Through the last twenty years, the knowledge on thyroid disease during pregnancy has rapidly expanded. It is well documented that women with overt hypothyroidism during pregnancy have an increased risk of pregnancy loss and adverse pregnancy outcome [
The persistency of mild (subclinical) hypothyroidism may differ according to ethnicity and age; however, TSH increase with age [
The aim of this study was to estimate the significance of TSH, thyroid peroxidase antibody (TPOAb), and mild (subclinical) hypothyroidism in women from The Danish General Suburban Population Study (GESUS) on the number of children born, the number of pregnancies, and the number of spontaneous abortions.
The Danish General Suburban Population Study (GESUS) was initiated in January 2010 and finished in October 2013. GESUS is a cross sectional study of the adult Danish suburban general population in Naestved Municipality (70 km south of Copenhagen) selected on the basis of the Danish Central Population Register Code. All individuals older than 30 years were invited. Due to financial reasons the GESUS study was designed to invite only 25% of younger women of 20–29 years age influencing the distribution of age [
The health examination included a comprehensive physical examination (body mass index (BMI)), biochemical tests and a self-administrated questionnaire (prevalent disease (diabetes mellitus, hypothyroidism, and hyperthyroidism), antihypertensive and cholesterol lowering medication, thyroid and antithyroid medication, contraception, smoking, income, education, employment, the number of pregnancies, the number of children born, age of first child, and the number of spontaneous abortions). The questionnaire did not include questions about induced abortion.
The GESUS study questionnaire can be viewed at
Thyroid hormones within the reference interval were defined as fT4 = 10.0–24.0 pmol/L, tT3 = 1.20–2.90 nmol/L, and TSH = 0.4–3.7 mU/L. Mild (subclinical) hypothyroidism was defined as TSH > 3.7 mU/L and fT4 and tT3 within the reference interval, no history of thyroid disease, and no intake of T4/T3 or antithyroid medication. Controls were defined as having 0.4 < TSH ≤ 3.7 mU/L and fT4 and tT3 within the reference interval, no history of thyroid disease, and no intake of T4/T3 or antithyroid medication [
Thyroid peroxidase antibody (TPOAb) positivity was defined by the cut-off value of TPOAb > 60 U/mL. All biochemical tests were performed at the same laboratory at Naestved Hospital.
Measurements of TSH and of thyroid hormones-free thyroxin (fT4) and total triiodothyronine (tT3) were performed using an electrochemiluminescent immunoassay (Roche Cobas 6000, Basel, Switzerland). Reference ranges for TSH are 0.40–3.70 mU/L (CV < 7%), fT4 reference range 10.0–24.0 pmol/L (CV < 5%), and tT3 reference range 1.20–2.90 nmol/L (CV < 4%). TPOAb was measured by KRYPTOR antiTPOn (BRAHMS, Henigsdorf, Germany), with detection limit of 10 kU/L.
All statistical analyses were performed using Stata version 13.0 for Windows (StataCorp, College Station, TX, USA). A value of
Continuous variables were compared between groups using Mann-Whitney- for the full cohort of women: linear regression analyses of TSH and TPOAb of children born and the number of pregnancies, logistic regression for spontaneous abortion; for women with prevalent hypothyroidism versus controls: logistic regression analyses for ≥1 children born, ≥1 pregnancies, and spontaneous abortion; for women with subclinical hypothyroidism versus controls: logistic regression analyses for ≥1 children born, ≥1 pregnancies, and spontaneous abortion.
Models designed were either age-adjusted or multifactorially adjusted using age, BMI, diabetes, contraception, education, income, employment, smoking, antihypertensive medication, cholesterol lowering medication, and menopause as listed in Table
Characteristics of women in The Danish General Suburban Population Study (GESUS).
