Maternal hypothyroidism and adverse outcomes of pregnancy.

OBJECTIVE: Hypothyroidism has been associated with pregnancy complications, but uncertainty prevail regarding the severity and the role of thyroid autoimmunity. This study aimed to evaluate adverse pregnancy outcomes by exposure to maternal hypothyroidism and thyroid autoimmunity. DESIGN: Retrospective cohort study. PATIENTS: 14,744 singleton pregnancies from the North Denmark Region Pregnancy Cohort (2011-2015). MEASUREMENTS: Maternal thyroid stimulating hormone (TSH), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (Tg-Ab) were retrospectively measured in early pregnancy blood samples (ADVIA Centaur XPT, Siemens Healthineers). Adjusted odds ratio (aOR) with 95% confidence interval (CI) was used to estimate associations between maternal hypothyroidism (TSH cut-offs: 6.0 and 10 mIU/L), thyroid autoimmunity (TPO-Ab cut-off: 60 U/ml, Tg-Ab cut-off: 33 U/ml), and adverse pregnancy outcomes. RESULTS: Pregnancy outcomes were 93.2% live births, 6.5% spontaneous abortions, and 0.3% stillbirths. The frequency of spontaneous abortion was 6.5% when TSH was below 6.0 mIU/L, 6.5% when above 6.0 mIU/L (aOR 1.0 [95% CI: 0.5-2.0]), and 12.5% when above 10 mIU/L (aOR: 2.0 [95% CI: 0.8-5.2]). For outcome of preterm birth, the frequency was 5.4% when TSH was below 6.0 mIU/L, 7.8% when above 6.0 mIU/L (aOR 1.5 [95% CI: 0.7-2.9]), and 11.4% when above 10 mIU/L (aOR: 2.6 [95% CI: 0.9-7.3]). No association was found between thyroid autoantibodies and spontaneous abortion (TPO-Ab: aOR: 1.0 [0.8-1.3], Tg-Ab: 1.0 [0.8-1.2]) or preterm birth (TPO-Ab: aOR: 1.0 [0.8-1.2], Tg-Ab: 0.9 [0.7-1.2]). CONCLUSION: A high frequency of adverse pregnancy outcomes was seen among pregnancies exposed to maternal TSH above 10 mIU/L, whereas no association with thyroid autoantibodies was seen.

Iodine status in Danish pregnant women after an increase in iodine fortification.

OBJECTIVE: Iodine fortification programmes are implemented in many countries and often associated with an increase in population iodine intake. However, the initial attempt may not be sufficient and in Denmark the level of iodine added to salt was increased in 2019. Sparse evidence is available on the impact of such modification in iodine fortification. The aim of this study was to evaluate iodine status in Danish pregnant women in 2021 after this increase in iodine fortification and compare to iodine status in 2012. DESIGN: Cross-sectional study. PATIENTS: Pregnant women in the North Denmark Region referred for routine obstetric ultrasound in 2021. MEASUREMENTS: Participants filled out a questionnaire and delivered a spot urine. Median urinary iodine concentration (UIC) was calculated and assessed according to the recommended range in pregnancy (150-249 µg/L). RESULTS: Altogether 147 pregnant women were included and 88% used iodine-containing supplements. Median UIC was overall 77 µg/L [95% confidence interval (CI): 61-96 µg/L], which was lower than in 2012 (101 µg/L [95% CI: 89-111 µg/L]) (p < 0.001). Considering sources of iodine intake in pregnancy, lower daily intake of dairy products (p = 0.008) and bread (p < 0.001) and a lower content of iodine in the supplement used (p < 0.001) was seen in 2021 compared to 2012. CONCLUSION: Despite an increase in iodine fortification and frequent use of iodine-containing supplements, iodine status in pregnant women in the North Denmark Region was insufficient. Results call for continued monitoring and attention to ensure adequate iodine status during pregnancy in Denmark.

Cut-offs for thyroid peroxidase and thyroglobulin antibodies in early pregnancy.

