Ebook Oxford handbook of endocrinology and diabetes (3rd edition): Part

(BQ) Part 2 book Oxford handbook of endocrinology and diabetes presents the following contents: Endocrinology in pregnancy, calcium and bone metabolism, paediatric endocrinology, neuroendocrine disorders, inherited endocrine syndromes and MEN, endocrine surgery,... and other contents.

Post-partum thyroid dysfunction 432

Thyroid cancer in pregnancy 433

Addison’s disease in pregnancy 445

Congenital adrenal hyperplasia 446

Phaeochromocytoma 447

Management of phaeochromocytoma 448

Thyroid and parathyroid disorders

Normal physiology

Effect of pregnancy on thyroid function

• Iodine stores Fall due to i renal clearance and transplacental transfer

to fetus

• Thyroid size Increase in thyroid volume by 10–20% due to hCG

stimulation and relative iodine deficiency

• Thyroglobulin Rise corresponds to rise in thyroid size.

• Thyroid-binding globulin (TBG) Twofold i in concentration as a result

of reduced hepatic clearance, and i synthesis stimulated by oestrogen Concentration plateaus at 20 weeks’ gestation and falls again post-partum

• Total T 4 and T 3 i concentrations, corresponding to rise in TBG.

• Free T 4 and T 3 There may be a small rise in concentration in first

trimester due to hCG stimulation, then fall into normal range During second and third trimester, FT4 concentration is often just below the normal reference range

• Thyroid-stimulating hormone (TSH) Within normal limits in pregnancy

However, suppressed in 13.5% in first trimester, 4.5% in second trimester, and 1.2% in third trimester due to hCG thyrotropic effect +ve correlation between free T4 and hCG levels, and –ve correlation between TSH and hCG levels in first half of pregnancy Upper limit of normal range is higher in pregnancy

• Thyrotropin-releasing hormone (TRH) Normal.

• TSH receptor antibodies When present in high concentrations in

maternal serum, may cross the placenta Antibody titre decreases with progression of pregnancy

Fetal thyroid function

• TRH and TSH synthesis occurs by 8–10 weeks’ gestation, and thyroid hormone synthesis occurs by 10–12 weeks’ gestation

• TSH, total and freeT4 and T3, and TBG concentrations increase progressively throughout gestation

• Maternal TSH does not cross the placenta, and although TRH crosses the placenta, it does not regulate fetal thyroid function Iodine crosses the placenta, and excessive quantities may induce fetal hypothyroidism Maternal T4 and T3 cross the placenta in small quantities and are important for fetal brain development in the first half of gestation

THYROID AND PARATHYROID DISORDERS 427

Maternal hyperthyroidism

(b see Thyrotoxicosis in pregnancy, p 44.)

Incidence

• Affects 0.2% of pregnant women

• Most are diagnosed before pregnancy or in the first trimester of pregnancy

• In women with Graves’s disease in remission, exacerbation may occur

in first trimester of pregnancy

Graves’s disease

• The commonest scenario is pregnancy in a patient with pre-existing Graves’s disease on treatment, as fertility is low in patients with untreated thyrotoxicosis Newly diagnosed Graves’s disease in pregnancy is unusual

• Aggravation of disease in first trimester, with amelioration in second half of pregnancy because of a decrease in maternal immunological activity at that time

• Symptoms of thyrotoxicosis are difficult to differentiate from normal pregnancy The most sensitive symptoms are weight loss and tachycardia Goitre is found in most patients

• Propylthiouracil (PTU) should be used in the first trimester in case

of teratogenic effects of carbimazole (check liver function monthly) Thereafter, carbimazole is recommended

• Carbimazole use in pregnancy was discouraged, as it was thought to be associated with aplasia cutis, a rare scalp defect, though recent studies have shown no increase in rate Studies have shown that carbimazole may be associated with choanal and oesophageal atresia, but the maternal hyperthyroidism may be a factor in this

• Propylthiouracil may rarely be associated with hepatocellular inflammation, which, in severe cases, can lead to liver failure and death A recent study also showed that PTU was associated with low birthweight infants

• A short course of 40mg of propranolol tds can be used initially for 2–3 weeks while antithyroid drugs take affect

• Most patients will be on a maintenance dose of ATD A high dose of ATD may be necessary initially to achieve euthyroidism as quickly as possible (carbimazole 20–40mg/day or propylthiouracil 200–400mg/day) in newly diagnosed patients, then use the minimal dose of ATD to maintain euthyroidism

• Do not use block and replace regime as higher doses of ATDs required, and there is minimal transplacental transfer of T4, thereby risking fetal hypothyroidism

• Monitor TFTs every 4–6 weeks

MATERNAL HYPERTHYROIDISM 429

• Aim to keep FT4 at upper limit of normal and TSH low normal

(<2.5mU/L—first trimester, <3.0mU/L—second trimester,

<3.5mU/L—third trimester)

• In 730% of women, ATD may be discontinued at 32–36 weeks’

gestation Consider if euthyroid for at least 4 weeks on lowest dose

of ATD, but continue to monitor TFTs frequently The presence of

a large goitre or ophthalmopathy suggests severe disease and the

chances of remission are low, so do not stop ATD Graves’s disease can flare in the post-natal period due to increase in the maternal

antibody levels, so patients should be monitored closely in the

post-partum period

• Risks of neonatal hypothyroidism and goitre are reduced if woman on carbimazole 20mg or less (200mg propylthiouracil or less) in last few weeks of gestation

• Breastfeeding is safe at doses of less than 150mg of PTU and 15mg carbimazole, as only small amounts pass into the breast milk (<0.7% PTU and 0.5% carbimazole)

• If higher doses are given, we recommend breastfeeding prior to taking medication, and the dose can be divided throughout the day Neonatal thyroid function needs to be monitored

