Thyroid disorders are prevalent in women of childbearing age and may therefore present during pregnancy. Awareness of the implications of thyroid disorders in pregnancy is therefore essential to ensure optimal outcomes for women and neonates (Lazarus, 2011). The key to good management of thyroid disease in pregnancy is close liaison between the GP, the midwife (in the community and in hospital), the endocrinologist and the obstetrician. This review will focus on the practical aspects of managing women with either hypothyroidism or hyperthyroidism in pregnancy and in the postpartum period.
Thyroid function is defined by levels of circulating thyroid hormones. When all thyroid parameters, namely free thyroxine (fT4), free triiodothyronine (fT3), and thyroid stimulating hormone (TSH), are abnormal, thyroid function is classified as either ‘overt hypothyroidism’ (thyroid deficiency) or ‘overt hyperthyroidism’ (thyroid hormone excess). If only TSH levels are abnormal but levels of fT4 and fT3 are normal, the disorder is termed ‘subclinical’; either subclinical hypothyroidism (TSH high) or subclinical hyperthyroidism (TSH low). The risks of both overt or subclinical thyroid disease will be discussed below.
Hypothyroidism
In pregnancy
For the first 10-12 weeks of pregnancy, the fetus is totally reliant on the mother for thyroid hormones. It is only at the end of the first trimester that the fetal thyroid starts to secrete thyroxine (Brown, 2004). The developing fetus continues to rely on its mother for a sufficient supply of iodine to synthesise thyroid hormones (Puig-Domingo and Vila, 2013). Levothyroxine is used to treat hypothyroidism and women need to be aware that requirements are likely to increase early in pregnancy. It is therefore vital that the woman continues her levothyroxine medication and does not miss doses. Thyroid hormones are critical for the development of the fetus' brain and nervous system (Skeaff, 2011).
The National Institute for Health and Care Excellence (NICE) states that levothyroxine should be taken before breakfast (not with food and not with coffee), and not with other medications such as calcium or iron supplements, as these interfere with absorption (NICE, 2016). British Thyroid Foundation (BTF) guidelines recommended that women do not take iodine supplements, provided they have a balanced and varied diet (BTF, 2018a) that includes good sources of iodine, such as milk, dairy products and fish. Kelp and seaweed supplements are not recommended as they contain potentially harmful amounts of iodine (BTF, 2018a).
It is expected that the dose of levothyroxine will need to be increased in pregnancy, perhaps by as much as 50% by 20 weeks (De Groot et al, 2012). This is because of the physiological adaptations in thyroid function that occur in pregnancy: in particular, the rise in circulating thyroid hormone binding proteins (Alexander et al, 2004).
Practice points
British Thyroid Association guidelines recommend that target TSH should be less than 2.5mU/l in the first trimester and below 3mU/l in later pregnancy (Okosieme et al, 2015). More recently, the American Thyroid Association (Alexander et al, 2017) has recommended a cut-off for TSH of 4.0mU/l in the first trimester, and this recommendation is likely to be increasingly adopted in the UK. Ideally, women with known hypothyroidism should be seen pre-pregnancy and counselled that they need to ensure their thyroid hormone levels are normalised before becoming pregnant so that the TSH is not elevated in the first trimester. This will minimise the risk of pregnancy loss (Maraka et al, 2017).
Women with pre-existing hypothyroidism should be advised to see their GP for a thyroid blood test measuring fT3, fT4 and TSH as soon as they become pregnant, as the dose of levothyroxine may need adjusting. Women should have normal values for all three parameters.
Depending on the initial blood result, the levothyroxine dose may need increasing because of changes in thyroxine-binding globulin in pregnancy (Lazarus, 2011). Women are not advised to increase doses without consulting a GP, as doses are usually increased in 25 microgram steps (BTF, 2018b).
Blood testing for thyroid function should be repeated at least once in each trimester because of the physiological changes in thyroxine-binding globulin throughout pregnancy (Lazarus, 2011). If the dose of levothyroxine is increased, then the blood test should be repeated 2-4 weeks later to ensure that free thyroid hormones and TSH are in range. It is also important that thyroid testing is performed 2-6 weeks after giving birth—particularly if the dose was increased during pregnancy—as most women will be able to return to their pre-pregnancy levothyroxine doses. Taking levothyroxine is no bar to breastfeeding (BTF, 2018b).
Most women with pre-existing hypothyroidism will have autoimmune hypothyroidism, also known as Hashimoto's disease (Lazarus, 2011). A small proportion may have had Graves' disease and become hypothyroid after radioiodine treatment or surgery. These women may still have persistent circulating TSH-receptor (TRAb) antibodies, which can cross the placenta and cause neonatal Graves' disease (Bucci et al, 2017). It is important to recognise this subgroup of hypothyroid women and, in the third trimester, to check if TRAb antibodies are still present. If TRAb-positive, the obstetric team needs to be informed as these women need to give birth in hospital with the paediatrician in attendance to manage neonatal Graves' disease if present (Ross, 2018).
