Machine learning to improve false-positive results in the Dutch newborn screening for congenital hypothyroidism.

OBJECTIVE: The Dutch Congenital hypothyroidism (CH) Newborn Screening (NBS) algorithm for thyroidal and central congenital hypothyroidism (CH-T and CH-C, respectively) is primarily based on determination of thyroxine (T4) concentrations in dried blood spots, followed by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurements enabling detection of both CH-T and CH-C, with a positive predictive value (PPV) of 21%. A calculated T4/TBG ratio serves as an indirect measure for free T4. The aim of this study is to investigate whether machine learning techniques can help to improve the PPV of the algorithm without missing the positive cases that should have been detected with the current algorithm. DESIGN & METHODS: NBS data and parameters of CH patients and false-positive referrals in the period 2007-2017 and of a healthy reference population were included in the study. A random forest model was trained and tested using a stratified split and improved using synthetic minority oversampling technique (SMOTE). NBS data of 4668 newborns were included, containing 458 CH-T and 82 CH-C patients, 2332 false-positive referrals and 1670 healthy newborns. RESULTS: Variables determining identification of CH were (in order of importance) TSH, T4/TBG ratio, gestational age, TBG, T4 and age at NBS sampling. In a Receiver-Operating Characteristic (ROC) analysis on the test set, current sensitivity could be maintained, while increasing the PPV to 26%. CONCLUSIONS: Machine learning techniques have the potential to improve the PPV of the Dutch CH NBS. However, improved detection of currently missed cases is only possible with new, better predictors of especially CH-C and a better registration and inclusion of these cases in future models.

Sex, menopause, and age differences in the associations of persistent organic pollutants with thyroid hormones, thyroxine-binding globulin, and peripheral deiodinase activity: A cross-sectional study of the general Korean adult population.

Persistent organic pollutants (POPs) can disrupt the thyroid hormone system in humans. We assessed the associations of several POPs with serum thyroid hormones (T3 and T4) and thyroid-stimulating hormone, and investigated the modulating effects of sex, menopausal status, and age on these associations, in a subgroup of the adult population (n = 1250) from the Korean National Environmental Health Survey. PCB105 and PCB118 were negatively associated with total T4 in premenopausal females and males aged <50, whereas the associations were insignificant in other groups. PCB180, p,p'-DDE, and p,p'-DDT showed positive associations with total T3 in postmenopausal females; however, among males aged ≥50, PCB118, PCB138, and p,p'-DDE showed negative associations with total T3. The effects of exposure to multiple POPs were examined in multi-factor analyses. Factor 2 comprised PCB52, hexachlorobenzene, and BDE-47 was associated with an increase in free T4 in premenopausal females (ß = 0.015, p = 0.024), while Factor 1, which contained most POPs, was associated with a change in total T3 in postmenopausal females (ß = 0.032, p = 0.040) and males aged ≥50 (ß = -0.039, p = 0.023). Changes in total T4 or total T3 could be explained by differences in thyroxine-binding globulin (TBG) and peripheral deiodinase activity (GD). Negative associations of TBG with PCB105 in premenopausal females and PCB153 in males aged <50 may mediate the effect of decreasing total T4. PCB180, p,p'-DDE, p,p'-DDT, and Factor 1 were positively associated with GD, which is consistent with an increased total T3 in postmenopausal females. PCB118 was negatively associated with GD and total T3 in males aged ≥50. BDE-47 and ß-hexachlorocyclohexane were associated with thyroid autoantibodies in premenopausal females and males aged <50. Our observations suggest that the thyroid-disrupting effects of POPs may differ by sex, sex hormonal status, and age, and may be mediated by TBG and GD.

Identification of a novel mutation in thyroxine-binding globulin (TBG) gene associated with TBG-deficiency and its effect on the thyroid function.

