Hypothyroidism in pregnancy: From unanswered questions to questionable answers

QUESTIONS

The American Thyroid Association (ATA) and The Endocrine Society (TES) have recently published comprehensive Pregnancy and Postpartum Thyroid Management guidelines. These elaborate documents discuss almost every conceivable aspect of thyroid function and dysfunction during pregnancy and the postpartum period. ATA lists X, while TES provides (only) 52 recommendations to help us care for pregnant women with hypothyroidism.[1,2]

Certain questions, hitherto unanswered, are indeed unique to the Indian (or developing nations’) context, which this editorial tries to focus upon. An effort has also been made to suggest practical answers to them, based partly on the recent guidelines of the Indian Thyroid Society (ITS).[3]

The ATA and TES guidelines, though exhaustive, up-to-date, and unbiased, do not answer the following questions for the Indian endocrinologist or gynecologist:

1. Should every antenatal patient be screened during first trimester?

2. Should every antenatal patient with subclinical hypothyroidism (thyroid stimulating hormone (TSH) >2.5 mIU/l) be treated?

3. What should the approach be in centers where thyroid antibody testing or accurate free thyroxine (FT4) estimation is unavailable or not affordable?

4. Should every patient with a normal TSH during first trimester be screened again during subsequent trimesters?

ANSWERS

The ATA, after an exhaustive summary of available evidence, concludes that it can neither recommend for or against universal TSH screening at first trimester”, but clearly states that “universal FT4 screening of pregnant women is not recommended”.[1] The lack of evidence to support any single clear-cut strategy is understandable, but this decision does not help the clinician in any way.

The TES guidelines seem to be bit more aggressive.[2] TES does not recommend universal screening, but encourages TSH measurement of ‘high-risk‘ individuals, and also promotes prenatal low-dose L-thyroxine (T4) therapy, with a target TSH of less than 2.5 mIU/l. Regarding universal screening for all newly pregnant women, TES committee could not reach a firm conclusion. While five authors favored universal TSH screening by 9^th gestation week or at first antenatal visit, eight authors proposed aggressive case-finding. The wordsmithing done by these eight authors, however, is enough to baffle the most ardent reader. They allow universal screening in case where an individual's risk status cannot be assessed: i.e., if the physician or gynecologist cannot take a basic history or perform a brief physical examination; he or she is justified in ordering a TSH!

There also exist (older) American College of Obstetricians and Gynecologists Statements on management of thyroid dysfunction in pregnancy. Some of the recommendations need updation as they are not based on the most recent evidence.[4,5]

Guidelines (and editorials, for that matter) should be written by authors, for readers, not for authors. Let us see if the ITS helps.

The ITS guidelines clearly recommend that “all pregnant women should be screened at 1^st antenatal visit by measuring TSH levels”, and highlight that “ideally screening should be carried out during pre-pregnancy evaluation or as soon as pregnancy is confirmed”.[3] The discussion that precedes these statements, however, repeats the findings of many researchers who advocate aggressive case finding, but not systematic screening, during pregnancy. The ITS guidelines list high-risk groups of patients, based on history and physical examination findings, who should be screened for thyroid disease. It goes on to recommend four specific high-risk groups in whom screening should include anti-thyroid peroxidase (TPO) antibodies. The discordance between the text of ITS chapter on Screening for Thyroid Dysfunction during pregnancy, and its final recommendations, leaves readers confused.

Due to the uncertainty of universal iodine sufficiency, and somewhat higher incidence of thyroid antibody positivity in India, it would be prudent for Indian health care providers to follow the ITS recommendations of universal screening for hypothyroidism during pregnancy. The patient should be actively involved in the decision making. A brief explanation of why the test is important for the mother and her unborn child goes a long way in preventing discontent, especially in a pay from pocket situation. It should be noted that lead authors of the ATA guidelines also recommend universal screening in pregnancy.[6]

The diagnostic dilemma just discussed is the beginning of the story. This is often replaced by a therapeutic dilemma, if the laboratory returns a high TSH value, i.e., >2.5 mIU/l in the first trimester, or >3.0 mIU/l in the second and third trimesters. The clinician is then faced with a tougher question: To treat or not to treat.

The ATA guidelines try to help clinicians in this regard. For a TSH value >10.0 mIU/l, L-thyroxine supplementation is mandatory. For those with a TSH <2.5 mIU/l during first trimester, no further investigations are needed.

A dilemma arises regarding patient with a TSH of 2.5-10 mIU/l. A FT4 estimation is indicated for these. A normal FT4 should ideally elicit a thyroid antibody test, a rather costly test, with therapy being initiated in all antibody-positive patients. It is left to the treating endocrinologist to decide whether or not to treat antibody-negative antenatal women with L-thyroxine if their first trimester is between 2.5 and 10 mIU/l. If FT4 levels are below 5^th percentile, however, (a very uncommon situation, i.e. in less than 5% of all patients), L-thyroxine therapy is mandatory. The ATA, thus, tries to provide a straightforward answer: treat all patients with overt hypothyroidism (TSH > 10 mIU/l; TSH > 2.5 miu/l with low FT4); and all subclinically hypothyroid patients with antibody positivity (TSH > 2.5 mIU/l, TAb+).[1]

The unanswered query remains: how to decide whether or not to treat a patient with TSH 2.5-10 mIU/l, with negative antibodies.

