Thyroid Disease in Pregnancy
By John C. Hobbins, MD, Professor of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora. Dr. Hobbins reports no financial relationships relevant to this field of study.
Overt maternal hypothyroidism and hyperthyroidism each complicate about 3/1000 pregnancies. However, subclinical hypothyroidism can accompany as many as 2.5% of pregnancies. Both problems require careful surveillance because of the potential to cause significant maternal and fetal complications.
Thyroid Physiology
During pregnancy, the maternal thyroid works overtime. A two-fold increase in thyroid binding globulin (TBG), along with elevated hCG levels in the first and second trimesters, stimulates maternal thyroid activity. With this increased work load, the thyroid gland swells by about 20% in size. The fetal thyroid is quiet in the first trimester as the fetus is dependent on maternal free triodothyronine (fT3) and maternal free thyroxin (fT4) for its needs. By 18 weeks, the fetus is self-sufficient and fetal thyroid hormone production is largely regulated through the fetal pituitary gland. With this self-regulation, the levels of fetal thyroid-stimulating hormone (TSH) rise.1
Various thyroid products have different placenta-traversing capabilities. These properties become important when the maternal thyroid is over- or underactive. For example, TSH does not cross the placenta but fT3, fT4, and thyroid-stimulating immunoglobulins (TSI) do. The placenta will de-iodinate much of the fT3 to reverse T3, which is essentially inactive. The fetal thyroid gland is especially busy in later pregnancy when it is more involved in oxygen consumption, carbohydrate metabolism, and fetal growth and development.
Hypothyroidism
This maternal problem is caused by insufficient production of maternal fT3 and fT4. By far, the most common cause in pregnancy is Hashimoto’s thyroiditis, an autoimmune condition associated with thyroid peroxidase (TPO) and/or thyroglobulin antibodies, which have a direct antithyroid effect. Type 1 diabetics are particularly susceptible to hypothyroidism. Mothers with untreated or undertreated hypothyroidism have increased rates of preeclampsia, preterm birth, and low birth weight. Additionally, inadequately treated pregnant women with hypothyroidism have children with increased risk for psychomotor abnormalities and lower IQs (even in a subclinical setting)2 — underscoring the need to recognize hypothyroidism early enough to initiate rather simple preventive treatment.
The signs and symptoms of hypothyroidism can be insidious. Patients generally have an even greater weight gain than expected in pregnancy and complain of symptoms such as fatigue, constipation, hair loss, muscle cramps, dry skin, and insomnia. They may or may not have a goiter. The diagnosis is simply made by demonstrating low levels of maternal fT3 and fT4 and elevated levels of TSH (usually 2.5-fold higher than expected). If caused by Hashimoto’s thyroiditis, the presence of TPO antibodies should clinch the diagnosis.
In women with pre-existing hypothyroidism, treatment consists of simply increasing the once-a-day dose of levothyroxine (Synthroid®) by about 40%. Increasing the dosage every 2 to 3 weeks to attain a TSH level that is in the low normal range and a T4 level in the high normal range is also accepted maintenance for pregnant women with established disease. In patients diagnosed for the first time in pregnancy, levothyroxine can be started at 0.1-0.15 mg a day and then the dosage can be altered according to the TSH levels.
Hyperthyroidism
Hyperthyroidism in pregnancy is mostly due to Graves’ disease, another autoimmune abnormality associated with the release of TSI, and increases maternal thyroid activity. TSH-binding inhibitory immunoglobulin is the immunoglobulin involved in about 30% of cases and can stimulate TSH receptors or, less commonly, block them.
Patients with this condition will have typical signs and symptoms of being in a hypermetabolic state, exhibiting hyper-irritability, elevated systolic blood pressures, tachycardia (not affected by a Valsalva maneuver), and exopthalmia. The clinical manifestations are often exacerbated by hyperemesis gravidarum. The diagnosis is easily made by assessing fT3 and fT4 levels, which are usually sky high, and TSH values, which are typically very low.
Most patients with Graves’ disease will have been diagnosed and treated before pregnancy. Managing pregnant women with Graves’ simply involves adjusting the dose of their antithyroid medication. The two most common medications used to counter the production of T3 and T4 are propylthiuracil (PTU) and methimazol. In newly diagnosed cases, the standard PTU starting dose is 100 mg every 8 hours, but it may take 6 weeks to normalize thyroxin output. This dose may be adjusted up or down, depending on fT4 values. Since TSH may be somewhat sluggish to respond, these levels are not used as commonly as fT4 to adjust the PTU dosage. Although easier to use because of a longer half-life, methimizole (with a starting dose of 20 mg/day) is often a second choice because of a very questionable possibility of teratogenicity (aplasia cutis).3 These medications should be adjusted so that fT4 is in the high normal and TSH is in the lower normal ranges.