Objective: Thyroid disease in women of reproductive age is mainly of autoimmune origin, and thyroid peroxidase antibodies (TPO-Ab) as well as thyroglobulin antibodies (Tg-Ab) are key markers. Adding to this, much focus in pregnancy is on euthyroid women who are thyroid antibody positive. Evidence to substantiate the cut-offs for the definition of thyroid autoantibody positivity in early pregnant women is warranted. Methods: Stored serum samples from 14,030 Danish pregnant women were used for the measurement of TPO-Ab, Tg-Ab, TSH, and free thyroxine (ADVIA Centaur XPT, Siemens Healthineers). Among all women, a reference cohort of 10,905 individuals was identified for the establishment of antibody cut-offs. Percentile cut-offs for TPO-Ab and Tg-Ab were determined using regression on order statistics (the reference cohort). The established cut-offs were then applied (the full cohort), and frequencies of early pregnancy as well as later diagnosis of hypothyroidism were evaluated. Results: The highest established cut-offs (95th, 97.5th, and 99th percentiles) were 59, 68, and 81 U/mL for TPO-Ab and 33, 41, and 52 U/mL for Tg-Ab. When the cut-offs were applied in the full cohort, 11.0, 10.2, and 9.7% were TPO-Ab positive, whereas 13.3, 12.3, and 11.2% were Tg-Ab positive. Antibody-positive women (TPO-Ab and/or Tg-Ab) had higher median TSH and were more likely to have hypothyroidism in early pregnancy and to be diagnosed with hypothyroidism during follow-up. Conclusions: This large study established and evaluated pregnancy-specific cut-offs for TPO-Ab and Tg-Ab. The findings are important regarding the classification of exposure in pregnancy and assessment of thyroid autoimmunity per se.

Classification of maternal thyroid function in early pregnancy using repeated blood samples.

Objective: The assessment of maternal thyroid function in early pregnancy is debated. It is well-established that pregnancy-specific reference ranges preferably should be used. We speculated if the use of repeated blood samples drawn in early pregnancy would influence the classification of maternal thyroid function. Methods: Pregnant women with repeated early pregnancy blood samples were identified in the North Denmark Region Pregnancy Cohort. Each sample was used for the measurement of TSH, free T4 (fT4), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (Tg-Ab) (ADVIA Centaur XPT, Siemens Healthineers). Method- and pregnancy week-specific reference ranges were used for the classification of maternal thyroid function. Results: Among 1466 pregnancies included, 89 women had TSH above the upper reference limit in the first sample (median pregnancy week 8) and 44 (49.4%) of these similarly had high TSH in the second sample (median week 10). A total of 47 women had TSH below the lower reference limit in the first sample and 19 (40.4%) of these similarly had low TSH in the second sample. Regarding women classified with isolated changes in fT4 in the first sample, less than 20% were similarly classified as such in the second sample. The percentage agreement between the samples was dependent on the level of TSH in the first sample and the presence of TPO- and Tg-Ab. Conclusion: In a large cohort of pregnant women, the classification of maternal thyroid function varied considerably with the use of repeated blood samples. Results emphasize a focus on the severity of thyroid function abnormalities in pregnant women.

Maternal adiposity, smoking, and thyroid function in early pregnancy.

OBJECTIVE: A high activity of the deiodinase type 2 has been proposed in overweight, obese, and smoking pregnant women as reflected by a high triiodothyronine (T3)/thyroxine (T4) ratio. We speculated how maternal adiposity and smoking would associate with different thyroid function tests in the early pregnancy. DESIGN: Cross-sectional study within the North Denmark Region Pregnancy Cohort. METHODS: Maternal thyroid-stimulating hormone (TSH), total T4 (TT4), total T3 (TT3), free T4 (fT4), and free T3 (fT3) were measured in stored blood samples (median gestational week 10) by an automatic immunoassay. Results were linked to nationwide registers, and live-birth pregnancies were included. The associations between maternal adiposity (overweight or obese), smoking, and log-transformed TSH, fT3/fT4 ratio, and TT3/TT4 ratio were assessed using multivariate linear regression and reported as adjusted exponentiated ß coefficient (aß) with 95% CI. The adjusted model included maternal age, parity, origin, week of blood sampling, and diabetes. RESULTS: Altogether 5529 pregnant women were included, and 40% were classified with adiposity, whereas 10% were smoking. Maternal adiposity was associated with higher TSH (aß 1.13 (95% CI 1.08-1.20)), whereas maternal smoking was associated with lower TSH in the early pregnancy (0.875 (0.806-0.950)). Considering the T3/T4 ratio, both maternal adiposity (fT3/fT4 ratio: 1.06 (1.05-1.07); TT3/TT4 ratio: 1.07 (1.06-1.08)) and smoking (fT3/fT4 ratio: 1.07 (1.06-1.09); TT3/TT4 ratio: 1.10 (1.09-1.12)) were associated with a higher ratio. CONCLUSIONS: In a large cohort of Danish pregnant women, adiposity and smoking showed opposite associations with maternal TSH. On the other hand, both conditions were associated with a higher T3/T4 ratio in early pregnancy, which may reflect altered deiodinase activity.

