Thyroid Physiology During Pregnancy Hypothyroidism: A Review of Current Literature - Ashley Hillsley

ANTA Member Article Autumn 2021

Ashley Hillsley

GradCertSci, BMedSci, AdvDip Naturopathy Program Director of Health Sciences, Torrens University Australia

Thyroid Physiology During Pregnancy and Hypothyroidism: A Review of Current Literature Introduction

From the onset of pregnancy, the maternal thyroid undergoes physiological changes to its function. These are required to ensure a successful pregnancy and for normal offspring development to occur1. It is therefore important to note that thyroid disorders can have significant impacts on the health of both mother and fetus. Some of the adverse reproductive outcomes which may present due to maternal thyroid dysfunction can include neonatal central nervous system underdevelopment, increased prevalence of abortion, postpartum haemorrhage and gestational hypertension2. Current research has further developed on evidence accumulated from over the last two decades, to highlight the significance and impact of thyroid hormones in fetal neurodevelopment and placentation3.

Recent reviews have identified that a combination of the maternal thyroid and the developing fetal thyroid function play an essential role in pregnancy. The maternal thyroid output is most important in first trimester when significant development occurs. The fetus increases its thyroid output in the second and third trimesters4.

This significance of early pregnancy maternal thyroid function highlights the need for accurate thyroid function testing against pregnancy-based reference ranges early on in pregnancy. Early and accurate detection of the most common thyroid conditions during pregnancy is an essential step in being able to provide appropriate intervention to avoid complications in fetal development5.

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This paper will outline the thyroid physiology changes that occur in pregnancy and play a key role in fetal development and on differentiating this output from the most common thyroid disorder, hypothyroidism.

Thyroid disorders have the second highest in prevalence of the endocrine disorders after only diabetes in women of the reproductive age6. The most common of the thyroid conditions in pregnancy which has evidence of significant impact to the fetus are the hypothyroidism disorders. Hypothyroidism can be further categorised as overt or subclinical hypothyroidism7. The epidemiology, pathophysiology of these conditions during pregnancy will be discussed in this review along with the associated significance of definitive pregnancy reference ranges to allow for measuring of the key thyroid hormones needed in the identification of thyroid disorders during pregnancy.

Overview of the Physiology of the Thyroid during Pregnancy

The Thyroid gland plays a key physiological role in the production of hormones that are essential for maintenance of the healthy adult such as regulating metabolic rate but are also critical for early brain development and somatic growth4. The thyroid gland undergoes significant changes in thyroid hormone (TH) regulation during pregnancy. During pregnancy, thyroid disorders can affect both the pregnant woman and the fetus. Research over the last 20 years shows significant evidence that maternal thyroid dysfunction

ANTA Member Article Autumn 2021 and subclinical presentations can have negative impacts on the pregnancy8. Additionally, insufficiency of TH during development may impair brain development of the fetus.

Specific clinical impacts of the lack of thyroid hormones depend on the gestational age or stage of pregnancy of the fetus affected. Extensive research has focused on the crucial role of TH on brain during neurodevelopment9.

The role of ensuring adequate iodine supply has been highlighted as essential for increased thyroid hormone production requirements during pregnancy.

Thyroid Hormone Levels

During pregnancy, there is a requirement for increased TH production. To be able to ensure normal thyroid function and supply of the fetus, between 20–50% increase in thyroxine is needed6. For this to occur adequate iodine must be present. This results in an increase demand for iodine during pregnancy and ensuring the absence of destructive autoimmune conditions of the thyroid becomes a greater focus to ensure there is no diminished function10.

Thyroid hormone production is impacted by some key changes during pregnancy. The clearance of iodine increases and serum levels of thyroxine binding globulin (TBG) increase. Importantly, an increase in the inner-ring of triiodothyronine (T3) and thyroxine (T4) deiodination by the placenta occurs11.

In normal functioning, the anterior pituitary regulates secretion of thyroid-stimulating hormone (TSH) via a negative feedback. Human chorionic gonadotropin (hCG) is increased during pregnancy and reduces the output of TSH12. Free Thyroxine (FT4) is available to both the fetus and the mother and provides the best indicator

of quantity of biologically active TH. Serum TBG does not affect the concentration of FT4 which is modulated by iodine levels. Increased TBG results in elevated first trimester T4 concentrations which decline in the second and third trimesters2.

