Endocrine disease in pregnancy.

Topics covered:

• Essentials
• Introduction
• Pituitary disease
• Thyroid disease
• Parathyroid disease
• Adrenal disease
• Miscellaneous endocrine conditions
• Further reading

Essentials

Endocrine function in the developing fetus is initially almost entirely dependent on the mother, with the fetus becoming less reliant on maternal hormones as the fetal glands develop and mature from the second trimester onwards.

Endocrine diseases particular to pregnancy

Lymphocytic hypophysitis—typically presents with symptoms of an expanding pituitary tumour; increasingly recognized as a cause of hypopituitarism occurring late in pregnancy and in the postpartum period.

Sheehan’s syndrome (postpartum hypopituitarism)—caused by pituitary infarction following significant hypotension occurring at the time of delivery.

Postpartum thyroiditis—characterized by transient hyperthyroidism followed by hypothyroidism; occurs in 50% of anti-thyroid peroxidase (anti-TPO) positive women and only rarely in antibody negative women.

Pregnancy in women with endocrine disorders

Hyperprolactinaemia—this must be corrected to allow ovulation and fertility. Prolactinomas may enlarge during pregnancy and cause visual impairment: the risk is 2% for a microprolactinoma and >15% for a macroprolactinoma.

Acromegaly—fertility is impaired in women with acromegaly, and management of pregnancy is difficult because there is a risk that the responsible pituitary adenoma may enlarge and cause visual impairment. Very close monitoring by testing of visual fields and pituitary MRI scanning is required.

Cushing’s syndrome—difficult to diagnose in pregnancy, and there is a high risk of maternal and fetal complications.

Hyperthyroidism—occurs in 0.2% of pregnancies, usually due to Graves’ disease, and is best diagnosed on the basis of an elevated serum free tri-iodothyronine (T₃) in association with a suppressed TSH. The baby is at risk of hyperthyroidism due to the transplacental passage of thyroid stimulating antibodies. Treatment can be by antithyroid drugs or surgery, but not by radio-iodine.

Hypothyroidism—associated with a number of complications in pregnancy, including fetal neurological problems ranging from cretinism to impaired child development. Pregnant patients with hypothyroidism should always be treated with thyroxine, with increased dose requirements during gestation.

Introduction

During pregnancy the endocrine physiology of the mother and fetus changes constantly. Endocrine function in the fetus is initially dependent on maternal function as most endocrine glands do not produce hormones until the second trimester. Thereafter the fetus is less reliant on maternal function, but the fetal glands are continually developing and maturing throughout pregnancy. This section will indicate the important therapeutic aspects of endocrine disease in pregnancy.

Pituitary disease

Prolactinoma

Pituitary adenomas are the most common pituitary disorder affecting pregnancy and prolactinomas are the most common of the hormone-secreting adenomas. Prolactinomas are a common cause of reproductive and sexual dysfunction and hyperprolactinaemia must be corrected to allow ovulation and fertility. The main concern during pregnancy is of symptomatic enlargement leading to visual impairment: there is less than a 2% risk of this happening with a microprolactinoma, but a greater than 15% risk with a macroprolactinoma. Bromocriptine is safe for use during gestation, but a macroadenoma may require debulking prior to pregnancy. Cabergoline has also been used during pregnancy with no deleterious effects. It is safe for patients to become pregnant following dopamine agonist treatment, when prolactinomas may decrease in size, show no change, or achieve complete resolution.

Acromegaly

Fertility is impaired in acromegaly due to concomitant hyperprolactinaemia and decreased gonadotropin reserve due to the expanding tumour. In an acromegalic woman wishing to conceive, prolactin (PRL) and growth hormone (GH) levels must be normalized to promote fertility. Patients with microadenomas should discontinue medical therapy (bromocriptine or somatostatin analogues) during pregnancy and be assessed at each trimester. In patients with macroadenomas removal before pregnancy leads to a greater risk of infertility, but if they are not resected there is a greater risk of pituitary enlargement and visual impairment during gestation.

