8.2.5 Endocrine disease in pregnancy

The major physiological changes involving the thyroid axis in pregnancy are an increase in thyroid-binding globulin (TBG); the stimulatory effect of β-human chorionic gonadotropin (βhCG) on the thyroid-stimulating hormone (TSH) receptor; a relative iodine deficiency; and altered thyroid hormone metabolism.

Serum TBG levels double by the second trimester due to oestrogen-driven increased hepatic synthesis and increased sialylation leading to reduced clearance. Total serum levels of thyroxine (T₄) and tri-iodothyronine (T₃) rise to compensate, resulting in relatively unchanged serum-free T₄ (fT₄) and T₃ (fT₃) levels, except for a fall in fT₄ by the 3rd trimester (see Table 8.2.5.1) (1). βhCG shares an identical α chain with TSH, and has weak activity at the TSH receptor; levels rise from fertilization and peak at 10–12 weeks gestation. Therefore, in the first trimester, βhCG levels may partially suppress TSH production, with reduced serum TSH levels. In certain pathological conditions this can be more marked, and may lead to biochemical hyperthyroidism, including hyperemesis gravidarum (see below) and hydatidiform mole. By the third trimester TSH levels tend to rise again to the upper limit (and beyond) of the nonpregnant reference range (1). There is a relative iodine deficiency in pregnancy, due to active transport of iodine across the placenta to the fetus and increased urinary iodine excretion, the latter due to an increased glomerular filtration rate and decreased renal tubular reabsorption. The thyroid gland increases uptake of iodine from the plasma 3-fold to compensate. This may be compounded if the woman has dietary iodine deficiency, leading to thyroid gland hypertrophy and goitre, and if compensation is insufficient can result in fetal cretinism. There are three deiodinases which regulate conversion of T₄ to T₃, as well as T₄ and T₃ to the inactive compounds reverse T₃ (rT₃) and T₂, in peripheral tissues. Types II and III have both been found in placental tissue, whereas type I is unchanged in pregnancy. This allows for a high concentration of iodine at the placenta, to ensure the fetus has adequate supply. Because of the above physiological changes, pregnancy-specific normal ranges should be used for assessment of thyroid function in pregnancy, with free rather than total T₄ and T₃ serum levels (see Table 8.2.5.1) (1).

Although a goitre has been considered a normal finding in pregnancy, this is not the case unless the woman is iodine deficient, as the size of the thyroid gland remains in the normal range, and other causes should be considered.

Pregnancy is characterized by increasing calcium demand from the fetus. A number of changes in calcium physiology occur to support this, without depleting the maternal skeleton (2). There is a rise in 1,25-dihydroxyvitamin D due to placental production, which mediates increased intestinal calcium absorption, while parathyroid hormone (PTH) levels decrease. Total calcium concentration falls because of physiological hypoalbuminaemia, but free ionized calcium levels are maintained. Calcium is actively transported across the placenta to the fetus, mediated by placental-derived PTH-related peptide (PTHrP).

Development of the fetal thyroid gland begins around 7 weeks’ gestation; with ability to concentrate iodine and produce thyroid hormones from 10–12 weeks’ gestation. TSH is also first detected at this gestation (3). Levels of thyroid hormones remain relatively low until 18–20 weeks’ gestation and then steadily increase to term, with concomitant maturation of the hypothalamic-pituitary-thyroid axis (3).

During the first trimester the fetus is dependent on transfer of maternal T₄ across the placenta (4). However, once the fetal thyroid is able to produce thyroid hormone it is independent from maternal thyroid status, apart from transplacental transfer of iodine. In those neonates with congenital absence of the thyroid or complete organification defects, cord serum concentrations of thyroid hormones are 20–50% of those found in normal infants, which suggests that some maternal thyroid hormone transfer to the fetus may occur throughout gestation if required.

At birth, there is a rapid rise in TSH peaking at 30 min, and then falling over the next 24–72 h. Serum T₄ and T₃ levels rise to values just above the upper normal limit for adults.

Hyperthyroidism occurs in 1 in 500–800 pregnancies, and most women will have been diagnosed, and usually treated, prior to pregnancy (5). 50% have a family history of autoimmune thyroid disease. The causes follow a similar pattern to outside of pregnancy, with the majority (85%) due to Graves’ disease (5). Pregnancy complications, such as hyperemesis gravidarum can give a picture of biochemical hyperthyroidism (6) (see below).

Many of the clinical features of hyperthyroidism can also be found in normal pregnancy, including tachycardia, palpitations, vomiting, increased appetite, heat intolerance, sweating, and anxiety. Certain features are more discriminatory for hyperthyroidism, including tremor, weight loss, lid lag and lid retraction. Additional signs of exophthalmos and pretibial myxoedema are specific for Graves’ disease, but may persist after the disease has been treated, and therefore will not always correlate with active disease.

Biochemically, the features are a raised fT₄ and/or fT₃, and suppressed TSH, based on pregnancy-specific normal ranges (see Table 8.2.5.1). Diagnostic radioiodine scans are contra-indicated during pregnancy, so cannot be used to help differentiate Graves’ from other causes, such as sub-acute thyroiditis.

Graves’ disease usually improves during pregnancy, as with many other autoimmune conditions, due to the altered immunological state leading to a fall in TSH receptor-stimulating antibodies (7). If exacerbations occur they are usually in the first trimester, possibly related to the hCG peak, or post-partum, when the pregnancy-related immunological changes are reversed. Pregnancy does not seem to affect the course of Graves’ ophthalmopathy.

Well-controlled hyperthyroidism is usually associated with a good pregnancy outcome for both mother and baby. Conversely, uncontrolled thyrotoxicosis, can lead to maternal and fetal complications (5). For the mother, these include cardiac failure and thyroid storm. For the fetus these include increased rates of miscarriage, fetal growth restriction, preterm delivery, and perinatal death. Subclinical hyperthyroidism (normal range fT₄ and suppressed TSH) does not appear to be associated with adverse pregnancy outcomes (5).

The mainstay of treatment is anti-thyroid drugs, and the most commonly used are carbimazole and propylthiouracil (PTU) (5, 7). Both cross the placenta, carbimazole more readily than PTU, but at doses of less than 15 and 150 mg/day, respectively, do not appear to cause problems for the fetus. In high doses they may cause fetal hypothyroidism and goitre. A rare scalp defect, aplasia cutis, and certain other congenital abnormalities, have occasionally been associated with methimazole, which is used in the USA and for which carbimazole is the prodrug (but these may be due to the disease, rather than the drug) (7). Because of these concerns, PTU is usually used as first line during pregnancy, but if a woman is well controlled on carbimazole prior to pregnancy, there is no indication to routinely change (5). Women should be warned of the maternal risks of rash, agranulocytosis, and hepatitis. The aim of treatment is to control the thyrotoxicosis as rapidly as possible, and then reduce the drug to the lowest dose possible to maintain maternal fT₄ in the upper part of the normal range (see Table 8.2.5.1). ‘Block and replace’ regimens are not used in pregnancy since the fetus is exposed to higher drug levels, and the thyroxine replacement does not cross the placenta in sufficient amounts to compensate (5). Thyroid function tests should be monitored monthly when treatment has been initiated or adjusted in pregnancy, but this can be reduced to once each trimester if the woman has been stable on treatment. Breastfeeding should be encouraged, especially if daily doses are less than 150 mg with PTU or less than 15 mg with carbimazole, as the dose received by the baby is 0.07 and 0.5%, respectively. If the mother is on higher doses then she should breast-feed prior to taking her dose, the dose can be split, and the baby should have thyroid function monitoring (5).