• Surgical management of thyrotoxicosis is rarely necessary in pregnancy Only indication: serious ATD complication (e.g agranulocytosis) or drug resistance There is a possible i risk of spontaneous abortion

or preterm delivery associated with surgery during pregnancy The second trimester is the optimal time for surgery, as organogenesis is complete and less chance of anaesthesia and surgery inducing labour

• Radioiodine therapy is contraindicated in pregnancy, during

breastfeeding, and for 4 months prior to conception

Infants born to mothers with Graves’s disease

• Risks to fetus of uncontrolled thyrotoxicosis:

• i risk of spontaneous miscarriage and stillbirth

• Fetal hypothyroidism May occur following treatment of mother

with high doses of ATDs (>200mg PTU/day; >20mg carbimazole),

particularly in the latter half of pregnancy This is rare and may be

diagnosed by demonstrating a large fetal goitre on fetal US in the

presence of fetal bradycardia

• Fetal hyperthyroidism May occur after week 25 of gestation It results

in IUGR, fetal goitre, and tachycardia (fetal heart rate >160bpm) and has high mortality if not treated It may develop if the mother has

high titres of TSH-stimulating antibodies (TSAb) which can cross the placenta Treat by giving mother ATD, and monitor fetal heart rate (aim

<140bpm), growth, and goitre size It is important to remember women with Graves’s disease who have been treated with radioiodine or

surgery can still have high antibody titres and therefore need monitoring

• Neonatal thyrotoxicosis Develops in 1% of infants born to thyrotoxic

mothers Transient, usually subsides by 6 months, but up to 30% mortality if untreated Treat with ATD and B-blockers

Hyperemesis gravidarum (gestational hyperthyroidism)

• Characterized by severe vomiting and weight loss Cause unknown

• Begins in early pregnancy (weeks 6–9 of gestation) and tends to resolve spontaneously by week 20 of gestation

• Biochemical hyperthyroidism in two-thirds of affected women, but T3

is less commonly elevated Mechanism: hCG has TSH-like effect, thus stimulating the thyroid gland and suppressing TSH secretion

• Degree of thyroid stimulation correlates with severity of vomiting

• No other evidence of thyroid disease, i.e no goitre, no history of thyroid disease, no ophthalmopathy, and –ve thyroid autoantibodies (10% population is +ve for thyroid antibodies)

• Antithyroid drugs not required and do not improve symptoms of hyperemesis

Causes of maternal hyperthyroidism

• Graves’s disease (85% of cases)

• Toxic nodule

• Toxic multinodular goitre

• Hydatidiform mole

Risks of suboptimal treatment during pregnancy

• Spontaneous miscarriage Twofold i risk.

• Pre-eclampsia 21% of suboptimally treated mothers have

pregnancy-induced hypertension (PIH)

• Also i risk of anaemia during pregnancy and post-partum

haemorrhage

• The fetus is dependent on maternal thyroxine until fetal production starts at 12 weeks

• Risk of impaired fetal intellectual and cognitive development

• i risk of perinatal death

• Other risks to fetus are those associated with PIH (IUGR, preterm delivery, etc.)

• The risk of congenital malformations is not thought to be i

• For women on thyroxine, optimize therapy prior to pregnancy

• If already on T4 before pregnancy, on confirmation of pregnancy,

increase dose by 30% (25–50 micrograms) because of increased TBG and thyroid hormone requirements

• Aim TSH—lower part of normal range; FT4—upper end of normal

• Many women are suboptimally replaced prior to pregnancy, so their dose needs to be increased in response to abnormal TFTs After

delivery, they should continue on this increased dose, with monitoring

of biochemistry

• NB Do not give FeSO4 simultaneously with T4—reduces its efficacy Separate times for drug ingestion by at least 2h

Causes of maternal hypothyroidism

• Hashimoto’s thyroiditis (most common cause)

• Previous radioiodine therapy or thyroidectomy

• Previous post-partum thyroiditis

• Hypopituitarism

Positive thyroid antibodies but euthyroid

• Twofold excess risk of spontaneous miscarriage

• No other complications

• No risk of neonatal hypothyroidism

• Risk of PIH not i

• The occasional mother will develop hypothyroidism towards the end

of the pregnancy, so check TFTs between weeks 28–32 of gestation

• i risk of post-partum thyroiditis, so check TSH at 3 months

post-partum

Post-partum thyroid dysfunction

Prevalence

• 5–10% of women within 1 year of delivery or miscarriage

• 3x more common in women with type 1 diabetes mellitus

• There may be an i risk of post-partum depression

• Hyperthyroidism followed by hypothyroidism (25%).

• Spontaneous recovery in 80% within 6–12 months of delivery.

Differential diagnosis

• Graves’s disease may relapse in the post-partum period This is differentiated from post-partum thyroiditis by a high uptake on radioiodine scanning

• Lymphocytic hypophysitis may cause hypothyroidism However, serum TSH concentrations are inappropriately low

Investigation

• Thyroid peroxidase antibodies are +ve in 80%

• Radionuclide uptake scans are rarely necessary However, there is low uptake during the thyrotoxic phase, differentiating it from Graves’s disease where uptake is i

Management

• B-blockers if thyrotoxic and symptomatic until TFTs normalize Antithyroid medication is unnecessary

• Levothyroxine if TSH >10 or if TSH between 4–10 and symptomatic

• No consensus as to how long to treat with thyroxine Two options:

• Halve dose at about 12 months post-natal, and check TFTs 6 weeks later If normal, then withdraw T4, and check TFTs 6 weeks later

• Withdraw treatment 1 year after completion of family

Prognosis

• Recurrence in future pregnancies in 25% of women

• Permanent hypothyroidism develops in up to 30% of women within

10 years If treatment is withdrawn, then annual TSH measurements are essential

THYROID CANCER IN PREGNANCY 433

Thyroid cancer in pregnancy

(b see Thyroid cancer and pregnancy, p 102.)