Classification of Thyroid Dysfunction in Pregnant Women Differs by Analytical Method and Type of Thyroid Function Test.

CONTEXT: Physiological alterations challenge the assessment of maternal thyroid function in pregnancy. It remains uncertain how the reference ranges vary by week of pregnancy, and how the classification of disease varies by analytical method and type of thyroid function test. DESIGN: Serum samples from Danish pregnant women (n = 6282) were used for the measurement of thyrotropin (TSH), total and free thyroxine (T4), total and free 3,5,3'-triiodothyronine (T3), and T-uptake using "Method A" (Cobas 8000, Roche Diagnostics). TSH and free T4 were also measured using "Method B" (ADVIA Centaur XP, Siemens Healthineers). MAIN OUTCOME MEASURES: Pregnancy week- and method-specific reference ranges were established among thyroid antibody-negative women (n = 4612). The reference ranges were used to classify maternal thyroid function, and results were compared by analytical method and type of thyroid function test. RESULTS: The reference ranges for TSH showed a gradual decrease during pregnancy weeks 4 to 14, a gradual increase was observed for total T4, total T3, and T-uptake, whereas free T4 and free T3 showed less variation. When TSH and free T4 were used, Method A classified 935 (14.9%) with abnormal thyroid function, Method B a total of 903 (14.4%), and the methods agreed on 554 individuals. When TSH and total T4 were used, 947 (15.1%) were classified with abnormal thyroid function, and classifications by either total T4 or free T4 agreed on 584 individuals. CONCLUSIONS: Even when pregnancy week- and method-specific reference ranges were established, the classification of maternal thyroid dysfunction varied considerably by analytical method and type of thyroid function test.

Management of thyrotoxicosis during pregnancy.

Thyrotoxicosis during pregnancy should be adequately managed and controlled to prevent maternal and fetal complications. The evaluation of thyroid function in pregnant women is challenged by the physiological adaptations associated with pregnancy, and the treatment with antithyroid drugs (ATD) raises concerns for the pregnant woman and the fetus. Thyrotoxicosis in pregnant women is mainly of autoimmune origin, and the measurement of thyroid stimulating hormone-receptor antibodies (TRAb) plays a key role. TRAb helps to distinguish the hyperthyroidism of Graves' disease from gestational hyperthyroidism in early pregnancy, and to evaluate the risk of fetal and neonatal hyperthyroidism in late pregnancy. Furthermore, the measurement of TRAb in early pregnancy is recommended to evaluate the need for ATD during the teratogenic period of pregnancy. Observational studies have raised concern about the risk of birth defects associated with the use of ATD in early pregnancy and challenged the clinical management and choice of treatment.

Thyroid function abnormalities and thyroid autoantibodies in Danish pregnant women.

OBJECTIVE: Abnormal thyroid function in pregnant women is a matter of concern. Knowledge on the occurrence of known and unidentified thyroid function abnormalities in a large unselected cohort of pregnant women is warranted as part of the debate on benefits and risks of routine testing. DESIGN: Cohort study. PARTICIPANTS: A total of 14 323 pregnant women in the North Denmark Region, who had a blood sample drawn as part of the prenatal screening program in early pregnancy (2011-2015). MEASUREMENTS: TSH, free thyroxine, thyroid peroxidase and thyroglobulin antibodies were measured in the stored blood samples using an automatic immunoassay (ADVIA Centaur XPT, Siemens Healthineers). Cohort-, method- and week-specific reference ranges were used for classification of maternal thyroid function, and a cut-off of 60 U/mL was used for thyroid autoantibodies. Information in Danish nationwide registers was used to identify diagnosed and treated maternal thyroid disease. RESULTS: Overall, 15.2% had thyroid function abnormalities in the early pregnancy and 14.9% were thyroid peroxidase and/or thyroglobulin antibody positive. Among women with known thyroid disease (n = 365), the frequency of abnormal thyroid function was 45.7%, and 62.8% in women (n = 172) who received current treatment in the pregnancy. When maternal thyroid disease was diagnosed in the years following pregnancy (n = 313), 46.7% had abnormal thyroid function and 54.3% were thyroid peroxidase and/or thyroglobulin antibody positive in the early pregnancy. CONCLUSION: Thyroid function abnormalities and thyroid autoantibodies were common in Danish pregnant women, particularly in women with known or later diagnosed thyroid disease, which raises concern about inadequately treated and unidentified abnormal thyroid function.