Beta-blockers can be used for symptom control, for the first few weeks after diagnosis, and a short course of propranolol 40 mg three times per day is safe for the fetus. Radioactive iodine is contraindicated in pregnancy and breastfeeding, since it is taken up by the fetal thyroid, leading to ablation of the gland and permanent hypothyroidism (7). Thyroid surgery may be performed, but is usually reserved for compressive symptoms due to a large goitre, when thyroid cancer is suspected, or when medical therapy cannot be tolerated. If required, it is usually undertaken in the second trimester, and patients must be carefully monitored postoperatively for hypothyroidism (up to 50%) and hypocalcaemia, to ensure these are treated promptly.

Fetal and neonatal thyrotoxicosis are due to transplacental passage of TSH-receptor stimulating immunoglobulins (TSI), and occur in 1–5% of women with Graves’, most commonly in those with poorly controlled disease in the third trimester (7). In utero features include fetal tachycardia, goitre and growth restriction, and untreated the mortality can be up to 50%. All women with a history of Graves’ disease should have fetal heart rate documented and growth assessed clinically at each visit. If she has active thyrotoxicosis, then maternal TSI levels should be measured, and if raised, serial ultrasound performed to check fetal growth and neck. Maternal TSI levels should also be checked in those with a history of Graves’ who have been treated with surgery or radioiodine, even if they are currently receiving thyroxine replacement to treat hypothyroidism, as maternal thyroid status will not reflect antibody levels. Invasive procedures such as umbilical vein sampling can be used to measure levels of fetal thyroid hormones directly, but carry significant risk of miscarriage or pre-term labour and so are rarely employed. Neonatal thyrotoxicosis may not present until a few days postpartum, due to delay in clearance of maternal antithyroid drugs or TSH receptor-blocking antibodies (7). Features include irritability, tachycardia, poor weight gain, feeding difficulties, and goitre, and in extreme cases congestive cardiac failure. If untreated, thyrotoxicosis can have adverse effects on neurological development and the mortality rate is 15%. Prompt treatment is required for both fetal and neonatal thyrotoxicosis with anti-thyroid drugs, and in the former these are given to the mother along with thyroxine replacement if required. Neonatal thyrotoxicosis resolves 1–3 months after birth once the TSH-receptor stimulating antibodies are cleared from the circulation, so treatment can be tapered and then stopped.

Hypothyroidism is more common than hyperthyroidism, affecting 1% of pregnancies (4), and is particularly found in those with a family history of thyroid disease. Most cases will have been diagnosed prior to pregnancy, and already be on thyroxine replacement. There is an association with other autoimmune diseases including type 1 diabetes mellitus and pernicious anaemia. Causes are the same as in the non pregnant, with most cases due to Hashimoto’s thyroiditis. Transient hypothyroidism may occur with post-partum thyroiditis (see below) or subacute (de Quervain’s) thyroiditis.

Similar to hyperthyroidism, many of the clinical features overlap with those of normal pregnancy, including lethargy, hair loss, dry skin, constipation, weight gain, fluid retention, and carpal tunnel syndrome. Those that are more specific to hypothyroidism are slow relaxing tendon reflexes, bradycardia, and cold intolerance.

Biochemically, the features are a low fT₄ and/or fT₃, and increased TSH, based on pregnancy-specific normal ranges (1).

Overt maternal hypothyroidism is usually not seen in pregnancy because of the association with anovulatory infertility and early miscarriage. If the pregnancy continues there is an increased risk of complications including pre-eclampsia, preterm delivery, fetal growth restriction, and perinatal mortality, as well as neuropsychological and cognitive impairment in childhood (4). If hypothyroidism is adequately treated then there are no adverse effects on pregnancy outcome, but there is much debate in the literature about what constitutes ‘adequate’ treatment (4). Some studies have suggested that subclinical hypothyroidism may also be associated with impaired neurodevelopment in the offspring (8, 9). Interpreting the data is complicated by the fact that studies have varied in their definition of subclinical hypothyroidism and whether women were untreated or undertreated, and have included those with a raised TSH and normal fT₄, a normal TSH and low fT₄, or even TSH in the upper part of the normal range and a normal fT₄. There is also some evidence that women who have high serum anti-thyroid peroxidize (TPO) antibody levels, even if euthyroid, may have an increased risk of miscarriage and preterm delivery, which could be reduced by thyroxine treatment (10).

Because of the concern regarding subclinical hypothyroidism, some experts recommend universal screening of all pregnant women for thyroid dysfunction, but currently most professional societies only advocate it for those who are at high risk, for example with a family or personal history of thyroid disease, or in those who have type 1 diabetes (11).

Treatment of hypothyroidism is with thyroxine replacement. There is also much controversy regarding the need to routinely increase thyroxine doses in pregnancy (4). Some studies have suggested that this is not required as long as the woman is adequately treated pre-pregnancy, but others believe that doses need to be increased by up to 50%. A reasonable approach is to measure thyroid function tests ideally prior to pregnancy and then as soon as pregnancy is confirmed, adjusting the dose if necessary, aiming for fT₄ within the normal range and TSH in the lower half of the normal range (see Table 8.2.5.1). Thyroid function tests should then be repeated once each trimester, or every 4–6 weeks if there has been a dose adjustment.

Transient fetal or neonatal hypothyroidism due to placental transfer of TSH-receptor blocking antibodies, as opposed to congenital hypothyroidism due to other causes including thyroid dysgenesis, is very rare (1 in 100–180 000 newborns). It will be detected by a raised TSH on the Guthrie heel prick test offered to all neonates, and resolves within 3 months once maternal antibodies are cleared.

Thyroid nodules are found in approximately 1% of women of child-bearing age, and up to 40% of those presenting in pregnancy may be malignant (12). A solitary nodule should be evaluated in the same way as outwith pregnancy, with the exception that a radioactive iodine uptake scan is contra-indicated (12). Fine needle aspiration and surgical biopsy can be performed safely in pregnancy. If surgery is required, then the second trimester is usually preferred. Postoperative suppressive thyroxine therapy should be given if malignant, but radioactive iodine treatment delayed until postdelivery. Papillary or follicular cancers are usually slow-growing so definitive surgery can often be delayed until after pregnancy, and studies have shown that this does not alter long-term prognosis (13).

If a woman has previously diagnosed and treated thyroid cancer then pregnancy does not appear to adversely affect their disease course. Thyroxine doses may need to be increased to maintain suppression of the TSH. Thyroglobulin levels are used outside of pregnancy for disease monitoring, but there is debate as to whether levels increase in normal pregnancy, although this may only be if the woman is iodine deficient.

Postpartum thyroiditis occurs in 5–10% of pregnancies, depending on screening strategy and dietary iodine intake (11). There is a strong association with anti-TPO antibodies, and postpartum thyroiditis occurs in 50–70% of women who have positive titres, and is also more common in women with other autoimmune disorders, such as type 1 diabetes mellitus where the incidence is up to 25%, a family history of thyroid disease, or previous postpartum thyroiditis (14). Some studies have suggested a link between postpartum thyroiditis and postnatal depression, but others found no correlation (14).

