Treating Hypothyroidism and hypothyroxinemia in pregnancy? Clinical dilemma continues.

Treating antenatal patients with levothyroxine who have hypothyroidism or hypothyroxinemia between 8 to 20 weeks of pregnancy did not result in better cognitive outcome and IQ in children through 5 years of age as compared to women who received placebo.

The study was published online on March 2, 2017 in the New England Journal of Medicine.

Earlier studies have shown that the fetus requires thyroxine for normal neurocognitive development specially in first half of pregnancy. Subclinical hypothyroidism is associated with numerous adverse pregnancy outcomes like miscarriage, preterm delivery, low birth weight, and lower-than-normal IQ in offspring.  

The debate to treat subclinical hypothyroidism in pregnancy continues as different societies recommend different guidelines for routine screening of all pregnant women for hypothyroidism. 

ACOG advises against routine screening of all pregnant women for hypothyroidism at this stage because of lack of clear cut benefits in absence of robust clinical trials evidence.

While American Thyroid Association (ATA), advises for treating subclinical hypothyroidism in pregnancy despite lack of clear cut benefits. In fact, ATA recently released new guidelines on thyroid disease in pregnancy. The article can be accessed here.

The current multicenter study by Casey et al. screened all study participants for subclinical hypothyroidism (TSH = 4mIU per liter or more and normal free thyroxine (T4) level (0.86 to 1.90 ng per deciliter) and hypothyroxinemia (normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T4 level (<0.86 ng per deciliter)

Women in either groups were randomized to receive thyroxine or placebo. Thyroid function was done monthly and the children were followed up for 5 years for cognitive development and IQ tested at 5 years.

There was no significant difference between IQ levels of children in subclinical hypothyroidism (97) and placebo (94) and hypothyroxinemia (94) and placebo (91) at 5 years of age.

No significant differences in maternal pregnancy outcome and neonatal morbidity were observed between the groups.

David Cooper, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, and Elizabeth Pearce, MD, Boston University School of Medicine, Massachusetts wrote an editorial accompanying the article in which they compared the study findings with several other earlier trials which also failed to show much maternal and neonatal benefits.

They concluded that starting the treatment for subclinical hypothyroidism and hypothyroxinemia is not much beneficial if done well into second trimester, but it is inexpensive and will do no harm. It could be beneficial if the screening and initiation of treatment is done well in first trimester. 

Adverse pregnancy and neonatal outcome in subclinical hypothyroidism: A Systematic Review and Meta-Analysis

Clinical Pearls:

• Subclinical hypothyroidism (SCH) is defined as elevated TSH levels with normal serum levels of thyroxine (T4). Recently ATA redefined the upper limit of TSH during pregnancy to 2.5 mIU/L during the first trimester and 3.0 mIU/L during the second and third trimesters
• The review confirms the association of SCH during pregnancy with multiple adverse maternal and neonatal outcomes, but there is not sufficient evidence to support the use of levothyroxine therapy to mitigate this association.
• Decision to start levothyroxine in such patients should be taken after an open and well informed discussion between patients and physicians.

  

Routine screening of all pregnant women for hypothyroidism is debatable because of conflicting data from previous studies. ACOG and American Thyroid Association (ATA) recommends against universal first trimester screening of pregnant women.

Subclinical hypothyroidism (SCH) is defined as elevated TSH levels with normal serum levels of thyroxine (T4). Recently ATA redefined the upper limit of TSH during pregnancy to 2.5 mIU/L during the first trimester and 3.0 mIU/L during the second and third trimesters.[1]

When screened according to the updated criteria’s, nearly 15% pregnant women in United states have SCH, which is almost 5 times the previous prevalence.

Many studies have reported adverse maternal and neonatal outcomes in pregnancy with SCH that includes an array of problems like including recurrent pregnancy loss, preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, placental abruption, premature rupture of membranes, intrauterine growth restriction, low birth weight, small for gestational age, low Apgar score, and neonatal death.

Some studies also report increased risk of cognitive deficits with rising TSH levels.

Other studies have not found any statistically significant association between SCH and adverse pregnancy outcomes.

This systemic review and meta-analysis estimates the effect of SCH on pregnancy outcome with patients who are euthyroid and the effect of levothyroxine on preventing the adverse pregnancy outcomes.

The study was published in the April issue of Journal Thyroid.[2]

The main outcome measures were pregnancy loss (miscarriage, IUD and fetal loss). Other outcome measure included various other complications of pregnancy.

Comprehensive search of data base from inception to January 2015, identified 1108 potentially eligible studies, of which 18 cohort studies comprising of total 3995 pregnant women with SCH were eligible. 

After meta-analysis and sensitivity analysis, it was seen that women with SCH were at higher risk for pregnancy loss, placental abruption, PROM, and neonatal death compared with euthyroid pregnant women.

The study also showed the prevalence of inconsistencies in defining SCH in different studies, absence of trimester specific range and cutoff that is used to start treatment with levothyroxine.

The ATA guidelines recommend treatment of pregnant women with SCH and positive TPO antibodies (Level B, fair evidence—USPSTF), but found insufficient evidence to recommend for or against universal levothyroxine treatment in pregnant women with SCH and negative TPO antibodies (Level I—USPSTF).[3]

The Endocrine Society panel recommends levothyroxine replacement in all pregnant women with SCH (weak recommendation, low-quality evidence).[4]although this will result in treating nearly 15% of pregnant women with levothyroxine, the guidelines panel opine that it will gain the benefits of replacing levothyroxine and reducing adverse effects as iatrogenic hyperthyroidism is unknown. 

The review stresses the importance and need of a large randomized trial to study the effects of levothyroxine supplementation on patients with SCH.  

