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Thyroid and other endocrine disorders in pregnancy
Review
Thyroid and other endocrine disorders in pregnancy
fetal brain development prior to the onset of fetal thyroid activity, which occurs late in the first trimester. Changes in placental iodinase enzymes at the end of the first trimester prevent the transfer of maternal T4 to the fetal circulation beyond this gestation: 0.008% of maternal T4 passes across at term. This applies to both endogenous T4 and pharmaceutical T4, and should be remembered when considering the management of pregnant women with hypothyroidism. In pregnancies where the fetus is athyrotic (i.e. is unable to produce thyroid hormones due to, for example, enzyme deficiency, failure of gland formation or profound iodine deficiency), alteration in placental iodinase enzymes – believed to be driven by changes on the fetal side of the circulation – allow transfer of T4 from the mother to the fetus to achieve levels one third of those expected. In the first trimester, human chorionic gonadotrophin (hCG) may influence thyroid function because the alpha subunits of hCG and TSH are identical, and therefore HCG has some thyrotropin-like effect. Beta subunits of TSH show considerable heterogeneity and in some pregnancies have greater TSH-like effect than others; this is particularly evident in multiple pregnancies, where the titre may be higher, and in hyperemesis gravidarum, and may result in a biochemical picture of thyrotoxicosis, with raised T4 and suppressed TSH: this is self-limiting and does not need treatment with antithyroid medication. True thyrotoxicosis, rarely, may present de novo in the firstt trimester and a careful history, including the time course of any symptoms and followup to ensure return to biochemical euthyroidism in the second trimester, is required.
Joanna Girling Christina Cotzias
Abstract Thyroid disorders are common endocrine problems encountered in pregnancy. To optimize pregnancy outcomes it is essential to understand the effects and treatments of both hyper- and hypo-thyroidism. Pituitary disease is not uncommon in pregnancy. Other endocrine pathologies are much rarer in pregnancy, often because of high levels of subfertility; they are often associated with significant maternal or fetal morbidity and even mortality if not recognized or treated adequately. This review summarizes the important consequences of thyroid and other endocrine diseases in pregnancy.
Keywords Addison’s disease; congenital adrenal hyperplasia; conn s yndrome; cushing syndrome; diabetes insipidus; hypopituitarism; phaeochromocytoma; pituitary adenomas; thyroid disease
Thyroid disorders in pregnancy
Hypothyroidism Around 1% of pregnant women have hypothyroidism, so this condition will be seen frequently in most units. A few women – those who have had surgery for thyroid cancer – will be on suppressive doses of thyroxine to render the TSH undetectable and so reduce the risk of recurrence. The majority of women with hypothyroidism will be on life-long thyroxine replacement therapy, usually because of: autoimmune hypothyroidism – Hashimoto disease, the consequences of thyroid surgery for benign nodules or goitre, or following treatment for autoimmune hyperthyroidism – Graves disease (both surgical and radioactive iodine treatment frequently result in hypothyroidism), with the aim being to maintain biochemical and clinical euthyroidism. These women usually have an annual thyroid function measurement and review of their thyroxine requirements. There is an unresolved debate in non-pregnant women regarding the best target for thyroid function tests (TFTs) (i.e. normal range TSH or low TSH) and whether dose changes should be based on TSH or fT4 concentrations, or both. In pregnancy these issues are no clearer. Although it has been suggested that women with treated hypothyroidism are more likely to have miscarriage, pre-eclampsia, prematurity and other adverse outcomes, there are no data to support this and these women do not need increased antenatal surveillance in respect of these complications. There are some data suggesting that the neonatal outcome of women who have under-treated hypothyroidism or untreated subclinical (i.e. asymptomatic) hypothyroidism in pregnancy may be less good than those women without hypothyroidism: one study suggested a maximum IQ deficit of 7 points compared with that in a control
Thyroid problems are common in pregnant women and have, together with their treatments, the potential to influence maternal well-being and the outcome of the pregnancy. It is therefore important that they are well understood. Thyroid physiology in pregnancy The half-life of thyroxine binding globulin [TBG; the main binding protein for thyroxine (T4) and tri iodothyronine (T3)] is prolonged by oestrogen-driven sialylation, which results in an increased circulating concentration of both TBG and therefore of total T4 and T3. It is for this reason that these hormones are not measured in pregnancy. Instead, freeT4 and freeT3, the biologically active hormones, are measured: these are not greatly changed in normal pregnancy, although the lower limit of normal is reduced slightly in the third trimester. Normal values for thyroid stimulating hormone (TSH) rise slightly in the third trimester, but otherwise are unchanged compared with nonpregnant ranges. TSH and T3 do not cross the placenta. In the first trimester, T4 does cross the placenta and is believed to play a role in
Joanna Girling MA MRCP FRCOG is a Consultant Obstetrician and Gynaecologist at West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, UK. Q1
Christina Cotzias BSc MRCOG is a Consultant Obstetrician and Gynaecologist at West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, UK.
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group. Unfortunately, neurological and psychomotor development in children has so many diverse influences that it is not easy to distinguish the role of the in utero thyroid environment and ex utero factors, including of course the possibility that a woman with untreated hypothyroidism may be subtly less able to carry out the role of motherhood. For example, multiple logistic regression analyses point to smoking, alcohol intake and maternal depression as being factors influencing the child’s development, as well as the mother’s thyroid status. Nonetheless, it seems logical, even if the evidence base regarding outcome is weak, to aim for the pregnant woman to be euthyroid, both for her sense of well-being and to ensure optimal transfer of T4 to the fetus in the first trimester. However, it is important to remember that after this period it is unlikely that adjustments to the maternal dose will have any influence on the fetal thyroid status or development. Blanket increase in thyroxine dose is not advised, not least because there is evidence from both thyrotoxic and thyroid hormone resistant pregnancy that excess thyroxine is associated with increased miscarriage and low birth weight. There is some debate about whether pregnant women with hypothyroidism should increase their dose of thyroxine with some recommending that they all should, and others advising that changes are made only on the basis of thyroid function tests. It is important when considering this to bear in mind the possible aims of dose changes, which might be to achieve biochemical euthyroidism, to improve maternal well-being or to influence the fetal environment. From the previous discussion it should be clear that the latter is unlikely to be possible after the first trimester. Those women with hypothyroidism who conceive when their thyroid function is well-controlled and their thyroxine dose is stable are relatively unlikely to need to increase their dose of thyroxine while they are pregnant. If they do, it is generally because of reduced absorption in the first trimester due to vomiting; reduced compliance due to unfounded concerns about teratogenicity; introduction of iron or calcium supplements (both of which reduce absorption and so should be taken separately from thyroxine); or, in the first trimester, transfer of small amounts of thyroxine to the fetus. In iodine replete areas, such as the UK, increased renal iodine loss does not influence maternal thyroid function. However, the natural fluctuations in a long term condition may necessitate a dose change, and women who conceive when their hypothyroidism is not well-controlled may need to increase thyroxine dose to ‘catch up’. Pragmatically, women should check their thyroid function prior to conception, and make any required thyroxine dose adjustments before they are pregnant. Further tests can be done early in pregnancy and again in the last trimester in women whose results are normal and whose condition is stable. Other women may need more frequent tests, but beyond the first trimester these would not be anticipated directly to influence the fetus. A common difficulty in interpretation of TFTs in hypothyroid pregnant women occurs when the TSH is high and the fT4 normal: this may reflect recently improved or fluctuating compliance, as TSH returns to normal more slowly than fT4 – the patient should be questioned regarding how long she has been taking the tablets regularly. Thyroxine is safe to take during lactation. Babies born to women with primary autoimmune hypothyroidism are not at
