Subclinical hypothyroidism in pregnancy

BMJ 349.7978Subclinical hypothyroidism, poor thyroid effect with thyroxine (T4) in the ‘normal’ range and thyrotropin (TSH) within ‘normal’ according to reference ranges of many labs, is a vital issue for both mother and baby. A ‘state of the art review‘ just published in BMJ (British Medical Journal) offers practitioners important reminders guidelines for subclinical hypothyroidism in pregnancy, a common and vital problem. The authors note:

“Subclinical hypothyroidism is associated with multiple adverse outcomes in the mother and fetus, including spontaneous abortion, pre-eclampsia, gestational hypertension, gestational diabetes, preterm delivery, and decreased IQ in the offspring.”

Defining subclinical hypothyroidism

These values of TSH (thyrotropin) are not often flagged as out of range by clinical laboratories:

“Subclinical hypothyroidism is defined as raised thyrotropin combined with a normal serum free thyroxine level. The normal range of thyrotropin varies according to geographic region and ethnic background…These discrepancies are probably the result of different daily intakes of iodine, varying prevalence of thyroid autoimmunity, genetic background, and environmental factors... In the absence of local normative data, the recommended upper limit of thyrotropin in the first trimester of pregnancy is 2.5 mIU/L, and 3.0 mIU/L in the second and third trimester.”

Special physiology of pregnancy

Pregnancy puts weighty demands on thyroid physiology:

“Pregnancy is a stress test for the thyroid. The thyroid gland must produce 50% more thyroid hormone for euthyroidism to be maintained and to provide enough thyroid hormone for the developing fetus. Simultaneously, the physiological changes that accompany pregnancy result in marked alterations in the normal range of thyroid function. Specifically, human chorionic gonadotropin, which peaks in the first trimester, crossreacts with the thyrotropin receptor, resulting in an upper limit of normal of thyrotropin of 2.5 mIU/L during the first trimester.

Causes of subclinical hypothyroidism

As noted in many reports here, by far the most common cause of hypothyroidism in developed countries is autoimmune thyroiditis (Hashimoto’s disease). The authors articulate a number of key points for clinicians to bear in mind:

“The leading cause of hypothyroidism in developing countries is severe iodine deficiency, whereas in developed countries it is autoimmune thyroiditis. Thyroid autoantibodies are detected in about half of pregnant women with subclinical hypothyroidism and in more than 80% with overt hypothyroidism. Antibodies directed against thyroid peroxidase (TPO-Ab) should therefore be measured in patients with subclinical hypothyroidism to establish a diagnosis of autoimmune thyroid disease.”

Personally I have found in practice that antibodies to thyroglobulin (TG-Ab) can crop up and should be measured as well:

“Although only positive TPO-Ab tests have been shown to be significantly associated with hypothyroidism, antibodies to thyroglobulin (TG-Ab) should also be measured. In a study of 992 unselected women who consulted a tertiary referral center for infertility, the overall prevalence of autoimmune thyroid disease was 16%. Of these women, 8% had both antibodies, 5% had TG-Ab only, and 4% had TPO-Ab only. Women with isolated TG-Ab had significantly higher serum thyrotropin concentrations than those without autoimmune thyroid disease…If thyrotropin concentrations are raised, TPO-Ab should be measured to establish a diagnosis of autoimmune thyroid disease. If TPO-Ab are present, the measurement of TG-Ab should be considered.”

Antibodies can be suppressed and might not show up when first measured

It is of great importance for clinicians to be aware that the results of any medical test involving antibodies may be obscured by any one of a number of factors that can suppress antibody expression. This includes pregnancy:

“Finally, it is important to realize that because the immune system is suppressed during pregnancy, thyroid antibody titers decrease on average by 60% in the second half of pregnancy. Consequently, in some women with autoimmune thyroid disease, thyroid antibody test will be negative during pregnancy but positive postpartum because the immunosuppression of pregnancy yields to an immunologic rebound during the first six months postpartum.”

Iodine deficiency during pregnancy

Although autoimmune thyroiditis accounts for most cases of hypothyroid in developed controls in general, there is a greater need for iodine during pregnancy that more easily result in deficiency.