The pathogenesis is of a subacute destructive thyroiditis, with lymphocytic infiltration of the thyroid gland. Initially, there is release of preformed thyroxine and then gradual depletion of the thyroid reserve. It is associated with a postpartum rise in anti-TPO antibodies, which may have been suppressed during pregnancy as a result of the altered immune state. Selenium supplementation may reduce the risk of postpartum thyroiditis in women who are anti-TPO antibody positive, due to an anti-inflammatory effect, but more work is required to confirm this (15).

This results in two possible phases to the clinical presentation. An initial hyperthyroid phase, in the first 3–4 months postpartum, which may be asymptomatic or give similar symptoms to Graves’ disease. It is differentiated from the latter by negative TSH-receptor stimulating antibody levels, and low uptake of radioactive iodine. There can then be a hypothyroid phase, usually 4–8 months postdelivery, which is usually symptomatic, although symptoms may be dismissed as being normal for the postpartum state. In one review (14), 32% of cases had only a hyperthyroid phase which then resolved; in 43% the women presented with hypothyroidism, the hyperthyroid phase having been subclinical; and in the remaining 25% a period of hyperthyroidism was followed by one of hypothyroidism.

Most patients will recover spontaneously, and treatment is often not required (14). Anti-thyroid drugs are not appropriate for the hyperthyroid phase, as there is increased thyroxine release, rather than synthesis, but women may require a beta-blocker if palpitations or tachycardia are troublesome (14). The hypothyroid phase often needs a period of thyroxine replacement (14). Treatment should be withdrawn after 6–8 months to check for spontaneous recovery, as only 3–4% will remain permanently hypothyroid. In practice some women fall pregnant again, while being treated with thyroxine and it may be difficult to determine whether they have permanent hypothyroidism or not. The possibility of postpartum thyroiditis as a cause for the need for thyroxine should be remembered, as it may be possible to withdraw thyroxine replacement.

10–25% will have a recurrence following a future pregnancy, so all these women should be advised to have thyroid function tests checked routinely at three to 4 months postpartum (11). If women are anti-TPO antibody positive then 20–30% will develop permanent hypothyroidism within 4 years, and annual measurement of thyroid function tests should be advised (11).

Hyperemesis gravidarum occurs in up to 1% of pregnancies, when severe nausea and vomiting lead to the woman being unable to maintain adequate hydration and nutritional intake. Abnormal thyroid function tests are found in up to two-thirds, usually a picture of biochemical hyperthyroidism with raised fT₄ and/or fT₃ and suppressed TSH, but with negative TSH-receptor stimulating antibodies (6). Apart from weight loss, the woman does not usually have any of the other clinical features of hyperthyroidism.

As discussed above, it is probably due to βhCG acting as a weak stimulator at the TSH-receptor (16). Thyroid function tests will resolve as the hyperemesis settles, and so treatment is mainly supportive, including rehydration and anti-emetics. If thyroid function tests remain abnormal then women should be investigated further as it is important to rule out Graves’ disease, in particular checking for a history of thyroid symptoms predating pregnancy or any Graves’-related eye signs.

Hyperparathyroidism during pregnancy is usually due to primary hyperparathyroidism, unless the patient has chronic renal failure. This may either be a parathyroid adenoma or hyperplasia. Women may be asymptomatic, especially as the hypercalcaemia can improve in pregnancy (2). The main maternal risks are acute pancreatitis and hypercalcaemic crisis, which may present postpartum when fetal demands are removed (17). The risks to the fetus include fetal growth restriction, preterm labour, and intrauterine death (17). Prolonged hypercalcaemia can cause fetal suppression of PTH, which then presents as neonatal tetany and hypocalcaemia, which may be when the maternal diagnosis is first made. Ultrasound of the neck is indicated, but isotope studies should be avoided in pregnancy. If the woman first presents during pregnancy, then conservative management with increased fluid intake and low calcium diet may be sufficient (17). However, a corrected serum calcium persistently above 2.8 mmol/l should prompt consideration of surgery to prevent neonatal hypocalcaemia. If surgery is required for neck exploration and parathyroidectomy then this is best performed during the 2nd trimester (2), but is also possible and appropriate in the early third trimester.

Hypoparathyroidism is usually either secondary to thyroid surgery or due to autoimmune disease. The risks of hypocalcaemia include late miscarriage, fetal hypocalcaemia and secondary hyperparathyroidism, bone demineralization, and neonatal rickets. Similar to hyperparathyroidism, the first presentation may be neonatal hypocalcaemia seizures. 1,25-dihydroxyvitamin D levels increase in pregnancy, but this may not be mediated by PTH, and so there is debate as to whether doses of calcium and vitamin D supplements need to be increased or not during pregnancy to maintain normocalcaemia (2). Serum calcium and albumin levels should be measured monthly to allow appropriate dose adjustment. Supplement doses should be reduced postpartum, as 1,25-dihydroxyvitamin D requirements fall during lactation (2).

Diabetes mellitus is one of the commonest medical problems seen in pregnancy. It can be divided into pre-existing and gestational diabetes, although there is much overlap in terms of fetal and maternal risks, and management during pregnancy.

There are marked changes in carbohydrate metabolism during normal pregnancy to allow adequate glucose supply to the fetus (18). Hyperplasia of maternal pancreatic ß-cells and increased insulin secretion (twofold by term) result in heightened insulin sensitivity early in pregnancy, but as pregnancy progresses there is increasing insulin resistance. This is mainly due to the diabetogeneic effect of many of the placental hormones, including growth hormone, corticotropin-releasing hormone, human placental lactogen, and progesterone. The result is relative impaired glucose tolerance, with transient postprandial hyperglycaemia. In contrast, fasting blood glucose levels tend to fall by 10–20%, due to a combination of fetal glucose consumption, increased peripheral glucose usage and tissue glycogen storage, and reduced hepatic glucose production. The pregnant woman preferentially uses fat for fuel, with increased lipolysis resulting in higher levels of free fatty acids, ketones and triglycerides, especially during starvation, thus allowing glucose and amino acids to be utilized by the fetus.

In addition, the renal tubular threshold for glucose falls in pregnancy, so glycosuria may be detected on dipstick in normal women who do not meet the criteria for gestational diabetes.

Pre-existing diabetes includes both type 1 and type 2. The recent CEMACH report (19) of pregnancies in women with type 1 and 2 diabetes in England, Wales, and Northern Island showed that pre-existing diabetes affected 0.38% of births, with 28% due to type 2, although this ranged from 13% in Wales to 45% in London. Both types of diabetes are increasing in the general population in developed countries, and of particular concern for pregnancy is the growing numbers with type 2 diabetes at a younger age, related to obesity, diet, and more sedentary lifestyles.

Occasionally, women may present for the first time in pregnancy with type 1 diabetes, and obstetricians should be alert to the classical symptoms of polyuria, polydipsia, and weight loss, as diabetic ketoacidosis is associated with significant fetal mortality.

The physiological changes in carbohydrate metabolism discussed above will impact on those women with pre-existing diabetes. The insulin sensitivity of the first trimester makes them much more prone to hypoglycaemia, especially when combined with hyperemesis. This is then replaced by increasing insulin resistance, with an accompanying need for increasing insulin doses. For women with type 1 diabetes, this results in a doubling of their prepregnancy requirements on average by term, and for women with type 2 diabetes, this adds to their existing insulin resistance, and often results in a need for supplemental insulin in addition to diet and metformin.

Due to the alterations in favour of fat metabolism, women with diabetes are prone to ketoacidosis at lower blood glucose levels, and this carries a fetal mortality rate of up to 50%. Therefore, women with type 1 diabetes should be encouraged to test for urine or blood ketones if blood glucose greater than 10 mmol/l or if they feel unwell.

