Adaptative changes in thyroid function
The changes in the maternal body during pregnancy are in a permanent interconnection with the function of the hypothalamic-pituitary-thyroid-ovarian pathway, especially those regarding the basal metabolism. Pregnancy requires a growth in the thyroid hormonal level, with multiple maternal and fetal consequences. The mechanism keeping the thyroid function in balance has a direct impact on the increased needs of the basal metabolism, responding to very small changes in hormonal levels.
The thyroid gland suffers changes both in structure and in function during pregnancy. Therefore, the thyroid pathology diagnosed before pregnancy can aggravate during this period, or pregnancy can be the trigger of such pathologies previously subclinical.
Structurally, the thyroid gland grows in volume up to 10% during pregnancy. However, in patients who are originally from areas known as iodine deficient, the volume can increase up to 20-40%.
Functionally, to maintain the required level of thyroid hormones during pregnancy, the production increases. The total level of hormonal concentrations increases up to 50% compared to the level prior to pregnancy. This can be observed from the first trimester. At about 20 weeks of pregnancy, the level reaches a new state of balance(1).
Human chorionic gonadotropin (bHCG) is a placental hormone initially secreted by the syncitiotrophoblasts from the nidation stage of conception and has the role of supporting the ovarian corpus luteum during the first weeks of pregnancy. The peak of bHCG is at 10-12 weeks. This hormone and the thyroid-stimulating hormone (TSH) are both glycoproteic hormones that have an identical a subunit. This resemblance explains the thyroid stimulating effects of the bHCG, resulting in a transitory hyperthyroidism in the first trimester of pregnancy. In most cases, this hyperthyroid status is not clinically observed. It can be only quantified by blood analyses that will show a decrease in the level of TSH and an increase of thyroid hormones thyroxine (T4) and triiodothyronine (T3)(1).
Thyroid hormone synthesis involves the coordinated signals from hypothalamus, pituitary and thyroid glands through thyrotropin-releasing hormone (TRH) and TSH. Almost 90% of circulating T3 is produced through conversion of T4 by iodothyronine deiodinase. Any genetic mutation in the genes responsible for this enzyme causes a decrease in the T3 level. It has been proven that there is a strong connection between genetic polymorphism and the severe forms of preeclampsia and placental insufficiency(2).
Iodine is crucial in thyroid hormone synthesis. The increase in glomerular filtration rate results in an increase in renal iodine clearance. This is what explains the higher need of iodine up to 50% during pregnancy.
Insufficient iodine intake can cause a decrease in hormone production and so the amount of hormones crossing the placenta.
In the first 18 weeks of pregnancy, the thyroid hormones are produced by the mother. After this period, the fetal thyroid begins synthetizing hormones. The subclinical maternal hypothyroidism, defined as a normal T4 level and a TSH level in the superior limit, can interfere with the fetal development and neurological development in early childhood(3).
Fetal T4 is involved in neurological development, in neuronal migration and in myelinisation. Iodine deficiency is also related to pregnancy loss, stillbirth, and increased perinatal and infant mortality. Children born in areas with iodine deficiency may exhibit cretinism as the crossing of hormones from mother to fetus before 32 weeks of pregnancy is the main mechanism of central hypothyroidism in the newborns(4).
An intake of 250 µg of iodine during pregnancy and lactation is sufficient for maintaining the correct hormonal balance both in mother and fetus(5).
However, an intake higher than 500 µg/day can cause hypothyroidism and fetal goiter, explained by the Wolff-Chaikoff phenomenon. This is defined as the autoregulatory mechanism of the thyroid, which means that the hormone synthesis is stopped if the iodine intake is too high(6).
Infertility and thyroid status
Irregular menses, ovulatory disfunctions and infertility are correlated in some cases with the thyroid status, therefore it has been observed that maintaining a thyroid homeostasis has a benefic effect on fertility.
