- Email: [email protected]
Other endocrine disorders in pregnancy
ARTICLE IN PRESS Current Obstetrics & Gynaecology (2004) 14, 387–394
www.elsevier.com/locate/curobgyn
Other endocrine disorders in pregnancy Hassan A. Shehataa,, Khalid Ahmedb a
Department of Obstetrics, Gynaecology and Maternal Medicine, Epsom and St. Helier University Hospitals, NHS Trust, Wrythe Lane, Carshalton, Surrey SM5 1AA, UK b West Middlesex Hospital, London, UK
KEYWORDS Pregnancy; Endocrine; Hypoparathyroidism; Hyperparathyroidism; Phaeochromocytoma; Cushing syndrome; Conn’s disease; Addison disease; Hyperprolactinoma; Diabetes insipidus; Acromegaly; Sheehan syndrome; Lymphocytic hypophysitis
Summary A variety of endocrine disorders can occur in pregnancy. The pathology of most of these disorders is due to autoimmune, tumour or iatrogenic causes. In this review we discuss in detail less common disorders than, for example, diabetes mellitus and thyroid disease. The review includes parathyroid, adrenal and pituitary gland disorders. r 2004 Elsevier Ltd. All rights reserved.
Parathyroid gland
of the rest, with parathyroid carcinoma accounting for 1–2% of cases.
Primary hyperparathyroidism Primary hyperparathyroidism is very rare in pregnancy. Less than 200 cases have been reported in the literature. The commonest cause in 90% of cases is a parathyroid adenoma. Hyperplasia of the four parathyroid glands accounts for the majority
Effect of hyperparathyroidism on pregnancy The majority of pregnant women with primary hyperparathyroidism are asymptomatic, and are detected on routine prenatal biochemical tests or postpartum, when the newborn develops symptomatic hypocalcaemia.
Corresponding author. Fax: +44-20-8648-2990.
E-mail address: [email protected] (H.A. Shehata). 0957-5847/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2004.07.003
ARTICLE IN PRESS 388 Nephrolithiasis is the most common symptomatic presentation of hyperparathyroidism during pregnancy, with an estimated incidence of 24–36%. Pancreatitis occurs in 7–13% of pregnant women with hyperparathyroidism. Hyperemesis gravidarum is also more frequent in pregnant patients with primary hyperparathyroidism. Fetal complications of maternal primary hyperparathyroidism in pregnancy have included intrauterine growth retardation, low birth weight, preterm delivery and neonatal hypocalcaemia. Even mild asymptomatic hypercalcaemia in the mother has been reported to cause neonatal parathyroid suppression and tetany. Awareness, vigilance and prompt calcium supplementation is vital to avoid this complication. Effect of pregnancy on hyperparathyroidism Pregnancy will theoretically improve hyperparathyroidism due to significant shunting of calcium to the fetus and improved renal excretion. However, postpartum severe exacerbation of hypercalcaemia and/or acute pancreatitis may occur. Untreated hyperparathyroidism may increase the risk of stillbirth, preterm deliveries and neonatal tetany. Management The diagnosis is confirmed by the presence of hypercalcaemia, hypophosphataemia with parathyroid hormone levels (PTH), which are inappropriate for the prevailing plasma calcium level, i.e. PTH could be elevated or unsuppressed within the normal range. The rare familial condition of hypocalcuric hypercalcaemia can be very difficult to differentiate from primary hyperparathyroidism. This is an autosomal dominant disorder due to heterozygous inactivation of the calcium sensing receptor gene. 24-h urinary calcium excretion can help in differentiating the two conditions. This is important as parathyroidectomy in familial hypocalcuric hypercalcaemia is not curative and is followed by a recurrence of the hypercalcaemia post-operatively. Rehydration is vital as significant dehydration accompanies hypercalcaemia. Parathyroidectomy in the second trimester is the treatment of choice for symptomatic patients with significantly elevated serum calcium. Regular follow-up would suffice in mild uncomplicated cases. Bisphosphonates and loop diuretics, used outside pregnancy, cross the placenta freely and are best avoided during pregnancy. Imaging to localise a parathyroid adenoma is not usually indicated in the presence of an experienced parathyroid surgeon.
H.A. Shehata, K. Ahmed
Practice points
Nephrolithiasis is the most common symptomatic presentation with an estimated incidence of 24–36% Pancreatitis occurs in 7–13% of pregnant women with hyperparathyroidism Fetal complications included intrauterine growth retardation, low birth weight, preterm delivery and neonatal hypocalcaemia Untreated hyperparathyroidism may increase the risk of stillbirth, preterm deliveries and neonatal tetany Rehydration is a vital part of management as significant dehydration accompanies hypercalcaemia
Primary hypoparathyroidism The commonest cause is parathyroid surgery or the inadvertent removal of parathyroid tissue during thyroidectomy. Rarely, it is due to autoimmune destruction of parathyroid tissue. Effect of hypoparathyroidism on pregnancy Untreated hypoparathyroidism with chronic hypocalcaemia may lead to fetal skeletal demineralisation. The fetal risks of large doses of vitamin D have not been established. Effect of pregnancy on hypoparathyroidism There is an increased tendency to develop hypocalcaemic tetany during pregnancy and labour due to hyperventilation. Calcium for intravenous administration should be at hand, especially during labour. Management Treatment is with 1,25-dihydroxycholecalciferol (calcitriol) or 1,alpha-hydroxycholecalciferol (alphacalcidol) and calcium supplements. Requirements can change steadily throughout gestation requiring regular follow-up and adjustment of replacement doses at a minimum of monthly intervals. Practice points
The commonest cause is parathyroid surgery or the inadvertent removal of parathyroid tissue during thyroidectomy Untreated hypoparathyroidism with chronic hypocalcaemia may lead to fetal skeletal demineralisation
ARTICLE IN PRESS Other endocrine disorders in pregnancy
There is an increased tendency to develop hypocalcaemic tetany during pregnancy and labour due to hyperventilation Calcium for intravenous administration should be available during labour
Adrenal gland Primary adrenocortical failure (Addison’s disease) This is rarely encountered in pregnancy. Most cases are due to autoimmune destruction or tuberculosis. The vast majority of cases are diagnosed before conception and are well established on replacement therapy. This is usually in the form of hydrocortisone (a total of 30 mg daily in divided doses) and fludrocortisone (up to 100 mg daily). The patients feeling of wellbeing and the lack of postural hypotension, hyponatraemia or hyperkalaemia gauge the adequacy of replacements. Clinical features include weight loss, vomiting, postural hypotension, lethargy and hyperpigmentation. Effect of Addison’s disease on pregnancy If treated, no complications are encountered. Effect of pregnancy on Addison’s disease Pregnancy has no effect on the disease if properly treated. Steroid replacement may need to be altered at certain times during pregnancy. Management The maintenance doses are not changed by pregnancy per se. However, an increase in dosage is vital during periods of stress such as hyperemesis gravidarum, procedures and infections, or during labour. Hydrocortisone is administered intravenously in doses of 100 mg every 6 h throughout the period of stress and reduced gradually over a period of days.
Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a family of inherited disorders of adrenal steroidogenesis, resulting from a deficiency of one of several enzymes necessary for normal adrenal steroid synthesis. It occurs in 1 in 5000 and 1 in 15 000 births in most populations. 21 hydroxylase deficiency (21-
389 OHD) is the commonest deficiency with a particularly high frequency and carrier rates of between 1.2% and 6% of the population. The gene frequency is 1 in 200–400 and is autosomal recessive. The risk of a subsequent child having the disorder is 1:4, if a couple have one affected child. 21-OHD deficiency leads to impaired production of glucocorticoids and mineralocorticoids. The sex steroid pathway is intact and thus provides the only option for the accumulating metabolites. The consequence is a markedly enhanced adrenal androgen production. Affected female fetuses are at risk of masculinisation. Male neonates are at risk of salt losing crises due to mineralocorticoid deficiency as well as precocious puberty. Effect of CAH on pregnancy There is an increased risk of miscarriage, Caesarean section, pre-eclampsia and intrauterine growth restriction. Effect of pregnancy on CAH No effect in treated patients. Management The aim of treatment is to ensure adequate glucocorticoid and mineralocorticoid replacement for the mother, as well as preventing virilisation of an affected female fetus. In women with CAH, increased antenatal surveillance should be put in place because of the increased risk of pre-eclampsia. Corticosteroid replacement is the mainstay of treatment. Mineralocorticoids are necessary in salt losing classical CAH. Monitoring with 17-hydroxyprogesterone levels is unreliable in pregnancy. In pregnancies with a fetus at risk of CAH, suppressing adrenocorticotrophic hormone (ACTH), the drive for the intact sex steroid production pathway, by giving dexamethasone in a dose of 250–500 mg daily is commonly used and continued throughout pregnancy. Fetal diagnosis should be made with sex determination, human leukocyte antigen (HLA) status and 21-hydroxylase zygoisty. Treatment should be started pre-conception or before 5 weeks gestation, prior to differentiation of the genitalia. All female neonates should receive corticosteroids to treat the CAH and because their adrenal glands will be suppressed following longterm high-dose maternal dexamethasone therapy. Male fetuses do not need to be treated in utero. Prevention of virilisation is not always successful, therefore parents should be counselled regarding benefits and risks, and termination of the pregnancy should be offered if the fetus is female.
ARTICLE IN PRESS 390
H.A. Shehata, K. Ahmed
Practice points
21 hydroxylase deficiency (21-OHD) is the commonest deficiency The risk of a subsequent child having the disorder is 1:4, if a couple have one affected child Affected female fetuses are at risk of masculinisation Male neonates are at risk of salt losing crises due to mineralocorticoid deficiency as well as precocious puberty Treatment should be started pre-conception or before 5 weeks gestation, prior to differentiation of the genitalia All female neonates should receive corticosteroids to treat the CAH and because their adrenal glands will be suppressed following long-term high-dose maternal dexamethasone therapy Male fetuses do not need to be treated in utero Prevention of virilisation is not always successful, therefore parents should be counselled regarding benefits and risks, and termination of the pregnancy should be offered if the fetus is a female
The gravid uterus may cause hypertensive attacks due to pressure on the tumour in the supine position. Management Management of hypertension and symptoms with an alpha-blocking agent such as phenoxybenzamine is mandatory. The dose is 10–30 mg, two to four times daily. Beta-blocking agents to control tachycardia can be added if required. Surgical removal is the only cure after control of the blood pressure is achieved by medication. If the patient is prior to 23 weeks gestation, then surgical resection is recommended. After 24 weeks, it is recommended that the surgery is postponed until fetal maturity is achieved and then performed either concurrently with Caesarean section or postpartum. Adequate alpha-blockade for at least 3 days prior to surgery and expert anaesthetic care are essential. Practice points
Phaeochromocytoma These are chromaffin tumours that secret catecholamines. This 10% tumour (10% bilateral, 10% extraadrenal, 10% malignant) is mostly located in the adrenal medulla. It is important to make the diagnosis as, if undiagnosed, it is associated with high maternal and fetal mortality. Clinical features include sustained or labile hypertension, palpitations, anxiety, sweating, headache, vomiting and glucose intolerance. Effect of phaeochromocytoma on pregnancy These tumours are rare but dangerous if they occur in pregnancy. Maternal mortality is about 18% in undiagnosed cases and fetal mortality is about 25% in undiagnosed cases and 15% in diagnosed cases. Maternal mortality most recently had decreased to about 5% in undiagnosed cases, with no maternal death when the diagnosis is made antepartum. The main causes of maternal mortality are cardiac arrythmias, cerebrovascular accidents or pulmonary oedema. Effect of pregnancy on phaeochromocytoma Moribund hypertensive crisis may be precipitated by labour, delivery, general anaesthesia or opiates.