TES makes it much easier for the practicing clinician, by recommending a starting dose of 50 μg/d or more in all patients with a TSH > 2.5 mIU/l in first trimester, or >3.0 mIU/l in second trimester.[2]

ITS is categorical in its recommendation.[3] Without any caveats, it recommends thyroxine treatment for all antenatal women with subclinical hypothyroidism, targeting the upper limit of normal reference range for TSH.

The editors do feel, however, that clinical aspects of thyroidology are not emphasized enough. While the symptoms and signs of hypothyroidism are non-specific, and can be confused with those of pregnancy, none of the current guidelines highlight the need to assess these. An astute clinician can pick up clues on history and general physical examination which help in clinical decision making. This dying art should be encouraged by all guidelines in thyroidology, as well as other endocrine sub-specialities.

While the ATA guidelines are very comprehensive, they do not address a situation where resource-challenged clinical setups are unable to offer accurate and/or affordable thyroid antibody testing to their patients, or patients refuse to accept the same.

The guidelines do highlight the intricacies involved in TSH and FT4 estimation in pregnancy, while sensitizing endocrinologists to the need for careful interpretation of laboratory data. It should be stressed once again, however, that the diagnostic threshold for hypothyroidism is lower in pregnancy than in non-pregnant individuals. The normal reference values for TSH are 0.1-2.5 mIU/l, 0.2-3.0 mIU/l and 0.3-3.0 mIU/l in the first, second and third trimesters of pregnancy.[1,2,3] Apart from the trimester-specific nature of these normal values of FT4, one should realize that these are method-specific as well. The optimal method of serum FT4 estimation in pregnancy is by measuring T4 in serum dialysate or ultrafiltrate using on-line extraction/liquid chromatography/tandem mass spectroscopy. Endocrinologists should be aware of the method used by their laboratory and should understand that serum TSH is a more accurate marker of thyroid status than suboptimally measured FT4.

TES, too recommends caution in interpreting FT4 values in woman with pregnancy if a free T4 assay is used.[2] It suggests a simpler method of circumventing this problem, such as multiplying the non-pregnant total T4 range (5-12 μg%) by 1.5 to arrive at a pregnancy-specific normal range for second and third trimesters. This method is practical and economical, and can easily be used in India. The FT4, index is also mentioned as a reliable investigation by TES.

The current ITS guidelines do not discuss these issues related to FT4 estimation. However, as they clearly recommend universal screening with TSH, and treatment of all sub-clinically thyroid woman with pregnancy, this is of less importance. Future ITS guidelines should cover relevant aspects of laboratory thyroidology as well, especially as direct access testing, with its attendant perils, becomes the norm in India.

Another situation which is not adequately addressed by ATA and TES is that of screening in second and third trimesters.

Pregnancy is nothing short of a stress test to evaluate thyroid reserve. As pregnancy progresses, the likelihood of hypothyroidism increases. ATA suggests regular TSH monitoring for euthyroid antibody positive woman throughout gestation. TES recommends screening in second trimester as well. However they make no recommendation for euthyroid antibody negative women. While this may not be of major concern in iodine replete countries, the chances of thyroid dysfunction developing during pregnancy may be higher in iodine-deficient nations.

ITS recommends monitoring only the thyroid antibody positive euthyroid women in each trimester, thus cutting down the number of individuals to be screened significantly.[3] But, it too, does not address the issue of further monitoring in euthyroid patient without antibody tests, or with negative antibodies.

While there is no evidence to strongly recommend TSH monitoring in every trimester for all antenatal women, a case can be made for targeted screening at 26-32 weeks gestation. Patients with symptoms and signs of hypothyroidism, including goitre, a past bad obstetric history, a history of thyroid disorder or neck surgery, or irradiation, history of other autoimmune illness, a family history of thyroid illness, or residence in an iodine-deplete area may be some of the clinical cues for ordering a repeat TSH.

This aspect too should be addressed by future Indian guidelines, as we still face iodine deficiency in many parts of the country.

CONCLUSION

Thyroidology and obstetrics intersect with each other to form a grey area, in which not much evidence is available. This makes it difficult for authors to formulate definitive recommendations which balance evidence, experience and end user expectations. In spite of this, writing committees of the ATA, TES, and ITS have done yeoman service by providing comprehensive documents of lasting value. From an Indian perspective, there still remain a few unanswered questions, which future trials and guidelines will definitely try to answer.