Category Archives: Thyroid Disease

Thyroid Disease

Thyroid Hormones and the Risk of Gestational Diabetes

Diabetes definitionThyroid hormones play an important role in glucose metabolism and homeostasis. They regulate hepatic gluconeogenesis, intestinal absorption of glucose, and glucose uptake in peripheral tissue. In addition, thyroid hormones modify circulating insulin concentrations. Thyroid function and metabolism undergo significant changes during pregnancy. For these reasons, thyroid hormones have been implicated in the development of gestational diabetes mellitus (GDM).

Published evidence has been conflicting about a possible relationship between overt or subclinical hypothyroidism and development of GDM. Recently, Rawal, et. al. reported an association between elevated concentrations of serum triiodothyronine (T3) and the ratio between elevated free T3 (fT3) and free thyroxine (fT4) ratio. This ratio is a surrogate marker for the body’s conversion of T4 to T3 and has been associated with development of GDM. 

The study was a multicenter and multiracial case-control study nested within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort.  GDM cases and 214 controls were included in the study. GDM was determined using the Carpenter-Coustan diagnostic criteria.   Blood was collected at four visits across pregnancy (targeted at gestational weeks8-13, 16-22, 24-29, and 34-37), and thyroid stimulating hormone (TSH), fT3, and fT4, were measured using the Roche Cobas e411. TSH concentrations that were ≤4 mIU/L were considered to be normal. Isolated low fT4 (hypothyroxinemia) was defined as having normal TSH with fT4 that was less than the 10th percentile of controls. Overt hypothyroidism was defines as elevated TSH with low or normal fT4 concentrations (less than the 90th percentile of controls).  

The authors reported that increased concentrations of fT3 and increased fT3:fT4 ratio were both associated with a greater risk of developing GDM even after adjusting for the pre-pregnancy body mass index and the family history of diabetes.  The fT3:fT4 ratio was most strongly associated with GDM with women in the highest quartile in the second trimester at a 14-fold increased risk, compared to women at the lowest quartile. Consistent with previous reports, the authors found lower concentrations of fT4 associated with GDM, but the associations were not significant after adjusting for confounders.

The authors suggest that higher fT3 concentrations (perhaps from increased conversion of T4 to T3) may be involved in the pathophysiology of GDM. They also conclude that their finding support the potential importance of thyroid screening for pregnant women. Naturally, these conclusions will need to be validated with a randomized controlled interventional study.

New Guidelines from the American Thyroid Association on Thyroid Disease During Pregnancy

Thyroid tests
Early in 2017, the American Thyroid Association (ATA) issued new guidelines for the diagnosis and management of thyroid diseases during pregnancy and the postpartum.   This 74 page document covers everything from thyroid function testing during pregnancy, to thyroid autoantibodies and pregnancy complications and thyroid disease and lactation. It is a comprehensive and well written document that is a must-read for anyone interested in thyroid function and laboratory testing during pregnancy.  There is no way I can summarize the whole document here, but I did want to highlight what I think are some important take-home points for laboratorians.

 Normal Reference Intervals for TSH During Pregnancy

In 2011 the ATA guidelines suggested the upper reference limit for serum TSH be set at 2.5 mU/L during the first trimester and 3.0 mU/L in the second and third trimesters. The 2017 guidelines point out that there are now studies demonstrating substantial variation between populations.  The ATA recommended that when possible, population-based trimester-specific reference intervals for serum TSH should be defined and utilized. This is excellent advice, but very difficult for laboratories to establish. When local assessments are not available, the panel now recommends that in the first trimester the non-pregnant reference interval be lowered by 0.4 mU/L at the low end and 0.5 mU/L at the high end (which equates to an upper reference limit of around 4.0 mU/L). This is a significant change from their previous recommendation.

T4 Assessment During Pregnancy

There have been publications which raise uncertainty about free T4 (fT4) measurements using immunoassays in pregnancy. The ATA again recommends that when possible, population-based trimester-specific reference intervals for fT4 should be defined and utilized. Again, such intervals are very difficult for laboratories to establish. When this is not possible, in lieu of measuring fT4, total T4 measurement can be used with the upper reference interval increased by 50% to account for the increased thyroid binding globulin present during pregnancy. They also indicate that free thyroid hormones can be assessed using equilibrium dialysis LC/MS/MS. This method is considered the gold standard, but it is more expensive. They also suggest use of the fT4 index, but I personally think that whenever possible, fT4 by equilibrium LC/MS/MS or total T4 should be used whenever possible rather than this antiquated method. I recently wrote an opinion piece about on this topic. fT4 index should not be used as a substitute for trimester-specific reference intervals. The guideline suggests that isolated hypothyroxinemia (low fT4 with normal TSH), should not be treated.