Parathyroid disorders

Calcium metabolism in pregnancy

• There are increased calcium requirements in pregnancy; 25–30g is transferred to the baby

• There is increased maternal intestinal absorption of calcium

• Due to increased renal blood flow, there is increase in the renal excretion of calcium

Primary hyperparathyroidism in pregnancy

• Rare—8 cases in 100,000 in women of childbearing age

• In pregnancy, the hypercalcaemia may improve due to the fetal transfer

of calcium

• Diagnosis is made by finding a raised PTH in the presence of a raised calcium

• Ultrasound can be used to locate the adenoma

• Can cause serious maternal morbidity which includes hyperemesis, nephrolithiasis, peptic ulcers, and pancreatitis It is also associated with pre-eclampsia, recurrent miscarriage, preterm labour

• Fetal complications include IUGR and neonatal death The high circulating maternal calcium can lead to suppression of fetal

parathyroid development, leading to hypocalcaemia of the fetus after delivery Neonates normally present at days 5–14 with poor feeding, tetany, and convulsions

Management

• Hypercalcaemia is treated with IV fluids

• If mild, women can be advised to increase their fluid intake Calcium levels should be monitored throughout pregnancy, with surgery arranged post-partum

• If calcium remains persistently high (>2.85mmol/L), then

parathyroidectomy can be arranged in the second or early third trimester

Hypoparathyroidism

• Pregnancy increases the demand for vitamin D Therefore,

replacement doses will need to be increased in pregnancy

• Maternal levels of corrected calcium and vitamin D should be checked monthly

• Untreated hypoparathyroidism leads to miscarriage, fetal

hypocalcaemia, and neonatal rickets

PARATHYROID DISORDERS 435

Further reading

Abalovich M, Amino N, Barbour LA, et al (2007) Management of thyroid dysfunction during

preg-nancy and post-partum: an Endocrine Society clinical practice guideline J Clin Endocrinol Metab

92(8 Suppl), S1–47.

Alexander EK, Marqusee E, Lawrence J, et al (2004) Timing and magnitude of increases in

levothy-roxine requirements during pregnancy in women with hypothyroidism N Engl J Med 351, 241–9.

Azizi F, Amouzegar A (2011) Management of hyperthyroidism during pregnancy Eur J Endocrinol

164, 871–6.

Chen C, Xirasager S, et al (2011) Risk of adverse perinatal outcomes with antithyroid treatement

during pregnancy: a national population based study BJOG 118, 1365–73.

Cooper S, Rivkees S (2009) Putting propylthiouracil in perspective J Clin Endocrinol Metab 94,

1881–2.

De Groot L, et al (2012) Management of thyroid dysfunction during pregnancy and post-partum: an

Endocrine Society clinical practice guideline J Clin Endocrinol Metab 97, 2543–65.

Lazarus JH (2011).Thyroid function in pregnancy Br Med Bull 97, 137–48

LeBeau SO, Mandell SJ (2006) Thyroid disorders during pregnancy Endocrinol Metab Clin North

Am 35, 117–36.

Norman J, et al (2009) Hyperparathyroidism during pregnancy and the effect of rising calcium on

pregnancy loss: a call for earlier intervention Clin Endocrinol (Oxf) 71, 104–9

Poppe K, Glinoer D (2003) Thyroid autoimmunity and hypothyroidism before and during nancy Hum Reprod Update 9, 149–61.

preg-Sato K (2008) Hypercalcemia during pregnancy, puerperium and lactation: Review and a case report of hypercalcemic crisis after delivery due to excessive productin of PTH-related protein (PTHrP) without malignancy (humoral hypercalcemia of pregnancy) Endocrin J 55, 959–66.

Stagnaro-Green A (2002) Post-partum thyroiditis J Clin Endocrinol Metab 87, 4042–7.

Pituitary disorders

Normal anatomical changes during pregnancy

• Prolactin (PRL)-secreting cells Marked lactotroph hyperplasia during

pregnancy

• Gonadotrophin-secreting cells Marked reduction in size and number.

• TSH and ACTH-secreting cells No change in size or number.

• Anterior pituitary Size increases by up to 70% during pregnancy May

take 1 year to shrink to near pre-pregnancy size in non-lactating women Gradual slight increase in size with each pregnancy

• MRI Enlarged anterior pituitary gland, but stalk is midline Posterior

pituitary gland may not be seen in late pregnancy

Normal physiology during pregnancy

• Serum PRL Concentrations increase markedly during pregnancy and fall

again to pre-pregnancy levels approximately 2 weeks post-partum in non-lactating women

• Serum LH and FSH Undetectable levels in pregnancy and blunted

response to GnRH because of –ve feedback inhibition from high levels

of sex hormones and PRL

• Serum TSH, T 4 , and T 3 TSH may be suppressed in the first trimester

of pregnancy Free thyroid hormones usually at the lower end of the normal range

• Growth hormone (GH) and IGF-I Low maternal GH levels and blunted

response to hypoglycaemia due to placental production of GH-like substance IGF-I levels are normal or high in pregnancy

• ACTH and cortisol CRH, ACTH, and cortisol levels are high in

pregnancy, as both CRH and ACTH are produced by the placenta In addition, oestrogen-induced increase in cortisol-binding globulin (CBG) synthesis during pregnancy will further increase maternal plasma cortisol concentrations During the latter half of pregnancy, there is

a progressive increase of ACTH and cortisol levels, peaking during labour Incomplete suppression of cortisol, following dexamethasone suppression test, and exaggerated response of cortisol to CRH stimulation However, normal diurnal variation persists

PROLACTINOMA IN PREGNANCY 437

Prolactinoma in pregnancy

Effect of pregnancy on tumour size

Risk of significant tumour enlargement (i.e resulting in visual field bances or headaches):