Pregnancy can have an impact on diabetic complications. Of particular concern is the risk of accelerated progression of retinopathy, related to high levels of oestrogen, but also contributed to by the rapid improvement in glycaemic control, which is often achieved in early pregnancy. This risk is low for those with only background retinopathy, but is more significant for those with moderate-severe nonproliferative retinopathy, and the Diabetes in Early Pregnancy Study showed that 29% of the latter group developed proliferative retinopathy during pregnancy (20).

Urinary protein excretion increases in all pregnant women in the second half of pregnancy, and for women with diabetic nephropathy, there may be significant increased proteinuria and/or decline in renal function during pregnancy. This is usually reversible postdelivery in those with only mild renal impairment, but the risk of irreversible decline in renal function becomes greater in those with moderate to severe renal impairment and/or hypertension (21).

The increased fetal and maternal risks associated with diabetes have been known for many years, and are summarized in Table 8.2.5.2 (22). The St. Vincent declaration of 1989 (19) aimed to reduce these risks to those of the general obstetric population, but the CEMACH report (19) found that in 2002–3 there was still a marked difference; with a 3 times greater risk of congenital abnormalities, and significantly increased stillbirth (4.7-fold), perinatal mortality (3.8-fold) and neonatal death (2.6-fold) rates. There is also growing evidence that in utero exposure to hyperglycaemia may have long-term effects on the baby, with adverse metabolic changes in childhood and adult life, including an increased rate of type 2 diabetes.

Traditionally, it was thought to be type 1 diabetes that was associated with adverse pregnancy outcomes, with type 2 diabetes having more of a benign prognosis in pregnancy, but the CEMACH report (19) dispelled this myth, showing that type 1 and type 2 diabetes have ‘different needs but equivalent risks’. Those women with type 2 diabetes are more likely to be socially deprived and from an ethnic minority, and their pregnancies carry a similar increased risk of congenital malformations and perinatal mortality.

The risk of pregnancy complications is usually higher in those with additional risk factors such as pre-existing hypertension and/or renal impairment, and also correlates with the degree of glycaemic control, especially early in pregnancy. Conversely, strict blood pressure and glycaemic control from early in pregnancy can help to reduce complication rates. Women with nephropathy are at particular risk of pregnancy complications, especially pre-eclampsia, FGR, and preterm birth (21). One cohort study of women with type 1 diabetes showed the incidence of pre-eclampsia rose from 6% in those with normal urinary albumin excretion, to 42% in those with microalbuminuria, and 64% in those with overt nephropathy (23).

Although diabetic pregnancies do carry significant increased risks for both mother and fetus, there are measures that can be used to minimize these, beginning preconception and continuing throughout pregnancy to the postpartum period. The most important of these being strict glycaemic control.

It is crucial that women with diabetes receive holistic care during their pregnancies, and their management will require a team consisting of obstetrician, midwife, diabetologist, diabetes specialist nurse, and dietician.

Only 40–60% of pregnancies are planned, and figures are similar for the diabetic population (19). This is of concern, as interventions preconception have been shown to have a significant impact on pregnancy outcome. It is therefore important that healthcare professionals caring for women with diabetes of child-bearing age consider the possibility of future pregnancy in their consultations. This will involve first raising the issue of pregnancy and the impact that diabetes would have; discussing the measures that can be used to minimize adverse outcomes; and the support that is available both pre- and during pregnancy to help achieve a successful outcome. Appropriate contraception should be discussed if pregnancy is not desired at present. Women with type 1 diabetes are usually known to hospital services, but many with type 2 will be managed in primary care with less frequent exposure to secondary-care services.

Ideally, all hospital diabetes services should offer a pre-pregnancy service in conjunction with their obstetric colleagues, but currently the majority do not. Box 8.2.5.1 outlines the important areas to cover in pre-pregnancy counselling. Potentially teratogeneic drugs such as angiotensin converting enzyme (ACE) inhibitors and statins should be stopped pre-conception, and high dose folic acid (5 mg) prescribed.

Strict glycaemic control periconception has been shown to reduce the risk of miscarriage and congenital malformations, and guidance from the National Institute for Clinical Excellence (NICE) (24) is to aim for a HbA1c less than 6.1% prepregnancy, strongly advising against pregnancy if the HbA1c is greater than 10%. Most women with type 1 diabetes will require a basal-bolus insulin regimen to achieve this. Short-acting insulin analogues are safe to use in pregnancy, but there are less data for long-acting analogues, and NICE still recommend isophane as the first-line basal insulin (24). Many clinicians will continue women on long-acting analogues if they are already established on these agents and control is good, especially as there is increasing evidence that they are also safe in pregnancy. The recent Metformin in Gestational (MiG) Diabetes Trial (25) was generally reassuring regarding the use of metformin in pregnancy, and NICE suggests that women with type 2 diabetes can continue on metformin (24), although supplemental insulin may be required, especially as pregnancy progresses. Glibenclamide (glyburide) can also be continued, as it is the only sulphonylurea not to cross the placenta (26), but other oral agents should be stopped.

Women with diabetes should be encouraged to book early in their pregnancy, to allow review by the diabetes team early in the first trimester. The areas outlined in Box 8.2.5.1 should be covered again, especially if the woman did not receive pre-pregnancy counselling.

The main concerns in the first trimester are optimizing glycaemic control, if this has not been achieved prepregnancy, and avoiding teratogeneic drugs. Women with type 1 diabetes may find hypoglycaemia a significant problem during this period, especially if they have hyperemesis or gastroparesis from associated autonomic neuropathy. 5 mg folic acid should be taken until 12 weeks, to reduce the risk of congenital malformations (24). The use of low dose aspirin (75 mg) as pre-eclampsia prophylaxis should be considered (27), especially for those with type 2 diabetes and additional risk factors such as hypertension or obesity.

Home blood glucose monitoring (HBGM) is essential to monitor glycaemic control, as HbA1c falls in pregnancy due to altered red cell turnover, thus altering normal ranges and also correlates less well with adverse pregnancy outcomes. Ideally, HBGM should be at least four times a day, including morning fasting and then postprandial levels. Studies have shown that postprandial values correlate better with fetal growth and risk of macrosomia than preprandial (28), and the current NICE targets are fasting levels less than 6.0 and 1 h postprandial less than 7.8 (24).

Women with diabetes will require more frequent antenatal visits, usually every 1–2 weeks to help reach these glycaemic targets. For those with type 1 diabetes they may be difficult to achieve without significant hypoglycaemia, and the use of a continuous subcutaneous insulin infusion (CSII) pump CSII should be considered (24). Continuous glucose monitoring system (CGMS) may also be of benefit in assessing blood glucose patterns if four times daily monitoring is not sufficient, and has been shown to improve pregnancy outcomes when used intermittently throughout pregnancy (29), probably due to improving previously unrecognized postprandial hyperglycaemia and nocturnal hypoglycaemia.

An ultrasound scan should be offered at 20–24 weeks gestation for detailed assessment of fetal anatomy, especially the fetal heart, and then monthly from 28 weeks to assess fetal growth and liquor volume (24).