Subclinical hypothyroidism or isolated hypothyroxinaemia before or in pregnancy
Overt hypothyroidism is defined as the combination of low serum fT4 plus increased TSH; these values being outside of the trimester-specific thyroid hormone reference ranges (Alexander et al, 2017). If the fT4 is normal but only the TSH is elevated, this is referred to as subclinical hypothyroidism (Alexander et al, 2017). This is more common in pregnancy than overt hypothyroidism. Conversely, if the serum fT4 is low, but the TSH is normal, this is termed maternal hypothyroxinaemia (Alexander et al, 2017).
While there is evidence that subclinical hypothyroidism and isolated hypothyroxinaemia are associated with adverse pregnancy outcomes, such as increased risk of miscarriages, it is unclear whether treatment with levothyroxine reduces these risks (Lazarus et al, 2014). At present, levothyroxine is not recommend for women with hypothyroxinaemia alone, but is recommended for those with subclinical hypothyroidism (De Groot et al, 2012). The presence of thyroid peroxidase antibodies in addition to the thyroid hormone abnormalities increases the risk of adverse outcomes (Lazarus et al, 2014). The Endocrine Society recommends levothyroxine for a woman with a history of recurrent miscarriages, subclinical hypothyroidism and positive thyroid peroxidase antibodies (De Groot et al, 2012). The results of the TABLET trial (Coomarasamy, 2018), in which euthyroid women with positive thyroid peroxidase antibodies have been treated with levothyroxine or placebo, are awaited with interest and are expected later this year. The study is investigating whether 50 micrograms of levothyroxine will increase the chance of a successful birth after 34 weeks gestation.
Practice points
Women with abnormal thyroid function tests should be referred to the consultant obstetrician and consultant endocrinologists as early as possible (BTF, 2018b). The decision to start levothyroxine should be made as soon as possible if there is to be any benefit. The obstetrician may wish to perform additional growth scans if there are concerns of intrauterine growth restriction (Tingi et al, 2016).
Women taking levothyroxine for subclinical hypothyroidism may well be able to stop treatment after pregnancy; this should be discussed with an endocrinologist at the postnatal review (De Groot et al, 2012).
Hyperthyroidism
In pregnancy
Hyperthyroidism in pregnancy is usually due to Graves' disease, an autoimmune condition almost always associated with circulating TSH-receptor (TRAb) antibodies (Barbesino and Tomer, 2013). Treatment of this condition in pregnancy is with anti-thyroid drugs (Lazarus, 2011). Radioiodine must not be given in pregnancy as this can lead to thyroid agenesis and other severe birth defects in the developing fetus (Hyer et al, 2011). In the first trimester, propylthiouracil is preferred to carbimazole because the latter is associated with an increased risk of choanal atresia (blocked nasal passage) and aplasia cutis (scalp defect) in the fetus (Lazarus, 2011). However, other, less severe birth defects, such as pre-auricular sinuses, can occur with propylthiouracil (Taylor and Vaidya, 2012). Women with Graves' disease who are trying to conceive should be offered propylthiouracil rather than carbimazole, acknowledging that propylthiouracil carries a small risk of liver dysfunction (BTF, 2018b).
Women may be naturally concerned about taking these drugs in pregnancy, but should know that untreated Graves' disease increases the risk of miscarriage, low birth weight, stillbirth and preterm birth (Table 1). The balance of risks is strongly in favour of taking propylthiouracil (first trimester) and carbimazole (second and third trimesters) at the minimum doses required to achieve good control of the patient's hyperthyroidism (De Groot et al, 2012).
| Mother | Fetus | Newborn | |
|---|---|---|---|
| Hyperthyroidism | |||
| Overt (low TSH, elevated fT4 and/or elevated fT3) | Miscarriage |
Miscarriage |
Low birth weight |
| Hypothyroidism | |||
| Overt (high TSH, low fT4) | Miscarriage |
Miscarriage |
Preterm birth |
| Subclinical (elevated TSH, normal fT4/fT3) | Miscarriage |
Miscarriage | Possible neuropsychological impairment |
TSH: thyroid stimulating hormone; fT3: free triiodothyronine; fT4: free thyroxine
As mentioned earlier, TRAb in maternal blood can cross the placenta giving rise to fetal or neonatal thyrotoxicosis, particularly if the antibody level is at high concentration. Any pregnant woman with a history of Graves' disease should have a blood test in the third trimester to check for the presence of TRAb antibodies, irrespective of the levels of the thyroid hormones (Association for Clinical Biochemistry et al, 2006). Since almost all women with Graves' disease will have evidence of TRAb antibodies, they should be advised give birth in hospital with the paediatrician in attendance to manage neonatal Graves' disease if it is present. Fetal Graves' disease should be suspected when there is fetal tachycardia (>160 beats per min), poor intrauterine growth, or fetal goitre (Léger, 2017).
