AACE 27th Annual Scientific & Clinical Congress:

Addressing the Complexity of Thyroid Disease Management During Pregnancy

With Erik K. Alexander, MD

Since informed evaluation and treatment of thyroid disease is critical to assure a healthy pregnancy, there is a tremendous amount of new data, which has nearly doubled in the past decade alone. This has prompted an update to the clinical guidelines for managing thyroid disease in pregnancy from the American Thyroid Association.1,2

Erik K. Alexander, MD, professor of medicine at Harvard Medical School, provided a comprehensive overview of the clinical challenges in managing thyroid disease in women who are pregnant, in a pre-conference session on Thyroid and Pregnancy,3 ahead of AACE 2018 in Boston, Massachusetts.  

In particular, he identified three “hot button” topics that deserve a closer look as well as emerging treatment considerations in response to recent studies findings when speaking to EndocrineWeb:

 

Evolving Areas of Clinical Care of Thyroid Disease in Pregnancy

Key Issues in Hypothyroidism
“Clinicians should be aware of the new guidelines that define when women who are pregnant should be treated for hypothyroidism. Previously, there was a cut off of TSH of 2.5 or 3.0 mUI/L was used but more recent data has suggested we use a value of 4.0 or perhaps a bit higher is reasonable. Perhaps more important in the use and analysis of maternal thyroid levels is thyroperoxidase antibodies (TPOAb) are important to check in women who are seeking to become pregnant or newly pregnant because this can affect pregnancy outcome,” Dr. Alexander told EndocrineWeb.

Key Issues in Hyperthyroidism/Grave’s Disease
“A final topic of note is how to best treat hyperthyroidism like Grave’s disease during pregnancy, which has changed with regard to both antithyroid drugs, propylthiouracil (PTU) and methimazole (MMI) , have been shown to carry risks for birth defects. Therefore, there is increasing discussion as to whether those medications can be stopped very early in pregnancy to avoid risk to the developing fetus,” Dr. Alexander told EndocrineWeb.

Exploring the Role of TPO in Hypothyroidism During Pregnancy

Recent data suggest that thyroperoxidase antibody (TPOAb) status does matter.3  In fact, it appears to independently amplify the harmful effects of maternal hypothyroid function levels even in otherwise healthy (euthyroid) pregnant women who are TPOAb positive.4

From findings of two prospective cohort studies of women who were diagnosed as infertile (n=1468), a TPOAb positive status conferred higher rates of miscarriage (43.9% vs 25.3%, P < 0.01) and lower rates of live births (17.1% vs 25.4%, P < 0.01).5  In fact, the risk of miscarriage may double or even triple based on TPO Ab status,3 said Dr. Alexander.

Further support for the significance of TPOAb was introduced by Korevaar et al,6 who reported a dose-dependent association between TPOAb and thyroid function and risk of premature delivery in women (n=11,212) under 20 weeks gestation modified by TSH concentrations.  

To consider treatment,2 the recommendations are as follows:

  • In TPO Ab-positive women with a TSH greater than their pregnancy-specific reference range;
  • In TPO Ab-negative women with a TSH greater than 10.0 mU/L
  • In TPO Ab-positive women with TSH levels > 2.5 mU/L but below the upper limit for their pregnancy-specific range.
  • Consider TPO status:  > 4 mU/L but only for TPO negative status with a TSH >10 mU/L.

Among euthyroid pregnant women who were TPOAb positive, those who received thyroid replacement therapy (50 mcg daily) in comparison to a control experienced a reduction in the rate of miscarriages from 16% to 0% (P = 0.02) such that the authors' suggest consideration of universal screening for all at-risk pregnant women.7

Impact of hCG Levels in Hypothyroidism During Pregnancy

Accessing serum human chorionic gonadotropin (hCG) as a marker for premature delivery or preterm premature rupture of membrane (pPROM), initial data offers intriguing results worthy of further assessment.8 It may be that pregnant women who are TPOAb-negative but have both high TSH and hCG may be at higher risk for these adverse pregnancy outcomes, said Dr. Alexander.

Is there reason for concern that a low-normal fT4 is harmful when TSH is normal?
“Since TSH is a surrogate marker for total thyroid function levels, it may be more necessary to measure T4 or T3. Increasingly low (even low-normal) fT4 has been associated with adverse pregnancy outcomes. Yet, there are no interventional trials to inform treatment decisions, which is complicated further by error and variability of measurements of fT4 concentrations,” said Dr. Alexander.