Iodine Assessment During Pregnancy

There is substantial day-to-day variation in urinary iodine intake and excretion. As such, urinary iodine concentrations cannot be used to identify patients with iodine deficiency. They suggest that all pregnant women should ingest ~250 ug of iodine daily and that excessive doses of iodine should be avoided.

Patients with Thyroid Autoantibodies     

There are increasing data indicating that there appears to be a greater risk for adverse events such as preterm delivery in pregnant women with thyroid autoantibodies compared to those who are thyroid antibody negative. The guidelines suggest that euthyroid pregnant women who are TPOAb or TgAb positive have TSH measured at the time of pregnancy confirmation and every 4 weeks throughout pregnancy in order to monitor them for the development of hypothyroidism.

Hypothyroidism During Pregnancy

Overt hypothyroidism during pregnancy is well known to be associated with adverse pregnancy complications (such as premature birth, low birth weight and pregnancy loss) and detrimental effects on fetal neurocognitive development (such as low IQ). For this reason, treatment of overt hypothyroidism is recommended during pregnancy. However, as we blogged about recently,  screening for and treatment of subclinical hypothyroidism is still being debated. Because of the averse outcomes associated with elevated TPO antibodies (mentioned above) the panel does have specific recommendations with regard to the screening and approach to subclinical hypothyroidism.  First, pregnant women with TSH concentrations >2.5 mU/L should be evaluated for TPO status. Second, subclinical hypothyroidism should be approached as follows:

T4 therapy is recommended for:

  • TPO positive and TSH greater than pregnancy specific reference interval
  • TPO negative and TSH greater than 10 mU/L

T4 therapy is considered for:

  • TPO positive and TSH greater than 2.5 mU/L and less than upper limit of pregnancy specific reference interval
  • TPO negative and TSH greater than pregnancy specific reference interval but less than 10 mU/L

T4 therapy is NOT recommended for:

  • TPO negative and TSH within pregnancy specific reference intervals

The panel suggests that thyroid hormone replacement therapy should target a treatment goal of maternal TSH concentrations below 2.5 mU/L.

Another Update on Subclinical Hypothyroidism in Pregnancy

Thyroid DiseaseWe have blogged previously about the ongoing debate regarding the treatment of subclinical hypothyroidism in pregnancy (here and here).  In brief, there was a study published in 1999 that demonstrated that 7-9 year old children, from women with abnormal thyroid measurements during pregnancy, performed slightly less well than the control children on 15 IQ tests. Of the 62 women with thyroid disease who were not treated for their hypothyroidism 48 had children who had significantly lower IQ scores than the control children. This report led to a number of follow-up studies to support or refute this study.

Another one of the follow-up studies was recently published in the New England Journal of Medicine.  The authors screened women <20 weeks gestation for: subclinical hypothyroidism TSH ≥4 IU/L with normal fT4 (n=677); and women with hypothyroxinemia normal TSH with fT4 <0.86 ng/dL (n=526). Women in those two groups were then randomly assigned to receive levothyroxine or placebo. The dosage was adjusted each month to maintain normal TSH or normal fT4 (depending on which arm of the study they were in). The children were then followed for 5 years. The authors found that in the subclinical hypothyroidism group, the median IQ in the treated group was 97 and 94 in the untreated group.  In the hypothyroxinemia group, the median IQ was 94 in the treated group and 91 in the untreated group. There were no significant differences between groups in either arm of the study suggesting that there was no benefit to treating.

This study is consistent with the findings in the CATS trial which we have discussed previously. However, as discussed in an editorial about this article, both this study and the CATS trial are limited by the late initiation of treatment (17 weeks in this study). This is important because the fetal thyroid becomes active at 16-20 weeks of gestation, therefore the fetus relies on maternal T4 prior to that time.

The authors of the editorial concluded that because early intervention is feasible and may be beneficial, they still endorse the American Thyroid Association recommendations that suggest screening of certain high risk women and early treatment as indicated.  I suspect we will be blogging about this topic again in the future.