PURPOSE: This study presents a case of familial transmission of thyroxine-binding globulin (TBG) deficiency. The SERPINA7-gene which codes for TBG is located on the X-chromosome (Xq21-22). More than 45 mutations have been reported to cause TBG- deficiency from various countries, but none from India so far. Genetic analysis of SERPINA7 gene was carried out to determine the cause of low TBG levels in one family. METHODS: DNA samples of the propositus and the family members were subjected to Polymerase Chain Reaction (PCR) followed by direct sequencing. Allele-specific PCR and Next-gen sequencing (NGS) were employed to confirm the site of the mutation. Thyroid function tests were estimated by Radioimmunoassay (RIA) and Immunoradiometric assay (IRMA) kits. X-chromosomal inactivation status was analyzed in the female members harboring the mutation. RESULTS: A mutational screening in this family revealed a novel frame-shift mutation S353Q, 354fs3X in the exon 4 of the SERPINA7 gene which will be referred to as TBG-complete deficiency-India (TBG-CD-Ind). One out of four female family members harboring the mutation showed selective X-chromosomal inactivation. The affected family members were clinically euthyroid initially, showed changes in the thyroid function when tested after a long time span. However, the changes in the thyroid function in the affected family members had an autoimmune etiology. CONCLUSION: This study presents the first report of TBG-CD from India wherein a novel frameshift mutation referred to as TBG-CD-Ind (S353Q, 354fs3X) in the SERPINA7 gene was detected. No apparent association was identified between thyroid function and the TBG-mutation in the affected subjects. A detailed biochemical and genomic testing to determine the exact cause of discordant TFT in the patients would certainly aid in the unequivocal diagnosis of the thyroid function and for the precise individualized treatment.

Detecting Congenital Central Hypothyroidism by Newborn Screening: Difficulty in Distinguishing from Congenital Thyroxine-Binding Globulin Deficiency.

BACKGROUND/AIMS: Congenital central hypothyroidism (CH-C) can be detected on newborn screening (NBS) by programs using thyroxine (T4)-reflex thyroid-stimulating hormone (TSH) test approach. CH-C must be distinguished from T4-binding globulin (TBG) deficiency. We sought to determine whether thyroid function tests reliably separate CH-C from TBG deficiency. METHODS: We analyzed NBS and serum free and total T4, T3 resin uptake (T3RU) or TBG, and TSH for infants in the Northwest Regional NBS Program (NWRSP) between the years 2008 and 2015 with either CH-C or TBG deficiency. RESULTS: We discovered a significant overlap in T3RU and TBG levels amongst 21 cases of CH-C and 250 cases of TBG deficiency. Mean serum TBG levels were lower in CH-C cases (20.3 µg/mL, range 14.2-33.3) than what is reported in healthy infants (28.6 µg/mL, range 19.1-44.6). Serum free T4 was lower in CH-C cases than TBG deficiency but did not always differentiate between the two conditions. CONCLUSION: CH-C benefits from detection on NBS but must be distinguished from TBG deficiency. The diagnosis of CH-C rests solely on subnormal serum free T4, but is supported by the demonstration of other pituitary hormone deficiencies. As an overlap exists, serum TBG (or T3RU) levels do not play a role in the diagnosis of CH-C.

Changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation.

OBJECTIVE: Thyroid hormone concentrations can be disturbed during critical illness. Our aim was to determine changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: We included 21 ECMO-treated neonates. Age-specific s.d. scores (SDS) of free and total thyroxine (FT4; TT4), reverse and total triiodothyronine (rT3; TT3), thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) were determined at six fixed time-points. Data were analyzed using general linear models. RESULTS: At baseline, mean SDS FT4 (-0.78, 95% CI: -1.37 to -0.19), TT4 (-1.97, 95% CI: -2.76 to -1.18), TT3 (-0.88, 95% CI: -1.13 to -0.63), TSH (-2.14, 95% CI: -2.93 to -1.35) and TBG (-3.52, 95% CI: -4.55 to -2.50) were low with high mean SDS rT3 (0.53, 95% CI: 0.28 to 0.78). One hour after start ECMO, TT4, TSH and TBG had further declined; 12 h after start ECMO TT3 had declined (all P<0.05). After this decline, mean SDS TSH increased to the baseline level 12 h after start ECMO (-2.50, 95% CI: -3.22 to -1.79), and was higher than baseline 48 h after start ECMO (-0.56, 95% CI: -1.29 to 0.17). This TSH increase was followed by increases in TT4 and TT3. FT4 remained constant within the normal range during ECMO. CONCLUSIONS: Thyroid hormone concentrations before ECMO were suggestive of non-thyroidal illness syndrome (NTIS). During ECMO, increases in TSH, TT4 and TT3 after an initial decline possibly reflect spontaneous restoration of the hypothalamic-pituitary-thyroid axis. FT4 remained constant within the normal range. This suggests that thyroxine therapy is not required during ECMO.