The postpartum period is typically the time when Graves' disease, previously in remission, relapses (Tingi et al, 2013), probably due to the restoration of immunity after pregnancy. Women, doctors and midwives need to be alert to this happening and arrange thyroid blood testing 2-6 weeks postpartum (De Groot et al, 2012). An exacerbation of Graves' disease postpartum needs to be distinguished from postpartum thyroiditis (see below).
Doctors and midwives need to be aware of transient mild hyperthyroidism occurring near the end of the first trimester and subsiding by 14-18 weeks' gestation (Labadzhyan et al, 2014). This condition is called transient gestational hyperthyroidism and corresponds with peak levels of human chorionic gonadotropin (hCG), which has weak thyroid-stimulating effects (Ross, 2018). Blood tests may show a mild rise in free thyroid hormones and reduced TSH. A similar picture is occasionally seen in women with hyperemesis gravidarum (Ross, 2018). These women rarely require anti-thyroid medication as the thyroid function often normalises spontaneously by 16-18 weeks gestation (Ross, 2018).
More severe hyperthyroidism can occur in women with a hydatidiform mole (gestational trophoblastic disease), when hCG concentrations can be very high. These women may require anti-thyroid medication before surgery for their molar pregnancy (Virmani et al, 2017).
Beta-blocking drugs such as propranolol can be used for symptomatic control of tachycardia and tremor in women with hyperthyroidism (NICE, 2016). Because these drugs can be associated with fetal growth restriction and hypoglycaemia, they are only used for short periods, typically 2-3 weeks, while waiting for the antithyroid medication to take effect (Meidahl Petersen et al, 2012).
Subclinical hyperthyroidism (suppressed TSH but normal fT4) in pregnancy does not require anti-thyroid treatment, as there is no evidence of improved outcomes (Ross, 2018).
Practice points
All women with hyperthyroidism in pregnancy should be assessed by a consultant endocrinologist and consultant obstetrician as early as possible to assess whether anti-thyroid treatment is needed and to change carbimazole to propylthiouracil. Women can revert to carbimazole at the start of the second trimester or continue propylthiouracil throughout the pregnancy (BTF, 2018b).
The frequency of blood testing for thyroid function for women on antithyroid medication in pregnancy will vary from woman to woman. Testing may need to be as often as every 3-4 weeks to ensure that thyroid hormones are in range and TSH <3 mU/l; the endocrinologist will advise on this (De Groot et al, 2012).
Women taking carbimazole or propylthiouracil should be advised to stop medication immediately if they develop a rash, severe sore throat, or fever; and should have their blood tested for neutropenia (NICE, 2016). Women with a rash may need to change drug but those with sore throat can resume their medication if their neutrophil count is normal. Women taking propylthiouracil should also have liver function checked, to avoid liver toxicity (Ross, 2018). If there is evidence of liver dysfunction, propylthiouracil should be discontinued.
Women with a history of Graves' disease should have TRAb antibodies measured at booking, irrespective of thyroid function test results (De Groot et al, 2012). Further measurements of TRAb antibodies later in pregnancy will be decided by the consultant obstetrician. If positive, more frequent fetal heart rate and growth monitoring will be required to assess for possible fetal hyperthyroidism. In this instance, a paediatrician will need to be informed and the infant tested for neonatal Graves' disease (Ross, 2018).
NICE (2017) considers women with hyperthyroidism to be high-risk and recommends planned birth at an obstetric unit rather than home birth.
Women with Graves' disease need careful monitoring in the postpartum period, as this is the time when relapses are likely (Stagnaro-Green, 2012). Women should be advised to have a blood test for thyroid function if they experience any symptoms suggestive of hyperthyroidism. A routine thyroid test should be performed at the postnatal clinic visit as this may show biochemical relapse before the patient becomes symptomatic (De Groot et al, 2012).
Breastfeeding is considered safe in women taking anti-thyroid medication (BTF, 2015b), although the minimal effective dose of carbimazole or propylthiouracil should be used (Karras and Krassas, 2012). Women taking these medications should be reassured that although tiny amounts of the drug can enter breast milk, they very rarely cause problems in the infant (BTF, 2015b). Taking medication after the baby has been fed will further minimise the amount that the baby receives.
Transient gestational hyperthyroidism, sometimes associated with hyperemesis gravidarum, is usually self-limiting and does not generally require anti-thyroid medication (De Groot et al, 2012). It is distinguished from Graves' disease by the absence of other clinical features, such as thyroid eye disease, and by negative TRAb antibodies (Ross, 2018). It may recur in subsequent pregnancies (De Groot et al, 2012).
