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Endocrine disorders in pregnancy
MEDICINE AND OTHER SPECIALTIES
Endocrine disorders in pregnancy
Key points C
The normal physiological changes of pregnancy make it hard to interpret many endocrine tests. In addition, endocrine disorders can mimic normal pregnancy symptoms
C
Optimization of pre-pregnancy disease is a crucial step towards ensuring good pregnancy outcomes
C
Most drugs used to treat endocrine disorders can be used in pregnancy, and schedules should not be altered without input from a clinician experienced in pregnancy
C
Untreated hyper- and hypothyroidism present greater risks to pregnancy than the harms associated with medication use
Harry Gibson Catherine Nelson-Piercy
Abstract Endocrine disorders are a significant reason for consultation during pregnancy. Many of these conditions are common in women of fertile age and can have a profound impact on fertility and pregnancy outcome if they are not managed optimally. Diagnosis is often difficult because of the wide range of symptoms that can be experienced, especially as many of them occur as part of an otherwise normal pregnancy. Pregnancy physiology alters the normal biochemical parameters for many hormones, and interpretation must take into account the trimester of pregnancy as well as view the results in the context of the clinical presentation. Optimal control of endocrine conditions before pregnancy is an important consideration for any physician caring for a woman of childbearing age. In addition, prompt recognition of endocrine disorders presenting during pregnancy and a knowledge of treatment options are essential.
suggested for the first trimester, gradually returning to nonpregnant values through the second and third trimesters.1 Parathyroid Calcium utilization is increased in pregnancy and lactation,2 with increased renal loss. Vitamin D requirements double to meet this demand.
Keywords Graves’ disease; hyperparathyroidism; hyperthyroid; hypopituitarism; hypothyroid; MRCP; pregnancy; prolactinoma; Sheehan’s syndrome; vitamin D
Pituitary The anterior pituitary increases in volume by up to 136% over the course of pregnancy. Prolactin levels increase 10-fold above baseline,3 falling after delivery, but only return to normal after breastfeeding has ceased. Gonadotropins are suppressed by high circulating oestrogen concentrations.
Normal endocrine physiology of pregnancy Thyroid The physiological changes that occur during pregnancy have a significant impact on the usual function of the pituitaryethyroid axis. Placental human chorionic gonadotropin (hCG) shares the same a-subunit as thyroid-stimulating hormone (TSH). In the first trimester, hCG levels rise, stimulating increased release of total thyroxine (T4) and triiodothyronine (T3). A simultaneous increase in the hepatic production of thyroidbinding globulin maintains relatively stable levels of free T4 and T3. The level of TSH varies, but is suppressed by approximately 0.5 mU/litre, and in some women without thyroid disease, TSH may be undetectable.1 In the second and third trimesters, hCG levels fall, free T4 and T3 remain lower than in non-pregnancy, and TSH rises accordingly. Population-based, trimester-specific levels must ideally be used when interpreting thyroid function tests. If these are unavailable, an empirical TSH upper limit of 4.0 mU/litre is
Adrenal Circulating cortisol levels increase towards the end of pregnancy. The placenta secretes corticotropin-releasing hormone (CRH), which in early pregnancy is bound by liver-derived CRH-binding proteins. Towards the end of pregnancy, CRH-binding proteins fall, leading to an overall higher concentration of circulating cortisol: up to 552 nmol/litre in the second trimester and 823 nmol/litre in the third.3 This contributes to the relative immunosuppressive state of pregnancy.
Thyroid disorders Hyperthyroidism Hyperthyroidism affects 0.2% of pregnancies, usually being caused by Graves’ disease. Toxic multinodular goitre, functional adenoma, adverse drug effects and TSH-secreting tumours are rarely encountered. Gestational transient thyrotoxicosis is more common (1e3% of pregnancies), occurring as a result of hCGmediated T4 release. It is especially likely when circulating hCG levels are particularly high, as occurs with hyperemesis gravidarum, multiple pregnancy, or gestational trophoblastic disease. Many symptoms of hyperthyroidism are also features of normal pregnancy. Table 1 illustrates symptoms that can be useful in discerning true from gestational hyperthyroidism. TSH suppression and free T4 or T3 elevated above the trimester-
Harry Gibson BA MB BS MRCOG MRCP(UK) is an Obstetric Medicine Fellow at St Thomas’ Hospital, London, UK. Competing interests: none declared. Catherine Nelson-Piercy MA FRCP FRCOG is a Consultant Obstetric Physician at Guy’s and St Thomas’ NHS Trust and Imperial College Healthcare NHS Trust, and Professor of Obstetric Medicine at King’s College, London, UK. Competing interests: none declared.
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Breastfeeding is considered safe with doses <15 mg/day of carbimazole or <150 mg/day of PTU. Women should be warned about the risk of a postpartum flare, and thyroid function re checked 4e6 weeks after pregnancy.