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increased risk of neonatal hypo- or hyper-thyroidism, but do have a small lifetime increased risk of hypothyroidism in adult life. Babies whose mothers are hypothyroid following treatment of hyperthyroidism do have an increased risk of both fetal and neonatal hyperthyroidism, as discussed below. Hyperthyroidism Hyperthyroidism affects around 2 in 1000 pregnancies. The majority is due to Graves disease, an autoimmune disorder in which clinical disease activity reflects the titre of TSH receptor stimulating antibodies. Pregnancy does not affect the long term course of hyperthyroidism. In the first trimester there may be deterioration in control, due to reduced absorption of medication secondary to vomiting or to hCG-driven stimulation of TSH receptors (see above). In the second and third trimesters, typically, treatment doses can be reduced as the immune effects of pregnancy result in an increase in TSH receptor inhibitory antibodies and a fall in the stimulatory ones: one third of women will be able temporarily to discontinue treatment at this time. The majority need to return to their prepregnant doses in the puerperium to prevent a disease flare. The drugs usually used in the treatment of hyperthyroidism, propylthiouracil (PTU) and carbimazole, are safe in pregnancy and should not be stopped because of concerns about teratogenicity. Indeed, a number of studies have shown that neonatal outcome is better, with fewer anomalies and lower chance of delivering prematurely, if euthyroidism is achieved prior to conception, when compared with those women in whom either control is achieved in early pregnancy or later pregnancy, in a stepwise manner. Older studies have linked carbimazole with aplasia cutis – a very rare condition resulting in deficits in the scalp and hair growth, but larger more recent studies show that either this link is spurious or at worst that the risk of the fetus developing this condition is extremely small. Both agents cross the placenta in similar amounts and, rarely, can cause fetal hypothyroidism: this risk can be minimized by ensuring that the patient takes the lowest doses of treatment to keep her clinically euthyroid and biochemically at the upper limit of the normal range. Fetal hypothyroidism rarely manifests clinically, in part because of the opposing stimulatory effect of transplacental TSH receptor antibodies. Fetal and neonatal hyperthyroidism are also rare, but should be looked for in women at risk, chiefly those with active Graves disease or previous Graves’ disease treated by surgery or radioactive iodine and in whom TSH receptor stimulating antibodies are present. This test should be requested early in the pregnancy of women who fall in these categories. The fetal thyroid can be stimulated by these antibodies beyond 24 weeks’ gestation and so women should be aware of the symptoms of fetal thyrotoxicosis (such as excessive fetal movements), have the fetal heart rate auscultated regularly to check for fetal tachycardia, and be serially scanned to exclude growth restriction or fetal goitre. If fetal thyrotoxicosis is suspected, delivery should be considered if the gestation is close to term. If not, the diagnosis should be confirmed by fetal blood sampling and then doses of maternal antithyroid medication should be increased, if necessary with the addition of thyroxine, which does not cross the placenta, to prevent hypothyroidism in the mother. Neonatal thyrotoxicosis typically presents after the first week of life, when the ‘protective’ effects of maternally derived antithyroid medication are no 350
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longer present, but the stimulatory effect of the TSH receptor antibodies, which have a longer half-life, persists. Paediatricians should be informed of these patients so that they can arrange local follow-up as indicated, and parents should be warned to report increased agitation or restlessness in their babies. Both PTU and carbimazole can be taken during lactation. However, PTU may be preferable, especially if high doses are required, as less of it crosses into breast milk. For this reason it is often the antithyroid agent of choice for women who need to start treatment in pregnancy. Pragmatically, in the management of hyperthyroidism in pregnancy, TFTs should be measured 4−6 weekly and more frequently if control is poor, and the dose of antithyroid medication titrated against maternal well-being and biochemical results. Serial clinical assessment must include weight, pulse, tremor and examination of the eyes and neck. Beta blockade should be used in the usual way to control anxiety or tachycardia, propranolol being the drug of choice as it is effective and is not associated with intrauterine growth restriction or other adverse outcomes.
is confirmed the treatment is usually stopped in women with microprolactinomas. In normal pregnancy the anterior pituitary expands. The clinical concern is that the prolactinoma will also expand and cause the pressure effects described above. Symptomatic microprolactinoma expansion occurs in only about 1.5% of cases, although 5% demonstrate asymptomatic expansion if regular CT or MRI scans are performed. The risk of symptomatic expansion is greater for macroprolactinomas, with up to 15% enlarging during pregnancy: this is why experts may continue dopamine agonist therapy through pregnancy in these women. All women with a prolactinoma who become pregnant should be warned of the potential risk of tumour expansion and the risk should be correlated with the size of the tumour. As prolactin production rises during pregnancy, its serum measurement is not useful to assess tumour expansion. All women with prolactinomas should be closely monitored, specifically questioning them about headache and assessing visual fields, which should be done formally every month in women with macroprolactinoma: the commonest abnormality is bitemporal hemianopia. Any suspicion of expansion should be further investigated with an MRI of the pituitary. If expansion is confirmed, dopamine agonist treatment should be restarted or the dose increased. There is good experience of bromocriptine use in pregnancy, and no evidence of congenital abnormalities or longer term intellectual development in children born to mothers who have taken the drug during pregnancy; the data for cabergoline use are less extensive but similarly reassuring. Labour and delivery are not affected by the presence of a prolactinoma. Women can breast feed without extra risk of tumour expansion, although use of a dopamine agonist may suppress lactation.
Pituitary disease The anterior lobe of the pituitary gland produces and secretes prolactin, growth hormone, adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), luteinizing (LH) and follicle stimulating hormone (FSH). The posterior pituitary secretes oxytocin and vasopressin (which have been produced in the anterior hypothalamus). Benign pituitary adenomas are the commonest cause of pituitary disease in the general population and in pregnancy. Pituitary adenomas cause problems by: • secreting excess hormone; or • when large, local pressure effects damage visual pathways and cause visual field defects, or pushing on the bony structures and meninges around the pituitary fossa causes headache; or • damaging surrounding pituitary tissue causing hypopituitarism.
Hypopituitarism Hypopituitarism can be caused by pituitary tumours compressing functional pituitary tissue, pituitary surgery, radiotherapy, Sheehan syndrome (infarction of the anterior pituitary during acute hypotension, classically at postpartum haemorrhage) or lymphocytic hypophysitis (a chronic inflammatory cell infiltrate of the anterior pituitary causing oedema, expansion and fibrosis without an adenoma, often occurring in the late third trimester or post partum). Presentation of hypopituitarism is with lethargy, hypothyroidism, failure to lactate, amenorrhoea and adrenocortical insufficiency. As well as visual field assessment and pituitary MRI to exclude a tumour, women need hormone replacement therapy (hydrocortisone, thyroxine and oestrogen) to maintain normal metabolism and response to stress. Women will need ovulation induction to conceive in the future, and glucocorticoid and thyroxine replacement must continue throughout pregnancy, with extra hydrocortisone to cover the stress of labour or intercurrent illnesses. Mineralocorticoid replacement is often not needed as aldosterone production is not solely ACTH dependent. Untreated, those women who manage to conceive have a very poor pregnancy prognosis, with high rates of miscarriage, stillbirths and maternal death, all of which can be normalized with adequate therapy.