Polychlorinated biphenyl exposure and deiodinase activity in young infants.

BACKGROUND: Several studies have shown effects of polychlorinated biphenyls (PCBs) on serum thyroid hormone levels in pregnant woman and their infants, while other studies did not find such effects. How PCBs might affect thyroid hormone metabolism, is still unclear. Potential mechanisms are direct influence on the thyroid gland, binding to thyroid binding proteins, increased excretion or metabolism of thyroid hormones by deiodinases or sulfatases. It is also not well known whether the effect on thyroid hormone levels is caused by PCBs themselves, or by their hydroxylated metabolites (OH-PCBs). OBJECTIVE: To determine the effects of perinatal exposure to PCBs and OH-PCBs on thyroid hormone levels in cord blood and in serum of newborn infants. METHODS: In a Dutch cohort of 100 mother-infant pairs, exposed to background PCB levels, correlations were assessed between 10 PCBs and 6 OH-PCBs in maternal blood during pregnancy and serum thyroxine (T4), T4 sulfate (T4S), triiodothyronine (T3), reverse T3 (rT3), thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) levels in cord blood and in serum of three- and 18-month-old infants. We corrected for age of the mother, gestational age, gender and type of feeding. RESULTS: After correction, prenatal levels of three of 10 measured PCBs showed a positive correlation with cord serum T3, and four PCBs showed a negative correlation with cord serum rT3. After correction, two PCBs and the sum of the 10 measured PCBs were positively correlated with the cord serum T3/rT3 ratio, an indicator of deiodinase 3 activity. No correlations were found between PCBs and T4, TSH and TBG in cord blood. 4-OH-PCB-107 was correlated with T4 at 3months and T4, T4S and T3 at 18months. CONCLUSION: Our results suggest that PCBs have a negative effect on deiodinase type 3 activity, as reflected by a positive correlation with the T3/rT3 ratio. We identified a potential mechanism by which PCBs may affect thyroid hormone metabolism during human development.

Exposure to pyrethroids insecticides and serum levels of thyroid-related measures in pregnant women.

Possible association between environmental exposure to pyrethroid insecticides and serum thyroid-related measures was explored in 231 pregnant women of 10-12 gestational weeks recruited at a university hospital in Tokyo during 2009-2011. Serum levels of free thyroxine (fT4), thyroid stimulating hormone (TSH) and thyroid biding globulin (TBG) and urinary pyrethroid insecticide metabolite (3-phenoxybenzoic acid, 3-PBA) were measured. Obstetrical information was obtained from medical records and dietary and lifestyle information was collected by self-administered questionnaire. Geometric mean concentration of creatinine-adjusted urinary 3-PBA was 0.363 (geometric standard deviation: 3.06) µg/g cre, which was consistent with the previously reported levels for non-exposed Japanese adult females. The range of serum fT4, TSH and TBG level was 0.83-3.41 ng/dL, 0.01-27.4 µIU/mL and 16.4-54.4 µg/mL, respectively. Multiple regression analysis was carried out by using either one of serum levels of thyroid-related measures as a dependent variable and urinary 3-PBA as well as other potential covariates (age, pre-pregnancy BMI, parity, urinary iodine, smoking and drinking status) as independent variables: 3-PBA was not found as a significant predictor of serum level of thyroid-related measures. Lack of association may be due to lower pyrethroid insecticide exposure level of the present subjects. Taking the ability of pyrethroid insecticides and their metabolite to bind to nuclear thyroid hormone (TH) receptor, as well as their ability of placental transfer, into consideration, it is warranted to investigate if pyrethroid pesticides do not have any effect on TH actions in fetus brain even though maternal circulating TH level is not affected.

