During pregnancy, the hypothalamic-pituitary-thyroid axis adapts to physiological changes in the pregnant woman and to the needs of the foetus. To do so, it is estimated that thyroid activity increases by around 50%. However, thyroid dysfunction is common and can have serious consequences for both mother and foetus, hence the importance of assessing thyroid function in pregnant women. The HAS (Haute Autorité de Santé in France) has recently issued recommendations on this subject, which we will present below.
Thyroid dysfunction during pregnancy can be classified according to three criteria:
- Hyper- or hypothyroid status, defined by serum TSH concentration;
- Clinical (confirmed) or subclinical (fruste) character, defined by the clinical picture and serum T4L concentration;
- Autoimmune aetiology, defined by the presence of anti-thyroperoxidase (TPO), anti-thyroglobulin (anti-Tg) or anti-TSH receptor (TSHr or TRAK) auto-Ac.
Hypothyroidism and pregnancy
Confirmed (clinical) hypothyroidism is defined by increased TSH and decreased free T4.
Subclinical hypothyroidism is defined by an increased TSH and normal free T4.
If TSH is above reference values (> 4 mIU/L in pregnant women), it must be confirmed with a second sample.
Isolated hypothyroxinaemia may also be found, defined as decreased T4L and normal TSH.
In France, the frequency of clinical hypothyroidism is estimated at between 0.3 and 0.5%, while subclinical hypothyroidism is at 2 and 5%, based on a TSH threshold value of > 4 mU/L, and between 10 and 15% based on a TSH threshold of > 2.5 mU/L. The prevalence of isolated hypothyroxinaemia is estimated at 2.2%, and the presence of anti-TPO Ac during pregnancy at 5-10%.
The reference values for TSH during pregnancy were redefined by the HAS in 2023: 0.1 to 4 mU/L, during any trimester.
T4L decreases physiologically during pregnancy, but the variations observed with different assay techniques mean that a consensus reference interval cannot be defined. The values given by the laboratory should be taken into account.
Aetiologies of hypothyroidism
Aetiologies of hypothyroidism vary according to geographic origin, ethnicity, age, body mass index (BMI) and iodine status.
The main aetiologies are iodine deficiency, autoimmune thyroiditis (in developed countries) or iatrogenic causes (surgery, I131, synthetic anti-thyroid drugs, etc.).
Consequences of hypothyroidism in pregnant women
The obstetrical consequences of untreated clinical hypothyroidism are potentially severe. These include early miscarriage or spontaneous abortion (60% in the case of clinical hypothyroidism, over 6% in the case of TSH > 2.5 mU/L), gestational hypertension (pre-eclampsia and eclampsia: 22% in the case of clinical hypothyroidism), placental abnormalities and abruption, anaemia, premature delivery (less than 32 weeks gestation: 60% in cases of clinical hypothyroidism), in utero growth retardation, foetal hypotrophy, respiratory distress (requiring transfer to neonatal intensive care), congenital anomalies, foetal death (in cases of severe clinical hypothyroidism), and post-partum haemorrhage.
The neonatal consequences of gestational dysthyroidism can also be serious. Thyroid hormones play a major role in neuronal maturation. In fact, there has been a significant reduction in the intelligence quotient (IQ) of children born to hypothyroid women, as well as a correlation between the severity of maternal hypothyroidism and a reduction in the IQ of children aged 7 to 9.
Hypothyroidism and pregnancy: systematic or targeted screening for the risk of dysthyroidism?
Currently, screening in France is targeted at those who show risk factors for dysthyroidism (cf. Table 1). Screening is recommended from the first consultation following the confirmation of pregnancy, based on a TSH assay (do not measure T4L or T3L, which are not involved in the decision to use replacement therapy).
A TSH value > 4 mIU/L should be confirmed with a second sample.
If TSH is > 2.5 mIU/L, anti-TPO assay is recommended to assess the risk of the situation developing into hypothyroidism.
Table 1: Risk factors for thyroid disease before or during pregnancy
- Age > 35 years according to HAS
- Body mass index (BMI) ≥ 40 kg/m2
- Treatment with amiodarone or lithium
- History of type 1 diabetes or autoimmune disease
- Obstetrical history:
- Premature delivery
- Foetal death
- Recurrent miscarriage
- Infertility
- Personal history of thyroid disease
- Indication of positive antithyroid antibodies
- Signs or symptoms of dysthyroidism
- Goitre
- Living in a region with moderate or severe iodine deficiency
- History of cervical radiotherapy or thyroid surgery
- Family history of thyroid disease (1st degree)
France is not an iodine-deficient country in general, but for pregnant women it may be.