Trimester-Specific Reference Intervals for TSH

Thyroid tests

In September 2011, The American Thyroid Association (ATA) published new guidelines on the diagnosis and management of thyroid disease during pregnancy and postpartum.  There are many recommendations in the guidelines, but I wanted to highlight one in particular.

Recommendation 2

"If trimester-specific reference ranges for TSH are not available in the laboratory, the following reference ranges are recommended: First trimester, 0.1-2.5 mIU/L; second trimester, 0.2-3.0 mIU/L; third trimester, 0.3-3.0 mIU/L."

 These reference intervals are lower than the non-pregnant reference intervals. This is due to the fact that hCG has mild thyroid-stimulating ability.  Therefore, hCG stimulates the thyroid and suppresses TSH. This is most apparent during the first trimester (7-11 weeks) when hCG is at its highest concentration. TSH concentrations actually decrease, although usually not below the normal, non-pregnant, reference interval.

This means that hypothyroidism during pregnancy needs to be defined using these pregnancy-specific reference intervals. Overt hypothyroidism is defined as decreased fT4 with TSH > 2.5 mIU/L. Subclinical hypothyroidism is defined as serum TSH 2.5-10 mIU/L with normal fT4. The ATA recommends treating overt hypothyroidism, but not subclinical hypothyroidism, unless women are also positive for anti-TPO antibodies. When patients are treated, the goal is to achieve the trimester-specific reference intervals listed above.

Interestingly, the ATA recommends that women who are taking T4 therapy have their dose adjusted to achieve a TSH concentration of 2.5 mIU/L before pregnancy. This reduces the risk of hypothyroidism during the first trimester. Likewise once women who are on T4 therapy get pregnant, their T4 therapy should be adjusted to keep them within the pregnancy-specific TSH reference intervals and serum TSH should be monitored approximately every 4 weeks during the first half of pregnancy. Serum TSH should also be checked again between weeks 26 and 32.

Similarly, according to the ATA, euthyroid (normal functioning thyroid gland) women who are not on T4 replacement therapy but are TPO antibody positive, should also have serum TSH monitored every 4 weeks during the first half of pregnancy and again between weeks 26 and 32.

Should I get my iodine measured during pregnancy?


The short answer is no, but let me explain why.

Iodine is necessary for the production of the thyroid hormones T3 and T4. A deficiency of iodine leads to decreased production of these hormones and can cause goiter (enlargement of the thyroid) and hypothyroidism.

During pregnancy, a number of normal changes occur that involve the thyroid gland and the need for iodine including:

  1. hCG is similar in structure to TSH, the hormone that stimulate the thyroid gland, and so hCG can also stimulate the thyroid gland;
  2. There is an increased demand for T3 and T4; and,
  3. Clearance of iodine through the kidneys is increased.

In areas where there is iodine deficiency, pregnancy is associated with a 20-40% increase in the size of the thyroid gland. In areas where iodine is replete, like the United States, the thyroid increases in size by only around 10% during pregnancy.

Because of these changes, dietary iodine requirements for pregnant women are higher than they are for non-pregnant women. If iodine intake was adequate before pregnancy, women should have sufficient iodine stores and therefore have no difficulty meeting the needs for iodine during pregnancy and lactation. If their iodine intake was not sufficient, it can result in overt hypothyroidism which is associated with miscarriage, stillbirth, and, in very severe cases, cretinism (characterized by severe mental retardation and deafness). Iodine deficiency is the leading cause of preventable mental retardation worldwide. According to public health experts, iodization of salt may be the world's simplest and most cost-effective measure available to improve health

While the U.S. is an iodine replete country, some studies have suggested that women of reproductive age may be at risk of iodine deficiency.  This might make one think that iodine status should be determined in these women. Iodine status is usually assessed by measuring urine iodine concentrations. However, there is significant day-to-day variation in urine iodine excretion, such that measurement in a single individual is not useful. Urine concentrations are most useful to assess the iodine status of a whole population.

In 2011, the American Thyroid Association (ATA) published guidelines for the diagnosis and management of thyroid disease during pregnancy and postpartum. In these guidelines, the ATA recommends that all pregnant and lactating women ingest a minimum of 250 ug of iodine daily. For U.S. women that means supplementing their diet with a daily oral supplement that contains 150 ug of iodine (optimally potassium iodide).