Permanent treatment of hyperthyroidism involves radioactive iodine (RIA) ablation of the thyroid. This approach has been successful in reversing signs and symptoms while normalizing thyroid function in 80% of patients. However, this is not the treatment of choice in pregnancy, and patients have been conservatively counseled to avoid becoming pregnant for 6 months following ablation.4 Nevertheless, if the patient does become pregnant before this time, the half-life of the RIA is 8 days and, therefore, the risk to the fetus should be low.
Surgery is now used less frequently and can be tricky because of the thyroid’s location near vital structures. In fact, one of our patients was treated with a “total” thyroidectomy but had significant tissue left behind (antigen). This led to the release of enough thyroid-stimulating antibodies to cause cardiac failure in her fetus. Despite this unusual case, surgery has been very successful in curing the condition in the majority of cases. Interestingly, now there is a suspicion that ablation, while succeeding in making patients clinically euthyroid, may actually increase the potential for release of immunoglobulins. For this reason, surgery may become the more favored procedure in women of child-bearing age. In both procedures, supplemental thyroid replacement is required.
Fetal Effects of Maternal Hyperthyroidism
fT3 and fT4 can traverse the placenta, accounting for 30% of thyroid hormone found in the fetal circulation. The IgG antibodies that can cause serious fetal problems are TSI, previously labeled “long-acting thyroid stimulating antibody.” An assay for TSI has been available for a few years, and although the test identifies only the stimulating antibodies, it misses 20% of antibodies capable of causing fetal hyperthyroidism. Another more recently used assay, now in its third generation, is thyrotropin-stimulating receptor antibody (TRab).5 This test is 95% sensitive for identifying antibodies capable of causing hyperactivity of the fetal thyroid, but the assay also pulls in the antibodies that, on rare occasions, can block these receptors, thereby causing fetal hypothyroidism.
These antibodies can create a hypermetabolic state in the fetus, leading to goiter in about 20% of cases, cardiac failure, and, if not dealt with, intrauterine demise. On occasion, the fetal thyroid gland can grow to a point where it can obstruct the upper airway at the time of birth. These fetuses are hyperactive and most often will have sustained tachycardia. Without treatment, some fetuses can have impaired cardiac function and, later, frank cardiac failure. Accompanying this downward course will be the emergence of a pericardial effusion, cardiomegaly, followed by hydrops.
Patients with high TSI and/or TRab levels need to be monitored closely for clinical signs of hyperthyroidism. The following represent reasons for concern:
- Persistent fetal tachycardia (> 160).
- Increased fetal activity perceived by the patient and assessed by ultrasound.
- Enlargement of the fetal thyroid as determined by ultrasound. This can be measured on cross-section at the gland’s widest diameter inside carotid arteries and jugular veins, or the circumference6 can be determined at the same level. It also can be quantified with 3-D volume analysis.7
- An increased intensity on color Doppler of the vascular circulation in the central portion of the fetal gland.
Fetuses of hyperthyroid patients can be difficult to “read” because they can have a hypothyroid goiter due to overdosage of antithyroid medication or, alternatively, a hyperthyroid goiter from an unrestrained outpouring of TSI, resulting in the need for more medication. Based on our recent experience, we have found the TRab to be more precise than TSI in predicting fetal hyperthyroidism.
Since the aim of today’s management of hyperthyroidism is to avoid the need for invasive measures to assess fetal thyroid status, we use ultrasound to provide clues as to whether the fetus has a hyper- or hypothyroid goiter. For example, in hypothyroid goiters, any increase in vascularity is generally peripheral, but in hyperthyroid fetuses, there is usually an increase in central vascularity. The entire gland will light up like a Christmas tree. One study from France in 39 patients with Graves’ disease showed that 68% of fetuses with hypothyroid goiters had peripheral vascularity, and none had central vascularity.8 Twenty percent of those with hyperactive goiters had peripheral vascularity and 50% had central distribution. Interestingly, 60% of fetuses with hypothyroid goiter had sustained tachycardia — diminishing the impact of FHR alone as a diagnostic tool. In our experience, however, the hyperthyroid fetuses had sustained heart rates in the 180s.