Pregnancy may influence the size of the adenoma, particularly as the pituitary gland enlarges during normal gestation and may increase by 45% during the first trimester. Pregnancy exacerbates acromegaly in about 17% of cases, and patients with adenomas larger than 1.2 cm are at greater risk of visual loss during pregnancy. Regular visual field checks and MRI examinations are required in such cases.

Cushing’s syndrome

Cushing’s syndrome during pregnancy has a high incidence of maternal and fetal complications; only one-quarter of patients have an uncomplicated pregnancy. Diagnosis is difficult because many biochemical features such as elevated cortisol levels and loss of the normal glucocorticoid feedback are present during normal pregnancy. Corticotropin-releasing hormone (CRH) and dexamethasone testing is helpful, as is MRI. Transphenoidal surgery is indicated following the enlargement of any pituitary tumour in pregnancy, especially when there is evidence of increasing visual field impairment.

Diabetes insipidus

Central diabetes insipidus may present during pregnancy. It is seen in women with Sheehan’s syndrome, partial postpartum hypopituitarism, and is associated with infiltrative disorders such as histiocytosis X. Synthetic 1-deamino-8-D-arginine-vasopressin (DDAVP) is normally used in the management of diabetes insipidus, with a therapeutic dose of about 30 µg (range 7.5–100 µg) given intranasally. Use during pregnancy seems to be safe for both mother and baby: DDAVP does not affect delivery and has no adverse effects on the neonate.

Postpartum hypopituitarism

Postpartum hypopituitarism due to Sheehan’s syndrome is now uncommon because of improved obstetric care. The syndrome is caused by pituitary infarction consequent on significant hypotension occurring at the time of delivery, the diagnosis typically being made when a woman who has survived such an insult fails to establish lactation or menstruation afterwards.

Lymphocytic hypophysitis is increasingly recognized as a cause of hypopituitarism occurring late in pregnancy and in the postpartum period, and around 60% of cases of women found to have adenohypophysitis are pregnant or have recently been delivered. Women may present with symptoms of an expanding pituitary tumour, with headaches and visual symptoms. Inability to lactate and amenorrhoea have been noted. Hyperprolactinaemia and elevated GH levels are also observed. Imaging (CT or MRI) reveals a pituitary mass mimicking an adenoma in about four-fifths of patients. Evaluation of pituitary function shows isolated or multiple anterior pituitary deficiency. ACTH secretion is impaired most frequently, followed by TSH, gonadotropins, GH, and PRL. Histology shows lymphocytic infiltration, which may extend up to the pituitary stalk to the infundibulum. Antibodies to pituitary tissue may be present but are often absent. Other autoimmune diseases, particularly postpartum thyroiditis, may be associated. In addition to the pituitary symptoms described, patients are at risk of adrenal failure and death has been reported, hence adrenal function should be assessed in all cases. Surgery may be required for diagnosis, but should be avoided if the condition is suspected beforehand and corticosteroids given, since these can reduce the size of the pituitary mass.

Thyroid disease

Maternal thyroid function during pregnancy

Thyroid volume increases in iodine-deficient areas but not in iodine-sufficient ones. Thyroxine binding globulin synthesis increases during pregnancy; free thyroxine increases during the first trimester and falls thereafter. Placental human chorionic gonadotropin (hCG), a weak thyroid activator, stimulates maternal thyroid function in the first trimester and results in TSH suppression.