It has been observed that a high presence of thyroid-peroxidase antibodies (TPOAb) in women diagnosed with polycystic ovarian syndrome (SOP) correlates with a decreased response to ovarian stimulation with clomiphene citrate(7).
The treatment with levothyroxine (LT4) is recommended for women with hypothyroidism who are trying to became pregnant. In the case of assisted reproductive therapy, the treatment with low doses of LT4 is recommended for patients with subclinical hypothyroidism. The same treatment is recommended for patients having TPOAb present, even though the thyroid status is in balance. In both cases, it results in a better outcome of assisted reproduction. The aim of the treatment is maintaining a serum level of TSH<2.5 U/l(8).
Autoimmune thyroid pathology
The incidence of antithyroid antibodies and TPOAb in the general population is up to 17%, without any clinical symptoms or hormonal imbalances. During pregnancy, this can change and more attention is needed(5).
For pregnant women with antibodies present, the TSH serum level is evaluated once a month throughout the entire pregnancy(5).
Hypothyroidism can be seen in women presenting antibodies because of the stress caused by pregnancy, as well as a low capacity of hormonal synthesis of the thyroid. The treatment with selenium during pregnancy does not bring any benefits and because it is associated with the development of type 2 diabetes, it is unnecessary during pregnancy(5).
There is also a connection between the presence of autoantibodies and early pregnancy loss. A decrease in pregnancy loss has been noticed in euthyroid women with autoantibodies treated from the first trimester of pregnancy with a dose of 25-50 µg LT4; however, the clinician and the patient decide together the necessity of the treatment(7).
Hypothyroidism during pregnancy
Hypothyroidism is defined by the increase of TSH serum level associated with a decrease in FT4 level. The most frequent cause after low iodine intake is Hashimoto thyroiditis. Thyroiditis is associated in a proportion of 30-60% of pregnant women with the presence of autoantibodies(5).
The serum level of TSH during pregnancy is different than the reference values in the general population and it varies as follows:
n First trimester: 0.1 up to 2.5 mU/L.
n Second trimester: 0.2-3 mU/L.
n Third trimester: 0.3-3 mU/L(8).
Specific serum levels of TSH should be calibrated in each laboratory regarding the general population of the area, based on the levels of women without TPOAb, with a proper iodine intake and without other thyroid pathology. If it is not possible to properly calibrate the levels, it is recommended to use the general value of TSH<4 mU/L, which is corelated with an increase of 0.5 mU/L from the level of non-pregnant women(5).
The screening of thyroid pathology is not mandatory. There is a series of risk factors that justify evaluating the TSH level at the beginning of the pregnancy:
1. Current symptoms/signs of thyroid dysfunction.
2. Residing in an area known as iodine insufficient.
3. Family history of thyroid disease.
4. Known thyroid antibody positivity or presence of goiter.
5. Type 1 diabetes or other autoimmune disorders.
6. History of pregnancy loss, preterm birth.
7. History of head or neck irradiation or prior thyroid surgery.
8. Morbid obesity IMC≥40 kg/m2.
10. Age >30 years old.
If the presence of major risk factors is confirmed, testing TSH serum level is recommended once every 4 weeks until 20 weeks of pregnancy, and at least once after 30 weeks(9).
The presence of hypothyroidism, with or without clinical symptoms, is corelated with the fallowing pregnancy complications: early birth loss (30%), preterm birth (<34 weeks), adverse neurocognitive effect of the newborn (cretinism). The therapy will be adapted to the TSH level and also in the presence or absence of TPOAb, as follows:
1. TPOAb positive and TSH >2.5 mUI/L.
2. TPOAb negative and TSH >10 mUI/L.
1. TPOAb positive and TSH >2.5 mUI/L, but lower than normal pregnancy levels.
2. TPOAb negative and TSH higher than normal level in pregnancy, but under 10 mUI/L.
Hypothyroxinemia (low levels of FT4) isolated during pregnancy should not be treated(5).
Regarding the therapeutic targets, they are specific for each trimester of pregnancy, and require maintaining TSH levels in the reference zones.
