Pregnancy, bipolar disorder, & thyroid function

This is the second part of our series on concerns for pregnant people with bipolar disorder. In part one, we discussed lithium and its risks and potential benefits.

In this second part of the series, we’ll explore thyroid function in the context of both pregnancy and bipolar, including:

Thyroid physiology during pregnancy
Thyroid function and bipolar disorder
How lithium affects thyroid function
The relationship between maternal thyroid hormone and bipolar risk in offspring

How Pregnancy Changes Thyroid Physiology and Thyroid Ranges

During early pregnancy, basal metabolic rate and oxygen consumption increase, creating a demand for more thyroid hormones. The fetus relies on maternal thyroid hormones during the first twelve weeks of pregnancy, and maternal thyroid hormone is critical for the healthy neurodevelopment of the fetus. Even minor imbalances in maternal thyroid hormone may alter neuronal migration and development in offspring (1, 2).

There is increased vascularization of the thyroid gland and hyperplasia of the thyroid gland to meet the higher demand for thyroid hormone. Practically speaking, this means that the thyroid may get imperceptibly bigger. Note that this differs from a goiter—a goiter always warrants medical attention.

Additionally, the increased hCG levels, especially in the first trimester and peaking around 10 to 12 weeks, affect the thyroid gland. This hormone attaches to TSH receptors, stimulating the thyroid to produce more thyroid hormones.

As a result, there is a spike in total T4 and total T3 and a peak in free T4 until the negative feedback loop causes the pituitary to produce less TSH.

Because of this, there’s a dramatic drop in TSH in the first trimester, reaching its lowest point at 10 to 12 weeks, while hCG reaches its highest point during that same timeframe.

Subsequently, TSH rises a bit throughout the rest of pregnancy but remains below non-pregnant levels (3,4,5).

So, whether or not your pregnant patients have bipolar disorder, their thyroid lab results need to be interpreted according to pregnancy-specific ranges adjusted by trimester.

Otherwise, patterns of hypothyroidism may be missed, and potentially normal patterns may be interpreted as hyperthyroidism.

Click here to learn more about our pregnancy-specific blood chemistry course if you’re looking for evidence-based guidance interpreting your preconception, pregnant, and postpartum patient’s blood tests.

What about thyroid function in bipolar disorder?

Hypothyroidism has been associated with an increased risk of bipolar disorder, and thyroid antibody levels tend to be higher in patients with bipolar disorder than those without.

Some researchers think that hypothalamic-pituitary-thyroid-axis dysfunction may be a contributing factor in the pathogenesis of bipolar disorder (6). A handful of small studies have found abnormalities in brain perfusion scans in adults with autoimmune hypothyroidism (7,8, 9).

A fascinating 2005 case study presented the case of a woman who developed mania in the early postpartum period within a week of delivering her healthy baby via C-section. After being treated with various antipsychotics and antidepressants, including lithium, her symptoms persisted and became severe. Eventually, she was discovered to have Hashimoto’s thyroiditis, and an abnormal EEG indicated cerebral dysfunction. It wasn’t until her EEG was normalized via corticosteroid therapy that her symptoms resolved. The study’s authors suggested that this was a case of bipolar disorder due to Hashimoto’s encephalopathy (10).

More recently, a 2022 review highlighted three case studies of women suffering from bipolar disorder with catatonic features and Hashimoto’s thyroiditis. All three had no improvement with standard treatment for bipolar catatonia; however, their symptoms improved dramatically after receiving corticosteroids to treat their autoimmune thyroid condition (11).

The importance of thyroid function on mood was also demonstrated in a 2018 double-blind, randomized control trial investigating the effectiveness of thyroid hormone treatment in rapid-cycling bipolar patients who were not responding to lithium (12).

In this novel study, 32 euthyroid patients were randomized into three groups: LT-4 (levothyroxine), T-3 (triiodothyronine), or placebo. They also continued taking psychiatric medication, including lithium, throughout the study.

The results showed that the group receiving adjunctive T4 therapy had a 33% increase in time spent in a euthymic state and significantly less time spent in a depressed and mixed state, -18.1% and -13.3%, respectively (12).

In comparison, the placebo group, who were only taking their prescribed psychiatric medications, spent less time in a euthymic state (-6.5%) and more time in a mixed state (+9.3%) (12).

“The L-T4 findings are consistent with prior open-label research in high-dose adjunctive L-T4 for bipolar patients 17. They also complement the recent findings of a randomized placebo-controlled trial of adjunctive L-T4 where reduction in depressive symptoms was associated with decreases in limbic network glucose metabolism as measured by positron emission tomography 34.

“This growing body of knowledge also confirms, in those with lithium-resistant bipolar illness, that evidence of peripheral hypothyroidism is not a necessary pre-condition to therapeutic response to supraphysiological doses of L-T4 (12).”