Prolactinomas Prolactin is the commonest hormone secreted by pituitary adenomas, although there are many other causes of hyperprolactinaemia, including hypothyroidism, polycystic ovarian syndrome, dopamine-antagonist drugs such as chlorpromazine (prolactin secretion from the pituitary is inhibited by dopamine released from neurones in the hypothalamus), lactation and pregnancy – which causes prolactin levels to rise by up to 10 times normal levels. Having excluded physiological and drug-related hyperprolactinaemia, suspicion of a pituitary adenoma should be investigated with visual field assessment and MRI of the pituitary. A pituitary mass measuring >10 mm and secreting prolactin is defined as a macroprolactinoma, although the majority will be microprolactinomas (i.e. <10 mm). Hyperprolactinaemia stimulates milk production and inhibits gonadotrophin releasing hormone (GnRH) production and, outside pregnancy, causes a/oligomenorrhoea, galactorrhoea and subfertility, as well as the above mentioned pressure effects due to a macroprolactinoma. Hyperprolactinaemia is controlled with dopamine agonists – bromocriptine being the longest-established therapy, although cabergoline is increasingly being used. Dopamine agonists are often necessary for women to conceive, although once pregnancy
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Diabetes insipidus Diabetes insipidus (DI) is caused by a deficiency (in amount or functional ability) of vasopressin [antidiuretic hormone (ADH)], which controls thirst and water balance by acting directly on the 351
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renal tubules to allow water re-absorption, thus reducing diuresis and retaining water. It also has a vasoconstrictive effect at high concentrations. Vasopressin is secreted in response to rising plasma osmolality levels, which in turn also stimulate thirst. In DI there is either a lack of vasopressin (cranial DI) or a poor renal response to it (nephrogenic DI). Urine cannot be concentrated, polyuria occurs, plasma osmolality rises towards or beyond the upper limit of normal (>295 mosm/kg) and a compensatory polydipsia occurs. Huge quantities (up to 10−15 L) of low (<300 mosm/kg) osmolality urine are produced. The symptoms are massive thirst (often drinking through the night) and huge polyuria. Fluid restriction will fail to concentrate the urine because vasopressin is either not secreted or is not functional. Treatment is with the synthetic vasopressin analogue, desmopressin (DDAVP), which is given as an intranasal spray sublingually or orally. Transient DI can occur in pregnancy: secretion of vasopressin from the posterior pituitary is unchanged, but production of the enzyme vasopressinase by the placenta may either unmask previous subclinical DI or be excessive; and liver damage in acute fatty liver of pregnancy (AFLP), severe pre-eclampsia or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) can reduce breakdown of vasopressinase. DI is rare in pregnancy. If the diagnosis is made prior to pregnancy, the cause will also be known and the treatment must be continued. In nephrogenic DI, carbemazepine is used to sensitize the renal tubules to vasopressin. In cranial DI, the commoner form in pregnancy, treatment is with DDAVP taken sublingually, orally or nasally: this is safe and is not associated with teratogenicity or other adverse fetal outcomes. It is not metabolized by vasopressinase and does not, unlike ADH, have any oxytocin-like effect. Symptoms will worsen through pregnancy in 60% of women (because of placental vasopressinase production exacerbating the breakdown of their remaining endogenous ADH and increased glomerular filtration rate), although symptoms may improve in 20%. It is essential to monitor fluid balance (intake/output), as well as serum electrolytes and plasma osmolality in order to avoid severe dehydration and electrolyte imbalance in pregnancy: the dose of DDAVP often needs to be increased. Women with DI can labour and breast feed normally; they can usually return to their pre-pregnancy treatment doses within the first week of delivery. Transient DI resolves within a few days after delivery. All new diagnoses of DI in pregnancy must be carefully assessed to establish the cause, which includes pituitary tumour expansion, lymphocytic hypophysitis, head injury, severe preeclampsia, AFLP and HELLP. Subclinical DI may be unmasked by pregnancy (as discussed above).
The adrenal gland has a three-layered outer cortex that produces steroids and an inner medulla that makes catecholamines. The steroids produced have glucocorticoid, mineralocorticoid and androgen activity. All steroids have the same basic skeleton and the chemical differences between them are slight (Figure 1).
hormone (CRH) are also secreted by the placenta, but pituitary ACTH is unchanged. Oestrogen increases cortisol binding globulin production and the net result is an increase in both total and free cortisol levels. Cushing syndrome is a state of increased circulating glucocorticoid. In Cushing disease, the hypercortisolism is caused by increased circulating ACTH from the pituitary or an ectopic source; in Cushing syndrome there is primary glucocorticoid overproduction by the adrenal gland from an adrenal tumour or hyperplasia. Outside pregnancy, 75% of cases are due to Cushing disease (with 10% being ectopic production of ACTH); in pregnancy 55% are due to Cushing syndrome (with 21% of adrenal tumours being malignant). The classic presentation is with a Cushingoid appearance, central weight gain, skin thinning, red/purple striae, plethora, impaired glucose tolerance, hypertension and hypokalaemia. Hyperpigmentation only occurs in Cushing disease, and is due to melanocyte stimulating hormone-like peptides in ACTH. These symptoms may not be easy to distinguish from the normal changes of pregnancy or common problems such as gestational diabetes or pre-eclampsia. However, Cushing syndrome can be aggressive, causing severe hypertension and hyperglycaemia. Fetal outcome is very poor with recorded fetal loss rates of up to 40%, and the severity of maternal illness has given rise to increased maternal mortality rates. Outside pregnancy, the diagnostic tool is the dexamethasone suppression test, whereby cortisol levels are assessed after dexamethasone administration In normal subjects, cortisol production is significantly suppressed in response, whereas this will not be demonstrated in those with Cushing syndrome; ACTH levels and appropriate imaging determine whether there is an adrenal or pituitary cause. In pregnancy, it is more difficult to make the diagnosis, due to the usual hypercortisol state of pregnancy, the partial lack of suppression of this physiological hypercortisolism, lack of experience and clarity in interpreting the results of suppression tests in these circumstances, and possibly raised levels of placental ACTH. However, it is particularly important to establish the diagnosis, because in pregnancy there is a higher incidence of adrenal Cushing (55% cf 25% outside pregnancy) and 21% of the adrenal tumours will be malignant. Adrenal tumour imaging is best achieved with MRI, bearing in mind that up to 10% of routine abdominal CT studies find a non-functioning adrenal adenoma. An adrenal cause of Cushing diagnosed during pregnancy should be treated surgically because the incidence of malignancy is high. If the Cushing is pituitary in origin (ACTH secreting), the decision to defer surgery until after pregnancy is acceptable, using medical treatment in the interim. This can be done with ketoconazole, which inhibits cortisol production, but consideration must be given to the fact that this crosses the placenta and interferes with fetal cortisol production. Cyproheptadine, a serotonin antagonist that decreases ACTH, has been used, but there are only a few case reports recording its fetal safety profile. Metyrapone, an 11-beta-hydroxylase blocker, has been used successfully; however, severe dangerous hypertension has also been reported, potentially because 11-beta-deoxycorticosterone levels increase.
Cushing syndrome ACTH from the pituitary stimulates cortisol production in the adrenal cortex. In pregnancy, ACTH and corticotrophin releasing
Addison disease In over 90% of cases, primary hypoadrenalism is caused by an autoimmune destruction of the adrenal gland reducing production
Q2
Q3
Adrenal disease
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Cholesterol
3BHSD
Dehydroepiandrosterone 17,20 lyase
3BHSD
17-hydroxypregnenolone 17 alpha hydroxylase
Pregnenolone
3BHSD
Progesterone
17-hydroxyprogesterone
Androstenedione
21 hydroxylase
21 hydroxylase
17 hydroxysteroid dehydrogenase
Deoxycorticosterone
11-deoxycortisol
Testosterone
11 beta hydroxylase
11 beta hydroxylase
Corticosterone
Cortisol
Oestrone
Oestradiol
18 hydroxylase
11 hydroxycorticosterone
18 dehydrogenase
Aldosterone Figure 1 Pathways and enzymes involved in glucocoticoid, mineralocorticoid and sex steroid metabolism within the adrenal cortex.