During pregnancy, the iodine requirement increases by about 50% because the woman needs to produce more thyroid hormone, renal loss of iodine is exacerbated by the increased glomerular filtration rate, and the fetus needs to produce thyroid hormone during the second half of pregnancy. The contribution of iodine deficiency to thyroid insufficiency depends on the severity of iodine deficiency, and inadequate iodine intake is seen in both developing and developed countries.In 2011, nearly 45% of Europeans, including pregnant women and those of child bearing age, were estimated to be iodine deficient…The National Health and Nutrition Examination Survey (NHANES) has documented a marked decrease in the median urinary iodine concentration over the past three decades, with the current value for pregnant women being 125 μg/L, indicating that pregnant women in the US are probably mildly iodine deficient.”

There are serious consequences of maternal iodine sufficiency for fetal brain development:

“The Avon Longitudinal Study of Parents and Children confirmed the central role that maternal iodine status plays in the development of childhood cognition…The results showed that after adjustment for confounders, children of women with an iodine to creatinine ratio less than 150 μg/g were more likely to have scores in the lowest quartile for verbal IQ, reading accuracy, and reading comprehension than children of mothers with ratios 150 μg/g or more. Moreover, when the less than 150 μg/g group was subdivided, scores worsened progressively in the less than 150 μg/g, 50-150 μg/g, and less than 50 μg/g subgroups.”

Clinical Note: Care must be taken in prescribing iodine supplementation because inappropriate amounts can trigger autoimmune thryoiditis in those who are vulnerable. See earlier posts on the accepted method for determining iodine deficiency (24 hour urine collection) and other studies pertinent to supplementation by typing ‘iodine’ in the search box above.

Screening for subclinical hypothyroidism in pregnancy

The authors support a rational approach to screening:

“Current evidence on subclinical hypothyroidism does not support universal screening. However, the incidence and impact of overt hypothyroidism and the ability of treatment to prevent associated adverse events is sufficient to justify universal screening for thyroid disease. In support of this position, a cost effective analysis showed that universal screening with the goal of identifying and treating overt hypothyroidism is cost effective. Because universal screening would also identify patients with subclinical hypothyroidism, these patients should be treated as indicated in current guidelines unless ongoing and future studies prove otherwise.”

Clinicians sharing patient care should note:

“…obstetricians and gynecologists provide the majority of pregnancy related care. Studies have reported that some obstetricians have limited knowledge about the association between thyroid disease and pregnancy.”

Treatment for subclinical hypothyroidism in pregnancy

Far too many women and their children currently still fall though the medical cracks. It should be remembered that subclinical hypothyroidism in the first trimester can worsen as the pregnancy progresses. The authors advance the following guidelines:

Subclinical hypothyroidism has been associated with multiple adverse maternal, fetal, and neonatal outcomes, and a preliminary intervention trial suggests that treatment is beneficial. On the basis of current evidence, we believe it is reasonable to recommend treating women with new onset subclinical hypothyroidism during pregnancy. Levothyroxine therapy during pregnancy is inexpensive and has been shown to be safe…Irrespective of the prepregnancy thyrotropin value, all patients should be instructed to have thyrotropin measured as soon as pregnancy is confirmed.”

Treatment algorithm for levothyroxine before pregnancyThe authors conclude with some important points:

“The past two decades have seen major advances in our understanding of the physiological changes that occur in the thyroid during pregnancy and the impact of subclinical hypothyroidism on adverse maternal and fetal outcomes. The normal upper range of thyrotropin is 2.5 mIU/L in the first trimester of pregnancy and 3.0 mIU/L in the second and third trimesters. Hypothyroidism is present in 2-15% of pregnant women. It is mainly caused by iodine deficiency in developing countries and autoimmune thyroid disease in developed countries. Subclinical hypothyroidism has been associated with multiple negative outcomes, including pregnancy loss, preterm delivery, gestational diabetes, and impaired neurologic development in the offspring. Women on levothyroxine before conception require careful management to ensure that the euthyroid state is maintained throughout pregnancy. “

Cognitive impairment associated with low but still ‘normal’ TSH

Journal of Clinical Endocrinology & MetabolismCognitive impairment can occur at any age with suboptimal thyroid function—neurons require thyroid stimulus as much as any other cells. A study just published JCEM (The Journal of Clinical Endocrinology & Metabolism) offers evidence that TSH (thyroid stimulating hormone) levels when low but still ‘normal’ are associated with cognitive impairment and dementia. The authors state:

“The association between subclinical hyperthyroidism and the risk of dementia has been validated in several studies. However, the effect of thyroid function within reference range on the risk of cognitive dysfunction including mild cognitive impairment (MCI) and dementia is still unclear…Our aim was to investigate the association between thyroid function and the risk of MCI and dementia in euthyroid elderly subjects.”