In 1924, the Morton Salt Company began distributing iodized salt nationally, which is a good source of iodine. While iodized salt is the main source of iodine in the American diet, only ~20% of the salt Americans eat contains iodine!  Reasons for this include:

  1. Increase in popular designer salts like sea salt and Kosher salts (see photo below); Salt
  2. Iodized salt is not used in most fast and processed foods or in the production of commercial breads; and,
  3. Patient concerns about salt intake & hypertension. Good dietary sources of iodine include kelp seaweed, seafood (cod, sea bass, haddock, and perch are good sources) and dairy products.

In summary, if you are pregnant make sure you are taking a supplement that contains iodine, but do not worry about having your iodine concentration measured.


Should all women be screened for hypothyroidism? An update

ThyroidA few months ago, I wrote about thyroid testing during pregnancy.    As I mentioned, there was a study published in 1999 that examined the association of hypothyroidism in mothers and the neurocognitive development in their children.  The study demonstrated that, at 7-9 years of age, children from the women with abnormal thyroid measurements performed slightly less well than the control children on 15 IQ tests. 48 of the 62 women with thyroid disease were not treated for their hypothyroidism and the children from those women had significantly lower IQ scores than the control children.

That study prompted a follow-up study to address the question of whether intervention (i.e. T4 treatment for hypothyroidism) would prevent the difference in IQ.  This study has been referred to as the CATS (Controlled Antenatal Thyroid Screening) study and it was recently published.    This was a prospective, randomized, controlled trial where pregnant women at 15 weeks 6 days gestation or less were assigned to a screening group, in which TSH and fT4 measurements were performed or a control group in which blood was drawn but not tested until after delivery. Women in the screening group who were found to have TSH concentrations above the 97.5th percentile, free T4 concentrations below the 2.5th percentile, or both were given daily T4 treatment.   

21,846 women in the UK and Italy provided blood samples for the study. Of those, 390 in the screening group and 404 women in the control group had abnormal thyroid hormone concentrations. The authors measured IQ in their children at 3 years of age, but found no statistical difference between the control and screening groups. These findings support the idea that there is not enough evidence for universal thyroid function screening of pregnant women or for treatment of subclinical hypothyroidism.

There are a number of limitations to this study which have been outlined nicely in an editorial that accompanies the CATS study publication.  First, the women in the CATS study had milder hypothyroidism than in the previous observational study. The previous study included women with a mean TSH concentration of 13.2 mIU/L whereas the present study had median TSH concentrations of 3.8 (UK) and 3.1 (Italy) mIU/L. Second, the T4 therapy was not started until a median gestational age of around 13 weeks which may be too late to obtain benefit from the T4 therapy. Third, the earlier observational study measured IQ in 7-9 year old children, whereas the present study examined 3 year olds. It is possible that it is too early to measure the differences in the IQs of the two groups. Follow-up studies in these children would be useful.

An additional randomized trial is in progress that will examine the IQ in children at 5 years of age as well as other maternal complications between treated and placebo treated groups. This study, which began in 2006, may help put this discussion to rest, however we will have to wait until 2015 until the results of the study are complete.

Should all pregnant women be screened for hypothyroidism?

Thyroid glandHypothyroidism affects about 2% of all women but occurs in only about 0.5% of pregnant women. The discrepancy is probably due to the known association between hypothyroidism and infertility. Other causes of inadequate thyroid function during and after pregnancy include iodine deficiency, Hashimoto’s disease, thyroidectomy, radioactive iodine treatment, and subacute. Inadequate treatment of hypothyroidism can have serious consequences for both the mother and fetus. Hypothyroidism during pregnancy has been associated with pregnancy-induced hypertension, placental abruption, postpartum hemorrhage, and an increase in the frequency of low birth weight infants.

A study published in 1999 examined the association of hypothyroidism in mothers and neurocognitive development in their children. Serum concentrations of thyroid stimulating hormone (TSH) were measured in 25,216 pregnant women and 62 had a TSH result that was greater than 98th percentile, suggesting that they had clinical or subclinical hypothyroidism. These 62 women were then matched with 124 healthy women and 15 tests of IQ were determined in their 7-9 year old children. The children from the 62 women with thyroid disease performed slightly less well than the control children on all 15 IQ tests. 48 of the 62 women with thyroid disease were not treated for their hypothyroidism and the children from those women had significantly lower IQ scores than the control children.

The study suggests an association between an underactive thyroid gland during pregnancy and delayed neurodevelopment in the offspring and begs the question:

"Should all pregnant women be screened for hypothyroidism?"