Over 6,000 pregnancies have occurred in women receiving bromocriptine

in early pregnancy, and the incidence of complications in these pregnancies with regard to fetal outcome is similar to that of the normal population, indicating that bromocriptine is probably safe in early pregnancy Data are available on children whose mothers received bromocriptine throughout pregnancy, and again the incidence of congenital abnormalities is negligible Children who are exposed to bromocriptine in utero have normal psycho-

logical development in follow-up

The FDA has withdrawn the licence for use of bromocriptine post-partum to suppress lactation, as there was an increased incidence

of adverse incidents which included myocardial infarction and stroke We would advise caution, particularly in women with pre-eclampsia

Cabergoline

Also probably safe in early pregnancy and has been used in >380 cies, with no i risk of fetal loss or congenital abnormalities, but fewer data are available There are more data on the long-term safety of bromocrip-tine, but cabergoline is being used increasingly as it is better tolerated

Management of prolactinoma

Microprolactinoma

• After recent MRI, initiate dopamine agonist therapy to induce normal ovulatory cycles and fertility

• Stop bromocriptine as soon as pregnancy is confirmed

• Assess for visual symptoms and headache at each trimester, although the risk of complications is low (<5%) Serum PRL levels are difficult to interpret during pregnancy, as they are normally elevated; therefore, they are not measured

• MRI is indicated in the occasional patient who becomes symptomatic

• In the post-partum period, recheck serum PRL level 2 months after cessation of breastfeeding Reassess size of microprolactinoma by MRI only if serum PRL level is higher than pre-pregnancy concentrations

• 40–60% chance of remission of microprolactinoma following

• May use bromocriptine or cabergoline to induce ovulation, and then stop it after conception However, patient must be monitored very carefully during pregnancy with monthly visual field testing

• If symptoms of tumour enlargement develop or there is deterioration

in visual fields, then MRI should be performed to assess tumour growth If significant tumour enlargement develops, then

bromocriptine therapy should be initiated

• Alternatively, the patient may undergo surgical debulking of the tumour and/or radiotherapy before seeking fertility This will

significantly reduce the risk of complications associated with

tumour growth However, this approach may render them

gonadotrophin-deficient These patients should again be monitored during pregnancy, using regular visual fields

MRI should be performed in the post-partum period in women with macroprolactinomas to look for tumour growth

Breastfeeding

• There is no contraindication to breastfeeding

• If the mother would like to breastfeed, dopamine receptor agonists will have to be discontinued prior to birth, as they inhibit lactation The decision to discontinue medication should be assessed on a case-by-case basis, dependent upon the potential risk of optic nerve/chiasm compression

• The diagnosis of Cushing’s syndrome is difficult to establish during

pregnancy However, the presence of purple striae and proximal

myopathy should alert the physician to the diagnosis of Cushing’s

syndrome

• If suspected, the investigation of Cushing’s syndrome should be carried out as in the non-pregnant state

• The circulating levels of cortisol rise during normal pregnancy This

is due to a combination of the increased levels of cortisol-binding

globulin, stimulated by the raised oestrogen, and the placental CRH production which is biologically active

• 24h urinary free cortisol measurements remain normal in the first

trimester but can increase by 3x by term in a normal pregnancy

• Non-suppression of cortisol production on a low-dose dexamethasone suppression test may be a feature of a normal pregnancy There are no internationally agreed normal values in pregnancy, so interpretation of dynamic testing is difficult

• The diurnal variation of cortisol secretion is, however, preserved in normal pregnancy

• Diagnosis is important, as pregnancy in Cushing’s syndrome is

associated with a high risk of maternal and fetal complications (see Table 5.1)

Management of Cushing’s syndrome

• Third trimester:

• i risk of diabetes mellitus

• Deliver baby as soon as possible (preferably by vaginal delivery to minimize the risk of poor wound healing following a Caesarean section), and instigate treatment

• Metyrapone used in doses of <2g/day generally well tolerated in pregnancy It can cause hypertension and has been associated with development of pre-eclampsia and fetal hypoadrenalism

• Ketoconazole has been used successfully in a few pregnancies; it is antiandrogenic in rats, so caution should be used if the infant is male

• Aminoglutethimide causes fetal masculinization so is not

recommended

• Post-operative glucocorticoid replacement therapy will be required

• Treatment of Cushing’s syndrome in pregnancy may reduce maternal and fetal morbidity and mortality

• See Table 5.1 for complications

Table 5.1 Complications of Cushing’s syndrome in pregnancy

Congestive cardiac

malformations Low risk; no risk of

virilization

NON-FUNCTIONING PITUITARY TUMOURS 441

Acromegaly

• Fertility in acromegaly is reduced, partly due to hyperprolactinaemia (if present), in addition to secondary hypogonadism However, there have been several reported cases of pregnancy in acromegaly

• Diagnosis in pregnancy is difficult, as the placenta secretes growth

hormone and, though different from maternal GH, assays may not be able to detect this IGF-1 also increases in normal pregnancy

• Acromegaly increases the risk of gestational diabetes and hypertension,

so women should be screened

• However, in the absence of diabetes mellitus, there does not appear

to be an excess of perinatal morbidity or mortality in babies born to women with acromegaly

• Significant tumour enlargement occasionally occurs, together with

enlargement of the normal pituitary lactotrophs, so monthly visual field testing is recommended

• Bromocriptine can be used in pregnancy, but there is less response compared to prolactinomas

• There are limited reports of somatostatin analogues and somatostatin receptor agonists use in pregnancy, with no apparent adverse events They do cross the placenta We would not advocate their use until more data are available on their safety in pregnancy Women are

generally advised to stop medication on conception

• Headaches may be helped with both somatostatin analogues and

bromocriptine

• Treatment may be deferred until after delivery in the majority of

patients

Non-functioning pituitary tumours

• These tumours are the second commonest pituitary tumours, but

there is little reported about the incidence in pregnancy Women may present with compression effects due to tumour enlargement

• If diagnosed pre-pregnancy, then visual field assessment in each

trimester is sufficient

• If field defects develop during pregnancy, bromocriptine may be used which will decrease the size of the normal lactotrophs and thereby improving field defects

(b see also Lymphocytic hypophysitis, p 194.)