Those women with diabetic complications will need careful monitoring for progression of these during pregnancy. Ideally, all women should have ophthalmological assessment prepregnancy, which will need repeating each trimester in those with no or minimal background retinopathy, and more frequently, in those with more severe retinopathy (24). If laser treatment is required, this should ideally be carried out prior to pregnancy, but may need to be repeated during pregnancy. Those with hypertension will need strict blood pressure control, especially if co-existing nephropathy (aim <140/90) (30). ACE inhibitors and angiotensin-2-receptor blockers are usually stopped prepregnancy, unless there is gross proteinuria outside of pregnancy only controlled on these agents in which case they may be stopped once pregnancy is confirmed. Methyldopa, calcium channel blockers and beta-blockers can all be safely used in pregnancy. Regular monitoring of renal function and quantification of proteinuria should be carried out in those with nephropathy, and thromboprophylaxis prescribed (low molecular weight heparin if proteinuria more than 2–3 g/day (24, 30)).

If a woman with diabetes is at risk of/requires pre-term delivery (less than 34 weeks) then corticosteroids should be administered for fetal lung maturity, but she will usually require supplemental insulin and/or a sliding scale to cover this period because of the temporary worsening of glycaemic control.

The NICE guidelines (24) recommend elective delivery at 38 weeks gestation (either induction of labour or Caesarean section), because of the increasing risk of stillbirth, and macrosomia and related problems, if pregnancy is allowed to continue. There is a lack of evidence in this area, with only one randomized trial comparing active induction of labour at 38–39 weeks gestation with expectant management, for insulin-requiring diabetics of which the majority had GDM (31). This showed a reduction in birth weight more than 90th centile (10 cf. 23%, p = 0.02) and shoulder dystocia (0 vs. 3%) in the active management group, with no difference in Caesarean section rate (25 vs. 31%), and half of the women in the expectant management group required induction eventually for obstetric reasons. Clinicians may extend the 38-week cut-off on an individual basis depending on the woman’s glycaemic control, insulin requirements, fetal measurements, and favourability for induction, for example, in a woman with excellent glycaemic control, normally grown fetus, and an unfavourable cervix, but most would not be comfortable for pregnancy in a woman with diabetes to go beyond 40 weeks gestation. The main concern is that many of these intrauterine deaths cannot be predicted, despite CTG and ultrasound monitoring. The downside of this policy is that the risk of Caesarean section (both emergency and elective) is high (67% in CEMACH study (19)), although the study above (31) suggests that this is not improved by expectant management.

Once a woman with diabetes is in labour, capillary blood glucose measurements should be made hourly, and an intravenous insulin and dextrose sliding scale used to maintain blood glucose values between 4 and 7 mmol/l (24).

Immediately after delivery of the placenta insulin requirements will fall back to prepregnancy levels, and the intravenous insulin infusion rate can usually be halved. Those on subcutaneous insulin prepregnancy should resume this as soon as possible, usually with their first meal, reverting to prepregnancy doses or lower, especially if breastfeeding. If the woman was managed with oral hypogylcaemics and she intends to breastfeed, then metformin and glibenclamide can be continued/resumed (24), but other agents should be withheld until after the period of breastfeeding, and she may need to continue supplemental subcutaneous insulin, albeit at lower doses.

The baby should be fed as soon as possible (within 30 min) and then every 2–3 h, to reduce the risk of neonatal hypoglycaemia. Neonatal blood glucose should be tested at 2–4 h of life. The aim should be to keep babies with their mothers, unless significant complications develop, rather then admit electively to the special care baby unit (24).

On discharge from hospital, arrangements should be made for women to return to their routine diabetes care arrangements. Contraception should be discussed, and the importance of accessing prepregnancy care if they are planning future pregnancies.

The WHO defines gestational diabetes (GDM) as ‘carbohydrate intolerance resulting in hyperglycaemia of variable severity with onset or first recognition during pregnancy’ (32). It will therefore include those with pre-existing diabetes (usually type 2) who have only been identified during pregnancy, and also those who would fall in the category of ‘impaired glucose tolerance’, rather than frank diabetes if using non-pregnancy criteria.

GDM usually develops in the second half of pregnancy due to the increasing insulin resistance and changes in carbohydrate metabolism discussed above. Women are generally asymptomatic and, hence, the need for biochemical screening, as discussed below. Sometimes the diagnosis may be made retrospectively following an intrauterine death or delivery of a macrosomic baby.

The prevalence of GDM will depend on the ethnic mix and other demographics of the particular population, with one UK study showing an overall incidence of 1.5%, but varying from 0.5% in the White population to 4.4% in those of Indian descent (24). It was also dependent on the screening criteria used.

The diagnosis of GDM is important for three main reasons, most notably the association between maternal hyperglycaemia and an increased risk of adverse pregnancy outcomes, such as macrosomia (33). Secondly, women with GDM have a much higher risk of developing type 2 diabetes in the future (up to 70% depending on the population and time period studied (34)), and early lifestyle modification may be able to reduce this. Thirdly, those with pre-existing diabetes, which has not previously been recognized, have an increased risk of congenital malformations and progression of diabetic complications, as discussed in the previous section, and should be managed accordingly if there is a high suspicion that this is the case.

The threshold at which glucose intolerance should be labelled as ‘gestational diabetes’ and/or treatment initiated to lower glucose levels, has been controversial. Few would disagree that those fulfilling the criteria for ‘frank diabetes’ should be treated, but there has been concern that including women at the ‘milder’ end of the hyperglycaemia spectrum, i.e. those with ‘impaired glucose tolerance’, will in and of itself increase the risk of medical interventions, such as induction of labour and Caesarean section, without significantly improving fetal outcome. The ACHOIS study (35) has been influential in helping to define practice in this area. This showed that treating women with 2-h values of 7.8–11.0 mmol/l (inclusive) on a 75 g oral glucose tolerance test (OGTT) reduced a composite outcome of perinatal morbidity and mortality from 4% to 1%, without increasing the Caesarean section rate, despite a higher rate of induction of labour. The recent Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study (33) has provided further evidence that there is a continuum of risk between glucose concentration and fetal weight, and adverse pregnancy outcomes, with no clearly defined threshold. The current NICE recommendations (24) are therefore to use the WHO diagnostic criteria for gestational diabetes, outlined in Table 8.2.5.3, based on a two hour 75 g OGTT.

There has also been controversy over who should be screened, with some centres advocating universal testing, while others favour the use of risk factors. NICE has now recommended the latter (24), and women with any of the risk factors detailed in Table 8.2.5.4 should be offered an OGTT at 24–28 weeks gestation. Those with GDM in a previous pregnancy should be screened earlier at 16–18 weeks, with either an OGTT or HBGM, and the test repeated at 28 weeks if the results of the first are normal, as the recurrence rate is high (75% if previously insulin treated).

Even if a woman has no risk factors, or the screening OGTT is normal, then testing later in the pregnancy may be required if there is concern over a fetus being large for dates, or polyhydramnios is detected on ultrasound.

Unless the woman has previously unrecognized diabetes which has only been diagnosed in pregnancy, GDM does not carry increased risk of congenital malformations. The main risks for the fetus relate to macrosomia and associated complications such as shoulder dystocia, and overlap with those outlined in the ‘late’ and ‘neonatal’ sections of Table 8.2.5.2 for pre-existing diabetes, although the incidence is lower (33). There is also an increased risk of pre-eclampsia.

Management during pregnancy is similar to that for type 2 diabetes, and identical blood glucose targets are recommended (24). Advice regarding diet, exercise and weight gain is crucial, and for 80–90% this will be sufficient to achieve the glycaemic targets (24). In the remaining 10–20%, metformin, glibenclamide, and/or insulin will need to be added. Monthly growth scans should be performed from 28 weeks gestation, and tight glycaemic control is particularly important in those where macrosomia and/or polyhydramnios are detected.