Hyperthyroidism

Hyperthyroidism, usually due to Graves’ disease, occurs in 0.2% of pregnancies and is associated with impaired fertility. Other causes include gestational thyrotoxicosis due to high hCG concentrations and hydatidiform molar disease. The diagnosis is made by noting an elevated serum free tri-iodothyronine (FT₃) in association with a suppressed TSH, the free thyroxine (FT₄) being elevated or at the upper limit of normal. Ideally each laboratory should establish pregnancy-related normal thyroid reference ranges. Untreated hyperthyroidism is associated with an increased risk of abortion, and if the pregnancy is completed the baby may be of low birth weight and be neonatally transiently hyperthyroid due to the transplacental passage of thyroid-stimulating antibodies. High concentration of TSH receptor antibodies at 28 to 36 weeks gestation suggests the possibility of neonatal thyrotoxicosis. This can also occur in infants whose mothers are currently being treated for Graves’ disease or who have received treatment in the past.

Bullet list 1 Management of Graves’ hyperthyroidism in pregnancy

Management of hyperthyroidism in pregnancy is either with antithyroid drugs (Bullet list 1) or surgery, the latter being optimally performed in the second trimester. Radio-iodine therapy is completely contraindicated during pregnancy, and nonpregnant women receiving radioiodine should be advised not to conceive for at least 6 months. There may be a case for therapeutic abortion if radio-iodine has been administered after 12 weeks gestation (i.e. after the fetal thyroid is functional). Propylthiouracil (PTU) is the preferred antithyroid drug as rare but significant side effects due to carbimazole (or methimazole) have been reported: these include aplasia cutis and a methimazole embryopathy characterized by choanal atresia and other defects.

Exacerbation of Graves’ disease often occurs postpartum, hence thyroid function tests should be checked routinely at this time. PTU does cross into breast milk, but in lower concentrations than carbimazole or methimazole, hence breastfeeding may normally be permitted, but thyroid function should be monitored in the neonate if breastfeeding is prolonged.

Hypothyroidism

Hypothyroidism is associated with relative infertility because of anovulation and menorrhagia, and the presence of thyroid antibodies is a marker for miscarriage and recurrent abortion even in euthyroid patients. There is an increased incidence of stillbirths and congenital malformations as well as maternal obstetric complications if the condition is untreated. In iodine-deficient areas the risk of neonatal brain damage is increased, resulting in cretinism in severe cases. This is due to maternal hypothyroxinaemia, particularly in the first trimester when the developing fetal nervous system is entirely dependent on maternal T₄. Even in iodine-sufficient areas mild gestational hypothyroidism (seen in 2.5% of pregnancies) is associated with impaired child development, hence there is a case for screening for thyroid function—including for thyroid antibodies—in early pregnancy. Patients with hypothyroidism of any degree should be treated with thyroxine and those already receiving T₄ when found to be pregnant should increase the dose by at least 50 µg per day, and more if necessary.

Fetal and neonatal thyroid dysfunction

Fetal hyperthyroidism is diagnosed by noting a high fetal heart rate and may be confirmed if necessary by fetal blood sampling. Treatment is by maternal administration of high-dose PTU (300–450 mg/day) together with thyroxine during gestation to prevent maternal hypothyroidism. Neonatal hypothyroidism may also occur at birth due to maternal TSH receptor blocking antibodies, maternal antithyroid drug administration, iodine deficiency and maternal goitrogen ingestion. All these conditions are transient and the mother can be reassured.

Postpartum thyroid disease

Anti-thyroid peroxidase (anti-TPO) antibodies, found in 10% of euthyroid pregnant women in early gestation, are a marker for development of postpartum thyroid dysfunction. Postpartum thyroiditis, a destructive process characterized by transient hyperthyroidism followed by hypothyroidism, occurs in 50% of anti-TPO positive women and only rarely in antibody negative women. The hyperthyroidism is relatively asymptomatic but may require treatment with β-adrenoreceptor blocking agents in some cases. By contrast, the hypothyroidism is often symptomatic and thyroxine therapy is required. Mild depressive symptomatology is more common in postpartum women with anti-TPO antibodies than those without. Following recovery from transient postpartum thyroid dysfunction nearly 50% will develop permanent hypothyroidism after 7 years, and recurrent disease follows future pregnancies up to 75% who have experienced a previous episode. Screening for TPO antibodies should be included in the suggested routine antenatal thyroid screening (see above).