It is important to make the diagnosis as, if undiagnosed, it is associated with high maternal and fetal mortality Clinical features include sustained or labile hypertension, palpitations, anxiety, sweating, headache, vomiting and glucose intolerance Moribund hypertensive crisis may be precipitated by labour, delivery, general anaesthesia or opiates Adequate alpha-blockade for at least 3 days prior to surgery and expert anaesthetic care are essential
Conn’s syndrome Hyperaldosteronism is caused by adrenal aldesteronomas in about 75% of cases and idiopathic bilateral adrenal hyperplasia in the remainder. Clinical features include hypertension and hypokalaemia. Management Diagnosis is by low serum potassium, suppressed renin activity and high plasma aldosterone. Management of hypertension is vital and is in the usual way. Potassium supplementation is also impotant. Spirinolactone, commonly used outside pregnancy, should be avoided in pregnancies with a male fetus because of its anti-androgen effects. Tumour resection is curative and laparoscopic adrenalectomy may prove to be useful during pregnancy.
ARTICLE IN PRESS Other endocrine disorders in pregnancy
Cushing syndrome Long-term exposure to glucocorticoids may lead to Cushing syndrome. The most common cause is iatrogenic, from corticosteroid therapy. Increased adrenal cortisol production causes endogenous Cushing syndrome. Most cases are due to corticotrophin-producing pituitary adenomas leading to bilateral adrenal hyperplasia (Cushing disease). The condition is very rare in pregnancy as most women with the disorder will have subfertility. The classical clinical features can be attributed to pregnancy and include weight gain, striae, hypertension, diabetes, hirsutism, headache and easy bruising. Effect of Cushing syndrome on pregnancy Maternal complications include hypertension in about 75% and gestational diabetes in about 50% of patients. Heart failure and severe pre-eclampsia are common. Buescher et al. reported a 5% maternal mortality rate among 65 pregnancies. Wound infection due to poor tissue healing is common. Perinatal morbidity, with 60% preterm delivery, and mortality (25%) are also high. Management Low adrenocorticotrophic hormone (ACTH) and high cortisol are suggestive of an adrenal cause. However, pregnancy-specific ranges for plasma and urinary cortisol must be used and the cortisol should be measured after a high-dose dexamethasone suppression test. Localisation is possible with adrenal ultrasound, CT or MRI, or pituitary CT or MRI. Long-term medical treatment is usually ineffective; however, ketoconazole blocking steroid production has been successful. Few cases during pregnancy have been successfully treated with oral ketoconazole, but there are concerns in a pregnancy with a male fetus due to blockage of testicular steroidogenesis. Surgery is the treatment of choice and it has been undertaken successfully during pregnancy.
391 tion is understandably slower in women who continue to breast-feed. This physiological change in the size of the pituitary gland does not result in visual field changes in women with a normal pituitary gland prior to the pregnancy. Prolactin levels increase by up to 10-fold during pregnancy and return to normal by 2 weeks after delivery, unless the woman breast-feeds. This increase is thought to be mediated via increases in the sex hormones and is related to the initiation and maintenance of lactation. Levels of leutinizing hormone (LH) and folliclestimulating hormone (FSH) are suppressed by the concentrations of oestrogen and progesterone. Basal growth hormone (GH), ant diuretic hormone (ADH) and pituitary adrenocorticotrophic hormone (ACTH) are unaltered in pregnancy.
Prolactinoma Prolactin-producing pituitary adenomas are the commonest pituitary adenomas encountered in pregnancy. They are classified according to size into microprolactimas (o10 mm in diameter) or macroprolactinomas (410 mm in diameter). Hyperprolactinaemia is associated with amenorrhoea, reduced fertility and hypo-estrogenaemia. Therefore the majority are diagnosed pre-conception and the pregnancy would have been the result of treatment with dopamine-receptor agonists. Management There are no known adverse effects to the fetus. The main risks are those posed by the potential expansion of the pituitary space-occupying lesion. This could potentially lead to visual field defects by impinging on the optic chiasm or to pituitary apoplexy with panhypopituitarism. Prolactin levels are of no value in the follow-up of these patients as they are elevated during pregnancy. Regular review with particular reference to symptoms and clinical examination is essential. This can be supported as appropriate by formal visual perimetry and magnetic resonance imaging of the pituitary fossa.
Pituitary gland
Microprolactinoma
Physiology
The risk of symptomatic expansion during pregnancy is minimal (1.6%). Most physicians discontinue dopamine agonists as soon as pregnancy is confirmed and rely on regular review of symptoms and clinical examination to decide on further investigations and treatment. Others continue dopamine agonists through pregnancy. There have
The volume of the anterior pituitary increases progressively during pregnancy by up to 35%. This is mainly due to an increase in the number and size of the lactotrophic cells. It returns to its prepregnancy size gradually after delivery. The reduc-
ARTICLE IN PRESS 392
H.A. Shehata, K. Ahmed
been no reports of adverse effects from these agents during pregnancy or breast-feeding.
stress. Hence, there is a need for vigorous regular follow-up of these patients throughout pregnancy.
Macroprolactinoma
Lymphocytic hypophysitis
The risk of symptomatic tumour expansion is 4.4% in treated patients compared to 15.5% in untreated patients. Treatment with dopamine agonists is continued throughout pregnancy by many endocrinologists. Regular follow-up is mandatory and there is a low threshold for performing pituitary imaging in the presence of headaches or symptoms suggestive of visual field defects or diabetes insipidus. Hypophysectomy is rarely necessary and is usually deferred to after delivery.
This is a condition unique to pregnancy, presenting either late in pregnancy or in the puerperium. It is characterised by autoimmune infiltration of the pituitary gland with consequent hypopituitarism and expansion of the pituitary gland. The features are those of an expanding pituitary tumour, with headaches, visual field defects, secondary hypothyroidism and secondary hypoadrenalism. Treatment is with the replacement of the deficient hormones.
