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. “

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