Hyperthyroid fetuses will mature their epiphyseal centers earlier. For example, normally a distal femoral epiphysis (DFE) will rarely be seen before 33 weeks, and if it is present, it appears as a thin dislike echogenic focus. It thickens into a ball-like structure by about 36 weeks.9 Our recent hyperthyroid fetuses have had detectable DFEs at 26 weeks and proximal tibial epiphyses (usually appearing after 36 weeks) before 32 weeks.
Occasionally, we have gotten enough mixed messages from the fetus, thereby requiring more precise information through fetal blood sampling (specifically fT4 levels).10 This will allow adjustment up or down of anti-thyroid medication to fit the thyroid status of the fetus. We have used doses of up to 600 mg of daily PTU to control fetal hyperthyroidism. TSH is sluggish to respond and is less useful diagnostically. In most cases, only one sampling is necessary to get a medication regimen on track and then the fetal status can be monitored noninvasively with ultrasound.
Protocol for Managing Maternal Hyperthyroidism
- At the initial visit, obtain blood levels of T3, T4, TSH, TSI, and TRab and increase the PTU according to the results (if the patient is already on this medication). If the diagnosis is newly made during pregnancy, then begin the regimen suggested above.
- From then on, titrate the PTU according to the patient’s signs and symptoms with the aim to get the TSH levels into the lower normal range and the T4 levels into the high normal range.
- Ultrasound should be employed every 1-2 weeks, depending upon whether the fetus appears affected.
- The fetal heart rate should be < 160 bpm.
- The fetus should not be hyperactive on subjective assessment.
- Thyroid size should be within normal limits.
- If a goiter is present, the tissue should be devoid of internal vascularity.
- If TRab levels are high, begin monitoring weekly.
- If no goiter is noted, then there is less concern for fetal compromise.
- If there is a goiter, if TRab levels are very high, if the heart rate is consistently above 160, and if internal vascularity does not diminish on increased doses of PTU, then consider fetal blood sampling to evaluate the status of T4 and TSH.
- Begin monitoring cardiac function through fetal echocardiography.
- Look for clinical signs of cardiac failure (pericardial effusion, cardiac enlargement, and any early signs of hydrops).
Two of the most difficult aspects of managing this condition are the inability to deal with the fetus directly and the unpredictable placental transfer of medications. There is little in the literature to guide the clinician regarding the adjunctive use of the beta-blockers (which has been used occasionally in the neonate), cardiotropic agents such as digoxin, or steroids to counter antibody production (although definitely a reach). Obviously, if the clinical situation deteriorates despite therapy, then delivery is an option if the fetus is at a salvageable gestational age.
In the past, treating thyroid disease in pregnancy has been difficult and confusing. Now with early recognition and collaborative management strategies, successful treatment and avoidance of neonatal complications is more possible in the pregnant patient with thyroid disease.
References
1. Pop VJ, et al. Low maternal free-thyroxine concentrations during early pregnancy are associated with impaired psycho motor development in infancy. Clinical Endocrinol (Oxf) 1999;50:149-155.
2. Burrow GN, et al. Maternal and fetal thyroid function. N Engl J Med 1994;331:1072-1078.
3. Abalovich M, et al. Management of thyroid dysfunction during pregnancy and postpartum. An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:(8 suppl):S1-S47. (Review).
4. Brent GA. Clinical practice: Graves’ disease. N Engl J Med 2008;358:2594-2605.
5. Zophel K, et al. Clinical review about TRAb assay’s history. Autoimmun Rev 2010;9:695-700.
6. Ranzini AC, et al. Ultrasonography of the fetal thyroid: Normograms based on biparietal diameter and gestational age. J Ultrasound Med 2001;20:613-617.
7. Nath CA, et al. Three-dimensional sonography in the evaluation and management of fetal goiter. Ultrasound Obstet Gynecol 2005;25:312-314.
8. Huel C, et al. Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound Obstet Gynecol 2009;33:412-420.
9. Goldstein I, et al. Ultrasonographic assessment of gestational age with the distal femoral and proximal tibial ossification centers in the third trimester. Am J Obstet Gynecol 1988;158:127-130.
10. Abuhamad AZ, et al. Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: Case report and review of the literature. Ultrasound Obstet Gynecol 1995;6:368-371.
Overt maternal hypothyroidism and hyperthyroidism each complicate about 3/1000 pregnancies. However, subclinical hypothyroidism can accompany as many as 2.5% of pregnancies. Both problems require careful surveillance because of the potential to cause significant maternal and fetal complications.Subscribe Now for Access
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