3 bHSD, 3 beta hydroxysteroid dehydrogenase
of glucocorticoids, mineralocorticoids and the sex steroids. The reduced cortisol levels cause increased CRH and ACTH production which in turn are responsible for the hyperpigmentation commonly found in Addisonian patients. It is a disease more common in women and, because of its autoimmune origin, is often (40%) associated with other autoimmune conditions. Presentation is with weight loss, malaise, postural hypotension, and syncopal attacks, and with hyponatraemia, hyperkalaemia and hypoglycaemia on biochemical analysis. Diagnosis is made from low cortisol and high ACTH in the morning, remembering that cortisol levels are increased during pregnancy and therefore low cortisol levels in a pregnant Addisonian woman may still be in the normal range for non- pregnant women. In Adddison, both glucocorticoid and mineralocorticoid are deficient; therefore both hydrocortisone and fludrocortisone are needed to restore weight, serum electrolytes and blood pressure control to normal. It is essential to continue these maintenance steroids through pregnancy and increase steroid replacement doses during stressful events or intercurrent illnesses, and especially during labour and delivery. Since the advent of full steroid replacement therapy, there is no increase in maternal mortality in women with Addison disease diagnosed before pregnancy, which was certainly not the case before hormone therapy was
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available. Hydrocortisone replacement during labour should be given intravenously, 100 mg 6 hourly, and continued for up to 6 days postnatally to prevent postpartum hypovolaemia. Conn syndrome Conn syndrome is hyperaldosteronism caused by an adrenal adenoma (often small and more common in young women), a malignant adrenal tumour or adrenal hyperplasia. Presentation is with severe hypertension, hypokalaemia and hypernatraemia. As plasma and urinary aldosterone production increase in pregnancy, biochemical test results should be correlated with normal pregnancy ranges. If a biochemical diagnosis of hyperaldosteronism is made, CT or MRI is needed to identify adrenal pathology. If an adrenal tumour causing Conn syndrome in pregnancy is identified, case reports demonstrate equal success with resection of tumour in the second trimester and with medical management during pregnancy to delay surgery until after delivery. Medical management includes supplementing potassium and controlling hypertension with methyldopa, nifedipine or labetolol, as necessary. Spironolactone (aldosterone antagonist, potassium sparing diuretic) should be avoided in pregnancy as it is anti androgenic and will feminize a male fetus. 353
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There are few reported cases of pregnancy in women with classic CAH, probably because they have reduced fertility, often combined with psychosexual problems as a result of the genital corrective surgery. Adequate replacement with glucocorticoids and mineralocorticoids should be continued at pre-pregnancy doses and replacement levels monitored with serum free testosterone analysis (17-hydroxy progesterone and androstenedione rise in pregnancy and are not reliable markers of suppression). Maternal placental aromatase converts high levels of maternal androgens and therefore helps to protect a female fetus from masculinization. Close observation for preeclampsia and growth restriction, especially in salt losers, is prudent and increased steroid doses are needed to cover labour and delivery. Ideally the partner of a homozygote mother should be tested for carrier status to assess the risk to the fetus. If this is not possible, the offspring should be screened by checking urinary 17-hydroxy progesterone. All affected families – either homozygous mothers planning a pregnancy or families with a child previously affected – should be offered genetic counselling. The family with a previously affected child has a 1 in 4 chance of having a subsequently affected offspring, and a 1 in 8 chance that the child will be a virilized female. Dexamethasone readily crosses the placenta. It should be started prior to 7 weeks’ gestation (when the external genitalia begin to differentiate) to suppress fetal ACTH excretion and androgen overproduction. This dexamethasone regimen, 1−1.5 mg daily, reduces the need for corrective surgery for virilization but is not always successful. Dexamethasone should be stopped if the fetus is male or an unaffected female, not least because maternal side effects may be significant. Early fetal sexing by identification of cell free DNA in maternal blood identifies a male fetus and means that dexamethasone can be stopped appropriately early. Alternatively a CVS at 11 weeks can be used to determine whether the female fetus is affected or not and therefore helps to time the cessation of dexamethasone therapy. ◆
Phaeochromocytoma The adrenal medulla produces adrenaline and noradrenaline. Phaeochromocytomas are tumours of the sympathetic nervous system, 90% of which are within the adrenal medulla (10% are malignant and up to 25% are multiple). They are very rare outside pregnancy, accounting for fewer than 1 in 1000 cases of hypertension, and are even more rarely encountered in pregnancy. However, because associated maternal and fetal mortality rates are high when undiagnosed, phaeochromocytoma should be considered in any woman presenting with symptoms and signs of catecholamine excess: intermittent or constant severe hypertension, anxiety, palpitations, sweating, headache and vomiting. Presentation can simulate severe pre-eclampsia. The diagnosis is confirmed by demonstrating elevated catecholamine metabolites in the urine, e.g. vanillylmandelic acid, metadrenaline and metnoradrenaline. Levels twice normal are highly suggestive, but values three times normal are diagnostic. MRI is important to identify the location of the lesion. Medical control is essential and complete alpha blockade with phenoxybenzamine should always be used before beta blockade with propanolol. Surgical removal is the only cure, and this is timed depending on the gestation at diagnosis, and only ever contemplated with expert anaesthetic and surgical involvement after adequate alpha blockade has been administered. Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a spectrum of autosomal recessive conditions in which there is a mutation in the coding of one of the many enzymes responsible for cortisol synthesis from cholesterol in the adrenal gland, resulting in defective enzyme production (see Figure 1). About 1 in 60 of the Northern Europe population is a carrier of CAH. The commonest enzyme deficiency is 21-hydroxylase (responsible for about 90% of CAH) and therefore 17-hydroxy progesterone is not converted into 11-deoxycortisol. Failure to produce cortisol causes increased ACTH secretion, and over-stimulation and hyperplasia of the adrenals, which in turn over-produce steroid precursors that are shunted along the androgen pathway. Classic CAH occurs in about 1 in 15 000 births and produces either: • a simple virilizing condition with normal aldosterone production in 25% of cases (thought to be when enzymes with 1−2% of normal activity are produced), or • a severe salt-wasting condition when aldosterone is also not produced (enzyme activity is totally ablated by the genetic mutation). There is also a milder, non-classic or late-onset CAH which produces signs of androgen excess later in life (associated with 20−60% normal enzyme activity). Female fetuses with classic CAH have early in utero exposure to excess androgen production, which causes virilization such as clitoral hypertrophy or complete phallus formation, whereby incorrect gender assignment can occur. If classic CAH with saltwasting occurs, acute hyponatraemic dehydration follows in the early neonatal period. Diagnosis is confirmed by identifying high serum/urinary 17-hydroxy progesterone levels. Treatment is with replacement glucocorticoid and, if necessary, (salt-losing form) mineralocorticoids. Genital virilization will need corrective surgery.
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Further reading Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements in women with hypothyroidism. N Engl J Med 2004; 351: 241–249. Anon. Hypothyroidism in the pregnant woman. Drugs Ther Bull 2006; 44: 53–56. Anselmo J, Cao D, Karrison T, et al. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004; 292: 691–695. Brewster UC, Hayslett JP. Diabetes insipidus in the third trimester of pregnancy. Obstet Gynecol 2005; 105(5 Pt 2): 1173–1176. De Swiet M. Diseases of the pituitary and adrenal gland. In: Medical disorders in obstetric practice, 4th edn. Blackwell; 2002. p. 439–458. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549–555. Lindsay JR, Jonklaas J, Oldfield EH, et al. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab 2005; 90: 3077–3083.
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Molitch ME. Pituitary diseases in pregnancy. Semin Perinatol 1998; 22: 457–470. Pang S, Pollack M, Marshall RN, et al. Prenatal treatment of congenital adrenal hyperlasia to 21-hydroxylase deficiency. N Engl J Med 1990; 332: 111–115.
• Macroprolactinomas above 10 mm require more intensive management in pregnancy than microprolactinomas due to their increased propensity to expand. • Treatment of diabetes insipidus with desmopressin is safe and effective, and does not influence labour or lactation. • Atypical hypertension in pregnancy should be carefully considered as occasionally Cushing, Conn and phaeochromocytoma may present in pregnancy and failure to reach the correct diagnosis is potentially dangerous to mother and baby. • Couples who have had a baby with congenital adrenal hyperplasia should be offered dexamethasone from 5 weeks’ gestation in order to minimize the risk of virilization of an affected girl: in order to do this, they need pre-pregnancy advice and direct access to maternity services.
Practice points • Adjustment of thyroxine after the first trimester in hypothyroid women on replacement doses of thyroxine is much less likely to benefit the fetus than pre- pregnancy or early first trimester changes. • Doses of antithyroid medication should be titrated against clinical and biochemical findings, and are likely to be lower in the second and third trimesters.