specific range may not discriminate between the two scenarios: a careful history of onset of symptoms, examination for discriminating physical signs, and early pregnancy ultrasound are all crucial. Risks: severe thyrotoxicosis causes subfertility, but risks during pregnancy include miscarriage, fetal growth restriction, preterm labour, maternal cardiac arrhythmias and thyroid crisis. Maternal thyroid receptor antibodies (TRAb) cross the placenta and in 1% of pregnancies cause fetal goitre and thyrotoxicosis. Autoimmune hyperthyroidism improves as gestation progresses, but can flare postpartum once the relative immunosuppression of pregnancy is lost. Management: disease optimization before conception is a key factor for a safe pregnancy in hyperthyroid disorders. Contraception should be advised until at least 3 months of satisfactory control has been achieved (6 months if radio-iodine has been used). Propylthiouracil (PTU) and carbimazole can be used in pregnancy, ideally at as low a dose as possible to maintain remission. Both cross the placenta and increase the absolute risk of fetal malformation by about 2e3%4; this must be balanced against the greater hazards of stopping treatment. Most pregnancy guidelines advocate advising women who are taking carbimazole to switch to PTU for the first trimester only, as PTU is considered less of a risk to the fetus.1 However, this approach can lead to a loss of previous good disease control and exposes mothers to the 1:10,000 risk of PTU-related hepatotoxicity. Furthermore, recent data suggest there is no corresponding reduction in congenital anomalies.4 If thyrotoxicosis is newly diagnosed in pregnancy, rapid control must be achieved with either PTU (first trimester) or carbimazole (second and third trimesters). Block-and-replace regimens are not recommended, as this results in fetal hypothyroidism. Propranolol can be used for symptom control. Thyroidectomy, if considered, is safest in the second trimester or after pregnancy. In women with poor disease control, thyroid function should be checked monthly. Measurement of TRAb levels helps to determine whether the fetus is at risk of fetal thyrotoxicosis.
Hypothyroidism Overt hypothyroidism affects 1% of pregnancies. It can be autoimmune, drug-induced, post-thyroiditis or iatrogenic after treatment for Graves’ disease. Iodine deficiency is rarely encountered in the UK. Table 1 illustrates the overlap between features of hypothyroidism and normal pregnancy symptoms. Diagnosis is by low free T4 or T3 with TSH elevated above the gestationspecific range. Thyroid autoantibody positivity helps confirm the diagnosis and can stratify risk. Subclinical hypothyroidism is the finding of an elevated (but <10 mU/litre) TSH with normal free T4 or T3 and no symptoms or signs. Historically, it was defined as TSH >2.5 mU/litre, but population studies demonstrated that this was too conservative. More recent guidance emphasizes gestation-specific cut-offs or, if these are not available, a TSH >4.0 mU/litre.1 Risks: untreated overt hypothyroidism causes anovulation and subfertility. In pregnancy, it is associated with miscarriage, fetal growth restriction, stillbirth, gestational hypertension and reduced childhood IQ.1 A woman must be significantly iodinedeficient to risk permanent fetal neurological damage (previously known as cretinism). Pregnancy outcomes are good when a woman is euthyroid on treatment. The risks of subclinical hypothyroidism are debated, and are inferred from the risks of overt hypothyroidism. T4 treatment has not been shown to improve outcomes in these women.5 Management: guidelines advocate an empirical increase in T4 dosing by 20e30% for all women in the first trimester,1 although this risks over-treatment and iatrogenic hyperthyroidism. We favour early thyroid function testing, and increasing the dose only in women with biochemical or symptomatic evidence of under-replacement. TSH should be targeted to within gestationspecific ranges. Any change in T4 dose during pregnancy should be followed up within 4e6 weeks with thyroid function testing; women on stable doses should have their TSH and free T4 checked every trimester and 6e12 weeks after delivery. It is safe to take T4 while breastfeeding. Subclinical hypothyroidism (TSH >4.0 mU/litre) in the context of positive thyroid autoantibodies carries the risk of progression to overt hypothyroidism; treatment is therefore currently recommended as benefit outweighs risk.1 A benefit has not, however, been established for autoantibody-negative women with subclinical hypothyroidism.
Distinguishing hyper/hypothyroidism from normal pregnancy symptoms
Features in common with normal pregnancy
Features suggesting thyroid disorder
Hyperthyroidism
Hypothyroidism
Heat intolerance Emotional lability Vomiting Palpitations/ tachycardia Symptoms precede pregnancy Tremor Weight loss Lid lag Ophthalmopathy
Weight gain/ oedema Lethargy Constipation Hair loss Symptoms precede pregnancy Other autoimmune disease Cold intolerance Slow relaxing reflexes
Postpartum thyroiditis Occurring 3e6 months after delivery, postpartum thyroiditis is autoimmune destruction of the thyroid gland, resulting in either a hyperthyroid, hypothyroid or biphasic thyroid state. The mean incidence is 7.5%. It is usually transient, resolving 4e8 months postpartum, but 3e4% of women remain permanently hypothyroid. It is associated with other autoimmune conditions, a family history of thyroid disease and positive thyroid peroxidase antibodies. Care must be taken to differentiate this from Graves’ disease and not attribute symptoms generally to a tired and worried
Table 1
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prolactinoma. Prolactinomas are classified according to their size on imaging: microlesions are <1 cm; macrolesions are >1 cm. The diagnosis is usually made before pregnancy because of subfertility. A new diagnosis is occasionally made in pregnancy after presentation with headache, visual field defects or diabetes insipidus. Cranial magnetic resonance imaging (MRI) without contrast is safe after the first trimester; before this, the risk must be balanced against the delay of diagnosis. Serum prolactin levels are not helpful in pregnancy. Risks: because of pituitary swelling in pregnancy, the risk of increase in size is 17e46% for macroprolactinoma and 1.6 e4.7% for microprolactinoma; with the latter, however, growth is usually asymptomatic.3 A significantly enlarging tumour impinges on the optic chiasm and causes new or worsening bitemporal hemianopia or quadrantanopia. Pituitary apoplexy is a risk. Prolactinomas have no impact on pregnancy outcome and are not a contraindication to breastfeeding. Management: women with a prior diagnosis will be taking dopamine receptor agonists (cabergoline, bromocriptine). There are no data to suggest that these are harmful in pregnancy, but they can usually be discontinued in microprolactinoma.3 Women should be regularly followed up and asked to report any new visual field symptoms. With macroprolactinoma, medication should be stopped only if the tumour remains within the boundaries of the sella turcica.3 Serial visual field testing should be arranged every 2 months. Reimaging needs to be arranged only if symptoms worsen. If tumour enlargement is confirmed, medication should be reintroduced. Breastfeeding is not contraindicated. The pituitary stimulus is less than that of pregnancy. However, women taking dopaminergic drugs may find it hard to establish breastfeeding. Therapy can be withdrawn before delivery to facilitate breastfeeding, but close surveillance with visual field scanning and MRI is imperative. Trans-sphenoidal surgery is safest outside pregnancy.