313 participants who were euthyroid (normal thyroid) and not demented at the beginning of their study were followed for 5 years and evaluated for baseline thyroid function and cognitive impairment or dementia during the study period. They found a significant association between low-normal TSH levels and cognitive impairment:

“At baseline evaluation, 237 subjects were cognitively normal, and 76 subjects were MCI. Diagnoses of cognitive function in 259 subjects remained unchanged or improved during the study period (non-progression group), whereas 54 subjects showed progression of cognitive impairment to MCI or dementia (progression group). In the progression group, baseline serum TSH levels were lower than those in non-progression group. Baseline serum free-T4 levels were not significantly different between these two groups. The association between lower baseline serum TSH levels and the development of MCI or dementia was maintained after adjustment for conventional baseline risk factors.”

Clinical note: Practitioners should bear in mind the various possible factors besides subclinical hyperthyroidism that can suppress TSH to low ‘normal’ levels that on their own contribute to cognitive impairment including chronic inflammation.

The authors conclude:

Lower serum TSH level within reference range was independently associated with the risk of cognitive impairment including MCI and dementia in elderly subjects.”

Borderline TSH can strongly predict future hypothyroidism

Summary: Borderline levels of TSH (thyroid stimulating hormone) still within the reference ranges typically printed in laboratory reports can indicate low thyroid function (and predict hyperthyroid on the other end of the scale). A thorough assessment of the more than two dozen patterns of thyroid dysfunction is necessary for an accurate diagnosis.

Clinicians and patients may often be misled by TSH levels that appear normal, but experienced practitioners know that they can mask the presence thyroid disorders. Because hypothyroidism affects function globally, a study just published in the Journal of Clinical Endocrinology & Metabolism that practitioners in all specialties should be vigilant. The authors state:

Serum TSH in the upper part of the reference range may sometimes be a response to autoimmune thyroiditis in early stage and may therefore predict future hypothyroidism. Conversely, relatively low serum TSH could predict future hyperthyroidism…The objective of the study was to assess TSH within the reference range and subsequent risk of hypothyroidism and hyperthyroidism.”

The authors examined 10,083 women and 5,023 men without previous thyroid disease who had a baseline TSH of 0.20–4.5 mU/liter for the predictive probabilities of developing hypothyroidism or hyperthyroidism according to categories of baseline TSH during follow-up 11 years later. Their data drew a strong result:

“During 11 yr of follow-up, 3.5% of women and 1.3% of men developed hypothyroidism, and 1.1% of women and 0.6% of men developed hyperthyroidism. In both sexes, the baseline TSH was positively associated with the risk of subsequent hypothyroidism. The risk increased gradually from TSH of 0.50–1.4 mU/liter [women, 1.1%; men, 0.3%] to a TSH of 4.0–4.5 mU/liter (women, 31.5%; men, 14.7%). The risk of hyperthyroidism was higher in women with a baseline TSH of 0.20–0.49 mU/liter (3.9%) than in women with a TSH of 0.50–0.99 mU/liter (1.4%) or higher (∼1.0%).”

Too many patients with thyroid dysfunction fall between the cracks of routine care. This evidence strongly supports the importance of a complete assessment of thyroid function when these disorders, especially autoimmune thyroid disease, are suspected. The authors conclude:

TSH within the reference range is positively and strongly associated with the risk of future hypothyroidism. TSH at the lower limit of the reference range may be associated with an increased risk of hyperthyroidism.”