Na+/I- symporter and type 3 iodothyronine deiodinase gene expression in amniotic membrane and placenta and its relationship to maternal thyroid hormones.

Placental type 3 iodothyronine deiodinase (D3) potentially protects the fetus from the elevated maternal thyroid hormones. Na(+)/I(-) symporter (NIS) is a plasma membrane glycoprotein, which mediates active iodide uptake. Our objectives were to establish the distribution of NIS and D3 gene expressions in the placenta and the amniotic membrane and to investigate the relationship between placental D3 and NIS gene expressions and maternal iodine, selenium, and thyroid hormone status. Thyroid hormones, urinary iodine concentration (UIC), and selenium levels were measured in 49 healthy term pregnant women. NIS and D3 gene expressions were studied with the total mRNA RT-PCR method in tissues from maternal placenta (n = 49), fetal placenta (n = 9), and amniotic membrane (n = 9). NIS and D3 gene expressions were shown in the fetal and maternal sides of the placenta and amniotic membrane. Mean blood selenium level was 66 ± 26.5 µg/l, and median UIC was 143 µg/l. We could not demonstrate any statistically significant relationship of spot UIC and blood selenium with NIS and D3 expression (p > 0.05). Positive correlations were found between NIS and thyroxine-binding globulin (TBG) (r = 0.3, p = 0.042) and between D3 and preoperative glucose levels (r = 0.4, p = 0.006). D3 and NIS genes are expressed in term placenta and amniotic membrane; thus, in addition to placenta, amniotic membrane contributes to regulation of maternofetal iodine and thyroid hormone transmission. Further studies are needed to clarify the relationship between maternal glucose levels and placental D3 expression and between TBG and placental NIS expression.

Thyroid disturbance related to chronic hepatitis C infection: role of CXCL10.

Association between autoimmune thyroid diseases (AITD) and hepatitis C is controversial, but may occur or worsen during alpha-interferon treatment. The mechanism responsible for autoimmune diseases in infected patients has not been fully elucidated. This study aims to evaluate the frequency of AITD in chronic hepatitis C and the association of chemokine (CXC motif) ligand 10 (CXCL10) and AITD. One hundred and three patients with chronic hepatitis C and 96 controls were prospectively selected to clinical, hormonal, thyroid autoimmunity and ultrasound exams, besides thyroxine-binding globulin (TBG) and CXCL10 measurements and hepatic biopsies. The frequency of AITD among infected subjects was similar to controls. TT3 and TT4 distributions were right shifted, as was TBG, which correlated to both of them. Thyroid heterogeneity and hypoechogenicity were associated with AITD. Increased vascularization was more prevalent in chronic hepatitis C.CXCL10 was higher in infected patients (p=0.007) but was not related to thyroid dysfunction. Increase in CXCL10 levels were consistent with hepatic necroinflammatory activity (p=0.011). In summary, no association was found between chronic hepatitis C and AITD. Infected subjects had higher TT3 and TT4 which were correlated to TBG. Increased CXCL10 was not associated to thyroid dysfunction in HCV-infected population.

Using changes in binding globulins to assess oral contraceptive compliance.

BACKGROUND: Validity of oral contraceptive pill (OCP) clinical trial results depends on participant compliance. Ethinyl estradiol (EE2) induces increases in hepatic binding globulin (BG) levels. Measuring these BG increases may provide an effective and convenient approach to distinguish noncompliant from compliant OCP users in research settings. This analysis evaluated the usefulness of measuring increases in corticosteroid-, sex-hormone- and thyroxine-binding globulins (CBG, SHBG and TBG, respectively) as measures of OCP compliance. METHODS: We used frozen serum from a trial that compared ovarian suppression between normal-weight and obese women randomized to one of two OCPs containing EE2 and levonorgestrel (LNG). Based on serial LNG measurements during the trial, 17% of participants were noncompliant. We matched noncompliant participants with compliant participants by age, body mass index, ethnicity and OCP formulation. We measured CBG, SHBG and TBG levels and compared change from baseline to 3-month follow-up between the noncompliant and compliant participants. Construction of receiver operator characteristic (ROC) curves allowed comparison of various BG measures. RESULTS: Changes in CBG and TBG distinguished OCP noncompliant users from compliant users [area under the ROC curve (AUROC), 0.86 and 0.89, p<.01]. Changes in SHBG were less discriminating (AUROC 0.69) CONCLUSIONS: EE2-induced increases in CBG and TBG provide a sensitive integrated marker of compliance with an LNG-containing OCP.