mother. Treatment involves managing hyperthyroid symptoms with b-adrenoceptor blockers, and an underactive thyroid with T4. After 6 months, treatment is withdrawn to determine whether resolution has occurred. There is a 10e25% risk of recurrence, and a 30% risk of future hypothyroidism if antibodies are present.
Parathyroid disorders Hyperparathyroidism Primary hyperparathyroidism has an incidence of 8 per 100,000 women of childbearing age and is caused by parathyroid adenoma or hyperplasia. Tertiary hyperparathyroidism is also encountered in women with history of chronic kidney disease. As with other endocrine conditions, many classic symptoms of hypercalcaemia overlap with findings of normal pregnancy, and many women are asymptomatic. Unexplained vomiting, hypertension or renal calculi should prompt serum calcium measurement and, if levels are raised, parathyroid hormone (PTH) measurement. Risks: the calcium demand of pregnancy can improve symptoms, but acute pancreatitis and renal calculi are still a risk, especially postpartum. Hypercalcaemia increases the risk of miscarriage, preterm birth, stillbirth and pre-eclampsia. Fetal PTH can be suppressed by the hypercalcaemic state, resulting in rebound neonatal hypocalcaemia; this presents as tetany or seizures, usually 1e2 weeks after birth. Management: plentiful hydration with oral or intravenous fluids increases renal calcium clearance. A low-calcium diet should also be followed. Surgery is safest in the second trimester but can be undertaken in the third trimester if the condition presents later in pregnancy. Serum calcium levels should be monitored every 2e4 weeks.
Vitamin D deficiency Hypopituitarism Pre-pregnancy hypopituitarism, caused by previous pituitary surgery or irradiation, tumour or apoplexy, causes secondary ovarian failure, so women will already be on treatment. Hypopituitarism that arises from an acute hypotensive episode after postpartum haemorrhage is known as Sheehan’s syndrome. Lymphocytic hypophysitis is an antibody-mediated infiltration of the anterior pituitary, and can be associated with other autoimmune conditions. In both situations, any number of pituitary hormones can be deficient, causing adrenal insufficiency (hypoglycaemia, hypotension, vomiting), hypothyroidism, failure of lactation, amenorrhoea and loss of secondary sexual characteristics. Pituitary imaging assists in establishing the diagnosis. Management: acutely, the patient should be treated with glucocorticoids and intravenous dextrose. Spontaneous resolution can occur, but in persistent hypopituitarism, ovulation and pregnancy can be achieved if gonadotropins are replaced. Once pregnancy is established, the feto-placental unit becomes selfsustaining. Women taking maintenance corticosteroids require higher doses during periods of stress e intercurrent infection, hyperemesis gravidarum and delivery.
This is a common finding in Northern Europe, especially in winter months. Obese women are most at risk (61%), as are those with pigmented skin (47e64%).2 Other risk factors include a vegan diet, short interpregnancy intervals, renal or liver disease and wearing clothes that fully cover the skin. Deficiency can cause hypocalcaemia, myopathy, myalgia, increased risk of preeclampsia or gestational diabetes mellitus and neonatal rickets, hypocalcaemic tetany or seizures. Management: supplementation with colecalciferol or ergocalciferol is recommended as follows:2 all pregnant women e 400 U/day at-risk women e at least 800e1000 U/day proven deficiency e 10,000e20,000 U/week for 4e6 weeks.