NICE recommendations do not separate GDM from pre-existing diabetes regarding timing of delivery, and therefore induction of labour or elective Caesarean section should be offered at 38 weeks gestation (24). As with pre-existing diabetes this may be extended, especially if the woman has not required insulin.

For labour and delivery, capillary blood glucose measurements should be maintained between 4 and 7 mmol/l. Those women who have required insulin during pregnancy will usually need an intravenous insulin and dextrose sliding scale to achieve this, but those on diet and/or oral hypoglycaemics may not.

Immediately after the birth, all insulin and oral hypoglycaemics can be stopped. Blood glucose levels should be checked prior to discharge to exclude persisting hyperglycaemia (24).

To exclude pre-existing diabetes a fasting plasma glucose level should be measured at the 6-week postnatal check, and yearly after that (24). Even if this is normal, it is crucial to stress the importance of continuing the lifestyle measures, such as weight control, diet, and exercise, to reduce the risk of future type 2 diabetes. There is a high risk of recurrence of GDM, and women should be offered an early OGTT or self-blood glucose monitoring in any future pregnancy (24).

In pregnancy, serum total and free cortisol concentrations and urinary cortisol excretion increase, due to placental corticotrophin-releasing hormone (CRH) production-stimulating adren corticotrophic hormone (ACTH) release from both pituitary and placenta (36). Hepatic synthesis of cortisol-binding globulin (CBG) increases two to three fold, so the rise in total cortisol is greater than that of free cortisol. The diurnal variation in cortisol and ACTH is maintained, but suppression of cortisol by exogenous steroid (e.g. dexamethasone) is blunted, especially later in pregnancy (36).

There are increased plasma levels of angiotensin II (2–4-fold), aldosterone (3–10-fold), and renin activity (2–3-fold) by the third trimester, due to stimulation of the renin-angiotensin-aldosterone system by reduced vascular resistance, fall in blood pressure and decreased vascular responsiveness to angiotensin II (36, 37).

The increase in sex-hormone binding globulin (SHBG) leads to increased total testosterone concentrations. By the end of the third trimester free testosterone and androstendione levels are higher than nonpregnant, but dehydroepiandrosterone sulphate (DHEAS) falls due to increased clearance.

Levels of urinary catecholamines, metanephrines, and vanillylmandelic acid (VMA) are not altered by pregnancy (36).

Cushing’s syndrome is rare in pregnancy, with less than 150 reported cases, due to associated anovulatory infertility (36). The pattern of causes differs in pregnancy, with around 60% due to ACTH-independent adrenal disease (50% adenoma and 10% carcinoma) compared with less than 20% outside of pregnancy, and the remaining 40% due to bilateral adrenal hyperplasia or pituitary adenoma (Cushing’s disease), with cases of ectopic ACTH being rare (36).

Clinical features can be mistaken for pregnancy-related changes, including striae, acne, hirsuitism, weight gain, hypertension, diabetes mellitus, and headache, although bruising and proximal myopathy are more discriminatory and the striae are usually vivid purple in colour with an extensive distribution.

Investigations should be carried out as for non-pregnant, but using pregnancy-specific ranges, as normal pregnancy is a hypercortisolaemic state (36). This can make diagnosis more difficult as, for example, a low-dose dexamethasone suppression test may fail to suppress even in normal pregnancy. As an adrenal source is more likely in pregnancy, measurement of plasma ACTH and imaging of the adrenal glands will be helpful. CT and/or MRI imaging of the adrenal or pituitary can be carried out safely in pregnancy, including with gadolinium contrast, but there is limited experience with the CRH stimulation test and inferior petrosal sinus sampling.

If Cushing’s syndrome is undiagnosed or inadequately treated then there can be significant maternal and fetal morbidity and mortality (38). Maternal complications include hypertension (up to 70%), poor wound healing (e.g. after Caesarean section), an increased risk of pre-eclampsia and gestational diabetes, and occasionally cardiac failure. The fetus is partly protected, as placental 11-β-hydroxysteroid dehydrogenase converts 85% of maternal cortisol to the biologically inactive cortisone and levels of CBG are raised (38), but there are still increased rates of spontaneous miscarriage, fetal growth restriction, preterm delivery and perinatal mortality, which are not completely explained by maternal diabetes or pre-eclampsia. There is also a small risk of neonatal adrenal suppression. In comparison, women who have previously treated Cushing’s usually do well in pregnancy.

The treatment for both adrenal and pituitary Cushing’s is ideally surgery, and this has been carried out successfully in pregnancy, when the fetus is too immature to be delivered prior to surgery. There is limited experience of drug treatment of adrenal Cushing’s in pregnancy. Metyrapone has been used, but is associated with a significant risk of severe hypertension, and ketoconazole is teratogeneic in animal studies (36). Pituitary irradiation can be considered in pituitary Cushing’s.

Phaeochromocytoma is a rare cause of hypertension in pregnancy, with a prevalence at term of 1:54 000 (36) and less than 250 reported cases (39).

Clinical features, in additional to hypertension, are similar to those outside pregnancy, the classic triad being episodic sweating, headache, and tachycardia/palpitations, although pregnant women are less likely than nonpregnant to present with these. Other symptoms include anxiety, dyspnoea, weakness, and hyperglycaemia. Hypertension is episodic in only 50%, being sustained in the rest, and may often be misdiagnosed as pre-eclampsia. Occasionally, hypertension is only found in the supine position, when the gravid uterus compresses the tumour.

Diagnosis is as for non-pregnant, with 24 h urinary fractionated (rather than total) catecholamines and metanephrines (metabolites of catecholamines), and increasingly plasma fractionated metanephrines. Normal ranges are not altered by pregnancy (39), but results can be affected by other factors, such as stress or medications. Once the diagnosis has been confirmed biochemically, tumour localization should be carried out, usually with MRI or ultrasound in the pregnant woman, rather than CT. 123-I-metaiodobenzylguanidine (MIBG) scan, to aid in localizing norepinephrine uptake, should be avoided in pregnancy. Genetic testing should be carried out if the diagnosis is confirmed, since up to 25% of cases are linked to familial syndromes, including MEN2 and neurofibromatosis type 1.

Traditionally, both maternal and fetal mortality has been high (40–50%) (39), especially if the diagnosis is not made antenatally. Potentially fatal hypertensive crises can be precipitated by labour, delivery, opiates, or general anaesthesia. Outcomes have improved in latter years, and the latest case series (40) quotes 4% maternal mortality and 11% fetal mortality overall, with the figures being 2 and 14%, respectively, for the 83% of cases diagnosed antenatally.

Initial treatment is medical; first with α-blockade to control blood pressure, and then beta-blockade to control tachycardia. Oral or intravenous phenoxybenzamine, oral prazosin, and intravenous phentolamine can all be used safely in pregnancy as α-blockers. There have been concerns about fetal growth restriction if certain β-blockers are used at high dose for long periods in pregnancy, but the benefits in this situation far outweigh any potential risks, and they should be used as necessary. There are few data on the use of the catecholamine synthesis inhibitor metyrosine in pregnancy (36).

Definitive treatment of phaeochromocytomas is surgery, usually laparoscopically, but the timing of this is more controversial. It the tumour is identified prior to 24 weeks’ gestation, then surgery is usually carried out as soon as pharmacological blockade is achieved, which will take at least 7 days. If diagnosis is after 24 weeks’ gestation, then the general consensus is to delay surgery until the fetus is more mature, usually after 34 weeks’, and then deliver the fetus prior to performing surgery. Elective caesarean section is thought to be preferable to vaginal delivery (36), and removal of the tumour can either be carried out at the same operation or, increasingly, after a delay for a period postnatally.