To conclude, the review confirms the association of SCH during pregnancy with multiple adverse maternal and neonatal outcomes, but there is not sufficient evidence   to support the use of levothyroxine therapy to mitigate this association.

Clinicians and patients must have a frank and informed discussion with the patients on use of levothyroxine in patients with SCH, while we wait for larger trials to be conducted on patients with SCH and use and benefits of levothyroxine.

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[1]A Stagnaro-Green, M Abalovich, E Alexander, F Azizi, J Mestman, R Negro, A Nixon, EN Pearce, OP Soldin, S Sullivan, W Wiersinga 2011 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21:1081–1125.

[2] Maraka Spyridoula, Ospina Naykky M. Singh, O'Keeffe Derek T., Espinosa De Ycaza Ana E., Gionfriddo Michael R., Erwin Patricia J., Coddington Charles C. III, Stan Marius N., Murad M. Hassan, and Montori Victor M.. Thyroid. April 2016, 26(4): 580-590. doi:10.1089/thy.2015.0418.

[3] A Stagnaro-Green, M Abalovich, E Alexander, F Azizi, J Mestman, R Negro, A Nixon, EN Pearce, OP Soldin, S Sullivan, W Wiersinga 2011 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21:1081–1125.

[4] L De Groot, M Abalovich, EK Alexander, N Amino, L Barbour, RH Cobin, CJ Eastman, JH Lazarus, D Luton, SJ Mandel, J Mestman, J Rovet, S Sullivan 2012 Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97:2543–2565.

Endocrine Society issues a position statement against custom compounded Hormone therapy

The Endocrine Society cautious physicians against the use of compounded hormone for treatment of menopausal symptoms, female sexual dysfunction, and thyroid disorders in a scientific statement issued at Endo 16, the Annual Meeting at Boston from April 1-4, 2016.

The Society  supported the use of  FDA approved therapies and asserted that custom compounded Hormone formulations should only be used when the patient is allergic or does not tolerate  the FDA approved drugs and treatment is cardinal to his/her health.

“By no means do I wish to disparage the practice of pharmacists who are measuring hormones and providing them to patients,” Nanette Santoro, MD, professor and chair of reproductive endocrinology and infertility, department of obstetrics and gynecology at the University of Colorado Denver, said during a press conference discussing the recommendations. “Where we get into scientific trouble ... is as soon as something is being custom compounded, it’s being measured out and added to a variety of agents and diluters that will make it into a pill or a gel. ... How these excipients influence how these hormones get into a person, and what that hormone does, is essentially unknown.”

She also opined that one third to one quarter of all the drugs prescribed for menopausal hormone therapy are custom compounds as observed in a recent survey. She was also appalled at the large amount bioidentical and formulations available in the market that are similar to FDA approved therapies. “It is also a perversion of the intent of the practice of custom compounding,” She added.

This statement is also endorsed by a number of other societies like American College of Obstetricians and Gynecologists and the North American Menopause Society; nonetheless almost 60% of clinicians prescribe so-called bioidentical compounded menopausal hormone therapy, against recommendations from major medical societies, according to a new survey.

Custom compound hormone is a big business, with annual sales of $ 1 billion, and  are largely popular among patients as many clinicians prescribe them telling they are without any side effects. But, the reality is the side effects have never been tested. “What has happened is the absence of evidence of harm is taken as proof of safety,” Santoro said. “This is very illogical, yet it pervades the media and the popular press. You see happy people with anecdotes ... what we don’t know are how much they’re getting and what are the biological endpoints?”

Currently, the only indication for prescribing compounding therapy is in a woman who needs testosterone since there is no good commercially available drug in market added Dr Sklar, who is an assistant professor of medicine and endocrinology at Georgetown University Medical Center and George Washington University Medical Center, Washington, DC.

The endocrine society new document provides detailed review of many FDA approved hormonal products:

• No randomized, double-blind, placebo-controlled trials demonstrating efficacy of compounded bioidentical drugs in relieving menopausal symptoms exists as also no trials comparing FDA approved therapy vs. compounding formulations  could be found.
• For Menopausal Hormone therapy, non oral formulations are associated with reduced risk of venous thromboembolism and stroke.
• Micronized Progesterone is a treatment of choice opted by some physician, and is considered safe biochemically, but evidence is lacking regarding benefit on clinical front.   
• Transdermal patches, gels, and intramuscular preparations of bioidentical testosterone are available and FDA approved for use in men with hypogonadism, but no FDA approved testosterone preparation for women.
• There are currently no FDA approved preparations available for dehydroepiandrosterone (DHEA), no indication for prescribing it except in few patients with low libido. The bioidentical preparations come with all the drawbacks of dosing, absorption and safety as estrogen and progesterone.
• Vaginal formulation is currently undergoing trial for vaginal atrophy, but no FDA approved preparation is available in the market.
• Levothyroxine (LT4) is bioidentical, and is a highly effective therapy in patients with hypothyroidism. It is converted to T3 at tissue level and acts on all the target receptors in the body. Some patients may still exhibit symptoms of hypothyroidism; inspite adequate dosing and the clinician should investigate them for other causes. Compounded hormone therapy can be used in such patients with close monitoring of TSH and free T4.

The statement was published online April 1, 2016 in the Journal of Clinical Endocrinology and Metabolism.

References:

http://www.healio.com/endocrinology/hormone-therapy/news/online/%7B810eb536-ab0d-4524-8f1d-c8302774b2df%7D/custom-compounded-hormones-linked-to-risks-side-effects-in-menopausal-women

http://press.endocrine.org/doi/abs/10.1210/jc.2016-1271?journalCode=jcem

http://www.medscape.com/viewarticle/861365#vp_3