Practice points
Prolactin producing pituitary adenomas are the commonest pituitary adenomas encountered in pregnancy They are classified according to size, into either microprolactimas (o10 mm in diameter) or macroprolactinomas (410 mm in diameter) Prolactin levels are of no value in the followup of these patients as they are elevated during pregnancy Regular follow-up with visual fields measurement is mandatory in macroprolactinoamas Low threshold for performing pituitary imaging in the presence of headaches or symptoms suggestive of visual field defects or diabetes insipidus Dopamine agonists are safe during pregnancy and breast-feeding
Hypopituitarism Hypopituitarism may precede pregnancy or present for the first time during pregnancy. The usual causes are pituitary or hypothalamic tumours, pituitary surgery or cranial radiotherapy. Causes more specific to pregnancy include lymphocytic hypophysitis and postpartum pituitary infarction (Sheehan’s syndrome). Management The vital hormone replacements are those of thyroxine and glucocorticoids. Requirements of the latter increase during periods of stress, and doses and route of administration may need to be changed based on the severity and nature of the
Sheehan’s syndrome This presents post-delivery following postpartum haemorrhage and hypotension. The enlarged pituitary of pregnancy is particularly vulnerable to hypotension with consequent pituitary infarction. Presenting features are due to deficiency of the relevant hormones. They include persistent amenorrhoea, failure of lactation, secondary hypothyroidism and secondary adrenocortical insufficiency. Treatment is with replacement of the deficient hormones.
Diabetes insipidus (DI) Central diabetes insipidus is caused by decreased production of vasopressin by the paraventricular nuclei of the hypothalamus. It complicates 1 in 15 000 deliveries. Clinical features include excessive thirst and polyuria. Pathogenesis DI can be due to: deficiency of ADH production (central); ADH resistance, commonly associated with chronic renal disease (nephrogenic); increased vasopressinase production by the placenta, or decreased breakdown by the liver, usually associated with pre-eclampsia or acute fatty liver (transient); or compulsive water drinking. Effect of DI on pregnancy No adverse effects are known. Effect of pregnancy on DI Established central DI worsens in pregnancy and sub-clinical central diabetes insipidus may be unmasked for the first time during pregnancy because of increased clearance of endogenous vasopressin by vasopressinase. It is estimated that
ARTICLE IN PRESS Other endocrine disorders in pregnancy during pregnancy 60% of established cases of central diabetes insipidus worsen, but 25% improve, and 15% remain the same. Management In pregnancy, central DI is best treated by 2–20 mg of desmopressin acetate (DDAVP) intranasally, twice daily. DDAVP is not degraded by vasopressinase. Transfer of DDAVP to breast milk is minimal, and breast-feeding is not contraindicated. Treatment of central maternal diabetes insipidus with DDAVP throughout pregnancy does not pose a risk to the infant. For nephrogenic DI, carbamazepine is safer than chlorpropamide, as the latter may cause fetal hypoglycaemia. Practice points
Established central DI worsens in pregnancy Transient DI is usually associated with preeclampsia or acute fatty liver DI is best treated by DDAVP
Acromegaly Acromegaly is a rare condition with an incidence of four new cases per million of population per year. It affects both sexes equally and peaks at the age of 40–60 years. It is characterised by excess growth hormone secretion. In over 99% of cases it is due to a benign pituitary adenoma. Rarely, it is due to excess growth hormone releasing hormone (GHRH) secretion from hypothalamic pituitary somatotroph hyperplasia, carcinoid tumour or a pancreatic neuro-endocrine tumour. Excess growth hormone can result in hypertension, left ventricular hypertrophy, diabetes mellitus and increased risk of colonic neoplasia. Life span is reduced mainly due to increased risk of cardiovascular disease. Effect of acromegaly on pregnancy Fertility is markedly reduced in acromegaly. This is due to hyperprolactinaemia that often prevails in acromegaly as well as disturbed gonadotrophin secretion. There is an increased risk of maternal diabetes mellitus and hypertension, with their usual associated risks to mother and fetus. Acromegaly is best treated with surgery, adjuvant radiotherapy and medical therapy if indicated prior to conception. Robust contraception is therefore strongly advised.
393 Maternal growth hormone does not cross the placenta and has no effect on fetal development and growth. Macrosomia is the result of maternal growth hormone induced diabetes mellitus. Effect of pregnancy on acromegaly There is an increased risk of enlargement of pituitary adenomas during pregnancy with the possibility of optic chiasm encroachment and visual field defects. Regular surveillance is therefore vital throughout the pregnancy. Macroadenomas (410 mm diameter) require monthly Goldman perimetric visual-field assessment and MRI confirmation in cases of suspected enlargement. This usually presents as headaches, visualfield defects, diabetes insipidus or rarely pituitary apoplexy. Growth hormone levels using conventional radioimmunoassays can be misleading, as they cannot differentiate between pituitary and placental growth hormone. The latter peaks during the later stages of pregnancy. Management Acromegaly is best treated prior to conception if possible. Surgical removal of the pituitary adenoma is the treatment of choice. Adjuvant radiotherapy is used if surgical cure is not complete. Long-acting somatostatin analogues by deep intra-muscular injection are the medical treatment of choice. They are used for symptom control prior to surgery and after surgery and radiotherapy, while awaiting the full effect of the latter. There are reports of safe and successful use during pregnancy but not enough data are available as yet. Therefore use is best avoided during pregnancy. Dopamine agonists (bromocriptine or cabergoline) are effective in reducing growth hormone in less than 50% of cases, especially when associated with high prolactin. They have no effect on tumour size and are therefore of limited value in pregnant women with acromegaly.
Further reading 1. Lazarus JH. Treatment of hyper- and hypothyroidism in pregnancy. J Endocrinol Invest 1993;16:391–6. 2. Lazarus J, Kokandi A. Thyroid disease in relation to pregnancy: a decade of change. Clin Endocrinol 2000;53(3): 265–80. 3. Nelson-Piercy C. A Handbook of obstetric medicine, 2nd ed. London: Martin Dunitz; 2002. 4. Burrow GN, Ferris TF. Medical complications during pregnancy, 4th ed. London: W. B. Saunders; 1995.
ARTICLE IN PRESS 394 5. Grossman A. Clinical Endocrinology, 2nd ed. Oxford: Blackwell Scientific Publications; 1997. 6. Herman-Bonest, Seliverstov M, Melmed S. Pregnancy in acromegaly, successful therapeutic outcome. J Clin Endocrinol Metab 1998;83:727–31.