Findings from an initial cohort study has introduced the possibility that subclinical hypothyroidism based on a low fT4 during the first trimester may increase the risk of gestational diabetes; while a low fT4 during the third trimester may confer a greater risk for preeclampsia.9 To complicate treatment consideration, recent results from Johns et al10 raised concerns that “increasing fT4 may not be without risk to the fetus, based on association data,” he said.

While the need for a healthy reference range in early pregnancy remains, most patients are generally young, iodine-sufficient, and have Hashimoto’s thyroiditis with a TSH that may be mildly elevated. For those with a subclinical TSH < 10 mIU/L, treatment to prevent risk of miscarriage and cognitive decline in the fetus may be warranted, according to Dr. Alexander.

Controversies in Managing Grave’s Disease in Pregnancy

Treatment Risks
In considering how to approach treatment of Grave’s thyroiditis in pregnancy, “we are faced with a paradox,” said Dr. Alexander. It appears that maternal hyperthyroidism is generally considered dangerous during pregnancy and to be avoided but the data on both antithyroid medications: propylthiouracil (PTU) and methimazole (MMI) clearly connect these medications with known teratogenic effects to the fetus.3

 “Increasingly, recent attention has turned to stopping treatment early in the pregnancy [of women with hyperthyroidism] to avoid imposing a risk to the developing fetus,” said Dr. Alexander. “The greatest danger is overtreatment. Therefore, when possible, it is advisable to stop both MMI and PTU, particularly in the newly pregnant patient.; however, if treatment is warranted, PTU is more favorable during the first half of pregnancy,”3 he said.

Attention to Ethnicity and Timing in Individual Patients
There is a need to account for trimester timing as well as ethnicity both of which appear to influence the ‘normalcy’ of TSH as defined by healthy pregnant women who are thyroid peroxidase antibody (TPOAb) negative with optimal iodine intake and no sign of thyroid impairment.3

Following a study by Negro et al,11 based on an evaluation of pregnancy loss among Italian women, compelling evidence supports a TSH limit of 2.5 mIU/L during the first trimester and under 3.0 mIU/L for the remainder of the pregnancy, which reflects the 2007 Endocrine Society Guidelines on thyroid and pregnancy.1,2 

Medici and colleagues followed more than 4,000 women in the Generation R study,12 reflecting varied ranges when TSH was evaluated by ethnicity. Other ethnicities appear to have different TSH ranges during pregnancy from 0.5 to 5. 0 mIU/L13,14. See Table 1 for a summary of the varying TSH ranges found among pregnant women.

Ethnicity appears to influence thyroid function levels requiring attention when considering treatment plan.Treatment for hypothyroidism during pregnancy must be individualized to account for ethnic variability.

 

“A more generous TSH threshold of > 4.0 appears as a more appropriate level to define hypothyroid disease in women who are pregnant; however, it is necessary to know the baseline thyroid function for the ethnicity of your patient in order to provide patient-specific guidance,” said Dr. Alexander.

Where Do We Go with Thyroid Treatment in Pregnancy?

The relative risk of TSH is not the same as ‘do no harm’ so it is important to rely on normalcy as it pertains to your community population,3 said Dr. Alexander.

Given that the studies looking at pregnancy associated elevated maternal TSH with harm (eg, increased risk of miscarriage, and in the fetus: ADHD and lower IQ), treatment for hypothyroidism has not demonstrated improvement in fetal cognition.3 Therefore, “we must treat with purpose to identify, treat, and to make a difference,” he said.

While we await further data, we will want to rely on a TSH cut off of ~4.0 as the threshold for treatment, recognizing that a normal thyroid function during pregnancy is important for maternal and fetal health, according to Dr. Alexander.

“However, a single recommendation for thyroid management during pregnancy would be too broad and too blunt given the heterogeneity of populations. As such, we must continue to seek a definition for “normal,” so treatment may become be more precisely determined,” Dr. Alexander said.

Dr. Alexander had no financial conflicts pertaining to this presentation.

 

Next Summary:
Clinical Takeaways: Microvascular Risk, Metabolic Disease, Continuous Glucose Monitoring
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