Hypothalamic-pituitary-thyroid axis function in women with a menstrually related mood disorder: association with histories of sexual abuse.

INTRODUCTION: We previously reported a unique hypothalamic-pituitary-thyroid (HPT) axis profile in women with a menstrually related mood disorder (MRMD) who also had a history of sexual abuse (SA). In the present study, we sought to extend that work by examining the association of an SA history with HPT-axis disturbance in both women with MRMD and women without MRMD. METHODS: Fifty-seven women met the prospective criteria for MRMD (23 with an SA history), and 52 women were non-MRMD (18 with an SA history). Thyroid-stimulating hormone, thyroxin (T4; total and free), and triiodothyronine (T3; total and free) were evaluated in serum, together with thyroid hormone ratios reflecting T4 to T3 conversion. RESULTS: Women with MRMD, compared with women without MRMD, had elevated T3/T4 ratios (p values ≤ .01; reflecting increased conversion of T4 to T3) and lower free and total T4 concentrations (p values = .01). Higher T3/T4 ratios and lower T4 concentrations predicted more severe premenstrual symptoms in all women. An SA history, irrespective of MRMD status, was associated with elevated thyroid-stimulating hormone concentrations (p = .03). However, in women with MRMD, an SA history was associated with elevated T3 concentrations (p = .049), whereas in women without MRMD, an SA history was associated with decreased T3 concentrations (p = .02). CONCLUSIONS: An MRMD and an SA history are associated with independent and interactive effects on the HPT axis. The evidence that an MRMD moderates the influence of SA on T3 concentrations contributes to a growing body of work suggesting that an SA history may identify a distinct subgroup of women with MRMD.

Thyroid hormone metabolism and environmental chemical exposure.

BACKGROUND: Polychlorinated dioxins and -furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism.Influences of brominated flame retardants, PCDD/F's and dioxin like-PCBs (dl-PCB's) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3', 5,5'tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3',5- triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort. METHODS: Vena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels. RESULTS: The current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group. CONCLUSION: Once again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.

Serum thyroid hormone levels in healthy children from birth to adulthood and in short children born small for gestational age.

CONTEXT: Age-appropriate reference ranges for thyroid hormones are required for detecting pediatric thyroid dysfunction. Data on thyroid hormones and peripheral thyroid metabolism in short children born small for gestational age (SGA) before and during GH treatment are lacking. OBJECTIVES: Our objectives were to obtain pediatric thyroid hormone reference ranges; to investigate thyroid hormones in short SGA children before puberty, during puberty, and during postponement of puberty by GnRH analog; and to evaluate thyroid hormones during GH treatment. PATIENTS AND DESIGN: In 512 healthy children (225 females; 0-18 yr), free T(4) (FT(4)), TSH, total T(4), T(3), rT(3), and T(4)-binding globulin were determined. Reference ranges were calculated using the linearity, median, and skewness method. In 125 short SGA children (62 females; mean age 11.3 yr), thyroid hormones were analyzed before and after 2 yr of GH treatment and additional GnRH analog. RESULTS: Thyroid references showed wide ranges postnatally and age-specific patterns thereafter, similar in boys and girls. Untreated short SGA children had similar FT(4) and T(4) levels as the reference population but significantly higher T(3), rT(3), and T(4)-binding globulin levels. During puberty and during GH treatment, FT(4) and rT(3) significantly decreased, whereas T(3) significantly increased. CONCLUSION: Age-specific thyroid reference ranges are presented. Puberty and GH treatment both induce changes in peripheral thyroid metabolism, resulting in more biologically active T(3) at the expense of less inactive rT(3), possibly mediated by IGF-I. GH treatment induces altered peripheral thyroid metabolism but does not result in thyroid dysfunction.