There are various arguments in favour of systematic or universal screening. Firstly, thyroid disorders are frequent in pregnancy. In addition, maternal and foetal complications are not negligible, despite the availability of effective and inexpensive treatment, and subclinical conditions (40-50%) requiring treatment are currently undiagnosed.
The arguments in favour of targeted or risk-based screening are that, in the case of asymptomatic dysthyroidism, there is no gestational risk, and that systematic screening would be anxiety-provoking and associated with a risk of over-treatment.
Nevertheless, the current trend is increasingly towards systematic or universal screening.
Managing hypothyroidism during pregnancy
In women already known to have hypothyroidism prior to pregnancy, and already who are receiving treatment, levothyroxine (LT4) should be substituted prior to trying to become pregnant (if the treatment was different), and LT4 doses increased by 20-30% as soon as pregnancy is known.
In women whose hypothyroidism is detected during pregnancy, levothyroxine treatment is indicated once TSH is above 4 mIU/L (in the absence or presence of signs of autoimmunity), or as early as 2.5 mIU/L if anti-TPO antibodies are positive (treatment discussed if TSH is between 2.5 and 4 mIU/L).
Pregnant women treated with levothyroxine should be monitored by TSH assay every 4 to 6 weeks up to 22 weeks’ amenorrhea, then once between 30 and 34 weeks’ amenorrhea, and at least once post-partum. The aim is to obtain a serum TSH value between the lower threshold and 2.5 mIU/L (close to 2.5 mIU/L).
The recommended treatment for pregnant women who develop clinical hypothyroidism during pregnancy is levothyroxine (HAS 2023).
In cases of subclinical hypothyroidism or isolated hypothyroxinemia, the foeto-maternal impact is less clearly established, and the value of levothyroxine treatment is still debated.
Hypothyroidism and assisted reproduction pregnancy
The recommendations are clear: systematic screening for thyroid disorders is indicated in all women prior to medically assisted reproduction. In the first instance, this screening is based on a TSH measurement. If the TSH is above 2.5 mU/L, it should be checked rapidly with a second sample. In the event of confirmed TSH > 2.5 mUI/L, a T4L assay is indicated (cascade assay) and must be combined with an anti-TPO Ac assay. If anti-TPO antibodies are negative, anti-thyroglobulin antibodies should be assayed and a thyroid ultrasound performed to check for autoimmune thyroiditis.
The indication for levothyroxine treatment in women undergoing assisted reproduction is based on the recommendations of the European Thyroid Association, individual patient data, infertility aetiology and obstetrical history.
Levothyroxine treatment is recommended in cases of clinical hypothyroidism and as soon as TSH is above 4 mU/L, regardless of serum anti-TPO or anti-Tg Ac concentrations.
Treatment with levothyroxine will be discussed on a case-by-case basis if the TSH is between 2.5 and 4 mUI/L, if the woman is over 35, and/or she has a history of recurrent miscarriage or ovarian infertility (polycystic ovary syndrome, iatrogenic ovarian insufficiency, genetic, autoimmune, etc.). Specialist advice is recommended.
Low doses (25 to 50 µg/day) should be started before ovarian stimulation, and then adjusted to achieve a TSH between the lower threshold and 2.5 mIU/L (close to 2.5 mIU/L).
TSH levels should be monitored every 3 to 6 months, given the risk of hypothyroidism.
Hypothyroidism and pregnancy: conclusion
During pregnancy, clinical or subclinical hypothyroidism is responsible for obstetrical, foetal and neonatal complications. The levothyroxine treatment of pregnant women with hypothyroidism can reduce maternal and foetal complications.
Whenever possible, managing female patients with hypothyroidism should be optimised by restoring euthyroidism prior to pregnancy. Euthyroidism during levothyroxine replacement therapy in pregnancy is not associated with maternal or foetal complications.
Hyperthyroidism and pregnancy
Hyperthyroidism during pregnancy is rare, affecting between 0.1% and 0.5% of pregnant women. Its diagnosis is clinical, and difficult if there only the “usual” signs of pregnancy are present, such as palpitations, thermophobia, hypersudation, tachycardia, vomiting and weight loss, and easier if there are signs of Graves’ disease: vascular goitre, exophthalmos, and pretibial myxedema.
Similarly, screening for hyperthyroidism is indicated in women wanting to become pregnant, or in pregnant women with risk factors for dysthyroidism (Table 1).
In the first instance, this screening is based on a TSH assay alone, followed by a T4L assay in cascade, if the TSH is immediately undetectable (< 0.1 mIU/L) or if the TSH is confirmed low (between 0.1 and 0.4 mIU/L) on a second assay at 6-week intervals. During a third intention, a cascade T3L assay is recommended if TSH is low or undetectable and T4L is within the laboratory’s reference range.