Postpartum thyroid dysfunction
Approximately 6-7% of women will have abnormal thyroid function after pregnancy, typically caused by a postpartum thyroiditis (Muller et al, 2001). This manifests as a transient hyperthyroid state or transient episode of hypothyroidism, or as a biphasic illness with a hyperthyroid followed by a hypothyroid phase (Stagnaro-Green, 2012). While most women with postpartum thyroiditis will recover within a year of giving birth, 30-50% will go on to have permanent hypothyroidism (Stagnaro-Green, 2012).
Postpartum thyroiditis is considered an autoimmune inflammatory condition and is associated with high levels of thyroid peroxidase antibodies, both at the beginning of pregnancy and after birth (Stagnaro-Green, 2012). The hyperthyroidism is usually mild and recovers without specific treatment in 1-2 months (Burman, 2018). Postpartum thyroid dysfunction has been associated with mood disorders such as depression (Le Donne et al, 2017), meaning that it is sometimes difficult to diagnose, since the symptoms (tiredness, irritability, weight gain, and mood changes), may be common to many new mothers (BTF, 2015a). If any symptom seems extreme and interferes with normal mothering activities, a woman should be advised to see her doctor.
Hypothyroidism is treated with levothyroxine when the TSH>10 mU/l (Okosieme et al, 2015). An attempt should be made to withdraw levothyroxine at 6-12 months to see if the thyroid has recovered. Even if the woman has made a full recovery, she is at risk of becoming permanently hypothyroid in the future and should have yearly thyroid function tests (Burman, 2018).
It is important to differentiate postpartum thyroiditis with hyperthyroidism from Graves' disease (new onset or relapse) (Tingi et al, 2016). There may be clinical or biochemical clues (for example, the presence of thyroid eye signs indicates Graves' disease, and high fT3 is more suggestive of Graves' disease than thyroiditis), but the presence of TRAb antibodies is the most useful result as its presence indicates Graves' disease (Burman, 2018).
Postpartum hypothyroidism could also be secondary to a lymphocytic hypophysitis, an inflammatory condition of the pituitary gland that typically occurs after pregnancy (Iuliano and Laws, 2011). However, the thyroid hormone profile is quite different from postpartum thyroditis in that, while fT4 and fT3 may be low in both conditions, TSH is inappropriately normal or low in a pituitary disease such as lymphocytic hypophysitis, and high in a primary thyroid disease such as thyroiditis (Persani, 2012).
Practice points
Universal screening for thyroid dysfunction in all women during the postpartum period is not recommended because there is no evidence it is superior to targeted screening of high-risk women (De Groot et al, 2012).
Postpartum thyroid testing is recommended for selected women at high risk of thyroid dysfunction, such as those with symptoms of hyper- or hypothyroidism, positive TPO antibodies or a history of postpartum thyroiditis (De Groot et al, 2012).
If a hyperthyroid profile is found, an endocrine opinion should be sought to differentiate postpartum thyroiditis from Graves' disease (Burman, 2018). Hyperthyroidism due to postpartum thyroiditis does not usually require anti-thyroid medication and resolves in 1-2 months (Burman, 2018).
If the blood profile shows hypothyroidism with a high TSH (>10 mU/l), levothyroxine should be started. Referral to the endocrinology team is indicated, as an attempt to withdraw treatment will be considered at 6-12 months (De Groot et al, 2012).
A hypothyroid profile with low thyroid hormones and low or normal TSH is suggestive of lymphocytic hypophysitis and women require urgent referral to an endocrinologist to confirm the diagnosis, as the pituitary secretion of other hormones such as cortisol may also be impaired (Iuliano and Laws, 2011).
Women with a history of postpartum thyroiditis are at risk of the condition recurring in future pregnancies. They are also at increased risk of permanent hypothyroidism in the future and require yearly thyroid function monitoring, which is best organised by their GP (Burman, 2018).
Conclusion
Thyroid disorders in pregnancy have deleterious effects on mother and fetus and require treatment. This article has summarised the practical aspects of management in the light of national guidelines. For women with Graves' disease, propylthiouracil in the first trimester and then carbimazole are the treatments of choice. Women, doctors and midwives need to be alert to the condition relapsing in the postpartum period and arrange thyroid testing at this time. The occurrence of hypothyroidism in pregnancy is significant, frequently subclinical and requires treatment with levothyroxine to reduce maternal and fetal complications and prevent neuropsychological and cognitive impairment in the developing child. Women already taking levothyroxine will often require an increase in their dose during pregnancy. The recommended management for women with thyroid disease in pregnancy is through a multidisciplinary team approach, in which the midwife plays a central role. It is hoped that the information summarised here will assist in providing optimal care for these women.