cortisol values between CAH positive and negative infants precludes the assay of cortisol from being used routinely as a reliable means of decision making.

A high incidence of transient neonatal hypothyroidism has been observed in premature infants after routine skin cleansing with iodine. Because these reports have been predominantly from Europe, a borderline, iodine-deficient area, we wished to determine whether this was also true in North America, an iodine-sufficient area. A prospective, controlled study was performed in premature babies < or = 36 weeks gestation admitted to a neonatal intensive care nursery. Thyroxine (T4) and thyrotropin (TSH) were measured at day 1, days 4 to 6, and 10 to 12 after skin preparation with iodine or with a noniodine-containing antiseptic solution (chlorhexidine) that served as control. If repeat cleansing was required, this sequence was repeated. Urinary iodine was quantitated on days 1 to 3 to estimate iodine exposure. There was no difference in the mean T4 concentration at any of the time points evaluated nor in the incidence of transient hypothyroidism between the iodine-exposed (2/17) and control babies (0/14) despite urinary iodine excretion up to 88 times the control value. Unexpectedly 5 iodine-exposed but 0 control babies developed severe hypothyroxinemia (T4 < 40 nmol/L), compatible with the sick euthyroid syndrome; one of them died. We conclude that, unlike in Europe, transient hypothyroidism is not a common sequela of routine skin cleansing with iodine in premature newborn infants in North America. This difference in incidence may be due to prior iodine status. Whether excessive iodine absorption in premature infants is associated with thyroid-independent toxic effects remains to be clarified.

We presented data showing a direct correlation of screening T4 values with birthweight in premature infants at this meeting three years ago.We opined that low T4 concentrations were due to decreased protein binding of T4. The next year,we reported data proving the speculation and showing lower binding was more than compensated for in term infants by increased TBG concentration. FT4 concentrations for term and VLBW infants were all within the normal adult range and the neonates had similar TSH concentrations indicating low T4 values were due to NTI. Further findings at 2 weeks in 5 of 32 VLBW infants suggest a Euthyroid Sick Syndrome. We compare clinical and hormonal values of these 5 with the remaining 27 infants in the tables.(cord v 2 wk- * p <.05 ** <.01) The FT4 method was validated by equilibrium dialysis.The correlation of immaturity and postnatal stress with the hormonal changes was also demonstrated by regression analyses. The values became normal in 3 of the 4 infants followed for 4 weeks. We believe the changes in hormonal values are due to a transient inhibitor of T4 binding unrelated to the diminished binding seen in both VLBW and term infants previously demonstrated. The putative transient inhibitor is associated with immaturity and stress.

Objectives: To supply normative data for screening thyroxine (T-4) and thyrotropin concentrations correlated with birth weight and age at screening of infants with birth weights ranging from 400 to 5500 gm, and to document the effects of screening of very low birth weight (VLBW) infants, because VLBW infants comprise 0.86% of surviving newborn infants and have very low total T-4 concentrations with normal or elevated free T-4 concentrations as a result of deficient protein binding of thyroid hormones.Study design. Both retrospective and prospectives studies were used. We conducted retrospective analyses of screening of T-4 and thyrotropin concentrations in 9,324 term, 18,946 low birth weight, and 3,450 VLBW infants in Massachusetts, and a prospective study of T-4 and thyrotropin concentrations in 48 VLBW infants at 2 weeks of age. Forty of the infants also had hormone measurements at 4 weeks, 29 at 8 weeks of age, and 24 had analysis of cord blood samples.Results: Median T-4 concentrations for each weight group (in 250 gm increments) increased progressively and significantly up to 2500 gm, Of the surviving VLBW infants, 1.5% had screening T-4 concentrations that were unmeasurably low (<3.9 nmol/L (0.3 mu g/dl)). The mean T-4 concentration varied with age at screening, increasing from cord blood concentrations to a peak at 1 to 3 days of age and thereafter decreasing to a nadir at about 2 weeks in both low birth weight and VLBW infants. In VLBW infants the mean concentrations return to the level of 1 to 3 days by 4 to 8 weeks of age. The incidence of screening thyrotropin concentrations greater than or equal to 40 mU/L correlates inversely with weight, The incidence of early, transient hypothyroidism in VLBW infants defined by this thyrotropin concentration was eight times that in term infants. Two infants had late-onset, transient hypothyroidism at 2 and 7 weeks, respectively.Conclusions: The normative data related to birth weight and age at screening allow proper interpretation of VLBW results for primary T-4 and primary thyrotropin screening programs, Screening of the concentrations of T-4 and thyrotropin in VLBW increases the number of secondary measurements of T-4 in a primary thyrotropin screening program and the number of secondary thyrotropin measurements in a primary T-4 screening program by 6% and 9%, respectively, We recommend screening analyses for VLBW infants in the latter part of the first week of life and again at 2 and 4 to 6 weeks of age. This protocol would increase the number of screening analyses by 1.6%.

SummaryBACKGROUND AND OBJECTIVE Thyroglobulin (Tg) has been found In varying concentrations In Infants and children with congenital hypothyroidism. Our primary goal was to ascertain whether Tg In filter paper blood specimens used for routine newborn screening would be a useful adjunct In the early diagnosis of newborn children with congenital hypothyroidism. Our secondary objective was to correlate the results of the Tg determinations with the results of thyroid scintigraphy in the same cohort of Infants with congenital hypothyroidism.DESIGN An RIA kit with high sensitivity for the measurement of Tg in serum was modified for use with filter paper blood specimens. Results of thyroid scintigraphy were obtained from the family physicians on 10 Infants with ectopic thyroid glands and 18 who were considered to be athyreotic.MEASUREMENTS Determinations of Tg were carried out retrospectively on newborn screening filter paper blood specimens from 61 full‐term normal Infants and 42 newborns with confirmed congenital hypothyroidism.RESULTS Thyroglobulin concentrations during the first week of life in the normal controls ranged between 17 and 160 μg/l, with a median of 66 μg/l. Tg values for Infants with ectopic thyroid glands ranged between 38 and 282 μg/l, with a median of 116 μg/l. In contrast, newborns who were considered athyreotic had Tg values ranging between undetectable and 104 μg/l with a median of 15/ig/l. Fifty per cent of the athyreotic patients and 50% of patients with ectopic thyroid glands had Tg values above or below the normal range and thus fell within the diagnostic category of hypothyroidism on the basis of Tg alone. Fifty per cent of patients who were considered athyreotic by scintigraphy had Tg concentrations ranging from 20 to 104 μg/l.CONCLUSION These studies have shown that thyroglobulin can be measured In the same filter paper blood specimens used for routine newborn screening. Estimation of thyroglobulin In screening specimens from hypothyroid and normal infants indicated that some Infants with congenital hypothyroidism could be Identified solely on the basis of the thyroglobulin concentration. Comparison of the results of scintigraphy with thyroglobulin levels In the same hypothyroid patients suggested that thryoglobulin provided a more reliable marker for the presence or absence of the thyroid gland than did scintigraphy.