Pituitary disorders Hyperprolactinaemia and prolactinomas Raised prolactin concentrations are normal in pregnancy. Pathological elevation is caused by prolactinoma, pituitary stalk lesions, hypothyroidism, post-ictal states and anti-dopaminergic drugs. Most cases in women of childbearing age are caused by
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Pregnancy considerations for rare endocrine disorders Condition
Diagnosis
Diabetes insipidus
C
C C
Acromegaly
C
Standard water deprivation test unsafe (short period of deprivation may be acceptable) Paired serumeurine osmolality Clinical response to desmopressin (central DI) Difficult to diagnose biochemically in pregnancy because of placental GH3
Risks C C
C C
Cushing’s syndrome
C
C
Conn’s syndrome
C
Low serum calcium Low PTH
C
40e50% from adrenal, 30% pituitary3 Pregnancy-specific cortisol ranges
C
As for non-pregnant
C
C
C C
C
C C C
C
Deterioration of DI in pregnancy Untreated risks seizures and oligohydramnios
C
C
Hypoparathyroidism
Management
C
Expansion of pituitary tumour, apoplexy Miscarriage Increased risk gestational diabetes mellitus Miscarriage Fetal hypocalcaemia with secondary [PTH Fetal loss, preterm labour Neonatal adrenal suppression Hypertension/pre-eclampsia Gestational diabetes mellitus Hypertension/pre-eclampsia
C C C
C C
C C
C C C
Phaeochromocytoma
C
As for non-pregnant
C C C
Addison’s disease
C
C C
Congenital adrenal hyperplasia
C
Use pregnancy-specific cortisol ranges Hyponatraemia Family history of autoimmune disease Rarely encountered in pregnancy owing to subfertility and masculinization of secondary sexual characteristics
C C
C
C C
Hypertensive crisis Maternal mortality up to 17% Fetal mortality 26% No puerperal exacerbation No adverse effects if well treated
C
Miscarriage, growth restriction, preterm Obstructed labour (android pelvis) 1:4 risk inheritance if partner is carrier
C
C C C
C
Exclude pre-eclampsia and acute fatty liver of pregnancy Central: intranasal desmopressin Nephrogenic: carbamazepine, water restriction, NSAID Contraindicated: chlorpropamide Dopamine agonist Surgery (second trimester) Avoid unless clear benefit: SST analogue (octreotide, lanreotide) Vitamin D (alfacalcidol, calcitriol) Oral calcium Surgery (second trimester) Avoid unless surgery contraindicated: ketoconazole, metyrapone Labetalol, nifedipine, methyldopa Amiloride (for YKþ) Contraindicated: spironolactone a-Adrenoceptor blockade: phenoxybenzamine, prazosin Surgery Hydrocortisone, fludrocortisone Adrenal suppression: [ hydrocortisone by 50 mg three times daily in labour or illness As with Addison’s If female fetus affected: high-dose dexamethasone to prevent masculinization
DI, diabetes insipidus; GH, growth hormone; NSAID: non-steroidal anti-inflammatory drug; PTH, parathyroid hormone; SST, somatostatin.
Table 2
Other endocrine disorders
scientific-impact-papers/vitamin_d_sip43_june14.pdf. [Accessed 22 October 2014]. 3 Bronstein MD, Paraiba DB, Jallad RS. Management of pituitary tumors in pregnancy. Nat Rev Endocrinol 2011; 7: 301e10. 4 Seo GH, Kim TH, Chung JH. Antithyroid drugs and congenital malformations, a nationwide Korean cohort study. Ann Intern Med 2018; 168: 405e13. 5 Wiles K, Jarvis S, Nelson-Piercy C. Are we overtreating subclinical hypothyroidism in pregnancy? Br Med J 2015; 351: h4726.
Rare endocrine disorders and their effects on pregnancy are detailed in Table 2. A KEY REFERENCES 1 Alexander EK, Pearce EN, Brent GA, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017; 27: 315e89. 2 Robinson S, Nelson-Piercy C, Harvey NC, Selby P, Warner JO. Vitamin D in pregnancy. Scientific Impact Paper No. 43. 2014, https://www.rcog.org.uk/globalassets/documents/guidelines/
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FURTHER READING Nelson-Piercy C. Handbook of obstetric medicine. 5th edn. Boca Raton, FL: CRC Press, 2015.
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TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. She used to take bromocriptine but this had been stopped several years before the pregnancy. On clinical examination she had a bitemporal upper quadrantanopia with no papilloedema or ophthalmoplegia.
Question 1 A 34-year-old woman, pregnant at 10 weeks’ gestation, presented with a 5-week history of persistent vomiting five or six times a day. She had lost 3 kg in weight in the previous 2 weeks. There was no family history of autoimmune disease. She was taking no medications. On clinical examination, her heart rate was 105 beats/minute. There was no exophthalmos or tremor.
Which of the following is the most important next management step? A. Arrange a neurosurgical review B. Arrange an urgent MRI of the pituitary C. Request an obstetric review to deliver the fetus D. Restart bromocriptine E. Arrange urgent visual field perimetry in the medical eye unit
Investigations Sodium 131 mmol/litre (137e144) Potassium 3.1 mmol/litre (3.5e4.9) Urea 7.8 mmol/litre (2.5e7.0) Creatine 85 micromol/litre (60e110) Serum thyroid-stimulating hormone 0.01 mU/litre (0.4 e5.0) Serum free T4 22 pmol/litre (10.0e22.0)
Question 3 A 42-year-old woman presented with lethargy and tiredness 5 months after the spontaneous vaginal delivery of her first baby. She was not coping well with caring for the baby, and had been unable to breastfeed. Her periods had not returned. The pregnancy had been complicated by early-onset gestational diabetes mellitus, and a postpartum haemorrhage of 2 litres. She had no past medical history before the pregnancy.
Which of the following medications is most appropriate for her at this time? A. Carbimazole 40 mg orally once daily B. Cyclizine 50 mg intravenously 8-hourly C. Ondansetron 4 mg oral 8-hourly D. Propylthiouracil 200 mg orally 12-hourly E. Sando-K effervescent tablet, one tablet 12-hourly
Which of the following tests would be most likely to lead to the diagnosis? A. 9 am cortisol B. HbA1c C. Free thyroxine (FT4) D. Serum prolactin E. Thyroid-stimulating hormone
Question 2 A 28-year-old woman, 32 weeks’ pregnant, presented with a 2week history of not noticing objects in the periphery of her vision. She had no loss of visual acuity and no headaches. Some years previously, she had been found to have a microprolactinoma.
