Graves disease and pregnancy

Graves disease has an interesting clinical course during pregnancy. Pregnant women with Graves disease typically go through an initial exacerbation of hyperthyroidism during the first trimester with gradual improvement during the second and third trimester.

Table of Contents

Background

In normal physiology, women without Graves disease usually become mildly thyrotoxic during the first trimester due to beta HCG-mediated stimulation of thyroid hormone synthesis. This is known as transient HCG-mediated hyperthyroidism. This physiologic state usually resolves by 14-18 weeks gestation without untoward side effects. For this reason, patients with Graves disease should be kept borderline thyrotoxic in the first trimester since the achievement of euthyroidism may lead to relative hypothyroidism in the developing fetus.

Table 1. Natural history of Graves disease in each trimester of pregnancy.

Stage of pregnancyMechanism
1st trimesterElevated levels of HCG (has structural homology with TSH) stimulates thyroid hormone synthesis
2nd and 3rd trimesterEstrogen-mediated increase in thyroxine-binding globulin (TBG). TBG subsequently binds free (active) thyroid hormone leading to an improvement in hyperthyroidism.
Suppression of thyroid autoimmunity by estradiol, progesterone, and cortisol
Post deliveryRebound thyroid autoimmunity due to withdrawal of protective placental steroids.

Table 2. Distinguishing various causes of hyperthyroidism in pregnancy

Parameter(s)Graves diseaseGestational thyrotoxicosisHyperemesis Gravidarum
Antithyroid drugs requiredYesNo May be required
Natural historyImproves at the end of the first trimester but persists into the 2nd and 3rd trimesters.Usually resolves at the end of the first trimesterUsually resolves at the end of the first trimester
Goiter, orbitopathy, or TSI antibody positivityPresentAbsentAbsent
Hyperemesis with weight loss, ketonemia and ketonuriaNoNoYes

Preconception planning

Women who are planning pregnancy should be rendered euthyroid prior to conception. A biochemically euthyroid patient on stable maintenance doses of antithyroid drugs may proceed with pregnancy. However, methimazole should be substituted for propylthiouracil (PTU) in the first trimester due to the risk of choanal atresia associated with methimazole.

Patients who either remain hyperthyroid on antithyroid medications or euthyroid on high doses of antithyroid drugs should be advised to proceed with definitive therapy (total thyroidectomy or radioiodine ablation) before conception. These patients are more likely to have a thyroid storm in the first trimester due to the deleterious effects of HCG (corpus luteum derived) in the setting of suboptimally controlled hyperthyroidism. Pregnancy would need to be deferred for at least six months before conception for patients who opt for radioactive iodine ablation.

Feto-maternal monitoring during pregnancy

1. TSH levels should be monitored every 4 to 6 weeks throughout pregnancy

2. Antithyroid medications (PTU and methimazole) are preferred in symptomatic patients with moderate to severe symptomatology. PTU is usually reserved for the first trimester of pregnancy due to the teratogenic effects of methimazole (aplasia cutis, choanal atresia, and tracheoesophageal fistula)

3. Beta-blockers have a utility in controlling hyperadrenergic symptoms but are associated with intrauterine growth restriction.

Neonatal thyrotoxicosis due to Graves disease

Thyrotropin receptor antibodies (TRAb) should be measured in pregnant patients with Graves disease during 20-24 weeks of pregnancy. TRAb levels > 3 times the upper limit of normal can reliably predict the risk of fetal thyrotoxicosis. Neonatal thyrotoxicosis is the development of overt hyperthyroidism in a newborn of a pregnant woman with Graves disease.

Thankfully this condition almost always resolves within 3-12weeks of delivery. It occurs due to the transplacental transfer of the mother’s TRAb’s to the baby during the delivery process. Nonetheless, if there is a lack of amelioration of symptoms in an infant after 3 to 6 months post-delivery, then an alternative diagnosis should be entertained. Possible diagnoses in this setting include McCune-Albright syndrome and TSH receptor-activating mutations.

References

  1. Leslie De Groot et al. Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 8, 1 August 2012, Pages 2543–2565
  2. Fantz CR, Dagogo-Jack S, Ladenson JH, Gronowski AM. Thyroid function during pregnancy. Clin Chem. 1999 Dec;45(12):2250-8.