Patients under hormonal substitutive treatment who become pregnant need to have a dosage increase up to 20-30% of previous dosage early in pregnancy, which means two tablets more per week. After birth, the doses need to be readjusted as prior to pregnancy with reevaluation 6 weeks post-birth.
Thyrotoxicosis is a clinical hypermetabolic and hyperactivity syndrome, frequently caused by preexisting Graves disease (GD) or, less frequently, by nodular toxic goiter or toxic adenoma(5).
About 1-3% of pregnancies are associated with transitory thyrotoxicosis associated with hyperemesis. They are also associated with diseases that may also involve an abnormal growth of bHCG levels, such as multiple pregnancies, molar pregnancies or choriocarcinoma.
The risks associated with thyrotoxicosis are pregnancy loss, pregnancy-induced hypertension, premature delivery, low birth weight, intrauterine growth restriction and still birth. After birth thyrotoxicosis, the fetal effect can be seen by neuronal deficient development, with neurobehavior and convulsions(10). The mother can be also affected, thyrotoxicosis crisis being associated with cardiac disfunction, even with cardiac insufficiency.
Because the TSH levels physiologically decrease at the beginning of the pregnancy, until 11-12 weeks, caused by the increase in bHCG, this can only suggest a dysfunction, and for confirmation it is necessary to evaluate the T3 and T4 hormonal levels. The differential diagnosis between a transitory thyrotoxicosis and a preexisting disease is very important. It is mandatory to evaluate the history and evaluate the symptoms and signs of the thyroid pathology. Regarding a transitory disorder, the clinical signs and symptoms are not very suggestive. Contrary, in case of a previous pathology, ophthalmopathy or goiter is already present. If another cause of hyperthyroidism is suspected, there are recommended to evaluate the level of TPOAb and the echography evaluation of the thyroid. Scintigraphy is not recommended during pregnancy.
Hyperemesis associated with thyrotoxicosis does not require antithyroid therapy; it only requires hydroelectrolytic rebalancing and beta-blocking therapy and, if needed, evaluating the symptoms(5).
Before conceiving, it is ideal to stabilize the hormonal levels. The equilibrium is defined by two results with the level within the reference interval, one month apart without any changes in the therapeutic plan. For obtaining stability in a patient with pregnancy plans, often the ablation of the thyroid gland is recommended, surgically or by radioactive ablative therapy.
It is important to remember that after radioactive ablation, the 131I serum level remains increased for many months, thus conceiving must be postponed with 6 months. This is the reason why in patients who have a high level of antibodies, the surgical ablation is recommended as first intention.
Because the treatment with 131I isn’t recommended during pregnancy, the first line of treatment is represented by thionamids and antithyroid drugs: methimazole (MMI), propilthiouracil (PTU), carbimazole (CM). For patients following this therapy during pregnancy, it is mandatory to assess the risk of fetal malformations(11).
The dosage during pregnancy is as follows: MMI 5-30 mg, CM 10-40 mg, and PTU 100-600 mg. The equivalent MMI:PTU is 1:20 (5 mg of MMI = 100 mg of PTU). These drugs are toxic and can have as side effects agranulocytosis, modifications in the hepatic metabolism, and skin allergies. PTU is mostly used in the first trimester of pregnancy, with the evaluation of liver enzymes, because of the teratogenic effect. MMI is associated with carbimazole embryopathy, representing an important facial dysmorphism. Regarding the stable patients and those considered in remission, it is recommended to stop the treatment as soon as possible (6-10 weeks of gestation) for avoiding the teratogenic effect, with the evaluation of the thyroid function every 1-2 weeks (once every 3-4 weeks in the second and third trimesters) and reinitializing the treatment if needed, PTU being considered less teratogenic than MMI. These side effects of the treatment make it vital to inform the patients regarding contraception or early diagnosis of pregnancy and stopping the therapy as soon as possible(5).