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Endocrine disorders in pregnancy
Key points C
The normal physiological changes of pregnancy make it hard to interpret many endocrine tests. In addition, endocrine disorders can mimic normal pregnancy symptoms
C
Optimization of pre-pregnancy disease is a crucial step towards ensuring good pregnancy outcomes
C
Most drugs used to treat endocrine disorders can be used in pregnancy, and schedules should not be altered without input from a clinician experienced in pregnancy
C
Untreated hyper- and hypothyroidism present greater risks to pregnancy than the harms associated with medication use
Harry Gibson Catherine Nelson-Piercy
Abstract Endocrine disorders are a significant reason for consultation during pregnancy. Many of these conditions are common in women of fertile age and can have a profound impact on fertility and pregnancy outcome if they are not managed optimally. Diagnosis is often difficult because of the wide range of symptoms that can be experienced, especially as many of them occur as part of an otherwise normal pregnancy. Pregnancy physiology alters the normal biochemical parameters for many hormones, and interpretation must take into account the trimester of pregnancy as well as view the results in the context of the clinical presentation. Optimal control of endocrine conditions before pregnancy is an important consideration for any physician caring for a woman of childbearing age. In addition, prompt recognition of endocrine disorders presenting during pregnancy and a knowledge of treatment options are essential.
suggested for the first trimester, gradually returning to nonpregnant values through the second and third trimesters.1 Parathyroid Calcium utilization is increased in pregnancy and lactation,2 with increased renal loss. Vitamin D requirements double to meet this demand.
Keywords Graves’ disease; hyperparathyroidism; hyperthyroid; hypopituitarism; hypothyroid; MRCP; pregnancy; prolactinoma; Sheehan’s syndrome; vitamin D
Pituitary The anterior pituitary increases in volume by up to 136% over the course of pregnancy. Prolactin levels increase 10-fold above baseline,3 falling after delivery, but only return to normal after breastfeeding has ceased. Gonadotropins are suppressed by high circulating oestrogen concentrations.
Normal endocrine physiology of pregnancy Thyroid The physiological changes that occur during pregnancy have a significant impact on the usual function of the pituitaryethyroid axis. Placental human chorionic gonadotropin (hCG) shares the same a-subunit as thyroid-stimulating hormone (TSH). In the first trimester, hCG levels rise, stimulating increased release of total thyroxine (T4) and triiodothyronine (T3). A simultaneous increase in the hepatic production of thyroidbinding globulin maintains relatively stable levels of free T4 and T3. The level of TSH varies, but is suppressed by approximately 0.5 mU/litre, and in some women without thyroid disease, TSH may be undetectable.1 In the second and third trimesters, hCG levels fall, free T4 and T3 remain lower than in non-pregnancy, and TSH rises accordingly. Population-based, trimester-specific levels must ideally be used when interpreting thyroid function tests. If these are unavailable, an empirical TSH upper limit of 4.0 mU/litre is
Adrenal Circulating cortisol levels increase towards the end of pregnancy. The placenta secretes corticotropin-releasing hormone (CRH), which in early pregnancy is bound by liver-derived CRH-binding proteins. Towards the end of pregnancy, CRH-binding proteins fall, leading to an overall higher concentration of circulating cortisol: up to 552 nmol/litre in the second trimester and 823 nmol/litre in the third.3 This contributes to the relative immunosuppressive state of pregnancy.
Thyroid disorders Hyperthyroidism Hyperthyroidism affects 0.2% of pregnancies, usually being caused by Graves’ disease. Toxic multinodular goitre, functional adenoma, adverse drug effects and TSH-secreting tumours are rarely encountered. Gestational transient thyrotoxicosis is more common (1e3% of pregnancies), occurring as a result of hCGmediated T4 release. It is especially likely when circulating hCG levels are particularly high, as occurs with hyperemesis gravidarum, multiple pregnancy, or gestational trophoblastic disease. Many symptoms of hyperthyroidism are also features of normal pregnancy. Table 1 illustrates symptoms that can be useful in discerning true from gestational hyperthyroidism. TSH suppression and free T4 or T3 elevated above the trimester-
Harry Gibson BA MB BS MRCOG MRCP(UK) is an Obstetric Medicine Fellow at St Thomas’ Hospital, London, UK. Competing interests: none declared. Catherine Nelson-Piercy MA FRCP FRCOG is a Consultant Obstetric Physician at Guy’s and St Thomas’ NHS Trust and Imperial College Healthcare NHS Trust, and Professor of Obstetric Medicine at King’s College, London, UK. Competing interests: none declared.
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Breastfeeding is considered safe with doses <15 mg/day of carbimazole or <150 mg/day of PTU. Women should be warned about the risk of a postpartum flare, and thyroid function re checked 4e6 weeks after pregnancy.