H.A. Shehata, K. Ahmed 7. Landolt AM, Schmid J, Wimpfheimer C, Karlsson ERC, Boerlin V. Successful pregnancy in a previously infertile woman treated with SMS 201-995 for Acromegaly. N Engl J Med 1989;320:671.
www.elsevier.com/locate/curobgyn
Other endocrine disorders in pregnancy Hassan A. Shehataa,, Khalid Ahmedb a
Department of Obstetrics, Gynaecology and Maternal Medicine, Epsom and St. Helier University Hospitals, NHS Trust, Wrythe Lane, Carshalton, Surrey SM5 1AA, UK b West Middlesex Hospital, London, UK
KEYWORDS Pregnancy; Endocrine; Hypoparathyroidism; Hyperparathyroidism; Phaeochromocytoma; Cushing syndrome; Conn’s disease; Addison disease; Hyperprolactinoma; Diabetes insipidus; Acromegaly; Sheehan syndrome; Lymphocytic hypophysitis
Summary A variety of endocrine disorders can occur in pregnancy. The pathology of most of these disorders is due to autoimmune, tumour or iatrogenic causes. In this review we discuss in detail less common disorders than, for example, diabetes mellitus and thyroid disease. The review includes parathyroid, adrenal and pituitary gland disorders. r 2004 Elsevier Ltd. All rights reserved.
Parathyroid gland
of the rest, with parathyroid carcinoma accounting for 1–2% of cases.
Primary hyperparathyroidism Primary hyperparathyroidism is very rare in pregnancy. Less than 200 cases have been reported in the literature. The commonest cause in 90% of cases is a parathyroid adenoma. Hyperplasia of the four parathyroid glands accounts for the majority
Effect of hyperparathyroidism on pregnancy The majority of pregnant women with primary hyperparathyroidism are asymptomatic, and are detected on routine prenatal biochemical tests or postpartum, when the newborn develops symptomatic hypocalcaemia.
Corresponding author. Fax: +44-20-8648-2990.
E-mail address: [email protected] (H.A. Shehata). 0957-5847/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2004.07.003
ARTICLE IN PRESS 388 Nephrolithiasis is the most common symptomatic presentation of hyperparathyroidism during pregnancy, with an estimated incidence of 24–36%. Pancreatitis occurs in 7–13% of pregnant women with hyperparathyroidism. Hyperemesis gravidarum is also more frequent in pregnant patients with primary hyperparathyroidism. Fetal complications of maternal primary hyperparathyroidism in pregnancy have included intrauterine growth retardation, low birth weight, preterm delivery and neonatal hypocalcaemia. Even mild asymptomatic hypercalcaemia in the mother has been reported to cause neonatal parathyroid suppression and tetany. Awareness, vigilance and prompt calcium supplementation is vital to avoid this complication. Effect of pregnancy on hyperparathyroidism Pregnancy will theoretically improve hyperparathyroidism due to significant shunting of calcium to the fetus and improved renal excretion. However, postpartum severe exacerbation of hypercalcaemia and/or acute pancreatitis may occur. Untreated hyperparathyroidism may increase the risk of stillbirth, preterm deliveries and neonatal tetany. Management The diagnosis is confirmed by the presence of hypercalcaemia, hypophosphataemia with parathyroid hormone levels (PTH), which are inappropriate for the prevailing plasma calcium level, i.e. PTH could be elevated or unsuppressed within the normal range. The rare familial condition of hypocalcuric hypercalcaemia can be very difficult to differentiate from primary hyperparathyroidism. This is an autosomal dominant disorder due to heterozygous inactivation of the calcium sensing receptor gene. 24-h urinary calcium excretion can help in differentiating the two conditions. This is important as parathyroidectomy in familial hypocalcuric hypercalcaemia is not curative and is followed by a recurrence of the hypercalcaemia post-operatively. Rehydration is vital as significant dehydration accompanies hypercalcaemia. Parathyroidectomy in the second trimester is the treatment of choice for symptomatic patients with significantly elevated serum calcium. Regular follow-up would suffice in mild uncomplicated cases. Bisphosphonates and loop diuretics, used outside pregnancy, cross the placenta freely and are best avoided during pregnancy. Imaging to localise a parathyroid adenoma is not usually indicated in the presence of an experienced parathyroid surgeon.
H.A. Shehata, K. Ahmed
Practice points
Nephrolithiasis is the most common symptomatic presentation with an estimated incidence of 24–36% Pancreatitis occurs in 7–13% of pregnant women with hyperparathyroidism Fetal complications included intrauterine growth retardation, low birth weight, preterm delivery and neonatal hypocalcaemia Untreated hyperparathyroidism may increase the risk of stillbirth, preterm deliveries and neonatal tetany Rehydration is a vital part of management as significant dehydration accompanies hypercalcaemia
Primary hypoparathyroidism The commonest cause is parathyroid surgery or the inadvertent removal of parathyroid tissue during thyroidectomy. Rarely, it is due to autoimmune destruction of parathyroid tissue. Effect of hypoparathyroidism on pregnancy Untreated hypoparathyroidism with chronic hypocalcaemia may lead to fetal skeletal demineralisation. The fetal risks of large doses of vitamin D have not been established. Effect of pregnancy on hypoparathyroidism There is an increased tendency to develop hypocalcaemic tetany during pregnancy and labour due to hyperventilation. Calcium for intravenous administration should be at hand, especially during labour. Management Treatment is with 1,25-dihydroxycholecalciferol (calcitriol) or 1,alpha-hydroxycholecalciferol (alphacalcidol) and calcium supplements. Requirements can change steadily throughout gestation requiring regular follow-up and adjustment of replacement doses at a minimum of monthly intervals. Practice points
The commonest cause is parathyroid surgery or the inadvertent removal of parathyroid tissue during thyroidectomy Untreated hypoparathyroidism with chronic hypocalcaemia may lead to fetal skeletal demineralisation
ARTICLE IN PRESS Other endocrine disorders in pregnancy
There is an increased tendency to develop hypocalcaemic tetany during pregnancy and labour due to hyperventilation Calcium for intravenous administration should be available during labour
Adrenal gland Primary adrenocortical failure (Addison’s disease) This is rarely encountered in pregnancy. Most cases are due to autoimmune destruction or tuberculosis. The vast majority of cases are diagnosed before conception and are well established on replacement therapy. This is usually in the form of hydrocortisone (a total of 30 mg daily in divided doses) and fludrocortisone (up to 100 mg daily). The patients feeling of wellbeing and the lack of postural hypotension, hyponatraemia or hyperkalaemia gauge the adequacy of replacements. Clinical features include weight loss, vomiting, postural hypotension, lethargy and hyperpigmentation. Effect of Addison’s disease on pregnancy If treated, no complications are encountered. Effect of pregnancy on Addison’s disease Pregnancy has no effect on the disease if properly treated. Steroid replacement may need to be altered at certain times during pregnancy. Management The maintenance doses are not changed by pregnancy per se. However, an increase in dosage is vital during periods of stress such as hyperemesis gravidarum, procedures and infections, or during labour. Hydrocortisone is administered intravenously in doses of 100 mg every 6 h throughout the period of stress and reduced gradually over a period of days.
Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a family of inherited disorders of adrenal steroidogenesis, resulting from a deficiency of one of several enzymes necessary for normal adrenal steroid synthesis. It occurs in 1 in 5000 and 1 in 15 000 births in most populations. 21 hydroxylase deficiency (21-
389 OHD) is the commonest deficiency with a particularly high frequency and carrier rates of between 1.2% and 6% of the population. The gene frequency is 1 in 200–400 and is autosomal recessive. The risk of a subsequent child having the disorder is 1:4, if a couple have one affected child. 21-OHD deficiency leads to impaired production of glucocorticoids and mineralocorticoids. The sex steroid pathway is intact and thus provides the only option for the accumulating metabolites. The consequence is a markedly enhanced adrenal androgen production. Affected female fetuses are at risk of masculinisation. Male neonates are at risk of salt losing crises due to mineralocorticoid deficiency as well as precocious puberty. Effect of CAH on pregnancy There is an increased risk of miscarriage, Caesarean section, pre-eclampsia and intrauterine growth restriction. Effect of pregnancy on CAH No effect in treated patients. Management The aim of treatment is to ensure adequate glucocorticoid and mineralocorticoid replacement for the mother, as well as preventing virilisation of an affected female fetus. In women with CAH, increased antenatal surveillance should be put in place because of the increased risk of pre-eclampsia. Corticosteroid replacement is the mainstay of treatment. Mineralocorticoids are necessary in salt losing classical CAH. Monitoring with 17-hydroxyprogesterone levels is unreliable in pregnancy. In pregnancies with a fetus at risk of CAH, suppressing adrenocorticotrophic hormone (ACTH), the drive for the intact sex steroid production pathway, by giving dexamethasone in a dose of 250–500 mg daily is commonly used and continued throughout pregnancy. Fetal diagnosis should be made with sex determination, human leukocyte antigen (HLA) status and 21-hydroxylase zygoisty. Treatment should be started pre-conception or before 5 weeks gestation, prior to differentiation of the genitalia. All female neonates should receive corticosteroids to treat the CAH and because their adrenal glands will be suppressed following longterm high-dose maternal dexamethasone therapy. Male fetuses do not need to be treated in utero. Prevention of virilisation is not always successful, therefore parents should be counselled regarding benefits and risks, and termination of the pregnancy should be offered if the fetus is female.
ARTICLE IN PRESS 390
H.A. Shehata, K. Ahmed
Practice points
21 hydroxylase deficiency (21-OHD) is the commonest deficiency The risk of a subsequent child having the disorder is 1:4, if a couple have one affected child Affected female fetuses are at risk of masculinisation Male neonates are at risk of salt losing crises due to mineralocorticoid deficiency as well as precocious puberty Treatment should be started pre-conception or before 5 weeks gestation, prior to differentiation of the genitalia All female neonates should receive corticosteroids to treat the CAH and because their adrenal glands will be suppressed following long-term high-dose maternal dexamethasone therapy Male fetuses do not need to be treated in utero Prevention of virilisation is not always successful, therefore parents should be counselled regarding benefits and risks, and termination of the pregnancy should be offered if the fetus is a female
The gravid uterus may cause hypertensive attacks due to pressure on the tumour in the supine position. Management Management of hypertension and symptoms with an alpha-blocking agent such as phenoxybenzamine is mandatory. The dose is 10–30 mg, two to four times daily. Beta-blocking agents to control tachycardia can be added if required. Surgical removal is the only cure after control of the blood pressure is achieved by medication. If the patient is prior to 23 weeks gestation, then surgical resection is recommended. After 24 weeks, it is recommended that the surgery is postponed until fetal maturity is achieved and then performed either concurrently with Caesarean section or postpartum. Adequate alpha-blockade for at least 3 days prior to surgery and expert anaesthetic care are essential. Practice points
Phaeochromocytoma These are chromaffin tumours that secret catecholamines. This 10% tumour (10% bilateral, 10% extraadrenal, 10% malignant) is mostly located in the adrenal medulla. It is important to make the diagnosis as, if undiagnosed, it is associated with high maternal and fetal mortality. Clinical features include sustained or labile hypertension, palpitations, anxiety, sweating, headache, vomiting and glucose intolerance. Effect of phaeochromocytoma on pregnancy These tumours are rare but dangerous if they occur in pregnancy. Maternal mortality is about 18% in undiagnosed cases and fetal mortality is about 25% in undiagnosed cases and 15% in diagnosed cases. Maternal mortality most recently had decreased to about 5% in undiagnosed cases, with no maternal death when the diagnosis is made antepartum. The main causes of maternal mortality are cardiac arrythmias, cerebrovascular accidents or pulmonary oedema. Effect of pregnancy on phaeochromocytoma Moribund hypertensive crisis may be precipitated by labour, delivery, general anaesthesia or opiates.