The evaluation of the therapy requires the determination of serum levels of FT4/FT3 and TSH every 4 weeks, and the target will be FT4 at the upper limit of reference in pregnancy.
During pregnancy, thyroidectomy can be a treatment plan in cases with allergies to the recommended drugs or the equilibrium cannot be reached at high doses of medicine. The ideal time for the intervention is the second trimester.
TSH receptor antibodies (TRAb) are positive in 95% of the patients diagnosed with Graves disease, but the evaluation of TRAb is not general.
The indications for the evaluation of TRAb are:
Patients with hyperthyroidism without treatment/treatment with antithyroid drugs.
History of Graves’ disease surgically treated or radioactive ablation.
History of newborn with hyperthyroidism.
History of thyroidectomy during pregnancy for hyperthyroidism.
The frequency of fetal hyperthyroidism in women with Graves’ disease, active or stable, is 1-5%. The ultrasound evaluation of the fetus is recommended in case of uncontrolled hyperthyroidism or if TRAb is three times over the normal value. Ultrasound assessment should include: fetal cardiac frequency (tachycardia >170 bpm over 10 minutes), intrauterine growth, fetal goiter (an early sign of thyroid fetal hypofunction), early bone maturation, cardiac insufficiency, fetal hydrops, and amniotic liquid level(4).
If the hyperthyroidism is caused by a toxic thyroid nodule, TRAb are absent, which means that the fetal hyroid gland is not stimulated. In conclusion, if antithyroid drugs are used, the risk of fetal hypothyroidism and fetal goiter is very high. The fallow-up of fetal complications should be very careful, and antithyroid drug dosage should be as low as possible.
Thyroid nodules and thyroid cancer
A very important issue in evaluating a pregnant woman is the assessment of family history, because it could raise awareness about investigating other thyroid diseases.
The frequency of discovering new thyroid tumors during pregnancy is 3% up to 21%. Analyzing the family history is important in case of thyroid cancer, because both medullar and papillary thyroid carcinoma are associated with MEN2 mutations (thyroid carcinoma associated with pheochromocytoma and other endocrine hyperplasia or neoplasia determined by the RET gene mutation, located on chromosome 10q11.2).
For the investigation and confirmation of the character of a thyroid nodule, a lot of investigations are needed: laboratory, ultrasound, biopsy and histological confirmation(11).
Thyroid ultrasound and thyroid function must be evaluated in case of any new discovery of a thyroid tumor. Biological findings should regard serum TSH, T3, T4 levels, as well as thyroglobulin and calcitonin, especially in the case of RET gene mutation.
Fine needle aspiration (FNA) guided by ultrasound can be performed any time during pregnancy. This will add information regarding the histological diagnosis. It is recommended when a new nodule is found, associated with high TSH level. If serum TSH level remains normal, FNA can be postponed until after birth, when a scintigraphy can be performed. The results of the biopsy indicate the treatment plan and surveillance during pregnancy. In case of histologic incertitude, without any malignant signs, the intervention can be postponed until after birth, when the spectrum of diagnosis enlarges, the treatment with LT4 not being necessary.
In case of diagnosing a papillary thyroid carcinoma during pregnancy, it is recommended the ultrasound surveillance of the tumor. The surgical intervention is not recommended during pregnancy, as long as it is diagnosed during the second trimester or later, and its evolution is stationary, without signs of locoregional extension. If it is diagnosed between 24 and 26 weeks of pregnancy, the tumor grows in volume (>50%) and in diameter (>20%), or suspicious ganglions are found, the surgical intervention should be performed during the second trimester(11).
If at the moment of diagnosis the tumor is advanced locally or the result of the biopsy indicates medullar thyroid carcinoma or anaplastic carcinoma, surgery will be the first intention therapy. During pregnancy, radio ablation and therapy with tyrosine kinase inhibitors are not recommended, due to their important teratogenic risks(4).
In case of identifying a papillary microcarcinoma, the ultrasound thyroid surveillance will be done in every trimester.
Conflict of interests: The authors declare no conflict of interests.