Persistency of Thyroid Dysfunction from Early to Late Pregnancy.

Background: Subclinical thyroid disease occurs in approximately 5-8% of all pregnancies and is associated with a higher risk of adverse outcomes such as miscarriage, preterm birth, and suboptimal child neurodevelopment. It is generally assumed that subclinical thyroid disease that persists from early to late pregnancy is associated with a higher risk of adverse outcomes than transient disease. However, it is unknown as to what percentage of women with subclinical disease during early pregnancy have persistent disease in the third trimester. Methods: This study comprised 42,492 mothers for whom early and late pregnancy thyrotropin (TSH), free thyroxine (fT4), triiodothyronine (T3), or TPOAbs were available and who did not receive thyroid treatment before or during pregnancy. We adjusted for potential confounders, including maternal age, parity, anthropometrics, and ß-hCG concentrations. Results: Subclinical hypothyroidism and hypothyroxinemia persisted in 24.8% and 17.7% of cases. Overt hyperthyroidism persisted in 8.4% of cases while subclinical hyperthyroidism persisted in 20.9% of cases. Low T3 persisted in 43.4% of cases while elevated T3 persisted in 15.7% of cases. TPOAb positivity persisted in 84.0% of cases. In women with subclinical hypothyroidism, a TSH below ∼5 mU/L at the time of diagnosis was associated with an up to 50% lower risk of persistency. The fT4 concentration at diagnosis predicted hyperthyroidism persistency and TPOAb positivity predicted persistency of all disease entities. Conclusions: Early pregnancy thyroid disease only persists until the third trimester in 8.4-24.8% of cases when left untreated. The main predictor for persistency is TPOAb positivity, with TPOAb-positive women having a lower risk that subclinical hypothyroidism or hypothyroxinemia persists, but a higher risk that (subclinical) hyperthyroidism persists.

The Association of Thyroid Function With Bone Density During Childhood.

Context: Although the skeleton is a well-known thyroid hormone target organ, very little data are available on the association of thyroid function with bone outcomes during childhood. Objective: To study the association of thyroid function with bone mass during childhood. Design, Setting, and Participants: Population-based prospective cohort including 4204 children with TSH and free T4 (FT4) measured at the age of 6 years. Main Outcome Measures: Bone density was assessed by a total body dual-energy X-ray absorptiometry scan at the median age of 6 years (95% range, 5.6 to 7.9) and at the age of 10 years (95% range, 9.0 to 10.9) in 4204 and 3404 participants, respectively. Results: There was an inverse association of TSH with bone mineral density (BMD) at the age of 6 (ß -0.028 ± 0.011, P = 0.009) and with follow-up measurements at the age of 10 (ß -0.027 ± 0.011, P = 0.014), but not with bone mineral content (BMC) at the age of 6 (ß -0.028 ± 0.015, P = 0.06) or for follow-up measurements of BMC at the age of 10 (ß -0.011 ± 0.015, P = 0.47). There was an inverse association of FT4 with BMD (ß -0.016 ± 0.006, P = 0.014) and BMC (ß -0.023 ± 0.009, P = 0.009) cross-sectionally, and also at the age of 10 years (BMD: ß -0.018 ± 0.007, P = 0.007; BMC: ß -0.021 ± 0.009, P = 0.020). Conclusion: A higher FT4 concentration is associated with lower bone mass at the age of 6 and at the age of 10 years. These data provide insights into the effects of thyroid function on bone physiology during childhood.

The Association of Thyroid Function With Maternal and Neonatal Homocysteine Concentrations.

Context: High homocysteine concentrations are associated with maternal pregnancy complications and low birth weight, jaundice, and cerebrovascular accidents in neonates. Thyroid hormone may interfere with homocysteine metabolism via stimulation of vitamin B12- and folate-dependent processes and via effects on enzymes of the remethylation pathway. Objective: Investigating the associations of maternal and neonatal thyroid function with homocysteine during pregnancy and after delivery, respectively. Design, Setting, and Participants: Within Generation R study, a population-based prospective cohort, we studied the associations of maternal and neonatal thyroid stimulating hormone (TSH) and free thyroxine (FT4) with homocysteine, folate, and vitamin B12 concentrations using multiple linear regression analyses. Main Outcome Measures: TSH, FT4, homocysteine, folate, and vitamin B12 concentrations were determined in early pregnancy (<18 weeks; N = 1094 women without folic acid supplementation) and in cord blood of 4475 neonates. Results: In neonates, there was a positive association of FT4 with homocysteine and an inverse association of TSH with homocysteine. The associations attenuated after adjustment for folate and vitamin B12 concentration (ß change: for FT4, 0.00559 ± 0.001, P < 0.0001, to 0.00310 ± 0.001, P = 0.015; and for TSH, -0.00165 ± 0.001, P = 0.005, to -0.00086 ± 0.001, P = 0.11). In mothers, there was a positive association of FT4 with homocysteine (P = 0.026) but no association of FT4 with folate or vitamin B12 (P ≥ 0.08). Conclusion: Higher thyroid function is associated with higher homocysteine concentrations in pregnant women and in neonates. These data provide new insights into the effects of thyroid hormone on folate- and vitamin B12-dependent processes during early growth and development.

Childhood Thyroid Function Reference Ranges and Determinants: A Literature Overview and a Prospective Cohort Study.

