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The importance of thyroid hormone from preconception to early pregnancy

The thyroid is a small gland located at the base of our neck that produces thyroid hormones, triiodothyronine (T₃) and thyroxine (T₄). The signal to produce thyroid hormone is given by the pituitary gland in the form of Thyroid Stimulating Hormone (TSH), a protein hormone. The pituitary incidentally is also the location of the signals for normal ovulation.

Thyroid hormones help the body make energy, keep body temperature regulated, and assist other organs in their function. Thyroid hormones affect reproductively aged women who are trying to conceive. Because the hypothalamic-pituitary unit that controls thyroid hormone release also signals to the ovary to regulate ovulation, untreated hypothyroidism is associated with abnormal or an absence of ovulation and consequently infertility. When pregnancy occurs, there is an increased prevalence of miscarriage, early delivery, and pregnancy-induced high blood pressure. These obstetrical complications contribute to the overall increase in the frequency of poor outcomes in the delivered infants, which includes prematurity and low birth weight. Thyroid hormones are also essential for fetal brain development. Before 12 weeks of pregnancy, the fetus’s own thyroid glands are not yet fully developed. Therefore, the early fetal brain relies entirely on maternal thyroid production. Doctors have appreciated for decades that hypothyroidism in pregnancy can lead to offspring with developmental delay. In the late 60’s, studies found that children born to mothers with even mild or subclinical hypothyroidism in pregnancy had lower IQ than children from mothers with normal thyroid function.

Hypothyroidism is not uncommon in pregnancy with a prevalence of 0.3-0.5% for overt hypothyroidism and up to 3-5% for subclinical hypothyroidism. Therefore, accurate detection and prompt treatment are warranted to minimize the associated risks. Obstetricians have found that poor outcomes associated with underactive thyroid may be corrected by supplementing with levothyroxine, a synthetic thyroid hormone. Pooling data from several studies, a method often utilized to enhance the statistical strength by increasing the total number of study subjects, showed that levothyroxine supplement in hypothyroid pregnant women was effective in decreasing rates of miscarriage by 55% and preterm delivery by 72%. Supplementing thyroid hormones has also been shown to improve childhood brain development.

There is little doubt that clinical hypothyroidism in pregnancy is harmful, and that thyroid hormone replacement is beneficial to both the mother and the baby. What about in patients with subclinical hypothyroidism? By definition, the levels of thyroid hormones are normal and patients do not have symptoms. Can only slightly elevated TSH indicate risk? It is speculated that subtle elevation in TSH in the context of normal thyroid hormones is a warning signal, sort of like the yellow traffic light before it turns red. This is particularly true in women with thyroid autoimmunity.

Although data on this question remain limited, most thyroid specialists have drawn the conclusion that subclinical hypothyroidism may be associated with miscarriage and preterm delivery. A 2010 study in Italy of over 4000 women showed that a high normal TSH (2.5 mIU/L – 5 mIU/L, average 3.14 mU/L) with normal thyroid hormones in the absence of autoimmunity is associated with almost twice the risk of miscarriage (6.3%) compared to women with TSH <2.5 mIU/L (3.9%, average TSH 0.82 mIU/L). The same Italian group also found that 19% of women with thyroid autoimmunity despite normal thyroid hormones and TSH in the first trimester developed abnormal levels by the end of pregnancy. These women were more likely to miscarry (13.8% vs. 2.4%) and deliver before 9 ¼ months of pregnancy (22.4% vs. 8.2%). Even in patients with low normal TSH (<2.5 mIU/L), the presence of autoimmunity was found to increase the risk of very early delivery before 8 ½ months (a more clinically meaningful threshold than 9 months as babies tend to do better if born after 8 ½ months) than in women without autoimmunity (4.5% vs. 1.8%). More importantly, these risks were mitigated by treatment with levothyroxine in the same studies.

In infertility patients, the presence of thyroid autoimmunity does not appear to influence the chance of becoming pregnant with IVF. However, published studies demonstrated a one-fold risk increase in miscarriage, and thereby decreased overall delivery rate. Treating patients who have either subclinical hypothyroidism or thyroid autoimmunity has been shown in pooled analysis of several randomized control trials to lower the miscarriage rate by 45% and improve delivery rate by 36%. There is not enough evidence currently to prove that thyroid hormone replacement in these patients improves the offspring’s brain development.

It is recommended by The Endocrine Society that hypothyroidism in pregnancy should be treated with thyroid hormone replacement. Subclinical hypothyroidism in the presence and absence of thyroid antibodies should also be treated with levothyroxine. The goal is to maintain TSH levels <2.5 mU/L during pregnancy. The American Society of Reproductive Medicine recommends screening infertility patients with the measurement of TSH and subsequent treatment if overt hypothyroidism is diagnosed. The guidelines for treating subclinical hypothyroidism or those who have thyroid autoimmunity have not been formalized. However, given the evidence of the associated adverse pregnancy outcomes, the benefit of levothyroxine in reducing these risks, and the relative benign side effect profile of levothyroxine, it is reasonable to start thyroid replacement prior to conception. At Pacific Fertility Center, we recommend TSH screening in all of our patients, including thyroid antibodies in those with recurrent miscarriages, and starting levothyroxine if the level is >2.5 mIU/L or if autoimmunity is present. We hope that early detection and aggressive treatment of thyroid disorder will improve our patients’ chances to achieve a successful and healthy pregnancy.

- Liyun Li, MD

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