Inverse log-linear relationship between thyroid-stimulating hormone and free thyroxine measured by direct analog immunoassay and tandem mass spectrometry.

BACKGROUND: Accurate measurement of free thyroxine (FT(4)) is important for diagnosing and managing thyroid disorders. Most laboratories measure FT(4) by direct analogue immunoassay methods. The validity of these methods have recently been questioned. The inverse log-linear relationship between FT(4) and thyroid-stimulating hormone (TSH) is well described and provides a physiological rationale on which to base an evaluation of FT(4) assays. METHODS: The study included 109 participants for whom FT(4) measurement was requested by their clinician. Samples were selected for inclusion to reflect a wide spectrum of TSH and albumin results. FT(4) and TSH were measured by use of the Siemens Immulite immunoassay (IA). FT(4) was also measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (MS-FT(4)). RESULTS: The inverse log-linear correlation coefficient between TSH and FT(4) was significantly better (P < 0.0001) for MS-FT(4) (0.84, 95% CI, 0.77-0.88) than for IA-FT(4) (0.45, 95% CI, 0.29-0.59). IA-FT(4) showed a significant correlation with albumin (Spearman correlation coefficient 0.45, 95% CI, 0.29-0.5, P < 0.0001) and thyroxine-binding globulin (TBG) (Spearman correlation coefficient 0.23, 95% CI, 0.05-0.41, P = 0.02). In contrast, FT(4) measurement by LC-MS/MS did not show a significant correlation with albumin or TBG. CONCLUSIONS: The inverse log-linear relationship between FT(4) and TSH was significantly better for FT(4) measured by LC-MS/MS than by IA. The MS-FT(4) method therefore provides FT(4) results that agree clinically with those obtained for TSH. Additionally, the significant correlation between IA-FT(4) with albumin and TBG suggests that this FT(4) method depends on binding protein concentrations and consequently does not accurately reflect FT(4).

Parameters of thyroid function throughout and after pregnancy in an iodine-deficient population.

BACKGROUND: The thyroid hormone milieu is of crucial importance for the developing fetus. Pregnancy induces physiological changes in thyroid homeostasis that are influenced by the iodine status. However, longitudinal studies addressing thyroid function during pregnancy and after delivery are still lacking in mild-to-moderate iodine-deficient populations. Here we characterize the serum parameters of thyroid function throughout pregnancy, and until 1 year after delivery, in a population of pregnant women whom we have previously reported to be iodine deficient (median urinary iodine levels below 75 microg/L). METHODS: One hundred eighteen pregnant women were studied. Clinical data were recorded and serum was collected. Serum total and free thyroxine (T(4)) and triiodothyronine (T(3)), thyroid-stimulating hormone, thyroxine-binding globulin, and thyroglobulin were measured. RESULTS: Mean total T(4) ranged from 159 at the start of gestation to 127 nmol/L at 1 year after delivery, free T(4) from 14.2 to 17.8 pmol/L, total T(3) from 2.4 to 2.1 nmol/L, free T(3) from 6.7 pmol/L to 6.4 pmol/L, thyroid-stimulating hormone from 1.2 to 1.4 mIU/L, T(4)-binding globulin from 62.0 to 26.9 mg/L, and thyroglobulin from 11 to 10 microg/L. CONCLUSION: The pregnant women in this study had an absence of the usual free T(4) spike and a smaller than expected increment in total T(4), described during pregnancy in iodine-sufficient populations. A greater number of women had subclinical hypothyroidism compared with iodine-sufficient populations. This hormonal profile, most likely due to iodine insufficiency, may result in inadequate thyroid hormone supply to the developing fetus. We conclude that care should be taken when reviewing the results of thyroid hormone tests in iodine-insufficient populations and when no gestation-specific reference values have been established. In addition, we recommend iodine supplementation in our population and populations with similar iodine status, particularly during pregnancy and lactation.