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Thyroid and other endocrine disorders in pregnancy
fetal brain development prior to the onset of fetal thyroid activity, which occurs late in the first trimester. Changes in placental iodinase enzymes at the end of the first trimester prevent the transfer of maternal T4 to the fetal circulation beyond this gestation: 0.008% of maternal T4 passes across at term. This applies to both endogenous T4 and pharmaceutical T4, and should be remembered when considering the management of pregnant women with hypothyroidism. In pregnancies where the fetus is athyrotic (i.e. is unable to produce thyroid hormones due to, for example, enzyme deficiency, failure of gland formation or profound iodine deficiency), alteration in placental iodinase enzymes – believed to be driven by changes on the fetal side of the circulation – allow transfer of T4 from the mother to the fetus to achieve levels one third of those expected. In the first trimester, human chorionic gonadotrophin (hCG) may influence thyroid function because the alpha subunits of hCG and TSH are identical, and therefore HCG has some thyrotropin-like effect. Beta subunits of TSH show considerable heterogeneity and in some pregnancies have greater TSH-like effect than others; this is particularly evident in multiple pregnancies, where the titre may be higher, and in hyperemesis gravidarum, and may result in a biochemical picture of thyrotoxicosis, with raised T4 and suppressed TSH: this is self-limiting and does not need treatment with antithyroid medication. True thyrotoxicosis, rarely, may present de novo in the firstt trimester and a careful history, including the time course of any symptoms and followup to ensure return to biochemical euthyroidism in the second trimester, is required.
Joanna Girling Christina Cotzias
Abstract Thyroid disorders are common endocrine problems encountered in pregnancy. To optimize pregnancy outcomes it is essential to understand the effects and treatments of both hyper- and hypo-thyroidism. Pituitary disease is not uncommon in pregnancy. Other endocrine pathologies are much rarer in pregnancy, often because of high levels of subfertility; they are often associated with significant maternal or fetal morbidity and even mortality if not recognized or treated adequately. This review summarizes the important consequences of thyroid and other endocrine diseases in pregnancy.
Keywords Addison’s disease; congenital adrenal hyperplasia; conn s yndrome; cushing syndrome; diabetes insipidus; hypopituitarism; phaeochromocytoma; pituitary adenomas; thyroid disease
Thyroid disorders in pregnancy
Hypothyroidism Around 1% of pregnant women have hypothyroidism, so this condition will be seen frequently in most units. A few women – those who have had surgery for thyroid cancer – will be on suppressive doses of thyroxine to render the TSH undetectable and so reduce the risk of recurrence. The majority of women with hypothyroidism will be on life-long thyroxine replacement therapy, usually because of: autoimmune hypothyroidism – Hashimoto disease, the consequences of thyroid surgery for benign nodules or goitre, or following treatment for autoimmune hyperthyroidism – Graves disease (both surgical and radioactive iodine treatment frequently result in hypothyroidism), with the aim being to maintain biochemical and clinical euthyroidism. These women usually have an annual thyroid function measurement and review of their thyroxine requirements. There is an unresolved debate in non-pregnant women regarding the best target for thyroid function tests (TFTs) (i.e. normal range TSH or low TSH) and whether dose changes should be based on TSH or fT4 concentrations, or both. In pregnancy these issues are no clearer. Although it has been suggested that women with treated hypothyroidism are more likely to have miscarriage, pre-eclampsia, prematurity and other adverse outcomes, there are no data to support this and these women do not need increased antenatal surveillance in respect of these complications. There are some data suggesting that the neonatal outcome of women who have under-treated hypothyroidism or untreated subclinical (i.e. asymptomatic) hypothyroidism in pregnancy may be less good than those women without hypothyroidism: one study suggested a maximum IQ deficit of 7 points compared with that in a control
Thyroid problems are common in pregnant women and have, together with their treatments, the potential to influence maternal well-being and the outcome of the pregnancy. It is therefore important that they are well understood. Thyroid physiology in pregnancy The half-life of thyroxine binding globulin [TBG; the main binding protein for thyroxine (T4) and tri iodothyronine (T3)] is prolonged by oestrogen-driven sialylation, which results in an increased circulating concentration of both TBG and therefore of total T4 and T3. It is for this reason that these hormones are not measured in pregnancy. Instead, freeT4 and freeT3, the biologically active hormones, are measured: these are not greatly changed in normal pregnancy, although the lower limit of normal is reduced slightly in the third trimester. Normal values for thyroid stimulating hormone (TSH) rise slightly in the third trimester, but otherwise are unchanged compared with nonpregnant ranges. TSH and T3 do not cross the placenta. In the first trimester, T4 does cross the placenta and is believed to play a role in
Joanna Girling MA MRCP FRCOG is a Consultant Obstetrician and Gynaecologist at West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, UK. Q1
Christina Cotzias BSc MRCOG is a Consultant Obstetrician and Gynaecologist at West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, UK.
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group. Unfortunately, neurological and psychomotor development in children has so many diverse influences that it is not easy to distinguish the role of the in utero thyroid environment and ex utero factors, including of course the possibility that a woman with untreated hypothyroidism may be subtly less able to carry out the role of motherhood. For example, multiple logistic regression analyses point to smoking, alcohol intake and maternal depression as being factors influencing the child’s development, as well as the mother’s thyroid status. Nonetheless, it seems logical, even if the evidence base regarding outcome is weak, to aim for the pregnant woman to be euthyroid, both for her sense of well-being and to ensure optimal transfer of T4 to the fetus in the first trimester. However, it is important to remember that after this period it is unlikely that adjustments to the maternal dose will have any influence on the fetal thyroid status or development. Blanket increase in thyroxine dose is not advised, not least because there is evidence from both thyrotoxic and thyroid hormone resistant pregnancy that excess thyroxine is associated with increased miscarriage and low birth weight. There is some debate about whether pregnant women with hypothyroidism should increase their dose of thyroxine with some recommending that they all should, and others advising that changes are made only on the basis of thyroid function tests. It is important when considering this to bear in mind the possible aims of dose changes, which might be to achieve biochemical euthyroidism, to improve maternal well-being or to influence the fetal environment. From the previous discussion it should be clear that the latter is unlikely to be possible after the first trimester. Those women with hypothyroidism who conceive when their thyroid function is well-controlled and their thyroxine dose is stable are relatively unlikely to need to increase their dose of thyroxine while they are pregnant. If they do, it is generally because of reduced absorption in the first trimester due to vomiting; reduced compliance due to unfounded concerns about teratogenicity; introduction of iron or calcium supplements (both of which reduce absorption and so should be taken separately from thyroxine); or, in the first trimester, transfer of small amounts of thyroxine to the fetus. In iodine replete areas, such as the UK, increased renal iodine loss does not influence maternal thyroid function. However, the natural fluctuations in a long term condition may necessitate a dose change, and women who conceive when their hypothyroidism is not well-controlled may need to increase thyroxine dose to ‘catch up’. Pragmatically, women should check their thyroid function prior to conception, and make any required thyroxine dose adjustments before they are pregnant. Further tests can be done early in pregnancy and again in the last trimester in women whose results are normal and whose condition is stable. Other women may need more frequent tests, but beyond the first trimester these would not be anticipated directly to influence the fetus. A common difficulty in interpretation of TFTs in hypothyroid pregnant women occurs when the TSH is high and the fT4 normal: this may reflect recently improved or fluctuating compliance, as TSH returns to normal more slowly than fT4 – the patient should be questioned regarding how long she has been taking the tablets regularly. Thyroxine is safe to take during lactation. Babies born to women with primary autoimmune hypothyroidism are not at