• Rare disorder thought to be autoimmune in origin

• Characterized by pituitary enlargement on imaging and variable loss of pituitary function

• Most commonly seen in women in late pregnancy or in the first year post-partum

• Symptoms are due to pressure effects, e.g visual field defects and headaches, or due to hormonal deficiency

• Most common hormonal deficiencies:

• Pituitary hormone replacement therapy, as required

• Surgical decompression if pressure symptoms persist

• A course of high-dose steroid therapy is controversial, with mixed results

Causes of hypopituitarism during pregnancy

• Pre-existing hypopituitarism

• Pituitary adenoma

• Lymphocytic hypophysitis

• Sheehan’s syndrome

Management of pre-existing hypopituitarism during pregnancy

• Hydrocortisone Dose may need to be i in the third trimester of

pregnancy by 10mg a day, as the increase in CBG will reduce the bioavailability of hydrocortisone Parenteral hydrocortisone in a dose of 100mg IM every 6h should be given during labour and the dose reduced back to maintenance levels in the post-partum period (24–72h)

HYPOPITUITARISM IN PREGNANCY 443

• Thyroxine Requirements may increase, as pregnancy progresses

Monitor free T4 each trimester, and increase T4 dose accordingly

• GH There are little data on the effects of GH on pregnancy, but

case reports do not suggest a detrimental effect on fetal outcome However, until more data accrue, GH should be stopped prior to

pregnancy Moreover, as the placenta synthesizes a GH variant, GH therapy is unnecessary

• Vasopressin The placenta synthesizes vasopressinase, which breaks down

vasopressin but not desmopressin Women with partial diabetes insipidus may, therefore, require desmopressin treatment during pregnancy Those already receiving desmopressin may require a dose increment during pregnancy Vasopressinase levels fall rapidly after delivery

Sheehan’s syndrome

Post-partum pituitary infarction/haemorrhage, resulting in hypopituitarism Increasingly uncommon in developed countries with improvements in obstetric care and management of post-partum haemorrhage

Pathogenesis

• The enlarged pituitary gland of pregnancy is susceptible to any

compromise to its blood supply

• Investigations will confirm hypopituitarism

Risk factors

• Post-partum haemorrhage

• Type 1 diabetes mellitus

• Sickle cell disease

Caron P, et al (2010) Acromegaly and pregnancy: a retrospective multicenter study of 59

pregnan-cies in 46 women J Clin Endocrinol Metab 95, 4680–7

Karaca Z, et al (2010) Pregnancy and pituitary disorders Eur J Endocrinol 162, 453–75

Kovacs K (2003) Sheehan syndrome Lancet 361, 520–2.

Lindsay JR, et al (2005) Cushing’s syndrome during pregnancy: personal experience and review of

the literature J Clin Endocrinol Metab 90, 3077–83.

Medicines and Healthcare Products Regulatory Agency (2008) Drug safety update 2(3).

Molitch M (2006) Pituitary disorders in pregnancy Endocrinol Metab Clin North Am 35, 99–116.

Molitch ME (2011) Prolactinoma in pregnancy Best Pract Res Clin Endocrinol Metab 25, 885–96

Sam S, Molitch M (2003) Timing and special concerns regarding endocrine surgery during nancy Endocrinol Metab Clin North Am 32, 337–54.

preg-Webster J (1996) A comparative review of the tolerability profiles of dopamine agonists in the

Adrenal disorders

Normal changes during pregnancy

Changes in maternal adrenocortical function

Markedly i concentrations of all adrenal steroids due to i synthesis and

d catabolism

Feto-placental unit

• Fetal adrenal gland DHEAS is produced in vast quantities by the fetal

adrenal gland This is the major precursor for oestrogen synthesis

by the placenta The fetal adrenal gland has a large capacity for steroidogenesis Stimulus for fetal adrenal gland unknown—possibly hCG or PRL

• Placenta:

• Maternal glucocorticoids are largely inactivated in the placenta by 11B-HSD Maternal androgens are converted to oestrogens by placental aromatase, thus protecting 5 fetus from virilization

• Maternal catecholamines are broken down by placental

catechol-O-methyl transferase and monoamine oxidase activity

ADDISON’S DISEASE IN PREGNANCY 445

Addison’s disease in pregnancy

• No associated fetal morbidity in women who have pre-existing primary adrenal insufficiency, as fetus produces and regulates its own adrenal steroids

• Management of Addison’s disease does not differ in pregnancy

• Glucocorticoids which are metabolized by placental 11B-HSD

preferred (i.e prednisolone or hydrocortisone) to avoid fetal adrenal suppression

• Increase hydrocortisone dose by about 10mg during the third

trimester of pregnancy and at any time in case of intercurrent illness

• High-dose intramuscular hydrocortisone should be given at the time of delivery to cover the stress of labour

• Doses may be tapered to normal maintenance doses in the

post-partum period (see Box 5.1)

• Addison’s disease developing in pregnancy may result in an adrenal crisis, particularly at the time of delivery, because of a delay in

diagnosis

• In early pregnancy, vomiting, fatigue, hyperpigmentation, and low

BP may be wrongly attributed to pregnancy However, persisting

symptoms should alert the clinician

• If suspected, the diagnosis is confirmed by the presence of low

serum cortisol concentrations, with failure to rise following ACTH stimulation, and high ACTH levels However, the normal ranges for serum ACTH and cortisol concentrations have not been established

in pregnancy One review suggests a value of <828nmol/L 30min after short Synacthen® test would be diagnostic in pregnancy, but this has yet to be agreed internationally

• Chronic maternal adrenal insufficiency may be associated with

intrauterine fetal growth restriction

• There is no i risk of developing Addison’s disease in the immediate post-partum period