A TSH receptor antibody assay (anti-TSHr or TRAK) is recommended as part of the etiological work-up; positive TRAKs are pathognomonic of Graves’ disease.
Aetiologies
Graves’ disease is the most common aetiology of hyperthyroidism (85%), linked to anti-TSHr antibodies. Clinically, it combines goitre, orbitopathy and pre-tibial myxedema. It usually gets relatively more severe in the first trimester, while improvement occurs during the second half of pregnancy; relapse is frequent post-partum.
Other aetiologies include:
- Non-autoimmune transient gestational thyrotoxicosis
- Hyperemesis gravidarum
- Familial gestational hyperthyroidism
- Hydatidiform mole and choriocarcinoma, linked to the TSH-like activity of hCG
- Hyperfunctional nodule and heteronodular goiter
- Subacute thyroiditis, factitious thyrotoxicosis
- Thyrotropic adenoma
Complications of thyrotoxicosis during pregnancy
Complications can be maternal, obstetric, foetal or neonatal.
- Maternal complications include anaemia, infections, gestational hypertension, pre-eclampsia (risk x 2), congestive heart failure, thyrotoxic crisis and even death.
- Obstetrical complications include early miscarriage, threatened premature delivery, intrauterine growth retardation, foetal hypotrophy and foetal death in utero.
- Fetal and neonatal complications include gastrointestinal anomalies (oesophageal atresia, tracheoesophageal fistula), choanal atresia and foetal death.
- Obstetrical complications depend on the duration and severity of thyrotoxicosis. Neonatal complications are linked to the level of anti-TSHr Ac, their passage through the blood-placental barrier leading to transient foetal and neonatal dysthyroidism (hyperthyroidism if the Ac are stimulating, or hypothyroidism if they are blocking).
Managing hyperthyroidism during pregnancy or in patients with Graves’ disease planning to become pregnant
Synthetic antithyroid drugs (ATS) are effective at controlling hyperthyroidism during pregnancy, but they cross the placenta and may be responsible for cutaneous or general allergic reactions (fever, polyarthralgia, myalgia, vasculitis), haematological complications (agranulocytosis), and liver toxicity with propylthiouracil, and they can have teratogenic effects (aplasia cutis, choanal atresia, omphalocele or embryopathy with carbimazole, uncorrelated with dose, and despite, more often than not, maternal euthyroidism).
The spectrum of malformations varies according to the ATS: with carbimazole (CBZ), choanal and oesophageal atresia, omphalomesenteric duct anomaly, omphalocele, cardiac or musculoskeletal malformations, dermal hypoplasia and urological malformations may occur; with propylthiouracil (PTU), facial and neck malformations and urological malformations. Generally speaking, teratogenic effects are not so rare with ATS (prevalence of embryopathies between 4 and 10%) and are less serious with PTU than with carbimazole.
Women of childbearing age treated with ATS must be on effective contraception. However, if pregnancy does occur, thyrotoxicosis must be treated.
In women with Graves’ disease, it is preferable that pregnancy is planned. A total thyroidectomy is indicated in patients with a large goitre who are planning one or more pregnancies, or treatment with TSA is required to normalise the anti TSHr level prior to pregnancy.
In the case of women with Graves’ disease treated with TSA who are planning to become pregnant, it is advisable to change from imidazole to PTU before pregnancy or as soon as pregnancy is known, or even to consider stopping TSA at this point. Women of childbearing age treated with ATS are advised to take a pregnancy test on the first day of delayed menstruation and, if the test is positive, to contact the referring physician immediately.
A therapeutic window is possible between the sixth and tenth week of pregnancy, calculated from the first day of the last menstrual period (period of maximum sensitivity to teratogenic agents). However, the question then arises as to whether treatment should be resumed beyond the tenth week of pregnancy, and a check-up should be carried out.
Depending on the initial severity, current disease activity, duration of TSA treatment, current dosage and results of the last thyroid work-up and anti-TSHr Ac, either remission is likely with a low risk of recurrence and TSA can be discontinued (under close supervision), or TSA must be continued and PTU should be used.
Hormonal monitoring is based on monthly T4L determinations, followed by T4L and TSH, as soon as TSH can be measured. Maternal T4L should be maintained at the upper limit of the normal range.
Conclusion
Close collaboration between gynaecologists, obstetricians, midwives and endocrinologists is necessary for the detection and management of hypothyroidism or hyperthyroidism, before and during natural pregnancy or medically assisted reproduction.