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increased risk of neonatal hypo- or hyper-thyroidism, but do have a small lifetime increased risk of hypothyroidism in adult life. Babies whose mothers are hypothyroid following treatment of hyperthyroidism do have an increased risk of both fetal and neonatal hyperthyroidism, as discussed below. Hyperthyroidism Hyperthyroidism affects around 2 in 1000 pregnancies. The majority is due to Graves disease, an autoimmune disorder in which clinical disease activity reflects the titre of TSH receptor stimulating antibodies. Pregnancy does not affect the long term course of hyperthyroidism. In the first trimester there may be deterioration in control, due to reduced absorption of medication secondary to vomiting or to hCG-driven stimulation of TSH receptors (see above). In the second and third trimesters, typically, treatment doses can be reduced as the immune effects of pregnancy result in an increase in TSH receptor inhibitory antibodies and a fall in the stimulatory ones: one third of women will be able temporarily to discontinue treatment at this time. The majority need to return to their prepregnant doses in the puerperium to prevent a disease flare. The drugs usually used in the treatment of hyperthyroidism, propylthiouracil (PTU) and carbimazole, are safe in pregnancy and should not be stopped because of concerns about teratogenicity. Indeed, a number of studies have shown that neonatal outcome is better, with fewer anomalies and lower chance of delivering prematurely, if euthyroidism is achieved prior to conception, when compared with those women in whom either control is achieved in early pregnancy or later pregnancy, in a stepwise manner. Older studies have linked carbimazole with aplasia cutis – a very rare condition resulting in deficits in the scalp and hair growth, but larger more recent studies show that either this link is spurious or at worst that the risk of the fetus developing this condition is extremely small. Both agents cross the placenta in similar amounts and, rarely, can cause fetal hypothyroidism: this risk can be minimized by ensuring that the patient takes the lowest doses of treatment to keep her clinically euthyroid and biochemically at the upper limit of the normal range. Fetal hypothyroidism rarely manifests clinically, in part because of the opposing stimulatory effect of transplacental TSH receptor antibodies. Fetal and neonatal hyperthyroidism are also rare, but should be looked for in women at risk, chiefly those with active Graves disease or previous Graves’ disease treated by surgery or radioactive iodine and in whom TSH receptor stimulating antibodies are present. This test should be requested early in the pregnancy of women who fall in these categories. The fetal thyroid can be stimulated by these antibodies beyond 24 weeks’ gestation and so women should be aware of the symptoms of fetal thyrotoxicosis (such as excessive fetal movements), have the fetal heart rate auscultated regularly to check for fetal tachycardia, and be serially scanned to exclude growth restriction or fetal goitre. If fetal thyrotoxicosis is suspected, delivery should be considered if the gestation is close to term. If not, the diagnosis should be confirmed by fetal blood sampling and then doses of maternal antithyroid medication should be increased, if necessary with the addition of thyroxine, which does not cross the placenta, to prevent hypothyroidism in the mother. Neonatal thyrotoxicosis typically presents after the first week of life, when the ‘protective’ effects of maternally derived antithyroid medication are no 350
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longer present, but the stimulatory effect of the TSH receptor antibodies, which have a longer half-life, persists. Paediatricians should be informed of these patients so that they can arrange local follow-up as indicated, and parents should be warned to report increased agitation or restlessness in their babies. Both PTU and carbimazole can be taken during lactation. However, PTU may be preferable, especially if high doses are required, as less of it crosses into breast milk. For this reason it is often the antithyroid agent of choice for women who need to start treatment in pregnancy. Pragmatically, in the management of hyperthyroidism in pregnancy, TFTs should be measured 4−6 weekly and more frequently if control is poor, and the dose of antithyroid medication titrated against maternal well-being and biochemical results. Serial clinical assessment must include weight, pulse, tremor and examination of the eyes and neck. Beta blockade should be used in the usual way to control anxiety or tachycardia, propranolol being the drug of choice as it is effective and is not associated with intrauterine growth restriction or other adverse outcomes.
is confirmed the treatment is usually stopped in women with microprolactinomas. In normal pregnancy the anterior pituitary expands. The clinical concern is that the prolactinoma will also expand and cause the pressure effects described above. Symptomatic microprolactinoma expansion occurs in only about 1.5% of cases, although 5% demonstrate asymptomatic expansion if regular CT or MRI scans are performed. The risk of symptomatic expansion is greater for macroprolactinomas, with up to 15% enlarging during pregnancy: this is why experts may continue dopamine agonist therapy through pregnancy in these women. All women with a prolactinoma who become pregnant should be warned of the potential risk of tumour expansion and the risk should be correlated with the size of the tumour. As prolactin production rises during pregnancy, its serum measurement is not useful to assess tumour expansion. All women with prolactinomas should be closely monitored, specifically questioning them about headache and assessing visual fields, which should be done formally every month in women with macroprolactinoma: the commonest abnormality is bitemporal hemianopia. Any suspicion of expansion should be further investigated with an MRI of the pituitary. If expansion is confirmed, dopamine agonist treatment should be restarted or the dose increased. There is good experience of bromocriptine use in pregnancy, and no evidence of congenital abnormalities or longer term intellectual development in children born to mothers who have taken the drug during pregnancy; the data for cabergoline use are less extensive but similarly reassuring. Labour and delivery are not affected by the presence of a prolactinoma. Women can breast feed without extra risk of tumour expansion, although use of a dopamine agonist may suppress lactation.
Pituitary disease The anterior lobe of the pituitary gland produces and secretes prolactin, growth hormone, adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), luteinizing (LH) and follicle stimulating hormone (FSH). The posterior pituitary secretes oxytocin and vasopressin (which have been produced in the anterior hypothalamus). Benign pituitary adenomas are the commonest cause of pituitary disease in the general population and in pregnancy. Pituitary adenomas cause problems by: • secreting excess hormone; or • when large, local pressure effects damage visual pathways and cause visual field defects, or pushing on the bony structures and meninges around the pituitary fossa causes headache; or • damaging surrounding pituitary tissue causing hypopituitarism.
Hypopituitarism Hypopituitarism can be caused by pituitary tumours compressing functional pituitary tissue, pituitary surgery, radiotherapy, Sheehan syndrome (infarction of the anterior pituitary during acute hypotension, classically at postpartum haemorrhage) or lymphocytic hypophysitis (a chronic inflammatory cell infiltrate of the anterior pituitary causing oedema, expansion and fibrosis without an adenoma, often occurring in the late third trimester or post partum). Presentation of hypopituitarism is with lethargy, hypothyroidism, failure to lactate, amenorrhoea and adrenocortical insufficiency. As well as visual field assessment and pituitary MRI to exclude a tumour, women need hormone replacement therapy (hydrocortisone, thyroxine and oestrogen) to maintain normal metabolism and response to stress. Women will need ovulation induction to conceive in the future, and glucocorticoid and thyroxine replacement must continue throughout pregnancy, with extra hydrocortisone to cover the stress of labour or intercurrent illnesses. Mineralocorticoid replacement is often not needed as aldosterone production is not solely ACTH dependent. Untreated, those women who manage to conceive have a very poor pregnancy prognosis, with high rates of miscarriage, stillbirths and maternal death, all of which can be normalized with adequate therapy.