Classical congenital adrenal hyperplasia (CAH) is rare in pregnancy. This is probably due to a combination of factors including poor compliance with treatment resulting in hyperandrogenism and suboptimal surgical reconstruction of the vaginal introitus, but also poor body image even after successful reconstructive surgery. Those with the salt-losing form appear to have much lower fertility rates than those with the simple virilizing form, but probably because they are less likely to attempt to conceive (41). There is also some suggestion that prenatal exposure of the brain to excess androgens may influence later sexual behaviour, including fewer heterosexual relationships for women with CAH.

Those desiring fertility are often swapped to nocturnal dexamethasone, as a more potent glucocorticoid, to achieve maximal ACTH suppression. For those who do conceive, higher rates of miscarriage, pre-eclampsia, gestational diabetes and fetal growth restriction have been reported. 17-hydroxyprogesterone and androstendione levels are raised in pregnancy, so cannot be used to monitor adequate androgen suppression, but free and total testosterone levels are reduced or unchanged (42). Steroid replacement therapy should continue as outside pregnancy, usually with prednisolone or dexamathasone as glucocorticoids, and additional fludrocortisone for those with the salt-losing form. Doses do not usually need to be routinely altered, but may need to be increased if there are additional stresses during pregnancy, such as hyperemesis, and should be increased to cover labour, when intravenous hydrocortisone (50–100 mg 8–12 hourly) is usually substituted for 24 h (42).

The main issues regarding management are usually around the risk of an affected child. CAH is an autosomal recessive condition, and the carrier gene frequency ranges from 1 in 17 to 1 in 400 depending on the population. Therefore, the risk of a homozygote mother having a child with CAH will be up to 1 in 34 if the father’s carrier status is unknown, and 1 in 2 if he is a known carrier. The issue to be addressed during pregnancy is the use of intrauterine therapy to reduce the risk of virilization of a female fetus (male fetuses are not at risk) (43). This requires high-dose oral dexamethasone to be given to the mother (1–1.5 mg/day), which crosses the placenta (as less susceptible than other steroids to placental aromatase) and suppresses fetal ACTH and, therefore, adrenal androgen production. The strategy is controversial, as treatment ideally needs to be started prior to 5 weeks gestation, before the start of fetal androgen production and genitalia development, when it is not yet known whether the fetus is affected or not. The fetal sex can be determined from a maternal blood sample at 9 weeks gestation, and steroids stopped if the fetus is male, and then chorionic villus sampling at 10–11 weeks gestation for prenatal diagnosis to identify if the fetus carries the genetic mutation (36). This will mean that three out of four fetuses are treated unnecessarily with high dose steroids for up to 6 weeks. A similar scenario exists if the couple have had a previously affected child and they have been found to be heterozygote for a CAH mutation, when the risk of an affected female fetus is 1 in 8. In both cases, the decision to start antenatal steroids needs to be taken after careful counselling of the couple. There is obviously concern about the potential side effects for both fetus and mother of prolonged high-dose dexamethasone treatment in pregnancy, as long-term follow-up data are lacking. If the fetus is found to be an affected female then high-dose dexamethasone should be continued until term, to prevent late masculinization and also potential neuroendocrine effects of exposure to high androgen levels. If the fetus is a male or unaffected female then the mother can revert back to her usual steroid maintenance regimen. Placental aromatase is very effective at converting high maternal androgen levels to oestrogens (42), thus protecting the female fetus, who only appears to be at risk of virilization if she herself is affected.

Women with non-classical CAH often have anovulatory infertility, and may require glucocorticoids alone or in combination with clomiphene to conceive (44). They may have a higher miscarriage rate (44). Although less common than with classical CAH, women with the nonclassical form may still have the potential risk of a child with the classical form, as they can be compound heterozygotes with both a classical and a variant allele (44), and therefore should be referred for genetic counselling.

Only around 30 cases of Conn’s syndrome or primary hyperaldosteronism have been reported in pregnancy (36). Usually, it has been diagnosed prepregnancy, but may be identified for the first time during the work-up for a women presenting with hypertension in pregnancy.

The cardinal features are hypertension and hypokalaemia. Diagnosis requires a raised aldosterone level and suppressed renin level, but the pregnancy-related increase in both of these must be taken into account (37). Imaging with ultrasound or MRI of the adrenal glands usually shows an adrenal adenoma, although adrenal carcinoma or bilateral adrenal hyperplasia are also possible causes. Abdominal CT and adrenal vein sampling are usually avoided during pregnancy.

Blood pressure usually increases in the second half of pregnancy, but in Conn’s the hypertension and hypokalaemia may improve due to anti-mineralocorticoid effects of elevated progesterone levels at the renal tubule (36). There is often deterioration postpartum.

Risks to the fetus are mainly those associated with any cause of pre-existing hypertension, including pre-eclampsia, fetal growth restriction, and placental abruption, with associated increase in perinatal mortality and preterm delivery rates. These are minimized if blood pressure remains well controlled. Prophylaxis with low-dose aspirin should be considered.

The mainstay of management during pregnancy is treatment of hypertension. Surgical removal of an adrenal adenoma can usually be delayed until after delivery, although there are reports of successful adrenalectomy during pregnancy, usually in the 2nd trimester (36). Standard anti-hypertensive agents used during pregnancy are usually adequate, although potassium supplements may need to be added. Amiloride can also be used (36), sometimes requiring high doses, but spironolactone should be avoided as it is an anti-androgen and may lead to feminization of a male fetus (36).

Addison’s disease, or primary adrenal failure, is only rarely encountered in pregnancy. The majority of cases in the UK will be due to autoimmune destruction of the adrenal gland, and will usually have been diagnosed pre-pregnancy.

Occasionally, it can present in pregnancy, when diagnosis may be delayed if the onset is insidious, as many of the symptoms may overlap with those of normal pregnancy, particularly in the first trimester, including vomiting, hyperpigmentation and low blood pressure (36). Rarely, it can present as an abdominal emergency with pain, vomiting, and shock, secondary to adrenal haemorrhage or thrombosis.

As in the nonpregnant, diagnosis is made by a low 9 a.m. cortisol and raised ACTH levels, and inadequate cortisol response to synthetic ACTH (Synacthen test). Pregnancy-related alterations in the cortisol axis should be taken into account (36), as an abnormally low cortisol level for pregnancy, may fall into the normal non-pregnant range.

If women are on adequate glucocorticoid and mineralocorticoid replacement (usually hydrocortisone and fludrocortisone), then there should be no adverse impact on the pregnancy (45). Because of the association with other autoimmune conditions, women should be tested for thyroid dysfunction and diabetes mellitus. Adrenal auto-antibodies do cross the placenta, but do not appear to have any significant clinical effect.

Women should continue with their usual steroid regimen throughout the pregnancy, with doses only needing to be increased to cover intercurrent illnesses, hyperemesis, and intravenous or intramuscular hydrocortisone substituted peridelivery (36). Women with Addison’s are particularly susceptible to becoming hypotensive with the physiological diuresis following delivery, and this can be prevented by slowly weaning over the 1st week postpartum the higher dose of steroids used to cover delivery, rather than reverting back to pre-pregnancy doses after 24 h as for other patients on maintenance steroids.