specific range may not discriminate between the two scenarios: a careful history of onset of symptoms, examination for discriminating physical signs, and early pregnancy ultrasound are all crucial. Risks: severe thyrotoxicosis causes subfertility, but risks during pregnancy include miscarriage, fetal growth restriction, preterm labour, maternal cardiac arrhythmias and thyroid crisis. Maternal thyroid receptor antibodies (TRAb) cross the placenta and in 1% of pregnancies cause fetal goitre and thyrotoxicosis. Autoimmune hyperthyroidism improves as gestation progresses, but can flare postpartum once the relative immunosuppression of pregnancy is lost. Management: disease optimization before conception is a key factor for a safe pregnancy in hyperthyroid disorders. Contraception should be advised until at least 3 months of satisfactory control has been achieved (6 months if radio-iodine has been used). Propylthiouracil (PTU) and carbimazole can be used in pregnancy, ideally at as low a dose as possible to maintain remission. Both cross the placenta and increase the absolute risk of fetal malformation by about 2e3%4; this must be balanced against the greater hazards of stopping treatment. Most pregnancy guidelines advocate advising women who are taking carbimazole to switch to PTU for the first trimester only, as PTU is considered less of a risk to the fetus.1 However, this approach can lead to a loss of previous good disease control and exposes mothers to the 1:10,000 risk of PTU-related hepatotoxicity. Furthermore, recent data suggest there is no corresponding reduction in congenital anomalies.4 If thyrotoxicosis is newly diagnosed in pregnancy, rapid control must be achieved with either PTU (first trimester) or carbimazole (second and third trimesters). Block-and-replace regimens are not recommended, as this results in fetal hypothyroidism. Propranolol can be used for symptom control. Thyroidectomy, if considered, is safest in the second trimester or after pregnancy. In women with poor disease control, thyroid function should be checked monthly. Measurement of TRAb levels helps to determine whether the fetus is at risk of fetal thyrotoxicosis.
Hypothyroidism Overt hypothyroidism affects 1% of pregnancies. It can be autoimmune, drug-induced, post-thyroiditis or iatrogenic after treatment for Graves’ disease. Iodine deficiency is rarely encountered in the UK. Table 1 illustrates the overlap between features of hypothyroidism and normal pregnancy symptoms. Diagnosis is by low free T4 or T3 with TSH elevated above the gestationspecific range. Thyroid autoantibody positivity helps confirm the diagnosis and can stratify risk. Subclinical hypothyroidism is the finding of an elevated (but <10 mU/litre) TSH with normal free T4 or T3 and no symptoms or signs. Historically, it was defined as TSH >2.5 mU/litre, but population studies demonstrated that this was too conservative. More recent guidance emphasizes gestation-specific cut-offs or, if these are not available, a TSH >4.0 mU/litre.1 Risks: untreated overt hypothyroidism causes anovulation and subfertility. In pregnancy, it is associated with miscarriage, fetal growth restriction, stillbirth, gestational hypertension and reduced childhood IQ.1 A woman must be significantly iodinedeficient to risk permanent fetal neurological damage (previously known as cretinism). Pregnancy outcomes are good when a woman is euthyroid on treatment. The risks of subclinical hypothyroidism are debated, and are inferred from the risks of overt hypothyroidism. T4 treatment has not been shown to improve outcomes in these women.5 Management: guidelines advocate an empirical increase in T4 dosing by 20e30% for all women in the first trimester,1 although this risks over-treatment and iatrogenic hyperthyroidism. We favour early thyroid function testing, and increasing the dose only in women with biochemical or symptomatic evidence of under-replacement. TSH should be targeted to within gestationspecific ranges. Any change in T4 dose during pregnancy should be followed up within 4e6 weeks with thyroid function testing; women on stable doses should have their TSH and free T4 checked every trimester and 6e12 weeks after delivery. It is safe to take T4 while breastfeeding. Subclinical hypothyroidism (TSH >4.0 mU/litre) in the context of positive thyroid autoantibodies carries the risk of progression to overt hypothyroidism; treatment is therefore currently recommended as benefit outweighs risk.1 A benefit has not, however, been established for autoantibody-negative women with subclinical hypothyroidism.
Distinguishing hyper/hypothyroidism from normal pregnancy symptoms
Features in common with normal pregnancy
Features suggesting thyroid disorder
Hyperthyroidism
Hypothyroidism
Heat intolerance Emotional lability Vomiting Palpitations/ tachycardia Symptoms precede pregnancy Tremor Weight loss Lid lag Ophthalmopathy
Weight gain/ oedema Lethargy Constipation Hair loss Symptoms precede pregnancy Other autoimmune disease Cold intolerance Slow relaxing reflexes
Postpartum thyroiditis Occurring 3e6 months after delivery, postpartum thyroiditis is autoimmune destruction of the thyroid gland, resulting in either a hyperthyroid, hypothyroid or biphasic thyroid state. The mean incidence is 7.5%. It is usually transient, resolving 4e8 months postpartum, but 3e4% of women remain permanently hypothyroid. It is associated with other autoimmune conditions, a family history of thyroid disease and positive thyroid peroxidase antibodies. Care must be taken to differentiate this from Graves’ disease and not attribute symptoms generally to a tired and worried
Table 1
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prolactinoma. Prolactinomas are classified according to their size on imaging: microlesions are <1 cm; macrolesions are >1 cm. The diagnosis is usually made before pregnancy because of subfertility. A new diagnosis is occasionally made in pregnancy after presentation with headache, visual field defects or diabetes insipidus. Cranial magnetic resonance imaging (MRI) without contrast is safe after the first trimester; before this, the risk must be balanced against the delay of diagnosis. Serum prolactin levels are not helpful in pregnancy. Risks: because of pituitary swelling in pregnancy, the risk of increase in size is 17e46% for macroprolactinoma and 1.6 e4.7% for microprolactinoma; with the latter, however, growth is usually asymptomatic.3 A significantly enlarging tumour impinges on the optic chiasm and causes new or worsening bitemporal hemianopia or quadrantanopia. Pituitary apoplexy is a risk. Prolactinomas have no impact on pregnancy outcome and are not a contraindication to breastfeeding. Management: women with a prior diagnosis will be taking dopamine receptor agonists (cabergoline, bromocriptine). There are no data to suggest that these are harmful in pregnancy, but they can usually be discontinued in microprolactinoma.3 Women should be regularly followed up and asked to report any new visual field symptoms. With macroprolactinoma, medication should be stopped only if the tumour remains within the boundaries of the sella turcica.3 Serial visual field testing should be arranged every 2 months. Reimaging needs to be arranged only if symptoms worsen. If tumour enlargement is confirmed, medication should be reintroduced. Breastfeeding is not contraindicated. The pituitary stimulus is less than that of pregnancy. However, women taking dopaminergic drugs may find it hard to establish breastfeeding. Therapy can be withdrawn before delivery to facilitate breastfeeding, but close surveillance with visual field scanning and MRI is imperative. Trans-sphenoidal surgery is safest outside pregnancy.