It is important to make the diagnosis as, if undiagnosed, it is associated with high maternal and fetal mortality Clinical features include sustained or labile hypertension, palpitations, anxiety, sweating, headache, vomiting and glucose intolerance Moribund hypertensive crisis may be precipitated by labour, delivery, general anaesthesia or opiates Adequate alpha-blockade for at least 3 days prior to surgery and expert anaesthetic care are essential
Conn’s syndrome Hyperaldosteronism is caused by adrenal aldesteronomas in about 75% of cases and idiopathic bilateral adrenal hyperplasia in the remainder. Clinical features include hypertension and hypokalaemia. Management Diagnosis is by low serum potassium, suppressed renin activity and high plasma aldosterone. Management of hypertension is vital and is in the usual way. Potassium supplementation is also impotant. Spirinolactone, commonly used outside pregnancy, should be avoided in pregnancies with a male fetus because of its anti-androgen effects. Tumour resection is curative and laparoscopic adrenalectomy may prove to be useful during pregnancy.
ARTICLE IN PRESS Other endocrine disorders in pregnancy
Cushing syndrome Long-term exposure to glucocorticoids may lead to Cushing syndrome. The most common cause is iatrogenic, from corticosteroid therapy. Increased adrenal cortisol production causes endogenous Cushing syndrome. Most cases are due to corticotrophin-producing pituitary adenomas leading to bilateral adrenal hyperplasia (Cushing disease). The condition is very rare in pregnancy as most women with the disorder will have subfertility. The classical clinical features can be attributed to pregnancy and include weight gain, striae, hypertension, diabetes, hirsutism, headache and easy bruising. Effect of Cushing syndrome on pregnancy Maternal complications include hypertension in about 75% and gestational diabetes in about 50% of patients. Heart failure and severe pre-eclampsia are common. Buescher et al. reported a 5% maternal mortality rate among 65 pregnancies. Wound infection due to poor tissue healing is common. Perinatal morbidity, with 60% preterm delivery, and mortality (25%) are also high. Management Low adrenocorticotrophic hormone (ACTH) and high cortisol are suggestive of an adrenal cause. However, pregnancy-specific ranges for plasma and urinary cortisol must be used and the cortisol should be measured after a high-dose dexamethasone suppression test. Localisation is possible with adrenal ultrasound, CT or MRI, or pituitary CT or MRI. Long-term medical treatment is usually ineffective; however, ketoconazole blocking steroid production has been successful. Few cases during pregnancy have been successfully treated with oral ketoconazole, but there are concerns in a pregnancy with a male fetus due to blockage of testicular steroidogenesis. Surgery is the treatment of choice and it has been undertaken successfully during pregnancy.
391 tion is understandably slower in women who continue to breast-feed. This physiological change in the size of the pituitary gland does not result in visual field changes in women with a normal pituitary gland prior to the pregnancy. Prolactin levels increase by up to 10-fold during pregnancy and return to normal by 2 weeks after delivery, unless the woman breast-feeds. This increase is thought to be mediated via increases in the sex hormones and is related to the initiation and maintenance of lactation. Levels of leutinizing hormone (LH) and folliclestimulating hormone (FSH) are suppressed by the concentrations of oestrogen and progesterone. Basal growth hormone (GH), ant diuretic hormone (ADH) and pituitary adrenocorticotrophic hormone (ACTH) are unaltered in pregnancy.
Prolactinoma Prolactin-producing pituitary adenomas are the commonest pituitary adenomas encountered in pregnancy. They are classified according to size into microprolactimas (o10 mm in diameter) or macroprolactinomas (410 mm in diameter). Hyperprolactinaemia is associated with amenorrhoea, reduced fertility and hypo-estrogenaemia. Therefore the majority are diagnosed pre-conception and the pregnancy would have been the result of treatment with dopamine-receptor agonists. Management There are no known adverse effects to the fetus. The main risks are those posed by the potential expansion of the pituitary space-occupying lesion. This could potentially lead to visual field defects by impinging on the optic chiasm or to pituitary apoplexy with panhypopituitarism. Prolactin levels are of no value in the follow-up of these patients as they are elevated during pregnancy. Regular review with particular reference to symptoms and clinical examination is essential. This can be supported as appropriate by formal visual perimetry and magnetic resonance imaging of the pituitary fossa.
Pituitary gland
Microprolactinoma
Physiology
The risk of symptomatic expansion during pregnancy is minimal (1.6%). Most physicians discontinue dopamine agonists as soon as pregnancy is confirmed and rely on regular review of symptoms and clinical examination to decide on further investigations and treatment. Others continue dopamine agonists through pregnancy. There have
The volume of the anterior pituitary increases progressively during pregnancy by up to 35%. This is mainly due to an increase in the number and size of the lactotrophic cells. It returns to its prepregnancy size gradually after delivery. The reduc-
ARTICLE IN PRESS 392
H.A. Shehata, K. Ahmed
been no reports of adverse effects from these agents during pregnancy or breast-feeding.
stress. Hence, there is a need for vigorous regular follow-up of these patients throughout pregnancy.
Macroprolactinoma
Lymphocytic hypophysitis
The risk of symptomatic tumour expansion is 4.4% in treated patients compared to 15.5% in untreated patients. Treatment with dopamine agonists is continued throughout pregnancy by many endocrinologists. Regular follow-up is mandatory and there is a low threshold for performing pituitary imaging in the presence of headaches or symptoms suggestive of visual field defects or diabetes insipidus. Hypophysectomy is rarely necessary and is usually deferred to after delivery.
This is a condition unique to pregnancy, presenting either late in pregnancy or in the puerperium. It is characterised by autoimmune infiltration of the pituitary gland with consequent hypopituitarism and expansion of the pituitary gland. The features are those of an expanding pituitary tumour, with headaches, visual field defects, secondary hypothyroidism and secondary hypoadrenalism. Treatment is with the replacement of the deficient hormones.