Thyroid dysfunction in pediatric disorders of learning, behavior and development

Thyroid dysfunction is not to be overlooked as a possible contributing cause to problems with learning, behavior and brain development. It can be expressed in a variety of ways, often requiring a nuanced functional analysis to detect and solve the problem. A study published in the journal Brain Research discusses an often overlooked type of thyroid dysregulation that can contribute to ADHD. The authors state:

Attention deficit disorders are a frequent manifestation of resistance to thyroid hormone (RTH), a disorder caused by mutations in the hormone-binding domain of the human thyroid hormone receptor β gene.”

They used PET scans to measure cerebral glucose metabolism in regions of the brain involved in attention, comparing normal subjects to those with RTH. A clear-cut difference was observed:

“Compared to the control group, performance on a continuous auditory discrimination task was severely impaired in the RTH subjects, while metabolism was higher both in the right parietal cortex and the anterior cingulate gyrus. Abnormally high functional activity of the anterior cingulate during sustained attention may be associated with a decreased signal-to-noise ratio for the neural processing of task stimuli in subjects with RTH.

In other words, resistance to thyroid hormone was associated with impaired function in the parts of the brain that are active in paying attention to and processing what we are trying to listen to. Other parts of the brain went into ‘hyperdrive’ in an attempt to compensate. Remember that this type of thyroid dysfunction, peripheral resistance to thyroid hormone, will appear normal on the usual lab tests.

A paper published in Pediatric Neurology directs our attention to the disruption of learning and behavior caused by subclinical hyperthyroidism—’subclinical’ meaning that no other overt signs of hyperthyroid are clinically apparent. The authors…

“…report three children who exhibited developmental learning disabilities (DLDs) associated with behavioral disturbances, such as attention deficit, hyperactivity, and autistic features. The thyroid function tests performed as a part of routine endocrinologic evaluation of children with DLDs revealed a hormonal profile consistent with hyperthyroidism. These children had no systemic signs of hyperthyroidism.”

Though it may not be the most sustainable long-term therapy from a functional perspective, they treated with medication to suppress thyroid hormone synthesis and reported that it…

“…resulted in good control of their hyperkinetic behavior and subsequent improvement in language function attributable to an increased attention span, thereby facilitating speech therapy.”

Although only a subset of children with learning and behavioral disorders will be found to found to have subclinical hyperthyroidism, it is a possibility that should be borne in mind and ‘crossed off the list’. The authors state:

“Although routine screening of all children with DLDs for thyroid dysfunction may not be cost-effective, selective screening of children with familial attention-deficit hyperactivity disorder and those with attention-deficit and hyperactivity in association with DLDs and pervasive developmental disorders appears to be justified.”

Another study published in the journal Psychoneuroendocrinology draws our attention to functional disturbances in thyroid hormone regulation from a different perspective. The authors state:

Thyroid abnormalities have been associated with attention deficit/hyperactivity disorder (ADHD) and with other childhood psychiatric disorders. The goal of this study was to determine the relationships between thyroid hormone concentrations, neurocognitive functioning, and psychiatric diagnosis in children.”

They examined 338 children referred to a clinic for learning and behavior problems, measuring their thyroid stimulating hormone (TSH) levels and free thyroxine index (FT4I) and correlating them with diagnostic and descriptive information. Not surprisingly, the data showed that it was the more subtle functional abnormalities rather than gross pathologic ones that discriminated different types of ADHD:

“Thyroid abnormalities were uncommon in children referred for ADHD. After excluding children with thyroid disease, there was a greater proportion with low concentrations of normal FT4I for ADHD–Predominantly Inattentive type, but not for ADHD–Combined Type. High concentrations of normal FT4I were associated with mood lability, preoccupations, and lower ratings of attention problems. Thyroxine concentrations within the normal range were differentially associated with ADHD–Combined Type compared to ADHD–Predominantly Inattentive, mood disorders, and pervasive developmental disorders.”

The authors sum up their findings for this group of children with subtle disturbances in thyroxine regulation:

Thyroxine concentrations were associated with mood symptoms and unusual behaviors, and were less strongly related to attentional functioning. Thyroxine concentrations were not related to hyperactivity.”