mother. Treatment involves managing hyperthyroid symptoms with b-adrenoceptor blockers, and an underactive thyroid with T4. After 6 months, treatment is withdrawn to determine whether resolution has occurred. There is a 10e25% risk of recurrence, and a 30% risk of future hypothyroidism if antibodies are present.
Parathyroid disorders Hyperparathyroidism Primary hyperparathyroidism has an incidence of 8 per 100,000 women of childbearing age and is caused by parathyroid adenoma or hyperplasia. Tertiary hyperparathyroidism is also encountered in women with history of chronic kidney disease. As with other endocrine conditions, many classic symptoms of hypercalcaemia overlap with findings of normal pregnancy, and many women are asymptomatic. Unexplained vomiting, hypertension or renal calculi should prompt serum calcium measurement and, if levels are raised, parathyroid hormone (PTH) measurement. Risks: the calcium demand of pregnancy can improve symptoms, but acute pancreatitis and renal calculi are still a risk, especially postpartum. Hypercalcaemia increases the risk of miscarriage, preterm birth, stillbirth and pre-eclampsia. Fetal PTH can be suppressed by the hypercalcaemic state, resulting in rebound neonatal hypocalcaemia; this presents as tetany or seizures, usually 1e2 weeks after birth. Management: plentiful hydration with oral or intravenous fluids increases renal calcium clearance. A low-calcium diet should also be followed. Surgery is safest in the second trimester but can be undertaken in the third trimester if the condition presents later in pregnancy. Serum calcium levels should be monitored every 2e4 weeks.
Vitamin D deficiency Hypopituitarism Pre-pregnancy hypopituitarism, caused by previous pituitary surgery or irradiation, tumour or apoplexy, causes secondary ovarian failure, so women will already be on treatment. Hypopituitarism that arises from an acute hypotensive episode after postpartum haemorrhage is known as Sheehan’s syndrome. Lymphocytic hypophysitis is an antibody-mediated infiltration of the anterior pituitary, and can be associated with other autoimmune conditions. In both situations, any number of pituitary hormones can be deficient, causing adrenal insufficiency (hypoglycaemia, hypotension, vomiting), hypothyroidism, failure of lactation, amenorrhoea and loss of secondary sexual characteristics. Pituitary imaging assists in establishing the diagnosis. Management: acutely, the patient should be treated with glucocorticoids and intravenous dextrose. Spontaneous resolution can occur, but in persistent hypopituitarism, ovulation and pregnancy can be achieved if gonadotropins are replaced. Once pregnancy is established, the feto-placental unit becomes selfsustaining. Women taking maintenance corticosteroids require higher doses during periods of stress e intercurrent infection, hyperemesis gravidarum and delivery.
This is a common finding in Northern Europe, especially in winter months. Obese women are most at risk (61%), as are those with pigmented skin (47e64%).2 Other risk factors include a vegan diet, short interpregnancy intervals, renal or liver disease and wearing clothes that fully cover the skin. Deficiency can cause hypocalcaemia, myopathy, myalgia, increased risk of preeclampsia or gestational diabetes mellitus and neonatal rickets, hypocalcaemic tetany or seizures. Management: supplementation with colecalciferol or ergocalciferol is recommended as follows:2 all pregnant women e 400 U/day at-risk women e at least 800e1000 U/day proven deficiency e 10,000e20,000 U/week for 4e6 weeks.