Box 5.1 Management of adrenal insufficiency during

During uncomplicated labour

• Hydrocortisone 100mg IM 6-hourly for 24h, then reduce to

maintenance dose over 72h

• Keep well hydrated

• Fludrocortisone may be discontinued while on high doses of

hydrocortisone

Congenital adrenal hyperplasia

• Fertility is reduced, particularly women with the salt-wasting form

• Fertility may be maximized by optimal suppression of hyperandrogenism

by glucocorticoid therapy (b see Management, p 324)

• No major complications in pregnancy are known in women with CAH, apart from a possibly i incidence of pre-eclampsia

• However, women are more likely to require Caesarean section for cephalopelvic disproportion

• Management is the same as in the non-pregnant woman, and steroids are i at the time of delivery as for Addison’s disease (b see p 266)

• Monitor serum testosterone and electrolytes every 6–8 weeks; if levels increase, then increase dose of corticosteroids

• Risk to fetus:

• No risk of virilization from maternal hyperandrogenism, as placenta will aromatize androgens to oestrogens

• Glucocorticoids do not increase the risk of congenital abnormalities

• If partner is a heterozygote or homozygote for CAH, then the fetus has a 50% risk of CAH Prenatal treatment with dexamethasone will then be necessary to avoid virilization of a 5 fetus (b see Management of pregnancy in CAH, p 325)

PHAEOCHROMOCYTOMA 447

Phaeochromocytoma

• Rare but potentially lethal in pregnancy Maternal mortality may still

be as high as 17% and fetal mortality as high as 30% if not treated

promptly

• Maternal death can be due to stroke, pulmonary oedema, arrhythmia, and myocardial infarction, with the greatest risk during labour

Placental vasoconstriction can lead to spontaneous fetal death,

intrauterine growth restriction, and fetal hypoxia

• Hypertensive crisis can be precipitated by labour, delivery, opiates, metoclopramide, and general anaesthesia

• Women can present with palpitations, sweating, headache, anxiety, dyspnoea, vomiting, and hyperglycaemia

• Phaeochromocytoma needs to be differentiated from women with pre-eclampsia, so suspect in women with hypertension, persistent or intermittent, especially in:

• The absence of proteinuria or oedema, or presence of other

features

• Hypertension developing before 20 weeks’ gestation, or

• Persistent glycosuria

• Prenatal screening in high-risk women, e.g those with a history or

family history of MEN-2 or von Hippel–Lindau syndrome

• Diagnose by 24h urinary catecholamine collection (normal ranges are unaltered in pregnancy) or raised plasma catecholamines

• Labetalol and methyldopa can give false +ves

• Tumour localization is important—MRI is the imaging of choice in

pregnancy

Management of phaeochromocytoma

• A-blockade: phenoxybenzamine Reduces fetal and maternal morbidity

and mortality Appears to be safe in pregnancy The starting dose is 10mg 12-hourly and is built up gradually to a maximum of 20mg every 8h Oral prazosin and IV phentolamine can also be used

• B-blockade: propranolol Only after adequate A-blockade May increase

the risk of intrauterine fetal growth restriction if started in the first trimester, but benefits outweigh risks Give in a dose of 40mg 8-hourly

• Surgery Timing is controversial Some recommend, before 24 weeks’

gestation, surgical removal of phaeochromocytoma (relatively safe following A- and B-blockade) After 24 weeks’ gestation, surgery should be deferred until fetal maturity The preferred method of delivery is usually elective Caesarean section Ensure adequate adrenergic blockade before surgery Surgery can be delayed until after delivery

Conn’s syndrome

• Rare in pregnancy, with <50 cases reported

• Diagnosed with hypertension and hypokalaemia

• Has been associated with placental abruption

• Maternal mortality has been reported

• Standard treatment for hypertension in pregnancy

• Amiloride can be used in pregnancy

• Spironolactone should be avoided, as associated with ambiguous sexual genitalia in male rats

Further reading

Ahlawat SK, Jain S, Kumaro S, Varma S, Sharma BK (1999) Phaeochromocytoma associated with pregnancy: case report and review of the literature Obstet Gynecol Surv 54, 728–37.

Hadden DR (1995) Adrenal disorders of pregnancy Endocrinol Metab Clin North Am 24, 139–51.

Lindsay JR, Nieman LK (2006) Adrenal disorders in pregnancy Endocrinol Metab Clin North Am

Other causes of hypercalcaemia 469

Familial hypocalciuric hypercalcaemia (FHH) 470

Calcium and bone physiology

Bone turnover

In order to ensure that bone can undertake its mechanical and metabolic functions, it is in a constant state of turnover (see Fig 6.1)

• Osteoclasts—derived from the monocytic cells; resorb bone.

• Osteoblasts—derived from the fibroblast-like cells; make bone.

• Osteocytes—buried osteoblasts; sense mechanical strain in bone.

Bone mass during life

(see Fig 6.2)

Bone is laid down rapidly during skeletal growth at puberty Following this, there is a period of stabilization of bone mass in early adult life After the age of 740, there is a gradual loss of bone in both sexes This occurs

at the rate of approximately 0.5% annually However, in ♀ after the menopause, there is a period of rapid bone loss The accelerated loss is maximal in the first 2–5 years after the cessation of ovarian function and then gradually declines until the previous gradual rate of loss is once again established The excess bone loss associated with the menopause is of the order of 10% of skeletal mass This menopause-associated loss, coupled with higher peak bone mass acquisition in ♂, largely explains why osteo-porosis and its associated fractures are more common in ♀

Bone lining cells

Formation Lining cells

Fig 6.2 Bone mass and age.

• Stimulus secretion coupling (e.g chromaffin cells).

Calcium in the circulation

Circulating calcium exists in several forms (see Fig 6.3)

• Ionized—biologically active

• Complexed to citrate, phosphate, etc.—biologically active

• Bound to protein, mainly albumin—inactive

IonizedComplexedProtein bound

5%

Fig 6.3 Forms of circulating calcium.