Practice points
Prolactin producing pituitary adenomas are the commonest pituitary adenomas encountered in pregnancy They are classified according to size, into either microprolactimas (o10 mm in diameter) or macroprolactinomas (410 mm in diameter) Prolactin levels are of no value in the followup of these patients as they are elevated during pregnancy Regular follow-up with visual fields measurement is mandatory in macroprolactinoamas Low threshold for performing pituitary imaging in the presence of headaches or symptoms suggestive of visual field defects or diabetes insipidus Dopamine agonists are safe during pregnancy and breast-feeding
Hypopituitarism Hypopituitarism may precede pregnancy or present for the first time during pregnancy. The usual causes are pituitary or hypothalamic tumours, pituitary surgery or cranial radiotherapy. Causes more specific to pregnancy include lymphocytic hypophysitis and postpartum pituitary infarction (Sheehan’s syndrome). Management The vital hormone replacements are those of thyroxine and glucocorticoids. Requirements of the latter increase during periods of stress, and doses and route of administration may need to be changed based on the severity and nature of the
Sheehan’s syndrome This presents post-delivery following postpartum haemorrhage and hypotension. The enlarged pituitary of pregnancy is particularly vulnerable to hypotension with consequent pituitary infarction. Presenting features are due to deficiency of the relevant hormones. They include persistent amenorrhoea, failure of lactation, secondary hypothyroidism and secondary adrenocortical insufficiency. Treatment is with replacement of the deficient hormones.
Diabetes insipidus (DI) Central diabetes insipidus is caused by decreased production of vasopressin by the paraventricular nuclei of the hypothalamus. It complicates 1 in 15 000 deliveries. Clinical features include excessive thirst and polyuria. Pathogenesis DI can be due to: deficiency of ADH production (central); ADH resistance, commonly associated with chronic renal disease (nephrogenic); increased vasopressinase production by the placenta, or decreased breakdown by the liver, usually associated with pre-eclampsia or acute fatty liver (transient); or compulsive water drinking. Effect of DI on pregnancy No adverse effects are known. Effect of pregnancy on DI Established central DI worsens in pregnancy and sub-clinical central diabetes insipidus may be unmasked for the first time during pregnancy because of increased clearance of endogenous vasopressin by vasopressinase. It is estimated that
ARTICLE IN PRESS Other endocrine disorders in pregnancy during pregnancy 60% of established cases of central diabetes insipidus worsen, but 25% improve, and 15% remain the same. Management In pregnancy, central DI is best treated by 2–20 mg of desmopressin acetate (DDAVP) intranasally, twice daily. DDAVP is not degraded by vasopressinase. Transfer of DDAVP to breast milk is minimal, and breast-feeding is not contraindicated. Treatment of central maternal diabetes insipidus with DDAVP throughout pregnancy does not pose a risk to the infant. For nephrogenic DI, carbamazepine is safer than chlorpropamide, as the latter may cause fetal hypoglycaemia. Practice points
Established central DI worsens in pregnancy Transient DI is usually associated with preeclampsia or acute fatty liver DI is best treated by DDAVP
Acromegaly Acromegaly is a rare condition with an incidence of four new cases per million of population per year. It affects both sexes equally and peaks at the age of 40–60 years. It is characterised by excess growth hormone secretion. In over 99% of cases it is due to a benign pituitary adenoma. Rarely, it is due to excess growth hormone releasing hormone (GHRH) secretion from hypothalamic pituitary somatotroph hyperplasia, carcinoid tumour or a pancreatic neuro-endocrine tumour. Excess growth hormone can result in hypertension, left ventricular hypertrophy, diabetes mellitus and increased risk of colonic neoplasia. Life span is reduced mainly due to increased risk of cardiovascular disease. Effect of acromegaly on pregnancy Fertility is markedly reduced in acromegaly. This is due to hyperprolactinaemia that often prevails in acromegaly as well as disturbed gonadotrophin secretion. There is an increased risk of maternal diabetes mellitus and hypertension, with their usual associated risks to mother and fetus. Acromegaly is best treated with surgery, adjuvant radiotherapy and medical therapy if indicated prior to conception. Robust contraception is therefore strongly advised.
393 Maternal growth hormone does not cross the placenta and has no effect on fetal development and growth. Macrosomia is the result of maternal growth hormone induced diabetes mellitus. Effect of pregnancy on acromegaly There is an increased risk of enlargement of pituitary adenomas during pregnancy with the possibility of optic chiasm encroachment and visual field defects. Regular surveillance is therefore vital throughout the pregnancy. Macroadenomas (410 mm diameter) require monthly Goldman perimetric visual-field assessment and MRI confirmation in cases of suspected enlargement. This usually presents as headaches, visualfield defects, diabetes insipidus or rarely pituitary apoplexy. Growth hormone levels using conventional radioimmunoassays can be misleading, as they cannot differentiate between pituitary and placental growth hormone. The latter peaks during the later stages of pregnancy. Management Acromegaly is best treated prior to conception if possible. Surgical removal of the pituitary adenoma is the treatment of choice. Adjuvant radiotherapy is used if surgical cure is not complete. Long-acting somatostatin analogues by deep intra-muscular injection are the medical treatment of choice. They are used for symptom control prior to surgery and after surgery and radiotherapy, while awaiting the full effect of the latter. There are reports of safe and successful use during pregnancy but not enough data are available as yet. Therefore use is best avoided during pregnancy. Dopamine agonists (bromocriptine or cabergoline) are effective in reducing growth hormone in less than 50% of cases, especially when associated with high prolactin. They have no effect on tumour size and are therefore of limited value in pregnant women with acromegaly.
Further reading 1. Lazarus JH. Treatment of hyper- and hypothyroidism in pregnancy. J Endocrinol Invest 1993;16:391–6. 2. Lazarus J, Kokandi A. Thyroid disease in relation to pregnancy: a decade of change. Clin Endocrinol 2000;53(3): 265–80. 3. Nelson-Piercy C. A Handbook of obstetric medicine, 2nd ed. London: Martin Dunitz; 2002. 4. Burrow GN, Ferris TF. Medical complications during pregnancy, 4th ed. London: W. B. Saunders; 1995.
ARTICLE IN PRESS 394 5. Grossman A. Clinical Endocrinology, 2nd ed. Oxford: Blackwell Scientific Publications; 1997. 6. Herman-Bonest, Seliverstov M, Melmed S. Pregnancy in acromegaly, successful therapeutic outcome. J Clin Endocrinol Metab 1998;83:727–31.
H.A. Shehata, K. Ahmed 7. Landolt AM, Schmid J, Wimpfheimer C, Karlsson ERC, Boerlin V. Successful pregnancy in a previously infertile woman treated with SMS 201-995 for Acromegaly. N Engl J Med 1989;320:671.