Thyroid nodules

Thyroid nodules occur in up to 10% of pregnant women and are usually benign, but 5 to 20% are either benign follicular adenomas or carcinomas of follicular or parafollicular (C-) cell origin. Fine-needle aspiration biopsy (ultrasound-guided if necessary) is the investigation of choice. Surgery should be performed during the second trimester to avoid abortion in the first trimester and premature labour in the third. Pregnancy does not adversely affect the rate of recurrence or distant metastases. A goitre found early in gestation should be evaluated, but the investigation of nodules presenting after 5 to 6 months gestation should occur postpartum. Differentiated thyroid cancer should not be a contraindication to pregnancy or an indication for abortion.

Parathyroid diseases

Diseases of the parathyroid glands are uncommon in women of childbearing age, but hyperparathyroidism during pregnancy can lead to acute pancreatitis, hypercalcaemic crisis, and toxaemia. There is an increased incidence of prematurity and neonatal hypercalcaemia if maternal calcium levels are high. Surgical management can be undertaken safely in the second trimester. Hypoparathyroidism is treated with vitamin D analogues, with dosage often needing to be increased during pregnancy to maintain normocalcaemia, hence calcium levels should be monitored regularly throughout pregnancy, at least in each trimester.

Adrenal disease

The diagnosis of adrenal disease in pregnancy is often delayed. Adrenal tumours are very rare, but their pathophysiological consequences for the mother and fetus are dire. Hypertension is a major feature in patients with phaeochromocytoma and may be initially mistaken for pregnancy-associated hypertension. Such uncommon cases should be managed medically during pregnancy, with surgical resection in the postpartum period, and a similar approach should be taken to the exceptionally rare problem of primary aldosteronism (Conn’s syndrome) presenting during pregnancy.

Addison’s disease

Addison’s disease is only rarely diagnosed during pregnancy but may present as an addisonian crisis in the postpartum. The diagnosis may be missed, with symptoms erroneously attributed to those of pregnancy or its complications. The condition is readily confirmed with measurement of plasma cortisol, the short Synacthen test, and ACTH levels. Antibodies to 21-hydroxylase should be measured to confirm the autoimmune nature of the disease, and the patient screened for other autoimmune conditions.

Congenital adrenal hyperplasia (CAH)

Women with severe CAH have decreased fertility because of oligo-ovulation due to elevated androgen levels. Successful conception requires careful endocrine monitoring and sometimes induction of ovulation. During pregnancy problems are seen in those women with 21-hydroxylase deficiency (P450c21 deficiency, OMIM 201910), 11-hydroxylase deficiency (P450c11, OMIM 610613), and 3-β-hydroxysteroid dehydrogenase deficiency (OMIM 201810). Gestational management must involve adequate adrenal steroid replacement and adrenal androgen suppression. Clinical status, serum electrolytes, and androgen levels should be measured regularly and glucocorticoid and mineralocorticoid therapy adjusted or increased as necessary. As many of the genes for the described enzymes have been isolated, accurate prenatal diagnosis of 21- and 11-hydroxylase deficiency is now possible. The infant should be evaluated clinically and, in most cases, biochemically.

Miscellaneous endocrine conditions

Bartter’s syndrome (OMIM 241200, 601678) is a rare renal tubular autosomal recessive disorder in which hypokalaemia, hyperaldosteronism, and sodium wasting occur. The main concern in pregnancy is to maintain normal serum potassium levels which, if done, results in a normal gestation. Gestational hypomagnasaemia may require replacement therapy.

Gonadal dysgenesis (Turner’s syndrome) is characterized by streak ovaries and infertility. However, advances in in vitro fertilization and embryo transplantation have made pregnancy possible for some women with this condition. 

Further reading