Introduction

Thyrotoxicosis is a condition characterised by excess thyroid hormone in the body. Cruicially, the thyroid hormone is responsible for the body’s metabolic regulation, which is the process of food being converted into energy. In thyrotoxicosis, the metabolism is sped up, triggering numerous symptoms that affect most body systems. The symptoms can range from being asymptomatic to life-threatening, a condition known as a thyroid storm.^1,2

The main cause of thyrotoxicosis is an overactive thyroid gland (hyperthyroidism), and other reasons include thyroiditis, toxic nodules and multinodular goitre, overuse of thyroid medication, and consuming an excess of thyroid hormone from your diet. The latter is a rare cause compared to the others.^1,2

Notable risk factors for thyrotoxicosis include being a person assigned female at birth (AFAB) and having recently delivered a baby.¹ Approximately 1-3.5% of pregnancies are affected by thyrotoxicosis, mainly due to gestational hyperthyroidism (GTT) and Graves’ disease.³

Gestational hyperthyroidism or gestational transient thyrotoxicosis (GTT) is a temporary type of thyrotoxicosis induced by overstimulation of the thyroid gland by human chorionic gonadotropin (hCG). This hypersensitivity is due to a mutation in the thyrotropin (TSH) receptor. This condition typically occurs within the first 12 - 16 weeks of pregnancy, and can affect around 1-3% of birth parents, particularly those with hyperemesis gravidarum and pregnant with multiple babies. Grave’s disease, on the other hand, is an autoimmune disease observed in 0.1-0.4% of pregnancies. The symptoms usually progress from severe in the first trimester to moderate in the second one and then completely diminish in the last trimester for about 20-30% of birth parents affected.³

Challenges in diagnosis

• Physiological thyroid changes in pregnancy mimicking thyrotoxicosis

During pregnancy, the birth parents’ metabolic needs are increased, leading to changes in thyroid physiology – elevated serum thyroxine-binding globulin (TBG), which increases thyroid hormone concentrations and the stimulation of the TSH receptor by hCG. Thyrotoxicosis is, therefore, often challenging to diagnose during pregnancy because of these physiologic changes.⁴

• Overlapping symptoms

The symptoms of thyrotoxicosis in pregnant birth parents are the same as nonpregnant individuals, i.e., sudden weight loss, or lack of weight gain, goitre, cardiac issues (tachycardia, arrhythmia), sensitivity to heat, anxiety, tremor and hyperreflexia^1,5

 In cases where the underlying cause is Graves’ disease, ophthalmopathy and a prolonged disease are also seen, while with GTT, there is persistent vomiting. This excessive nausea and vomiting are also seen in hyperemesis gravidarum, a condition normally noticed during the first trimester of pregnancy but can last until labour and delivery.^5,6

• Laboratory findings 

TSH suppression

The specified guidelines must outline the normal level of thyroid-related hormones during pregnancy. For example, the serum TSH concentrations for birth parents are usually lower during pregnancy compared to non-pregnant persons. The recommended trimester-specific ranges for TSH are 0.1–2.5 mIU/L, 0.2–3.0 mIU/L, and 0.3–3.0 mIU/L for the first, second, and third trimesters, respectively. Values as low as 0.02 mIU/L can also be seen as normal.^4,5

Variability of free T4

Thyroxine (T4) hormone is the main component of thyroid hormone, and it can either be found in the bound state, where it is attached to proteins, or free state in the blood, where it can easily enter tissues. For pregnant individuals, the percentage of free T4 varies distinctly, and so there is a lack of a normal reference range.^5,6

Total T4, T3, and free T4 index

A proposition indicates that the use of serum total thyroxine (T4) and triiodothyronine (T3) levels can assess thyroid function. The increase in thyroid-binding globulin (TBG) subsequently causes total T4 levels to rise, which can be as much as 50% during the first trimester. Currently, the normal upper limit for serum total T4 concentrations during pregnancy is 1.5 times higher than that of non-pregnant persons. However, there is still a lack of a well-established reference range.⁵

Utilising the free T4 index (FTI), which corrects for binding proteins, has also been suggested as a diagnostic test, but it has only been tested in one study.⁵ 

Role of TSH receptor antibodies (TRAb)

The presence of TSH (thyrotropin) receptor antibodies (TRAb) helps to distinguish the cause of thyrotoxicosis, specifically whether it is due to Graves’ disease or GTT. It is recommended that TRAb is measured at 20-24 weeks of pregnancy for those with a past or present history of Graves’ disease.⁵

• Importance of distinguishing from other causes 

Although the main causes of thyrotoxicosis in pregnancy are gestational hyperthyroidism and Graves’ disease, there are other infrequent causes, including thyroiditis, toxic multinodular goitre, toxic adenoma, excess thyroid hormone diet, iodine-induced and drug-induced thyroid dysfunction, and struma ovarii. A rare cause is trophoblastic disease.^3,4,5

For this reason, it is crucial to determine the exact cause of thyrotoxicosis based on the signs and symptoms presented, as well as proper diagnostics. This will allow for proper management and treatment approaches to be established. 