BACKGROUND: Reported cutoffs for childhood thyrotropin (TSH) and free thyroxine (fT4) reference ranges vary widely, and knowledge on the determinants of childhood thyroid function is sparse. This study aimed to summarize the existing studies on thyroid function reference ranges in children. Furthermore, the objective was to investigate the determinants of childhood TSH and fT4 concentration in a population based-prospective cohort. METHODS: First, to identify studies on childhood thyroid reference ranges, The National Library of Medicine's PubMed, Embase, Ovid Medline, Web of Science, and Google Scholar databases were systematically searched. Second, in a non-selected sample of 4273 children (median age 6.0 years, range 4.9-9.1 years) from the cohort, the associations of age, sex, anthropometric characteristics, ethnicity, maternal education, and time and season at venipuncture were studied with TSH and fT4 concentrations. The study also investigated to what extent between-individual variations in the determinants of TSH and fT4 could influence the calculation of reference ranges. RESULTS: Published reference ranges for TSH and fT4 differ per age range and within age ranges (cutoffs low TSH: 0.13 to >1 mIU/L; high TSH: 2.36 to >10 mIU/L; low fT4: 7.0 to >10 pmol/L; high fT4: 15.5 to >30 pmol/L). In the present cohort, weight, sex, and ethnicity were determinants of TSH (p ≤ 0.03) and fT4 concentrations (p ≤ 0.01), and height and time at venipuncture were determinants of TSH only (p < 0.0001). The between-individual variation depending on clinical determinants for TSH ranged between 0.64 and 0.96 mIU/L (total population 0.87 mIU/L) for the lower limit and 4.30 and 5.62 mIU/L (total population 5.20 mIU/L) for the upper limit, whereas for fT4, the lower limit ranged between 13.6 and 14.2 pmol/L (total population 13.8 pmol/L) and the upper limit ranged between 20.2 and 23.0 pmol/L (total population 20.8 pmol/L). CONCLUSIONS: Considerable differences exist in the reported reference ranges for childhood TSH and fT4 across and within age ranges and assays. The present cohort shows only a minimal association between TSH and fT4, suggesting that the hypothalamus-pituitary-thyroid axis remains unaffected by thyroid interfering factors. Various determinants of TSH and fT4 in children were identified, which accounted for a considerable variation of reference range cutoffs.

Childhood thyroid function, body composition and cardiovascular function.

OBJECTIVE: The cardiovascular system is a known target for thyroid hormone. Early-life cardiovascular alterations may lead to a higher risk of cardiovascular disease in adulthood. Little is known about the effects of thyroid hormone on cardiovascular function during childhood, including the role of body composition in this association. DESIGN: Population-based prospective cohort of children (n = 4251, median age 6 years, 95% range: 5.7-8.0 years). METHODS: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured to assess thyroid function. Left ventricular (LV) mass was assessed with echocardiography. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (CFPWV). Systolic and diastolic blood pressure (BP) was measured. Body composition was assessed by dual-energy X-ray absorptiometry scan. RESULTS: FT4 was inversely associated with LV mass (P = 0.002), and with lean body mass (P < 0.0001). The association of FT4 with LV mass was partially mediated through variability in lean body mass (55% mediated effect). TSH was inversely associated with LV mass (P = 0.010), predominantly in boys. TSH was positively associated with systolic and diastolic BP (both P < 0.001). FT4 was positively associated with CFPWV and diastolic BP (P < 0.0001, P = 0.008, respectively), and the latter association attenuated after adjustment for CFPWV. CONCLUSIONS: At the age of 6 years, higher FT4 is associated with lower LV mass (partially through effects on lean body mass) and with higher arterial stiffness, which may lead to higher BP. Our data also suggest different mechanisms via which TSH and FT4 are associated with cardiovascular function during early childhood.

Human chorionic gonadotropin (hCG) concentrations during the late first trimester are associated with fetal growth in a fetal sex-specific manner.

Human chorionic gonadotropin (hCG) is a pregnancy-specific hormone that regulates placental development. hCG concentrations vary widely throughout gestation and differ based on fetal sex. Abnormal hCG concentrations are associated with adverse pregnancy outcomes including fetal growth restriction. We studied the association of hCG concentrations with fetal growth and birth weight. In addition, we investigated effect modification by gestational age of hCG measurement and fetal sex. Total serum hCG (median 14.4 weeks, 95 % range 10.1-26.2), estimated fetal weight (measured by ultrasound during 18-25th weeks and >25th weeks) and birth weight were measured in 7987 mother-child pairs from the Generation R cohort and used to establish fetal growth. Small for gestational age (SGA) was defined as a standardized birth weight lower than the 10th percentile of the study population. There was a non-linear association of hCG with birth weight (P = 0.009). However, only low hCG concentrations measured during the late first trimester (11th and 12th week) were associated with birth weight and SGA. Low hCG concentrations measured in the late first trimester were also associated with decreased fetal growth (P = 0.0002). This was the case for both male and female fetuses. In contrast, high hCG concentrations during the late first trimester were associated with increased fetal growth amongst female, but not male fetuses. Low hCG in the late first trimester is associated with lower birth weight due to a decrease in fetal growth. Fetal sex differences exist in the association of hCG concentrations with fetal growth.