Investigation of bone

Bone turnover markers

Used in some centres

May be useful in:

• Assessing overall risk of osteoporotic fracture

• Judging response to treatments for osteoporosis

Resorption markers

• Collagen crosslinks These are products of collagen degradation The

small fragments of the ends of the collagen molecule are known as

telopeptides (NTX and CTX), and the measurement of these in blood

is the preferred biochemical measure of bone resorption

Formation markers

• Total alkaline phosphatase is not specific to bone and is also found in

liver, intestine, and placenta It is also insensitive to small changes in bone turnover and is only of general use in monitoring the activity of Paget’s disease

• Bone-specific alkaline phosphatase is a more specific and reliable

measure of bone formation

• Osteocalcin is a component of bone matrix, and the serum level of

osteocalcin reflects osteoblast activity

• P1NP is a procollagen fragment released from the N terminal as type

1 collagen is laid down When measured in serum, it is the most sensitive and specific marker of bone formation

The clinical utility of routine measurements of bone turnover markers is not yet established

• Not useful for assessing bone density.

Isotope bone scanning

Bone-seeking isotopes, particularly 99mtechnetium-labelled nates, are concentrated in areas of localized i bone cell activity Isotope bone scans are useful for identifying localized areas of bone disease, such

bisphospho-as fracture, metbisphospho-astbisphospho-ases, or Paget’s disebisphospho-ase However, isotope uptake is not selective, and so i activity on a scan does not indicate the nature of the underlying bone disease Hence, subsequent radiology of affected regions

is needed to establish the diagnosis

Isotope bone scans are particularly useful in Paget’s disease to establish the extent and sites of skeletal involvement and the underlying disease activity

Bone mass measurements

(See Table 6.1.)

Interpretation of results

• Bone mass is quoted in terms of the number of standard deviations (SD) from an expected mean The most useful way of expressing this

is as T scores T scores represent observed bone mass in comparison

to a sex-matched young, healthy population Z scores are sometimes quoted and relate to bone density, according to a sex- and an age-matched group

• A reduction of one SD in bone density will approximately double the risk of fracture

• WHO has established criteria for the diagnosis of osteoporosis in post-menopausal ♀ (see b p 493)

• No similar criteria have been set in ♂, but the same thresholds are generally accepted

• For some s causes of osteoporosis, particularly glucocorticoid use,

a less stringent criterion of T score <–1.5 should be used as a bone density-determined treatment intervention threshold

Table 6.1 Measurement of bone density

Bone mineral per unit area (g/cm 2 )

71µSv per site <1% at spine<2% at femur

BONE BIOPSY 455

Bone biopsy

Bone biopsy is occasionally necessary for the diagnosis of patients with complex metabolic bone diseases This is usually in the context of sus-pected osteomalacia Bone biopsy is not indicated for the routine diagno-sis of osteoporosis It should only be undertaken in highly specialist centres with appropriate expertise.

Investigation of calcium, phosphate, and magnesium

Blood concentration

Calcium

Measurement of serum calcium does not require patients to be fasted Blood for parathyroid hormone (PTH) and phosphate level measurements should, however, ideally be collected after an overnight fast

In most clinical situations, direct measurement of ionized calcium centration is unnecessary However, it is important to adjust the measured calcium concentration for the prevailing serum albumin concentration (see Box 6.1)

con-Phosphate and magnesium

Measurements of plasma phosphate and magnesium are not ally adjusted for plasma protein concentrations

convention-Box 6.1 Adjustment of measured calcium concentration

Adjusted Ca = measured Ca + 0.02 × (40 – albumin)

(Where calcium is in mmol/L and albumin in g/L.)

URINE EXCRETION 457

Urine excretion

Calcium

Measurement of 24h urinary excretion of calcium provides a measure

of risk of renal stone formation or nephrocalcinosis in states of chronic hypercalcaemia In other circumstances, particularly in the assessment

of the cause of hypercalcaemia (p hyperparathyroidism versus familial hypocalciuric hypercalcaemia), an estimate of the renal handling of cal-cium is more useful This is most commonly estimated from the ratio of the renal clearance of calcium to that of creatinine in the fasting state (see Box 6.2) If all values are in mmol/L, the ratio is typically >0.02 in p hyper-parathyroidism; values <0.01 are suggestive of hypocalciuric hypercalcae-mia (Exclude other causes of hypocalciuria, including renal insufficiency, vitamin D deficiency.)

Phosphate

A 24h measurement of phosphate excretion largely reflects dietary phate intake and has little clinical utility

phos-Box 6.2 Calculation of calcium/creatinine excretion ratio

CaE = [Urine calcium (mmol)/urine creatinine (mmol)]

x [(plasma creatinine (micromol)/1000)/plasma calcium (mmol)]

= <0.01 in FHH

= >0.02 in primary hyperparathyroidism

Calcium-regulating hormones

Parathyroid hormone

Careful attention should be paid to local requirements for collecting blood for PTH measurement Since PTH secretion is suppressed by calcium ingestion, it should be measured in the fasting state The reference range depends on the precise assay employed, but typical values are 10–60pg/

mL (1–6pmol/L)

Vitamin D and its metabolites

25OH vitamin D (25OHD)

This is the main storage form of vitamin D, and the measurement of ‘total vitamin D’ is the most clinically useful measure of vitamin D status.Internationally, there remains controversy around a ‘normal’ or ‘opti-mal’ concentration of vitamin D Levels over 50nmol/L are generally accepted as satisfactory and values <25nmol/L representing deficiency True osteomalacia occurs with vitamin D values <15nmol/L

Low levels of 25OHD can result from a variety of causes (b see Vitamin D deficiency, p 484) It is unlikely that serious intoxication will occur with 25OHD concentrations of <125nmol/L

1,25(OH) 2 vitamin D (1,25(OH) 2 D)