All | Mild (subclinical) hypothyroidism | |||
---|---|---|---|---|
No | yes |
|
||
|
11254 (100) | 8770 | 758 | |
Age | 56.3 (45.5–66.2) | 55.4 (44.8–65.6) | 55.6 (44.9–65.9) | 0.43 |
Menopause, yes (%) | 7129 (63.4) | 5405 (61.6) | 463 (61.1) | 0.77 |
TSH, mU/L | 1.8 (1.2–2.6) | 1.7 (1.2–2.3) | 4.6 (4.1–5.5) | <0.001 |
Total T3, nmol/L | 1.6 (1.5–1.9) | 1.7 (1.5–1.9) | 1.6 (1.5–1.8) | 0.38 |
Free T4, pmol/L | 15 (14–17) | 15 (14–17) | 14 (13–15) | <0.001 |
TPOAb, U/mL | 13 (20–32) | 19 (12–27) | 28 (15–699) | <0.001 |
Body mass index (BMI), kg/m² | 25.3 (22.6–28.8) | 25.2 (22.5–28.7) | 25.5 (22.8–29.2) | 0.06 |
Smoker, yes (%) | 1899 (16.9) | 1527 (17.5) | 66 (8.7) | <0.001 |
Prevalent hypothyroidism, yes (%) | 922 (9.4) | NA | NA | |
Prevalent hyperthyroidism, yes (%) | 391 (4.2) | NA | NA | |
Diabetes mellitus, yes (%) | 576 (5.1) | 392 (4.5) | 40 (5.3) | 0.31 |
Antihypertensive medication, yes (%) | 2457 (21.8) | 1816 (20.7) | 140 (18.5) | 0.14 |
Cholesterol lowering medication, yes (%) | 1510 (8.5) | 1096 (12.5) | 91 (12.0) | 0.69 |
Contraception, yes (%) | 953 (8.5) | 772 (8.8) | 66 (8.7) | 0.93 |
Income below EUR 60,000 € | 4744 (43.7) | 3588 (42.4) | 292 (40.1) | 0.25 |
Unemployment, yes (%) | 6284 (55.8) | 3690 (42.1) | 318 (42.0) | 0.95 |
Education, no (%) | 1713 (15.2) | 1291 (14.7) | 95 (12.5) | 0.57 |
Age at 1st child born | 25 (22–28) | 25 (22–28) | 25 (22–29) | 0.02 |
No children born, |
1171 (10.5) | 897 (10.3) | 98 (13.0) | 0.02 |
No pregnancies, |
952 (8.5) | 733 (8.4) | 77 (10.2) | 0.09 |
Spontaneous abortion, yes (%) | 2261 (21) | 1747 (20.8) | 149 (20.6) | 0.87 |
For continuous variables: median (interquartile range).
For SCH,
The study was approved by the Regional Ethics Committee of Zealand, Denmark (Reg. number RVK SJ-177, SJ-113, and SJ-114), registered with ClinicalTrial.gov (
The study conformed to the principles of the Declaration of Helsinki. Written consent was obtained from all participants prior to participation in the GESUS study.
Table
Association between TSH (mU/L) and TPOAb (U/mL) levels and the number of children born, the number of pregnancies, and spontaneous abortion.
Age-adjusted | Multiadjusted |
|||
---|---|---|---|---|
Coefficient (95% CI) |
|
Coefficient (95% CI) |
|
|
Number of children born | ||||
|
−0.046 (−0.068–(−0.023)) | <0.001 | −0.050 (−0.072–(−0.0272)) | <0.001 |
|
−0.020 (−0.037–(−0.003)) | 0.02 | −0.021 (−0.038–(−0.004)) | 0.02 |
|
||||
Number of pregnancies | ||||
|
−0.081 (−0.132–(−0.030)) | 0.002 | −0.085 (−0.136–(−0.033)) | 0.001 |
|
−0.019 (−0.055–0.017) | 0.31 | −0.021 (−0.058–0.016) | 0.27 |
|
||||
Spontaneous abortion (yes versus no) | ||||
|
0.96 (0.91–1.01) | 0.12 | 0.95 (0.89–1.01) | 0.08 |
|
1.00 (0.95–1.04) | 0.86 | 1.00 (0.96–1.04) | 0.94 |
Correlation between TSH and TPOAb and number of children born and number of pregnancies are measured was by linear regression.
Association between TSH and TPOAb and spontaneous abortion (yes vs. no) was by logistic regression.
Mild (subclinical) hypothyroidism was associated with a risk of not having children and a risk of not getting pregnant in age-adjusted and multiadjusted models. Prevalent hypothyroidism was not associated with the number of children born, the number of pregnancies, or spontaneous abortions (Table
Table of odds ratios for ≥1 children born, ≥1 pregnancy, and spontaneous abortion in patients with prevalent hypothyroidism versus controls and in patients with mild (subclinical) hypothyroidism versus controls.
Prevalent hypothyroidism | Mild (subclinical) hypothyroidism | |||||||
---|---|---|---|---|---|---|---|---|
Odds ratio (95% CI) |
|
Odds ratio (95% CI) |
|
Odds ratio (95% CI) |
|
Odds ratio (95% CI) |
|
|
Age-adjusted | Multiadjusted |
Age-adjusted | Multiadjusted |
|||||
≥1 children born versus none | 0.84 (0.67–1.06) | 0.14 | 0.87 (0.69–1.10) | 0.25 | 0.75 (0.60–0.94) | 0.01 | 0.71 (0.56–0.90) | 0.004 |
≥1 pregnancy versus none | 0.83 (0.65–1.07) | 0.15 | 0.85 (0.66–1.1) | 0.22 | 0.79 (0.61–1.01) | 0.06 | 0.75 (0.58–0.97) | 0.03 |
Spontaneous abortion (yes versus no) | 1.05 (0.88–1.24) | 0.6 | 1.02 (0.89–1.22) | 0.78 | 0.99 (0.82–1.19) | 0.87 | 0.96 (0.79–1.17) | 0.69 |
In the present study, we showed that with higher TSH levels the less number of children born and the less number of pregnancies. Furthermore, with higher TPOAb levels the less number of children born. Coefficients for logTSH were higher than for logTPOAb; thus, the effect of TSH seems higher than for TPOAb. Mild hypothyroidism was also associated with a higher age of first child born and risk of not having children and not getting pregnant. TPOAb was not a significant confounder in the models, and there was no interaction with age.
This analysis is cross sectional and in a way retrospective for those women who are now menopausal. Also, for women who are premenopausal we may not have the life-time full number of children born, the number of pregnancies, and the number of spontaneous abortions.
The prevalence of TSH elevations increases with age [
We were not able to detect an effect on spontaneous abortion. This may be caused by the fact that, during fertile life, early miscarriage may have gone unnoticed or been “forgotten.” Liu et al. had recently reported that women with a combination of subclinical hypothyroidism and thyroid autoimmunity were found to have the highest risk of miscarriage before 20 weeks of gestation compared to only TPOAb positivity or subclinical hypothyroidism [
Accordingly, in our study we observed that elevated TSH above the upper reference limit in mild hypothyroidism correlated with the number of pregnancies and child births. Several studies have reported a possible association between thyroid dysfunction during pregnancy and specific adverse pregnancy outcome like preeclampsia [
It has been suggested that higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism [
This retrospective cross sectional study showed that among women without any history of thyroid disease or antihyperthyroid/antihypothyroid medication 6.7% had mild (subclinical) hypothyroidism. The prevalence of mild hypothyroidism was comparable to previous studies [
The presence of mild hypothyroidism influenced the level of fT4 within the reference range as fT4 was decreased in women with mild hypothyroidism. This could be explained by an increased intracellular deiodination of T4 to T3 in women with mild hypothyroidism to avoid decreased levels of active intracellular thyroid hormone concentrations. A major problem is to determine separate effects of TPOAb positivity and mild hypothyroidism. We are not able to determine the status during pregnancy as the present study is retrospective, but it seems unlikely that TPOAb would have an effect directly on metabolism and peripheral thyroid hormone regulated cellular function. However, we cannot exclude the possibility that the women presenting with mild hypothyroidism have had a previous normalized TSH level.
This population study was performed in Naestved Municipality eastern Denmark representing a mild iodine deficiency [
The present study is limited by the fact that all clinical observations are self-reported questionnaire data. Furthermore, we did not have any information about the numbers of induced abortions which could influence the data of child births although it is rarely recommended to induce an abortion only due to high levels of TSH during first trimester of pregnancy.
In addition, individuals were classified based on a single blood test; thus, we cannot distinguish between transient and permanent TSH elevation; however, Somwaru et al. showed that subclinical hypothyroidism was persistent in 56% after 4-year follow-up [
The strength of our study was the high number of participants with blood samples of TSH, fT4, tT3, and TPOAb in 11254 women. Furthermore, for the analyses of mild (subclinical) hypothyroidism we excluded women with any self-reported thyroid disease or use of T4/T3 or antithyroid medication and only compared euthyroid and mild hypothyroid women.
Taken together, we observed that with higher TSH levels the less number of children born and the less number of pregnancies. Furthermore, with higher TPOAb levels the less number of children born. Mild hypothyroidism was also associated with a higher age of first child born and risk of not having children and not getting pregnant. In conclusion, we observed that impaired fertility is associated with TSH, TPOAb, and mild (subclinical) hypothyroidism in a Danish population of women.
Body mass index
Free thyroxine
Danish General Suburban Population Study
Mild (subclinical) hypothyroidism
Thyroid peroxidase antibody
Thyroid stimulating hormone
Total triiodothyronine.
The authors declare no conflict of interests.
This study was supported by grants from Region Zealand’s Medical Research Foundation and the Medical Research Foundation of Hospital South, Region Zealand, Denmark. The GESUS was funded by the Region Zealand Foundation, Naestved Hospital Foundation, Edith and Henrik Henriksens Memorial Scholarship, Johan and Lise Boserup Foundation, TrygFonden, Johannes Fog’s Foundation, Region Zealand, Naestved Hospital, The National Board of Health, and the Local Government Denmark Foundation.