Maternal benign thyroid conditions are strongly associated with thyroid cancer risk in offspring


A recent study by prof. Tone Bjørge, University of Bergen, and her team shows that thyroid cancer is related to in-utero exposures.

Thyroid cancer is diagnosed at a younger age than most other malignancies and the incidence is higher in women than men.

“The only established modifiable risk factors for thyroid cancer are childhood exposure to ionizing radiation and obesity. Few in-utero and early life risk factors have so far been identified” says Bjørge, professor at Department of Global Public Health and Primary Care, University of Bergen.

Maternal hypothyroidism, hyperthyroidism, goiter, and benign thyroid neoplasms related to higher risk

The teamconducted a nested case-control study using nationwide registry data from four Nordic countries (Denmark, Finland, Norway, and Sweden). The study included 2,437 thyroid cancer cases and 24,362 matched controls aged 0-48 years during 1967-2015.

“Maternal benign thyroid conditions such as hypothyroidism, hyperthyroidism, goiter, and benign thyroid neoplasms were strongly associated with thyroid cancer risk in offspring. Also, high birth weight, congenital hypothyroidism, maternal history of diabetes, and maternal postpartum hemorrhage were associated with increased risk,” says Bjørge.

Motivates further research

The study supports a link between in-utero exposures and an increased risk of thyroid cancer later in life.

“These findings should motivate additional research into early-life exposures that might cause thyroid cancer,” says Bjørge.

Thyroid dysfunction features altered thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations (1) and is involved in pathophysiological conditions of multiple systems (2–7). In addition to overt thyroid disease, mild thyroid function abnormality, such as subclinical hyperthyroidism and hypothyroidism with normal range FT4 levels, and isolated hypothyroxinemia in the setting of normal TSH levels, has broad implications as well (8, 9). Birth weight is an essential predictor of intrauterine exposures and infant health.

Recent studies suggested that normal thyrotropin within the upper reference range or subclinical hypothyroidism may exert positive (10, 11), negative (12, 13), or null (14, 15) effects on offspring birth weight. Apart from the inconsistency, evidence from previous case-control or prospective cohort studies was prone to various confounders.

Thus, whether maternal normal range TSH or FT4 levels are associated with newborn birth weight, and whether large or small for gestational age, remains inconclusive.

Mendelian randomization (MR) has been advancing as a powerful genetic-epidemiological tool to make causal inference and yield robust estimate (16). MR studies employs single nucleotide polymorphisms (SNPs) which are identified from genome-wide association studies (GWAS) as instrumental variables for biological traits of interest.

By courtesy of Mendel’s laws, independent assortment of alleles during gamete formation renders a more natural and ideal randomization than in randomized controlled trials. MR studies are capable of giving evidence of high-level strength and adequate power, especially when sufficiently large sample size of mother–offspring duos is hardly feasible (17, 18). Here we performed a two-sample MR study to investigate the association between maternal normal range TSH and FT4 with offspring birth weight.

Birth weight has long been postulated to affect susceptibility to diseases in later life, known as the fetal origin of adult diseases hypothesis (26–28). Identifying influences of maternal exposures on birth weight should be meaningful (18). Previous observational studies hinted at the role for mild abnormalities of thyroid function in birth weight, nonetheless, with heterogeneous results.

Meanwhile, triangulating evidence across multiple study designs should be worthwhile when assessing the influence of maternal TSH and FT4 on birth weight. Therefore, we conducted the first MR study to provide supplementary evidence and effect estimates for the associations of normal range thyroid function with offspring birth weight.

We failed to identify a statistically significant causality between genetically predicted TSH and FT4 concentrations and birth weight in the European population.

One recent cohort (12) incorporated 1521 European women with thyroid function tests in the first trimester, and manifested that women with normal range TSH levels at upper limit were related to lower neonatal birth weight, with an adjusted odds ratio in reference to the normal group of 21.38 (95%CI, 1.29 to 353.39; P = 0.032).

In a real-word data setting or traditional observational design, it was virtually impossible to allow for and adjust for all cofounding conditions such as gestational diabetes. Previous effect estimates for the maternal-fetal relationship still warranted replications in large well-designed cohorts. Another recent meta-analysis (29) aggregated individual-level data of 48,145 mother–child pairs from 20 observational cohorts and detected an inverse association between maternal TSH and FT4 within the normal range and birth weight. Specifically, each 1 SD higher maternal TSH and FT4 was associated with 6 g lower (95%CI, −10 to −2; P = 0.003) and 21 g lower (95%CI, −25 to −17; P < 0.0001) birth weight, respectively. Notably, in addition to the European population, more than 20% participants were of Asian ancestry (China, Japan and Pakistan).

Although Newcastle–Ottawa scale and I2 statistic suggested low to moderate bias and heterogeneity in the meta-analysis, without stratified analysis we could not rule out the possibility of an overwhelmingly significant effect in the Asians alone, which overweighed the null effect in the Europeans.

Besides, currently available GWAS statistics on normal range TSH and FT4 were in the general rather than female-specific population. Population and gender difference might be another explanation for the null finding in our study.

To enlarge the sample size in the MR setting, we utilized instrumental SNPs associated with lifelong circulating TSH or FT4 to surrogate gestational thyroid function, instead of directly trimester-specific measurement as in traditional cohorts. Reference intervals of thyroid function altered along with the gestation trimester (30), and individual TSH and FT4 levels during pregnancy could manifest minimum differences from pre-gestational ones.

It raised concern that genetically predicted thyroid function here was not the most appropriate proxies yet. Nevertheless, the two-sample MR framework (18) still provided an ideal supplement for traditional observational and original MR studies which were built on restricted sample size of mother–offspring duos.

Further GWAS—dedicated to reveal genetic contributions to maternal serum and placental TSH and FT4 levels during pregnancy, would pave the way for elucidating effects of uterine thyroid function on fetal growth.

Several limitations existed in this study. First, summary-level data-based MR could not ascertain non-linear associations between maternal thyroid function and birth weight. Thus, we could not rule out that normal range TSH or FT4 exerted its influence within extremely upper or lower limit. Second, common variants identified by current GWAS still explained a relatively small proportion of variance. Hence, this study had restricted power to identify weak associations.

Thirdly, the current MR analysis was restricted in the European-ancestry datasets and great caution should be exercised when generalizing the conclusion. Lastly, we couldn’t rule out the possibility that genetic variants underlying thyroid function during pregnancy was different from the current instrumental-SNP set and to which extent the difference might be, and we failed to take into account sex stratification and age difference within two datasets, which might affect the MR estimates.

To conclude, this MR study did not support the casual effects of maternal normal range TSH and FT4 on offspring birth weight in the European population. Triangulation of evidence across cohort studies, meta-analyses and MR studies was deemed necessary as well.

reference link :

More information: Cari M Kitahara et al. Maternal health, in-utero, and perinatal exposures and risk of thyroid cancer in offspring: a Nordic population-based nested case-control study, The Lancet Diabetes & Endocrinology (2020). DOI: 10.1016/S2213-8587(20)30399-5


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