Several medical associations have weighed in on this subject. Guidelines from the American Association of Clinical Endocrinologists, indicate that TSH screening should be routine before pregnancy or during the first trimester. If the TSH is greater than 10 mU/L or if the TSH is 5-10 mU/L and the patient has goiter or positive anti-thyroid peroxidase antibodies, then thyroid hormone replacement therapy should be initiated.

The American Thyroid Association and the Endocrine Society agree that there are not enough data for or against universal screening but also acknowledge that just because there is no evidence of benefit doesn’t mean that there is no benefit. They recommend the screening of pregnant women who are at high risk of overt hypothyroidism (e.g. history of thyroid dysfunction, TPO antibody positive, goiter etc). If the TSH is greater than 10 mU/L, this indicates overt hypothyroidism, and thyroid hormone replacement therapy should be initiated.

However, the American Congress of Obstetricians and Gynecologists has recommended against screening all pregnant women for hypothyroidism. They argue that there is lack of clear evidence that the identification and treatment of women with subclinical hypothyroidism will improve maternal or infant outcomes.

To date, there is no clear evidence to suggest that the treatment of pregnant women with subclinical hypothyroidism prevents neurodevelopmental in their offspring. Perhaps a clinical trial funded by the National Institute of Child Health & Human Development will clear away the controversy.

hCG and the thyroid gland

Thyroid tests First things first. The main job of human chorionic gonadotropin (hCG) hormone is to increase the synthesis of progesterone in early pregnancy. Without steadily increasing concentrations of progesterone, an early pregnancy will fail. hCG usually has nothing to do with the thyroid gland.

As a reminder, the thyroid gland, located in the neck in close proximity to the larynx (voice box), is basically responsible for controlling our body's metabolism. It is regulated by a different hormone: thyroid stimulating hormone or TSH.

So hCG maintains pregnancy and TSH regulates the thyroid gland. Sometimes, however, hCG can act like TSH and crank up the function of the thyroid gland. When the thyroid gland is in an over-active state the condition is called hyperthyroidism. Symptoms of hyperthyroidism include weight loss, increased appetite, heat intolerance, hair loss, weakness and fatigue, irritability, and sweating. In extreme cases, hear palpitations, and shortness of breath can occur. How can hCG cause hyperthyroidism? The answer lies in the molecular structure of these two hormones.

As it turns out, hCG and TSH are rather similar to each other. Both are composed of two different protein subunits. One of those protein subunits is called "alpha" and the other "beta." The alpha subunits of hCG and TSH are identical but the beta subunits are a different; but not by much. The beta subunits of hCG and TSH are about 40 percent identical. When present a very high concentrations, hCG can actually stimulate the thyroid gland sending it a message to go into over-drive. In other words, hCG can sometimes act like TSH. Fortunately, this doesn't happen unless the amount of hCG in the blood gets to be very, very elevated.

How elevated? Well, that has been the subject of some recent investigations. Conventional wisdom was that hyperthyroidism could occur in women with an hCG concentration that was greater than 50,000 IU/L. While this hCG concentration may seem very elevated, it's actually quite normal in pregnant women who are in their first trimester. Because the vast majority of pregnant women in early pregnancy do not have symptoms of hyperthyroidism, the 50,000 IU/L threshold didn't seem accurate.

In one study (disclaimer: I participated in that study), an hCG threshold of 400,ooo IU/L was identified as the concentration above which actual symptoms of hyperthyroidism could occur. The lower hCG concentration of 200,000 IU/L was identified as the threshold above which a majority of women demonstrated biochemical signs of hyperthyroidism (i.e. decreased TSH) but they did not have actual symptoms of hyperthyroidism until the hCG increased to twice that amount.

Another study reported that women developed suppressed TSH and/or symptoms of hyperthyroidism only when the hCG concentration was greater than 100,000 IU/L.

A normal, singleton, intrauterine pregnancy doesn't usually produce such sustained elevations of hCG. This means that the vast majority of pregnant women will never have symptoms of hCG-induced hyperthyroidism. However, extreme elevations of hCG can be produced in women with gestational trophoblastic disease (GTD). These are a family of diseases that arise from an abnormal fertilization event so hCG is produced even in the absence of a viable fetus.

The bottom line is that extremely high hCG concentrations can cause biochemial and physical signs of hyperthyroidism but these are rarely the result of the hCG concentrations found in normal pregnancy.