Although this is the active form of vitamin D, measurement of its tration is rarely indicated It is sometimes useful diagnostically in condi-tions of extrarenal synthesis of 1,25(OH)2D, such as in sarcoidosis

concen-Parathyroid hormone-related peptide (PTHrP)

It is possible to measure the level of this oncofetoprotein in serum, but this

is very rarely indicated Sample collection involves specific requirements

Calcitonin

Calcitonin assays are available, but their utility is confined to the diagnosis and monitoring of medullary carcinoma of the thyroid There is no role for calcitonin measurements in the routine investigation of calcium and bone metabolism

CALCIUM-REGULATING HORMONES 459

Many different disease states can lead to hypercalcaemia These are listed

by order of importance in hospital practice in Box 6.3 In asymptomatic community-dwelling subjects, the vast majority of hypercalcaemia is the result of hyperparathyroidism

Clinical features

Notwithstanding the underlying cause of hypercalcaemia, the clinical tures are similar With adjusted serum calcium levels <3.0mmol/L, signifi-cant related symptoms are unlikely With progressive increases in calcium concentration, the likelihood of symptoms increases rapidly

fea-The clinical features of hypercalcaemia are well recognized (see Box 6.4); unfortunately, they are non-specific and may relate to underlying illness

Clinical signs of hypercalcaemia are rare With the exception of band keratopathy, these are not specific It is important to seek clinical evidence

of underlying causes of hypercalcaemia, particularly malignant disease

In addition to specific symptoms of hypercalcaemia, symptoms of long-term consequences of hypercalcaemia should be sought These include the presence of bone pain or fracture and renal stones These indicate the presence of chronic hypercalcaemia

Investigation of hypercalcaemia

Confirm the diagnosis

Serum calcium (adjusted for albumin)

Determine the mechanism

• i PTH Parathyroid overactivity (p or tertiary hyperparathyroidism

can also occur in familial hypocalciuric hypercalcaemia and in lithium therapy due to faulty calcium-sensing)

• d PTH Parathyroid-independent cause.

• Normal PTH:

• May imply parathyroid overactivity—incomplete suppression

• May imply altered calcium sensor—familial hypocalciuric

hypercalcaemia—calcium/creatinine excretion ratio will be low

• Urine calcium to determine calcium/creatinine excretion ratio (not correlated with the risk of stones)

Seek underlying illness (where indicated)

• History and examination

• Chest X-ray

• FBC and ESR

• Biochemical profile (renal and liver function)

• Thyroid function tests (exclude thyrotoxicosis)

• Familial hypocalciuric hypercalcaemia.

• Sarcoidosis and other granulomatous diseases

Box 6.4 Clinical features of hypercalcaemia

• Polyuria • Anorexia • Confusion • Pruritus

• Polydipsia • Vomiting • Lethargy • Sore eyes

• Constipation • Depression

• Abdominal pain

• 25OHD (rarely 1,25(OH)2D)

• Plasma and urine protein electrophoresis (exclude myeloma)

• Serum cortisol (short Synacthen® test (exclude Addison’s disease))

To determine end-organ damage

• 24h urine calcium (9 urine creatinine for reproducibility)

• Renal tract ultrasound (calculi, nephrocalcinosis)

• Skeletal radiographs (lateral thoracolumbar spine, hands)

• BMD by DXA

• (Bone turnover markers.)

Primary hyperparathyroidism

Present in up to 1 in 500 of the general population where it is nantly a disease of post-menopausal ♀ (14/100,000 ♂, 28/100,000 ♀).The normal physiological response to hypocalcaemia is an increase in PTH secretion This is termed s hyperparathyroidism and is not patho-

predomi-logical in as much as the PTH secretion remains under feedback control Continued stimulation of the parathyroid glands can lead to autonomous production of PTH This, in turn, causes hypercalcaemia which is termed

tertiary hyperparathyroidism This is usually seen in the context of renal

dis-ease but can occur in any state of chronic hypocalcaemia, such as vitamin

D deficiency or malabsorption

Pathology

• 85% single adenoma

• 14% hyperplasia (may be associated with other endocrine

abnormalities, particularly multiple endocrine neoplasia (MEN) types

1 and 2 (b see MEN type 1, pp 586–7; MEN type 2, pp 592–3)

• <1% carcinoma (express the lectin galectin-3)

(See Box 6.6.) Potential diagnostic pitfalls:

• FHH—differentiate with calcium/creatinine excretion ratio (b see Familial hypocalciuric hypercalcaemia (FHH), pp 457, 470) (<0.01 in FHH; >0.02 in hyperparathyroidism)

• Long-standing vitamin D deficiency where the concomitant

osteomalacia and calcium malabsorption can mask hypercalcaemia which becomes apparent only after vitamin D repletion Consider other causes of a raised PTH (see Box 6.7)

• Drugs associated with hypercalcaemia (e.g thiazides and lithium).Investigation is, therefore, primarily aimed at determining the presence of end-organ damage from hypercalcaemia in order to determine whether operative intervention is indicated

lamina dura (around teeth), and bone cysts.

• Osteitis fibrosa cystica:

• Not on lithium or thiazide diuretic

• PTH >3.0pmol (20% patients have PTH within upper part NR)

• Drugs (e.g lithium, thiazides)

Exclusion of underlying condition

• p hyperparathyroidism (PHP) can be associated with genetic

abnormalities, especially MEN-1 and 2, as well as familial

hyperparathyroidism

• These conditions should be sought in patients presenting with PHP and a family history in ≥1 first-degree relatives or at a young age

(<40 years)

Localization of abnormal parathyroid glands

This should only form part of a preoperative assessment and is not cated in the initial diagnosis of hyperparathyroidism

indi-• Localization with two separate techniques (usually US and

99mTc-sestamibi) is imperative before minimally invasive

parathyroidectomy

• Otherwise, open bilateral neck exploration by an experienced surgeon

is optimal in the first instance

• After failed neck exploration, other localizing techniques are required, which include: