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Sofie Bliddal, Malene Boas, Linda Hilsted, Lennart Friis-Hansen, Ann Tabor and Ulla Feldt-Rasmussen

Objective

Aberrations in maternal thyroid function and autoimmunity during pregnancy have been associated with negative obstetric outcome. In Denmark, a national iodine fortification program was implemented in the year 2000 with the aim to alleviate the mild-moderate iodine deficiency. Following the iodine implementation, there has been an increase in thyroid autoimmunity in the background population. This study investigates the thyroid status of pregnant Danish women following the iodine fortification program, and a possible association with preterm delivery.

Design

Historical cohort study of 1278 randomly selected pregnant Danish women attending the national Down's syndrome screening program.

Methods

The main outcome measures were thyroid status according to laboratory- and gestational-age-specific reference intervals, and association with risk of abnormal obstetric outcome. Antibody-positivity was defined as an antibody-level (thyroid peroxidase and/or thyroglobulin antibodies) above 60 U/ml.

Results

Establishing laboratory-specific gestational-age-dependent reference intervals, we found a prevalence of maternal thyroid dysfunction of 10%–15.8% by use of the cut-off suggested by the American Thyroid Association. Thyroid dysfunction was significantly associated with antibody-positivity (P<0.05). No associations were found between preterm delivery and thyroid dysfunction (adjusted OR 0.6, 95% CI: 0.1–2.3) or autoimmunity (adjusted OR 1.1, 95% CI: 0.4–2.7).

Conclusions

After the implementation of the Danish iodine fortification program, the prevalence of thyroid dysfunction and autoimmunity in Danish pregnant women is high – even higher by use of pre-established reference intervals from international consensus guidelines. However, no associations were found with abnormal obstetric outcome. Large randomized controlled trials are needed to clarify the benefit of treating slight aberrations in pregnant women's thyroid function.

Free access

Malene Boas, Ulla Feldt-Rasmussen, Niels E Skakkebæk and Katharina M Main

There is growing evidence that environmental chemicals can disrupt endocrine systems. Most evidence originates from studies on reproductive organs. However, there is also suspicion that thyroid homeostasis may be disrupted. Several groups of chemicals have potential for thyroid disruption. There is substantial evidence that polychlorinated biphenyls, dioxins and furans cause hypothyroidism in exposed animals and that environmentally occurring doses affect human thyroid homeostasis. Similarly, flame retardants reduce peripheral thyroid hormone (TH) levels in rodents, but human studies are scarce. Studies also indicate thyroid-disruptive properties of phthalates, but the effect of certain phthalates seems to be stimulative on TH production, contrary to most other groups of chemicals. Thyroid disruption may be caused by a variety of mechanisms, as different chemicals interfere with the hypothalamic–pituitary–thyroid axis at different levels. Mechanisms of action may involve the sodium–iodide symporter, thyroid peroxidase enzyme, receptors for THs or TSH, transport proteins or cellular uptake mechanisms. The peripheral metabolism of the THs can be affected through effects on iodothyronine deiodinases or hepatic enzymes. Even small changes in thyroid homeostasis may adversely affect human health, and especially fetal neurological development may be vulnerable. It is therefore urgent to clarify whether the animal data showing effects of chemicals on thyroid function can be extended to humans.

Free access

Sofie Bliddal, Ulla Feldt-Rasmussen, Malene Boas, Jens Faber, Anders Juul, Torben Larsen and Dorthe Hansen Precht

Objectives

Correct interpretation of thyroid status during pregnancy is vital to secure fetal development. Pregnancy-related changes in maternal thyroid status necessitate the use of gestational age-specific reference ranges. In this study, we investigated between-laboratory reproducibility of thyroid reference ranges in pregnant women.

Design

Comparison of two longitudinal prospective cohort studies including 255 (cohort 1) and 101 (cohort 2) healthy antibody-negative Danish pregnant women attending prenatal care at Copenhagen University Hospital.

Methods

Different immunoassays were used to measure thyroid hormone levels in the two cohorts. Thyroid hormone reference ranges were established for every 5 weeks of gestation. Differences between cohorts were explored through mixed-model repeated measures regression analyses. By applying reference ranges from one cohort to the other, the proportion of women who would be misclassified by doing so was investigated.

Results

TSH increased and free thyroxine (FT4) decreased as pregnancy progressed. Results indicated highly significant differences between cohorts in free triiodothyronine (F=21.3, P<0.001) and FT4 (F=941, P<0.001). TSH levels were comparable (P=0.09). Up to 90.3% of the women had FT4 levels outside their laboratory's nonpregnant reference range, and up to 100% outside the other cohort's gestational-age-specific reference ranges. Z-score-based reference ranges markedly improved comparison between cohorts.

Conclusion

Even in the same region, the use of gestational-age-specific reference ranges from different laboratories led to misclassification. Up to 100% of maternal FT4 levels fell outside the other cohort's reference range despite similar TSH levels. In clinical practice, thyroid testing of pregnant women without adding method specificity to gestational age-dependent reference ranges will compromise patient safety.

Free access

Sofie Bliddal, Malene Boas, Linda Hilsted, Lennart Friis-Hansen, Anders Juul, Torben Larsen, Ann Tabor, Jens Faber, Dorthe Hansen Precht and Ulla Feldt-Rasmussen

Objective

The presence of thyroid antibodies in pregnancy has been associated with preterm birth. In the non-pregnant population, the implementation of the Danish iodine fortification program has increased the prevalence of thyroid antibodies. This study investigated the prevalence of thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) in pregnant Danish women before, during and after implementation of the iodine fortification program and association with preterm birth.

Design

Comparative cohort study of 1368 pregnancies from three cohorts gathered before (1996–1998), during (2000–2003) and after (2008–2009) the iodine fortification program.

Methods

In cohort 1 (n = 297), TPOAbs were measured (DYNOtest (BRAHMS)). In cohorts 2 (n = 148) and 3 (n = 923), both TPOAbs and TgAbs were measured (Kryptor immunofluorescent assay (BRAHMS)). The prevalence and effect of antibody positivity were explored using three cut-offs: TPOAbs and/or TgAbs >100 kU/L, TPOAbs and/or TgAbs >60 kU/L and TPOAbs >30 and/or TgAbs >20 kU/L. National preterm birth data were extracted from the National Birth Registry.

Results

In the three cohorts, TPOAb levels >60 kU/L were found in 5.4, 8.1 and 12.0% (χ 2(2, n = 1367) = 11.7, P = 0.003) respectively, and TPOAbs and/or TgAbs >60 kU/L in 8.1 and 16.2% in cohorts 2 and 3 respectively (χ 2(2, n = 1070) = 6.5, P = 0.01). TgAb levels (>20 kU/L) had increased plenty-fold from cohort 2 to 3 (χ 2(1, n = 1071) = 136.5, P < 0.001). Preterm birth occurred in 4.1% of all pregnancies with no effect from antibody positivity (TPOAbs and/or TgAbs >60 kU/L, χ 2(1, n = 1039) = 0.0, P = 0.98, aOR = 1.1, 95% CI (0.4–2.7)). The national preterm birth-rate showed no increase over the same period.

Conclusions

Thyroid antibody positivity in Danish pregnant women has more than doubled upon the implementation of the iodine fortification program without an increase in preterm birth-rate.

Free access

Malene Boas, Julie Lyng Forman, Anders Juul, Ulla Feldt-Rasmussen, Niels Erik Skakkebæk, Linda Hilsted, Marla Chellakooty, Torben Larsen, Jørgen Falck Larsen, Jørgen H Petersen and Katharina M Main

Background

Adaptive alterations in maternal physiology cause changes in thyroid hormone levels throughout pregnancy, and precise biochemical evaluation is thus highly dependent on gestation-specific reference intervals and expected intra-individual variation.

Objective

The aim of the study was the assessment of the intra-individual variation as well as the longitudinal course of thyroid hormones during normal pregnancy and factors that influence the normal reference range for thyroid function. For this purpose, a longitudinal statistical model was applied.

Design

In a cohort of 132 pregnant women, serial blood samples were obtained and ultrasound scans were performed throughout pregnancy.

Methods

Serum levels of TSH, free and total thyroxine (T4), free and total triiodothyronine (T3) as well as autoantibodies against thyroid peroxidase and thyroglobulin were measured in 979 serum samples.

Results

Intra-individual variations of thyroid hormone concentrations were smaller than inter-individual variations (individuality index range: 0.38–0.71). Maternal height was positively associated with free T4 (FT4) (b=0.003; P=0.031) and pre-pregnancy body mass index with T3 and free T3 (b=0.017; <0.001 and b=0.007; P<0.001). Smoking was positively associated with T4 and FT4, but it was modulated by gestational age. Gestation-specific reference intervals for thyroid function variables from autoantibody-negative participants are presented.

Conclusions

In accordance with the data from nonpregnant adults, intra-individual variations of thyroid hormones were smaller than inter-individual variations also during pregnancy. In the evaluation of thyroid function in pregnancy, the individual longitudinal course of thyroid hormones rather than absolute values should be considered. We present a longitudinal model for the prediction of maternal thyroid function tests in pregnant women.

Free access

Malene Boas, Kirsten A Boisen, Helena E Virtanen, Marko Kaleva, Anne-Maarit Suomi, Ida M Schmidt, Ida N Damgaard, Claudia M Kai, Marla Chellakooty, Niels E Skakkebæk, Jorma Toppari and Katharina M Main

Objective: Infant boys show a brief activation of their hypothalamic–pituitary–gonadal axis shortly after birth, the physiological significance of which is poorly understood. The objective of the study was to investigate the correlation between endogenous testosterone levels and penile size and growth.

Design: Prospective, longitudinal population-based study taking place at two large primary obstetric centres at the University Hospitals of Copenhagen, Denmark, and Turku, Finland.

Methods: Infant boys, 728 Danish and 1234 Finnish, underwent clinical examinations at 0, 3, 18 and 36 months in Denmark and at 0, 3 and 18 months in Finland with blood samples taken at 3 months (n = 630). Penile length and growth were registered and reproductive hormones (testosterone, sex hormone binding globulin, oestradiol) were analysed.

Results: Penile length increased from birth (3.49±0.4 cm) to 3 years of age (4.53±0.51 cm) with the highest growth velocity from birth to 3 months (1.0 mm/month). Penile length and growth were significantly, positively correlated to serum testosterone (r = 0.31 and 0.076, P = 0.006 and 0.001 respectively) and to free testosterone index (r = 0.385 and 0.094, P = 0.0001 and 0.0001 respectively).

Conclusions: We found that endogenous testosterone was significantly associated with penile size and growth rate in infant boys. Thus, the postnatal surge in reproductive hormones appears to be important for genital growth. Our data may serve as an updated reference for normal penile length in Caucasian boys up to 3 years of age.