Thyroid Hormone Maternal Supply vs Fetal Production

Thyroid hormones are supplied to the developing fetus tissues through two sources, the maternal thyroid gland and the developing fetal thyroid gland. Maternal TH supply is especially important during the first half of the pregnancy when the fetal thyroid is not yet developed.

The transfer of thyroid hormones from the maternal thyroid occurs via the placenta. Placental deiodinases regulate the amount of T4 that can pass to the fetus13.

Maturation of fetal thyroid function involves development of key structures that include the pituitary, hypothalamus and the thyroid gland and ability to secrete hormones.

The development and initiation of function in these structures is mostly completed at the 12–14 week mark. T4 and T3 can begin being detected at the 11–12 week mark in the fetal serum. At this stage TH is supplied by both mother and fetus. TSH in the first trimester has an upper reference range of 2.5mIU/L14.

Key Factors that Influence Thyroid Hormones Supply in Pregnancy As TBG is a globulin binding thyroid hormone that is modulated in part by estrogen levels, the high levels of TBG in pregnancy cause an overall higher binding of the thyroid hormones that results in less free hormones in the blood. Increased TBG leads to TSH production being

Figure 1: Thyroid Gland and the main Thyroid Hormones

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ANTA Member Article Autumn 2021 stimulated and increased TH levels follow6.

Tissue levels of TH are regulated by iodothyronine deiodinases. These remove iodine from various TH molecules such as inactivating T3 into reverse T3.

There are three types of iodothyronine deiodinases which regulate supply of TH molecules in activated and inactivated forms13. The iodothyronine deiodinases purpose is to prevent the negative effects of excessive amounts of active TH molecules.

The type 1 iodothyronine deiodinase (D1) catalyses T4 to T3 conversion. D1 is less active in pregnancy which results in lower T3 concentrations in the fetus13.

The other two deiodinases are both present in the fetal brain from the seven week mark in low concentrations.

These are the type 2 deiodinase (D2) and the type 3 deiodinase (D3). D2 catalyses the T4 to T3 conversion, while D3 catalyses the T4 to T3. These are the main deiodinases present in the fetus and play a key role in maintenance of the T3 levels of the fetal brain9.

It is important to note that D3 is present as an enzymatic barrier in the placenta. D3 limits the exposure of the fetus to maternal thyroid hormones protecting the fetus from overexposure to maternal T46.

Thyroid Disorder Pathophysiology, Detection and Clinical Significance During Pregnancy Iodine Deficiency Iodine deficiency is considered a major public health issue and evidence indicates it affects two billion people worldwide, not only in extreme deficiency, but mildmoderate cases6. Iodine deficiency is noted as the main cause of preventable mental impairment. Iodine deficiency is noted as the most frequent cause of hypothyroidism in countries with factors that limit iodine intake, and it is directly linked to hypothyroxinaemia. During pregnancy, maternal iodine intake must increase by 50%6. This is as a result of the fetal iodine needs for TH production, increased maternal thyroid hormone production occurs to offset increased iodine losses15.

During iodine deficiency Thyroglobulin (Tg) is released in higher quantity into the blood, and its levels align with thyroid volume. Tg levels also increase in early pregnancy, remain static during mid-pregnancy and then increase during late pregnancy5. Tg returns to level after birth. Recent studies have reported on the potential for assessment of serum Tg level as a marker for iodine deficiency16. While the possibility of Tg in estimation of iodine status appears promising, some issues have been noted with this method. The results are influenced by age and pregnancy and have high variability within data. If it were possible to find a solution for these concerns this could prove a useful test for early identification of iodine deficiency in pregnancy in the future.

A cross-sectional study of approximately 7,000 pregnant women was able to show that high urinary iodine PAGE 36 | AUTUMN 2021 | THE NATURAL THERAPIST VOL36 NO.1

Figure 2: Late Developmental Stage of Pregnancy was an indicator for an increased risk of subclinical hypothyroidism and hypothyroxinaemia. This study demonstrates another example of potential early identification method for iodine deficiency5.