In addition to the relationship between hypothyroidism and bipolar disorder, lithium has been documented to accumulate in the thyroid gland and suppress thyroid function, as discussed by Czarnywojtek et al., 2020:

“Because of the active transport of Na+ /I – ions, lithium, despite its concentration gradient, is accumulated in the thyroid gland at a concentration 3 – 4 times higher than that in the plasma. It can inhibit the formation of colloids in thyrocytes, change the structure of thyroglobulin, weaken the iodination of tyrosines, and disrupt their coupling. In addition, it reduces the clearance of free thyroxine in the serum, thereby indirectly reducing the activity of 5-deiodinase type 1 and 2 and reducing the deiodination of these hormones in the liver (13).”

“Lithium may also block the synthesis of thyroid hormones. It may also influence thyroid iodine uptake, change the conformation of thyroglobulin (it can change the structure of thyroglobulin), and impair the binding of iodotyrosine (it may weaken the iodination of tyrosines, thus disrupting their conjugation), resulting in decreased hepatic deiodination and decreased clearance of free thyroxine (T4) (13).”

So, while the prevalence of hypothyroidism and autoimmune thyroiditis are higher in bipolar patients, adding lithium into the mix may further exacerbate the inclination toward hypothyroidism.

Indeed, the relationship between lithium and hypothyroidism was shown in a 2017 article in Psychiatry Research investigating the prevalence of autoimmune disease in those with mental illness.

The rate of hypothyroidism was 19.5% in those with bipolar and 4.4% in controls (aOR: 5.5, CI: 4.7–6.4). However, when the researchers adjusted for lithium use by asking the participants if their thyroid symptoms began before or after starting lithium, the prevalence dropped to 5.7% vs. 4.4% (aOR: 1.4, CI: 1.1–1.7) (14).

Hypothyroid mom, increased bipolar risk in offspring?

During pregnancy, the mother’s thyroid hormone helps shape and develop fetal brain development.

Research shows that thyroid dysfunction during pregnancy may have long-lasting effects on the child’s neurological function (15). Hypothyroidism during pregnancy may also increase the risk of bipolar disorder in offspring. This fascinating connection was examined in a study that followed up on adult offspring born to a cohort of women between 1959 and 1966.

The results showed that fetal exposure to maternal hypothyroxinemia resulted in a 5-fold increased risk of bipolar with psychotic features (OR: 5.77, CI: 1.19-27.9) (16). The strength of this association was mostly due to female offspring, as the connection between maternal thyroxine and bipolar risk varied by sex. There was no significant relationship between the risk of bipolar in male offspring and maternal thyroid hormones. This may be the reason for the wide confidence interval (1.19-27.9), indicating a minimal association for some offspring and an extremely strong association for others.

Importantly, hypothyroxinemia presents as normal TSH but low thyroxine (T4). Thus, this crucial clinical abnormality could be missed if a lab report only looked at TSH.

Interestingly, classic hypothyroidism was not significantly associated with the risk of bipolar in offspring. Additionally, I found it clinically relevant that the original design was intended to include maternal hyperthyroid; however, there were insufficient maternal cases of hyperthyroidism in the study sample and the control group to produce meaningful findings, and thus, only hypothyroidism was examined.

There may also be a connection between maternal T4 and schizophrenia risk.

The same research group found a significant connection between maternal hypothyroxinemia during the early-mid gestational period and the risk of schizophrenia in offspring (17). In this group, there was a nearly 2-fold increased risk of schizophrenia for adults born to mothers with hypothyroxinemia (OR:1.75, 95% CI: 1.22-2.50, p=.002).*

There has been an ongoing discussion over the past two decades regarding the relationship between bipolar disorder and schizophrenia, and recent MRI evidence shows significant similarities and overlap between the two diseases (18).

So, what does all of this tell us?

It is possible that low thyroid hormone levels in pregnant mothers may increase the lifetime risk of psychosis in offspring. It is essential to look at thyroid health during preconception, not only because hypothyroidism increases the risk of infertility and pregnancy loss but also for long-term mental health outcomes in the offspring.

This might seem like a bit of a leap, but because upwards of 90% of hypothyroidism is autoimmune and thyroid autoimmunity can present as psychosis (10, 11, 19, 20, 21), perhaps autoimmune activity rather than low thyroid hormone function is the primary risk factor for psychosis.

Additionally, there is a higher incidence of celiac disease and non-celiac gluten sensitivity in people with thyroid autoimmunity, and sometimes psychosis in people with autoimmune thyroid disease will resolve with a gluten-free diet (22).

Unfortunately, the study discussed above on maternal hypothyroidism and bipolar disorder in offspring didn’t look at anti-thyroid antibodies, and mainstream medicine does not yet recommend routinely checking for antibodies.

However, in my nutritional therapy practice, I suggest running a full thyroid panel with antibodies during preconception, postpartum, and, when warranted, pregnancy.

*Popular influences of the late 1950s and early ’60s, such as extreme diet culture/pressure to be thin, smoking while pregnant, or the prevalent use of Valium among many homemakers, immortalized in the Rolling Stones’ song “Mother’s Little Helper” may have contributed to thyroid dysfunction and subsequent mental health issues in offspring (23, 24, 25, 26).

References