Pituitary disorders Hyperprolactinaemia and prolactinomas Raised prolactin concentrations are normal in pregnancy. Pathological elevation is caused by prolactinoma, pituitary stalk lesions, hypothyroidism, post-ictal states and anti-dopaminergic drugs. Most cases in women of childbearing age are caused by
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Pregnancy considerations for rare endocrine disorders Condition
Diagnosis
Diabetes insipidus
C
C C
Acromegaly
C
Standard water deprivation test unsafe (short period of deprivation may be acceptable) Paired serumeurine osmolality Clinical response to desmopressin (central DI) Difficult to diagnose biochemically in pregnancy because of placental GH3
Risks C C
C C
Cushing’s syndrome
C
C
Conn’s syndrome
C
Low serum calcium Low PTH
C
40e50% from adrenal, 30% pituitary3 Pregnancy-specific cortisol ranges
C
As for non-pregnant
C
C
C C
C
C C C
C
Deterioration of DI in pregnancy Untreated risks seizures and oligohydramnios
C
C
Hypoparathyroidism
Management
C
Expansion of pituitary tumour, apoplexy Miscarriage Increased risk gestational diabetes mellitus Miscarriage Fetal hypocalcaemia with secondary [PTH Fetal loss, preterm labour Neonatal adrenal suppression Hypertension/pre-eclampsia Gestational diabetes mellitus Hypertension/pre-eclampsia
C C C
C C
C C
C C C
Phaeochromocytoma
C
As for non-pregnant
C C C
Addison’s disease
C
C C
Congenital adrenal hyperplasia
C
Use pregnancy-specific cortisol ranges Hyponatraemia Family history of autoimmune disease Rarely encountered in pregnancy owing to subfertility and masculinization of secondary sexual characteristics
C C
C
C C
Hypertensive crisis Maternal mortality up to 17% Fetal mortality 26% No puerperal exacerbation No adverse effects if well treated
C
Miscarriage, growth restriction, preterm Obstructed labour (android pelvis) 1:4 risk inheritance if partner is carrier
C
C C C
C
Exclude pre-eclampsia and acute fatty liver of pregnancy Central: intranasal desmopressin Nephrogenic: carbamazepine, water restriction, NSAID Contraindicated: chlorpropamide Dopamine agonist Surgery (second trimester) Avoid unless clear benefit: SST analogue (octreotide, lanreotide) Vitamin D (alfacalcidol, calcitriol) Oral calcium Surgery (second trimester) Avoid unless surgery contraindicated: ketoconazole, metyrapone Labetalol, nifedipine, methyldopa Amiloride (for YKþ) Contraindicated: spironolactone a-Adrenoceptor blockade: phenoxybenzamine, prazosin Surgery Hydrocortisone, fludrocortisone Adrenal suppression: [ hydrocortisone by 50 mg three times daily in labour or illness As with Addison’s If female fetus affected: high-dose dexamethasone to prevent masculinization
DI, diabetes insipidus; GH, growth hormone; NSAID: non-steroidal anti-inflammatory drug; PTH, parathyroid hormone; SST, somatostatin.
Table 2
Other endocrine disorders
scientific-impact-papers/vitamin_d_sip43_june14.pdf. [Accessed 22 October 2014]. 3 Bronstein MD, Paraiba DB, Jallad RS. Management of pituitary tumors in pregnancy. Nat Rev Endocrinol 2011; 7: 301e10. 4 Seo GH, Kim TH, Chung JH. Antithyroid drugs and congenital malformations, a nationwide Korean cohort study. Ann Intern Med 2018; 168: 405e13. 5 Wiles K, Jarvis S, Nelson-Piercy C. Are we overtreating subclinical hypothyroidism in pregnancy? Br Med J 2015; 351: h4726.
Rare endocrine disorders and their effects on pregnancy are detailed in Table 2. A KEY REFERENCES 1 Alexander EK, Pearce EN, Brent GA, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017; 27: 315e89. 2 Robinson S, Nelson-Piercy C, Harvey NC, Selby P, Warner JO. Vitamin D in pregnancy. Scientific Impact Paper No. 43. 2014, https://www.rcog.org.uk/globalassets/documents/guidelines/
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FURTHER READING Nelson-Piercy C. Handbook of obstetric medicine. 5th edn. Boca Raton, FL: CRC Press, 2015.
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TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. She used to take bromocriptine but this had been stopped several years before the pregnancy. On clinical examination she had a bitemporal upper quadrantanopia with no papilloedema or ophthalmoplegia.
Question 1 A 34-year-old woman, pregnant at 10 weeks’ gestation, presented with a 5-week history of persistent vomiting five or six times a day. She had lost 3 kg in weight in the previous 2 weeks. There was no family history of autoimmune disease. She was taking no medications. On clinical examination, her heart rate was 105 beats/minute. There was no exophthalmos or tremor.
Which of the following is the most important next management step? A. Arrange a neurosurgical review B. Arrange an urgent MRI of the pituitary C. Request an obstetric review to deliver the fetus D. Restart bromocriptine E. Arrange urgent visual field perimetry in the medical eye unit
Investigations Sodium 131 mmol/litre (137e144) Potassium 3.1 mmol/litre (3.5e4.9) Urea 7.8 mmol/litre (2.5e7.0) Creatine 85 micromol/litre (60e110) Serum thyroid-stimulating hormone 0.01 mU/litre (0.4 e5.0) Serum free T4 22 pmol/litre (10.0e22.0)
Question 3 A 42-year-old woman presented with lethargy and tiredness 5 months after the spontaneous vaginal delivery of her first baby. She was not coping well with caring for the baby, and had been unable to breastfeed. Her periods had not returned. The pregnancy had been complicated by early-onset gestational diabetes mellitus, and a postpartum haemorrhage of 2 litres. She had no past medical history before the pregnancy.
Which of the following medications is most appropriate for her at this time? A. Carbimazole 40 mg orally once daily B. Cyclizine 50 mg intravenously 8-hourly C. Ondansetron 4 mg oral 8-hourly D. Propylthiouracil 200 mg orally 12-hourly E. Sando-K effervescent tablet, one tablet 12-hourly
Which of the following tests would be most likely to lead to the diagnosis? A. 9 am cortisol B. HbA1c C. Free thyroxine (FT4) D. Serum prolactin E. Thyroid-stimulating hormone
Question 2 A 28-year-old woman, 32 weeks’ pregnant, presented with a 2week history of not noticing objects in the periphery of her vision. She had no loss of visual acuity and no headaches. Some years previously, she had been found to have a microprolactinoma.
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