Maternal Thyroid Function, Use of Antithyroid Drugs in Early Pregnancy, and Birth Defects.

CONTEXT: Antithyroid drug (ATD) therapy in early pregnancy is associated with birth defects, but more data are needed to substantiate the risk associated with different types of ATD. Furthermore, the role of abnormal maternal thyroid function per se remains unclarified. OBJECTIVE: To evaluate the risk of birth defects associated with the use of ATD in an extended nationwide cohort and the role of abnormal maternal thyroid function in birth cohorts including stored maternal blood samples from early pregnancy. PARTICIPANTS: Danish pregnant women and their live-born children, including 1,243,353 children from a Nationwide Register-Based Cohort (NRBC), 1997 to 2016; 8830 children from the Danish National Birth Cohort (DNBC), 1997 to 2003; and 14,483 children from the North Denmark Region Pregnancy Cohort (NDRPC), 2011 to 2015. MAIN OUTCOME MEASURES: Birth defects diagnosed before 2 years of age. RESULTS: In the NRBC, altogether 2718 (0.2%) children had been exposed to ATD in early pregnancy. The overall frequency of birth defects was 6.7% (95% CI, 6.7% to 6.8%) in nonexposed children and higher after exposure to methimazole/carbimazole (9.6%; 95% CI, 8.2% to 11.2%) and propylthiouracil (8.3%; 95% CI, 6.7% to 10.3%). On the other hand, the frequency of maternal thyroid dysfunction in early pregnancy was similar in the random cohort and in cases of birth defect in the DNBC (12.4 vs 12.6%, P = 0.8) and the NDRPC (15.1 vs 15.4%, P = 0.8). CONCLUSIONS: Results corroborate an increased risk of birth defects associated with the use of ATD in early pregnancy and suggest that abnormal maternal thyroid function is not a major risk factor for birth defects.

Pregnancy Week-Specific Reference Ranges for Thyrotropin and Free Thyroxine in the North Denmark Region Pregnancy Cohort.

BACKGROUND: Physiological changes in maternal thyroid function during pregnancy necessitate the use of pregnancy-specific reference ranges. Dynamic changes in thyrotropin (TSH) within the first trimester of pregnancy have been reported, but more evidence is needed to substantiate the findings. The objective of this study was to estimate pregnancy week-specific reference ranges for maternal TSH and free thyroxine (fT4) in early pregnancy. METHODS: The study consecutively recruited serum residues from blood samples collected as part of the prenatal screening in the North Denmark Region, 2011-2015. TSH, fT4, thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured using an ADVIA Centaur XPT immunoassay. The reference cohort included 10,337 pregnant women who had no thyroid disease or other autoimmune diseases and were TPOAb- and TgAb negative. The main outcome measures were lower and upper reference limits (2.5th and 97.5th percentiles) for TSH and fT4 stratified by week of pregnancy. RESULTS: Blood samples were drawn in pregnancy weeks 4-20 (median week 10), and 92% of the pregnancies ended with a live birth. TSH varied considerably in the first trimester of pregnancy, and the levels were highest in early pregnancy (weeks 4-6: 0.6-3.7 mIU/L) followed by a gradual decline to lower levels in weeks 9-11 (0.1-2.8 mIU/L) and 12-14 (0.03-2.8 mIU/L). Maternal fT4 showed less variation (weeks 4-6: 12-20 pmol/L; weeks 9-11: 13-21 pmol/L; weeks 12-14: 13-20 pmol/L). CONCLUSIONS: The results corroborate dynamic week-specific changes in maternal TSH in early pregnancy. The use of uniform lower and upper reference limits for TSH in early pregnancy may be too simple.