Prolactinomas Prolactin is the commonest hormone secreted by pituitary adenomas, although there are many other causes of hyperprolactinaemia, including hypothyroidism, polycystic ovarian syndrome, dopamine-antagonist drugs such as chlorpromazine (prolactin secretion from the pituitary is inhibited by dopamine released from neurones in the hypothalamus), lactation and pregnancy – which causes prolactin levels to rise by up to 10 times normal levels. Having excluded physiological and drug-related hyperprolactinaemia, suspicion of a pituitary adenoma should be investigated with visual field assessment and MRI of the pituitary. A pituitary mass measuring >10 mm and secreting prolactin is defined as a macroprolactinoma, although the majority will be microprolactinomas (i.e. <10 mm). Hyperprolactinaemia stimulates milk production and inhibits gonadotrophin releasing hormone (GnRH) production and, outside pregnancy, causes a/oligomenorrhoea, galactorrhoea and subfertility, as well as the above mentioned pressure effects due to a macroprolactinoma. Hyperprolactinaemia is controlled with dopamine agonists – bromocriptine being the longest-established therapy, although cabergoline is increasingly being used. Dopamine agonists are often necessary for women to conceive, although once pregnancy
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Diabetes insipidus Diabetes insipidus (DI) is caused by a deficiency (in amount or functional ability) of vasopressin [antidiuretic hormone (ADH)], which controls thirst and water balance by acting directly on the 351
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renal tubules to allow water re-absorption, thus reducing diuresis and retaining water. It also has a vasoconstrictive effect at high concentrations. Vasopressin is secreted in response to rising plasma osmolality levels, which in turn also stimulate thirst. In DI there is either a lack of vasopressin (cranial DI) or a poor renal response to it (nephrogenic DI). Urine cannot be concentrated, polyuria occurs, plasma osmolality rises towards or beyond the upper limit of normal (>295 mosm/kg) and a compensatory polydipsia occurs. Huge quantities (up to 10−15 L) of low (<300 mosm/kg) osmolality urine are produced. The symptoms are massive thirst (often drinking through the night) and huge polyuria. Fluid restriction will fail to concentrate the urine because vasopressin is either not secreted or is not functional. Treatment is with the synthetic vasopressin analogue, desmopressin (DDAVP), which is given as an intranasal spray sublingually or orally. Transient DI can occur in pregnancy: secretion of vasopressin from the posterior pituitary is unchanged, but production of the enzyme vasopressinase by the placenta may either unmask previous subclinical DI or be excessive; and liver damage in acute fatty liver of pregnancy (AFLP), severe pre-eclampsia or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) can reduce breakdown of vasopressinase. DI is rare in pregnancy. If the diagnosis is made prior to pregnancy, the cause will also be known and the treatment must be continued. In nephrogenic DI, carbemazepine is used to sensitize the renal tubules to vasopressin. In cranial DI, the commoner form in pregnancy, treatment is with DDAVP taken sublingually, orally or nasally: this is safe and is not associated with teratogenicity or other adverse fetal outcomes. It is not metabolized by vasopressinase and does not, unlike ADH, have any oxytocin-like effect. Symptoms will worsen through pregnancy in 60% of women (because of placental vasopressinase production exacerbating the breakdown of their remaining endogenous ADH and increased glomerular filtration rate), although symptoms may improve in 20%. It is essential to monitor fluid balance (intake/output), as well as serum electrolytes and plasma osmolality in order to avoid severe dehydration and electrolyte imbalance in pregnancy: the dose of DDAVP often needs to be increased. Women with DI can labour and breast feed normally; they can usually return to their pre-pregnancy treatment doses within the first week of delivery. Transient DI resolves within a few days after delivery. All new diagnoses of DI in pregnancy must be carefully assessed to establish the cause, which includes pituitary tumour expansion, lymphocytic hypophysitis, head injury, severe preeclampsia, AFLP and HELLP. Subclinical DI may be unmasked by pregnancy (as discussed above).
The adrenal gland has a three-layered outer cortex that produces steroids and an inner medulla that makes catecholamines. The steroids produced have glucocorticoid, mineralocorticoid and androgen activity. All steroids have the same basic skeleton and the chemical differences between them are slight (Figure 1).
hormone (CRH) are also secreted by the placenta, but pituitary ACTH is unchanged. Oestrogen increases cortisol binding globulin production and the net result is an increase in both total and free cortisol levels. Cushing syndrome is a state of increased circulating glucocorticoid. In Cushing disease, the hypercortisolism is caused by increased circulating ACTH from the pituitary or an ectopic source; in Cushing syndrome there is primary glucocorticoid overproduction by the adrenal gland from an adrenal tumour or hyperplasia. Outside pregnancy, 75% of cases are due to Cushing disease (with 10% being ectopic production of ACTH); in pregnancy 55% are due to Cushing syndrome (with 21% of adrenal tumours being malignant). The classic presentation is with a Cushingoid appearance, central weight gain, skin thinning, red/purple striae, plethora, impaired glucose tolerance, hypertension and hypokalaemia. Hyperpigmentation only occurs in Cushing disease, and is due to melanocyte stimulating hormone-like peptides in ACTH. These symptoms may not be easy to distinguish from the normal changes of pregnancy or common problems such as gestational diabetes or pre-eclampsia. However, Cushing syndrome can be aggressive, causing severe hypertension and hyperglycaemia. Fetal outcome is very poor with recorded fetal loss rates of up to 40%, and the severity of maternal illness has given rise to increased maternal mortality rates. Outside pregnancy, the diagnostic tool is the dexamethasone suppression test, whereby cortisol levels are assessed after dexamethasone administration In normal subjects, cortisol production is significantly suppressed in response, whereas this will not be demonstrated in those with Cushing syndrome; ACTH levels and appropriate imaging determine whether there is an adrenal or pituitary cause. In pregnancy, it is more difficult to make the diagnosis, due to the usual hypercortisol state of pregnancy, the partial lack of suppression of this physiological hypercortisolism, lack of experience and clarity in interpreting the results of suppression tests in these circumstances, and possibly raised levels of placental ACTH. However, it is particularly important to establish the diagnosis, because in pregnancy there is a higher incidence of adrenal Cushing (55% cf 25% outside pregnancy) and 21% of the adrenal tumours will be malignant. Adrenal tumour imaging is best achieved with MRI, bearing in mind that up to 10% of routine abdominal CT studies find a non-functioning adrenal adenoma. An adrenal cause of Cushing diagnosed during pregnancy should be treated surgically because the incidence of malignancy is high. If the Cushing is pituitary in origin (ACTH secreting), the decision to defer surgery until after pregnancy is acceptable, using medical treatment in the interim. This can be done with ketoconazole, which inhibits cortisol production, but consideration must be given to the fact that this crosses the placenta and interferes with fetal cortisol production. Cyproheptadine, a serotonin antagonist that decreases ACTH, has been used, but there are only a few case reports recording its fetal safety profile. Metyrapone, an 11-beta-hydroxylase blocker, has been used successfully; however, severe dangerous hypertension has also been reported, potentially because 11-beta-deoxycorticosterone levels increase.
Cushing syndrome ACTH from the pituitary stimulates cortisol production in the adrenal cortex. In pregnancy, ACTH and corticotrophin releasing
Addison disease In over 90% of cases, primary hypoadrenalism is caused by an autoimmune destruction of the adrenal gland reducing production
Q2
Q3
Adrenal disease
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Cholesterol
3BHSD
Dehydroepiandrosterone 17,20 lyase
3BHSD
17-hydroxypregnenolone 17 alpha hydroxylase
Pregnenolone
3BHSD
Progesterone
17-hydroxyprogesterone
Androstenedione
21 hydroxylase
21 hydroxylase
17 hydroxysteroid dehydrogenase
Deoxycorticosterone
11-deoxycortisol
Testosterone
11 beta hydroxylase
11 beta hydroxylase
Corticosterone
Cortisol
Oestrone
Oestradiol
18 hydroxylase
11 hydroxycorticosterone
18 dehydrogenase
Aldosterone Figure 1 Pathways and enzymes involved in glucocoticoid, mineralocorticoid and sex steroid metabolism within the adrenal cortex.