Hypothyroidism Hypothyroidism is the most prevalent disorder of the thyroid gland in pregnancy. Hypothyroidism affects around 0.3–0.5% of pregnant women17. Overt hypothyroidism is diagnosed by TSH elevation and simultaneous hypothyroxinemia. The exception to this is in pregnancy where TSH readings of 10.0mIU/L or higher are categorised as overt hypothyroidism regardless of the FT4 levels present.

In circumstances where TSH elevation is present but with normal Thyroxine levels, this not overt hypothyroidism but rather termed subclinical hypothyroidism18. Subclinical hypothyroidism is identified when TSH exceeds the 4mIU/L reference range for first trimester19, and therefore; is significantly more common. Iodine deficiency and autoimmunity are the most common causes of both types of hypothyroidism18.

It has been well described across the literature that hypothyroidism in pregnancy can lead to significant adverse effects and cause irreversible damage to the fetus including mental underdevelopment, failure of sexual development, failure of the nervous system cells to differentiate9. There are also significant studies showing that maternal hypothyroidism can lead to psychomotor underdevelopment including significant intelligence

ANTA Member Article Autumn 2021 quotient (IQ) score reductions. When maternal TSH is greater than 6mIU/L during the second trimester, there is a four times higher risk of fetal death5.

Considerations for Reference Values for Thyroid Markers During Pregnancy

There have been numerous studies on thyroid function test parameters during pregnancy published over the last two decades20, 8. These have explored and identified the importance of some of the risk factors for the development of hypothyroidism during pregnancy. These include iodine intake, Body Mass Index (BMI), ethnicity and hCG concentrations and these provide further considerations for how to assess thyroid dysfunction4.

Ethnicity considerations encompass genetic differences, dietary variations and both environmental and cultural factors and as a result the population-based reference ranges vary around the world for TSH and T45.

Around the world several immunoanalytical systems are used for the measurement of thyroid parameters. Each of these use with significantly different reference intervals recommended by the manufacturers5. This raises the issue of quantifying an agreed TSH cut off to ensure accurate defining of thyroid dysfunction. The commonly agreed upper cut off for TSH in the first trimester has been set at 2.5mIU/L by the World Health Organisation (WHO)20.

Research has consistently demonstrated that BMI is also a determinant of thyroid function during pregnancy. Higher BMI is directly correlated to higher TSH levels with T3/ T4 variations and in early pregnancy the sharp increase in hCG levels lead to a spike in T4 levels and the result is a reduction in TSH21.

It is recommended that new trials and research be conducted that investigate further tests that can incorporate these outlined risk factors more effectively.

These factors are currently not well represented in the current test methodology22. Combining new innovative methods with the current test methods to ensure better evaluation of the development of thyroid disease in pregnancy should enable more accurate testing for

varying circumstances.

Conclusion

Appropriate identification and treatment of thyroid disorders as early as possible during gestation is essential for improving the developmental and health outcomes of the fetus. Current research and literature from the last two decades have provided significant advances in our understanding of the differences of normal physiology of the thyroid during pregnancy and in disorder states.

Thyroid disorders in pregnancy are common and they constitute a major epidemiological risk. Pregnant women with reduced thyroid function due to iodine insufficiency or thyroid autoimmunity fail to increase the thyroid hormone production significantly to meet maternal requirements and develop subclinical or overt hypothyroidism.

The most accepted way in the literature to define reference ranges for detection of disorder states is still by using population study data. There are a significant number of studies, including some as recent as 2018 testing TH levels to ensure the evidence is available for the establishment of population data driven threshold values. It must also be noted that a significant number of studies have indicated that references ranges may not be the best approach as the results can be an incorrect diagnosis if looked at in isolation without the context of the individual presentation including ethnicity and BMI. Many of the negative developmental outcomes outlined also appear to be correlated to physiological factors not measured for in the reference ranges such as hCG concentrations. Further exploration into other assessment methods to complement the reference ranges is critical with other novel tests being proposed for specific concerns such as the noted Tg assay and urinary iodine tests for iodine deficiency with a view to developing more detection methods that may provide the right mixture to indivualise tests ordered based on clinical presentation.

Further research is needed to address these concerns.

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Figure 3: Fetal Development Stages

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