Maternal and fetal complications

Risks to the birth parents

Multiple problems can arise that directly affect the birth parent from thyrotoxicosis in pregnancy. These include:^3,4,5

• Hypertension.
• Preeclampsia.
• Congestive heart failure.
• Thyroid storm or thyrotoxic crisis.
• High risk of miscarriage.
• Premature labour and pre-term delivery. 

Risk to the foetus and newborn

Thyrotoxicosis can also lead to foetal and neonatal complications. Examples are:^3,4,5

• Fetal hyperthyroidism.
• Goitre.
• Intrauterine growth restriction.
• Stillbirth or newborn death. 
• Low birth weight baby. 
• Central hypothyroidism.

Management strategies

Generally, the main goals of treating hyperthyroidism in pregnant birth parents are to maintain mild maternal hyperthyroidism and avoid foetal hypothyroidism. Firstly, to maintain mild maternal hyperthyroidism, the free T4 and/or total T4 should be maintained at the upper limit for the normal pregnancy reference range. To manage thyrotoxicosis in pregnancy, the options are based on the cause and severity. Gestational thyrotoxicosis disregards treatment during pregnancy, so the following options relate to Graves’ disease.⁴

Medical therapy

• Antithyroid drugs (thioamides)

Propylthiouracil (PTU) – the first-line treatment in the first trimester – and methimazole (MMI) are the most typically prescribed medications. Importantly, propylthiouracil is utilised in the first trimester as MMI can’t be used at this time due to potential teratogenic effects. After the first trimester, when the major foetal organs have formed, birth parents can then switch to methimazole. As these drugs can cross the placental barrier, the lowest dose is indicated to achieve a lower-than-normal TSH level and an upper-limit free T4 level. Notably, if these levels are within the normal ranges, then the foetus is likely to be exposed to much thioamides, which can cause hypothyroidism.^3,4,5  

Methimazole has been shown to cause multiple congenital abnormalities such as embryopathy, aplasia cutis, abdominal wall defects, omphalocele, oesophagal atresia, choanal atresia, eye, urinary tract, and circulatory defects. Propylthiouracil, on the other hand, is associated with hepatotoxicity due to prolonged use beyond the first trimester.^3,4,5 

• Beta-blockers

Beta-blockers like propranolol and metoprolol can be used for a short time to control symptoms of thyrotoxicosis. However, as these medications can lead to intrauterine foetal growth retardation, extended use should be avoided.⁴

Radioiodine therapy

Radioiodine treatment (I-131) is a prior-pregnancy option since it is contraindicated throughout gestation due to the harmful effects of radiation on the foetus and possible foetal thyroid ablation.. Unfortunately,  this can lead to persistently elevated levels of TRab and birth parents are suggested to avoid conceiving for six months after treatment.^3,5  

Surgery

In thyrotoxicosis, surgery is suggested in the second trimester in the case of severe adverse reactions to antithyroid drugs. Also, thyroidectomy is indicated when large doses of these antithyroid drugs prove ineffective, patients are nonadherent or for birth parents with large goitres causing compression issues. Surgery may increase the risk of maternal complications.^3,4,5

Monitoring

For gestational thyrotoxicosis, the maternal serum TSH, free thyroid hormone levels, etc, should be monitored every 2-6 weeks using thyroid function tests. For the foetus, ultrasound monitoring is advised in birth parents with elevated TRAb (as in Graves’ disease) or those taking antithyroid drugs from 18-22 or 20-24 weeks of pregnancy. This will determine any foetal thyroid dysfunction. Cordocentesis may also be utilised in warranted cases.³ 

Postpartum considerations

Risk of relapse and postpartum thyroiditis

Postpartum thyroiditis is a circumstance involving thyrotoxicosis, hypothyroidism, or thyrotoxicosis followed by hypothyroidism in the first year after childbirth in birth parents who had a healthy thyroid before pregnancy. This condition is thought to be generated by an autoimmunity-induced discharge of preformed hormone from the thyroid and affects almost exclusively birth parents who are thyroid antibody positive.^4,7

Breastfeeding and antithyroid drug safety

For birth parents who are breastfeeding, antithyroid drugs are regarded as safe and can be taken in moderate doses. It is recommended that these drugs be administered in divided doses immediately after each feeding and that the baby be monitored for the possible development of thyroid dysfunction.⁵

Summary

Thyrotoxicosis in pregnancy, primarily caused by gestational transient thyrotoxicosis (GTT) and Graves’ disease, accelerates metabolism and poses risks to both mother and foetus. Diagnosis is challenging due to physiological thyroid changes and overlapping symptoms with other conditions. Thyrotoxicosis caused by Graves’ disease requires antithyroid drugs, while GTT usually resolves without treatment. Severe cases may necessitate beta-blockers or thyroidectomy. Postpartum risks include relapse and thyroiditis, requiring continued monitoring. Careful management ensures better maternal and neonatal outcomes.