We can gain additional insight into the issue of thyroid hormone resistance and ADHD from a case report published in the journal Deutsche Medizinische Wochenschrift (German Medical Weekly). The authors state:

“Two siblings with goiter and attention deficit-hyperactivity disorder were presented. Earlier laboratory tests showed increased serum levels of thyroid hormones in association with non-suppressed serum levels of thyrotropin (TSH) in both children.”

Review for lay readers: as in the first paper cited, elevation of thyroid hormones in hyperthyroidism is accompanied by low levels of TSH (thyroid stimulating hormone ‘aka’ thyrotropin, which is  produced in the pituitary; it stimulates thyroid hormone production in the thyroid gland on a feedback loop). Resistance to thyroid hormone by its receptors in the rest of the body can cause TSH to be high even when thyroid hormones are elevated. Peripheral resistance can also cause a low thyroid state with labs that look normal. The doctors in this case did what was necessary to rule out hyperthyroid disease:

“Because hyperthyroidism caused by inappropriate secretion of thyrotropin was suspected, a cerebral MRI was performed. A pituitary adenoma was excluded in both children. Before antithyroid drug treatment was initiated, both patients were referred to our hospital. Careful medical history, clinical examination of the patients and careful interpretation of the laboratory results finally led to the diagnosis resistance to thyroid hormone (RTH).”

This spared the children inappropriate aggressive thyrostatic treatment (thyroid suppression or destruction). Moreover, there are functional therapies for RTH. I certainly concur with the authors’ conclusion:

“Careful medical history, correct interpretation of laboratory results, comprehensive clinical examination and molecular genetic analysis are important in the diagnosis of RTH.”

A paper recently published in the Journal of Affective Disorders sheds more light on how profound thyroid dysregulation evidenced by an increase TSH can be. The authors begin by observing:

“The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of psychiatric children and adolescents with and without the CBCL-DP.”

They correlated the CBCL-DP scores according to each behavioral phenotype with serum levels of TSH, fT3 (free T3) and fT4 (free T4). What did their data show?

“In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels.

Here again we see the manifestation of resistance to thyroid hormone, this time with elevated TSH and normal fT3 and fT4. It is likely, in our experience, that the chronic microinflammation resulting in peripheral resistance to thyroid hormone (RTH) is due to autoimmune/allergic phenomena that are simultaneously activating microglial cells (immune cells in the brain) to produce neuroinflammation. In this case the brain gets a ‘double whammy’—RTH and brain inflammation.

Bringing the matter even more up to date, an excellent and important paper recently published in the journal Clinical Endocrinology clearly articulates why it is mandatory for clinicians to be alert to functional changes in thyroid hormone measurements that are usually within the ‘normal’ laboratory reference range.The authors stated their initial objective:

Thyroid hormone concentrations outside the normal range affect brain development, but their specific influence on behaviour and mental abilities within normal values is unknown. The objective of this study was to investigate whether thyroid hormone concentrations are related to neurodevelopment and ADHD (attention deficit and hyperactivity disorder) symptoms in healthy preschoolers.”

They assessed mental and motor development with McCarthy’s scales for neuropsychological outcomes and ADHD-DSM-IV for ADHD symptoms, correlating them with thyroid hormones TSH, free T4 and T3. What did the data show?

Children with TSH concentrations in the upper quartile of the normal range performed lower on McCarthy’s scales and were at higher risk for attention deficit and hyperactivity/impulsivity symptoms. In the Menorca cohort, a decrease of 5·8 and 6·9 points was observed in memory and quantitative skills, respectively. In contrast, high T4 concentrations were associated with decreased risk of having 1–5 attention deficit symptoms…No associations were observed with T3.”

Bottom line: when there are symptoms of learning, behavioral or developmental disorders, the astute parent or clinician must ask “Is there any indication that thyroid function needs to be investigated in this case?” If so, it must be borne in mind that there are types of thyroid dysfunction that occur in the presence of ‘normal’ values for TSH, T3 and T4. The authors emphasize this in their conclusion:

Despite being within the normal range, high TSH concentrations are associated with a lower cognitive function and high TSH and low free T4 with ADHD symptoms in healthy preschoolers. Statistically significant differences were observed in the highest quartiles of TSH, suggesting a need for re-evaluation of the upper limit of the normal TSH range.