3 bHSD, 3 beta hydroxysteroid dehydrogenase
of glucocorticoids, mineralocorticoids and the sex steroids. The reduced cortisol levels cause increased CRH and ACTH production which in turn are responsible for the hyperpigmentation commonly found in Addisonian patients. It is a disease more common in women and, because of its autoimmune origin, is often (40%) associated with other autoimmune conditions. Presentation is with weight loss, malaise, postural hypotension, and syncopal attacks, and with hyponatraemia, hyperkalaemia and hypoglycaemia on biochemical analysis. Diagnosis is made from low cortisol and high ACTH in the morning, remembering that cortisol levels are increased during pregnancy and therefore low cortisol levels in a pregnant Addisonian woman may still be in the normal range for non- pregnant women. In Adddison, both glucocorticoid and mineralocorticoid are deficient; therefore both hydrocortisone and fludrocortisone are needed to restore weight, serum electrolytes and blood pressure control to normal. It is essential to continue these maintenance steroids through pregnancy and increase steroid replacement doses during stressful events or intercurrent illnesses, and especially during labour and delivery. Since the advent of full steroid replacement therapy, there is no increase in maternal mortality in women with Addison disease diagnosed before pregnancy, which was certainly not the case before hormone therapy was
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available. Hydrocortisone replacement during labour should be given intravenously, 100 mg 6 hourly, and continued for up to 6 days postnatally to prevent postpartum hypovolaemia. Conn syndrome Conn syndrome is hyperaldosteronism caused by an adrenal adenoma (often small and more common in young women), a malignant adrenal tumour or adrenal hyperplasia. Presentation is with severe hypertension, hypokalaemia and hypernatraemia. As plasma and urinary aldosterone production increase in pregnancy, biochemical test results should be correlated with normal pregnancy ranges. If a biochemical diagnosis of hyperaldosteronism is made, CT or MRI is needed to identify adrenal pathology. If an adrenal tumour causing Conn syndrome in pregnancy is identified, case reports demonstrate equal success with resection of tumour in the second trimester and with medical management during pregnancy to delay surgery until after delivery. Medical management includes supplementing potassium and controlling hypertension with methyldopa, nifedipine or labetolol, as necessary. Spironolactone (aldosterone antagonist, potassium sparing diuretic) should be avoided in pregnancy as it is anti androgenic and will feminize a male fetus. 353
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There are few reported cases of pregnancy in women with classic CAH, probably because they have reduced fertility, often combined with psychosexual problems as a result of the genital corrective surgery. Adequate replacement with glucocorticoids and mineralocorticoids should be continued at pre-pregnancy doses and replacement levels monitored with serum free testosterone analysis (17-hydroxy progesterone and androstenedione rise in pregnancy and are not reliable markers of suppression). Maternal placental aromatase converts high levels of maternal androgens and therefore helps to protect a female fetus from masculinization. Close observation for preeclampsia and growth restriction, especially in salt losers, is prudent and increased steroid doses are needed to cover labour and delivery. Ideally the partner of a homozygote mother should be tested for carrier status to assess the risk to the fetus. If this is not possible, the offspring should be screened by checking urinary 17-hydroxy progesterone. All affected families – either homozygous mothers planning a pregnancy or families with a child previously affected – should be offered genetic counselling. The family with a previously affected child has a 1 in 4 chance of having a subsequently affected offspring, and a 1 in 8 chance that the child will be a virilized female. Dexamethasone readily crosses the placenta. It should be started prior to 7 weeks’ gestation (when the external genitalia begin to differentiate) to suppress fetal ACTH excretion and androgen overproduction. This dexamethasone regimen, 1−1.5 mg daily, reduces the need for corrective surgery for virilization but is not always successful. Dexamethasone should be stopped if the fetus is male or an unaffected female, not least because maternal side effects may be significant. Early fetal sexing by identification of cell free DNA in maternal blood identifies a male fetus and means that dexamethasone can be stopped appropriately early. Alternatively a CVS at 11 weeks can be used to determine whether the female fetus is affected or not and therefore helps to time the cessation of dexamethasone therapy. ◆
Phaeochromocytoma The adrenal medulla produces adrenaline and noradrenaline. Phaeochromocytomas are tumours of the sympathetic nervous system, 90% of which are within the adrenal medulla (10% are malignant and up to 25% are multiple). They are very rare outside pregnancy, accounting for fewer than 1 in 1000 cases of hypertension, and are even more rarely encountered in pregnancy. However, because associated maternal and fetal mortality rates are high when undiagnosed, phaeochromocytoma should be considered in any woman presenting with symptoms and signs of catecholamine excess: intermittent or constant severe hypertension, anxiety, palpitations, sweating, headache and vomiting. Presentation can simulate severe pre-eclampsia. The diagnosis is confirmed by demonstrating elevated catecholamine metabolites in the urine, e.g. vanillylmandelic acid, metadrenaline and metnoradrenaline. Levels twice normal are highly suggestive, but values three times normal are diagnostic. MRI is important to identify the location of the lesion. Medical control is essential and complete alpha blockade with phenoxybenzamine should always be used before beta blockade with propanolol. Surgical removal is the only cure, and this is timed depending on the gestation at diagnosis, and only ever contemplated with expert anaesthetic and surgical involvement after adequate alpha blockade has been administered. Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a spectrum of autosomal recessive conditions in which there is a mutation in the coding of one of the many enzymes responsible for cortisol synthesis from cholesterol in the adrenal gland, resulting in defective enzyme production (see Figure 1). About 1 in 60 of the Northern Europe population is a carrier of CAH. The commonest enzyme deficiency is 21-hydroxylase (responsible for about 90% of CAH) and therefore 17-hydroxy progesterone is not converted into 11-deoxycortisol. Failure to produce cortisol causes increased ACTH secretion, and over-stimulation and hyperplasia of the adrenals, which in turn over-produce steroid precursors that are shunted along the androgen pathway. Classic CAH occurs in about 1 in 15 000 births and produces either: • a simple virilizing condition with normal aldosterone production in 25% of cases (thought to be when enzymes with 1−2% of normal activity are produced), or • a severe salt-wasting condition when aldosterone is also not produced (enzyme activity is totally ablated by the genetic mutation). There is also a milder, non-classic or late-onset CAH which produces signs of androgen excess later in life (associated with 20−60% normal enzyme activity). Female fetuses with classic CAH have early in utero exposure to excess androgen production, which causes virilization such as clitoral hypertrophy or complete phallus formation, whereby incorrect gender assignment can occur. If classic CAH with saltwasting occurs, acute hyponatraemic dehydration follows in the early neonatal period. Diagnosis is confirmed by identifying high serum/urinary 17-hydroxy progesterone levels. Treatment is with replacement glucocorticoid and, if necessary, (salt-losing form) mineralocorticoids. Genital virilization will need corrective surgery.
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Further reading Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements in women with hypothyroidism. N Engl J Med 2004; 351: 241–249. Anon. Hypothyroidism in the pregnant woman. Drugs Ther Bull 2006; 44: 53–56. Anselmo J, Cao D, Karrison T, et al. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004; 292: 691–695. Brewster UC, Hayslett JP. Diabetes insipidus in the third trimester of pregnancy. Obstet Gynecol 2005; 105(5 Pt 2): 1173–1176. De Swiet M. Diseases of the pituitary and adrenal gland. In: Medical disorders in obstetric practice, 4th edn. Blackwell; 2002. p. 439–458. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549–555. Lindsay JR, Jonklaas J, Oldfield EH, et al. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab 2005; 90: 3077–3083.
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Molitch ME. Pituitary diseases in pregnancy. Semin Perinatol 1998; 22: 457–470. Pang S, Pollack M, Marshall RN, et al. Prenatal treatment of congenital adrenal hyperlasia to 21-hydroxylase deficiency. N Engl J Med 1990; 332: 111–115.
• Macroprolactinomas above 10 mm require more intensive management in pregnancy than microprolactinomas due to their increased propensity to expand. • Treatment of diabetes insipidus with desmopressin is safe and effective, and does not influence labour or lactation. • Atypical hypertension in pregnancy should be carefully considered as occasionally Cushing, Conn and phaeochromocytoma may present in pregnancy and failure to reach the correct diagnosis is potentially dangerous to mother and baby. • Couples who have had a baby with congenital adrenal hyperplasia should be offered dexamethasone from 5 weeks’ gestation in order to minimize the risk of virilization of an affected girl: in order to do this, they need pre-pregnancy advice and direct access to maternity services.
Practice points • Adjustment of thyroxine after the first trimester in hypothyroid women on replacement doses of thyroxine is much less likely to benefit the fetus than pre- pregnancy or early first trimester changes. • Doses of antithyroid medication should be titrated against clinical and biochemical findings, and are likely to be lower in the second and third trimesters.
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