The volume of the anterior pituitary gland can more than double during normal pregnancy (46). Prolactin levels increase from the first trimester, and by term are 10-fold greater than in the non-pregnant, in preparation for lactation (47). LH and FSH are suppressed by the high levels of oestrogen and progesterone. Pituitary production of growth hormone falls from mid-pregnancy, as levels of placental growth hormone and related human placental lactogen (hPL) increase (48). Changes in ACTH and TSH have already been discussed.

In the posterior pituitary, antidiuretic hormone (ADH) levels usually remain unchanged, although there is increased metabolic clearance of ADH due to placental vasopressinase (49). Oxytocin levels increase in preparation for labour and lactation (50).

The most common hormone-secreting pituitary tumours are prolactinomas. Most will have been diagnosed prior to pregnancy, because of the associated oligo/amenorrhoea, infertility, and galactorrhoea (51), and will rarely present for the first time in pregnancy.

Many women will require treatment of hyperprolactinaemia prior to pregnancy to restore fertility, but there is no evidence for an association of prolactinomas with adverse pregnancy outcomes.

The main concern during pregnancy is expansion of the adenoma, due to the stimulatory effect of oestrogen on lactotrophs, which could lead to impingement on the optic chiasm. The risk appears to be small (<2%) with microadenomas, but may be as high as 30% for macroadenomas, although the latter is reduced if the tumour is debulked prior to pregnancy (51). As there is a progressive physiological rise in prolactin levels during normal pregnancy (47), these cannot be used as a marker of increasing tumour size and should not be measured routinely.

Women with microadenomas can usually stop treatment with dopamine agonists once pregnancy is confirmed. They should be reviewed once each trimester for assessment of visual fields, and asked to report urgently if they develop a severe headache, visual disturbance, or polyuria. Symptoms of an expanding tumour should be investigated further with formal visual field testing and pituitary MRI. It is more difficult to advise those with a macroadenoma, but many will elect to stop treatment during pregnancy, and they should be monitored more closely. Treatment with dopamine agonists can be continued or initiated in pregnancy, and data regarding both bromocriptine and cabergoline are reassuring concerning risks to the fetus, although there has been more experience with bromocriptine (51). Rarely, trans-sphenoidal surgery and/or pituitary radiotherapy are required.

Management of labour and delivery is not affected, unless there is an expanding tumour, when elective instrumental delivery may be required for the second stage if there is concern regarding raised intracranial pressure. Women should be able to breastfeed, unless they are receiving a dopamine agonist when it may be more difficult, and there is no evidence that breast feeding causes an increase in tumour size (51). Therefore, unless there is a clinical indication, re-introduction of dopamine agonists should be delayed until the woman has finished breast-feeding (51).

Acromegaly caused by a growth hormone-secreting pituitary adenoma is much more uncommon in pregnancy than prolactinomas, with less than 70 reported cases (52). It is a rare tumour anyway, and may also be associated with subfertility, if there is hyperprolactinaemia due to co-secretion or pituitary stalk compression.

Diagnosis is more difficult in pregnancy, as insulin-like growth factor-1 (IGF-1) increases in normal pregnancy (48), and growth hormone assays may also detect placental growth hormone or hPL.

Growth hormone-secreting pituitary adenomas are less likely to expand during pregnancy, but similar surveillance should occur as for prolactinomas.

Growth hormone does not cross the placenta, so the only increased risks for the fetus are those associated with active acromegaly, in particular, maternal impaired glucose tolerance and hypertension. Women should be screened for gestational diabetes and have their blood pressure carefully monitored.

If there is tumour expansion then management is similar to that for a prolactinoma. growth hormone-secreting adenomas tend to respond less well to dopamine agonists, and the somatostatin analogue octreotide may need to be used, although there is little experience with this in pregnancy (51).

As with many other endocrine problems, this has usually been diagnosed and treated prior to pregnancy, as untreated it is associated with infertility. There are specific causes that may present during pregnancy or postdelivery, and these include Sheehan’s syndrome and lymphocytic hypophysitis.

Sheehan’s syndrome usually presents post-partum, associated with massive postpartum haemorrhage (PPH) (53). The anterior pituitary is particularly vulnerable to hypotension due to the marked expansion that occurs during pregnancy. Symptoms of note in the postpartum woman include failure of lactation and persistent amenorrhoea, although the presentation can be more acute. Sheehan’s syndrome is now seen much less frequently in developed countries, as obstetric management of PPH has improved.

Lymphocytic hypophysitis is an uncommon autoimmune disorder, but may be seen in late pregnancy or postpartum (53). The pathogenesis involves an inflammatory infiltrate of the anterior pituitary, leading to pituitary expansion and, therefore, it presents with similar symptoms to an enlarging pituitary tumour. Lymphocytic infiltration is followed by destruction of pituitary cells, and then usually replacement by fibrosis. Antipituitary antibodies can be found, and in 20% it is associated with autoimmune diseases affecting other glands including thyroid and adrenal.

If presenting for the first time in pregnancy or postpartum, then investigations should be carried out as in the nonpregnant, including baseline pituitary function tests and pituitary MRI. Definitive diagnosis of lymphocytic hypophysitis requires pituitary tissue for histology, but MRI features can be helpful in distinguishing it from an adenoma and avoiding biopsy (53).

Specific management will depend on the cause. Corticosteroids have been used to treat lymphocytic hypophysitis (53), although many undergo pituitary surgery if misdiagnosed as a pituitary tumour. Some cases resolve spontaneously, as can also be the case with Sheehan’s.

Regardless of the cause, treatment with end-organ hormone replacement, should be continued or initiated in the pregnancy, depending on the specific hormone deficits. This usually includes hydrocortisone and thyroxine. Corticosteroid doses should be increased in specific circumstances as discussed above. If a woman with hypopituitarism wishes to conceive then she may require ovulation induction with gonadotropins, and successful pregnancies have been reported after both Sheehan’s and lymphocytic hypophysitis.

If hypopituitarism is adequately treated there should be no adverse impact on the pregnancy for either mother or fetus, whereas undiagnosed or inadequately treated there are increased risks, including miscarriage, stillbirth, and maternal hypoglycaemia and hypotension. Lymphocytic hypophysitis can recur in subsequent pregnancies.

The incidence and causes of diabetes insipidus (DI) are generally as for the non-pregnant population, although transient DI can be seen with the pregnancy-specific conditions of pre-eclampsia, HELLP (Haemolysis, Elevated Liver enzymes, and Low Platelets) syndrome, and acute fatty liver of pregnancy (AFLP) (54).

Established or subclinical DI may deteriorate during pregnancy, due to physiological changes affecting vasopressin (anti-diuretic hormone (ADH)), including increased glomerular filtration rate, placental production of vasopressinase (responsible for ADH breakdown), and increased renal resistance to ADH (probably mediated by prostaglandins) (49).

Diagnosis is usually by a prolonged fluid deprivation test, but this should be avoided in pregnancy due to the harmful effects of dehydration. Simple measurement of paired samples of urine and plasma, for osmolality and sodium, may be sufficient to demonstrate inappropriately raised plasma sodium and osmolality in the context of a dilute urine and polyuria. If this is insufficient, then an overnight fluid deprivation test could be undertaken with the woman as an inpatient. Once the diagnosis is established then the cause should be investigated, in particular including those specific to pregnancy.

If DI is adequately treated then there should be no adverse effects on the pregnancy. No special precautions are required for labour and delivery, and the woman can breastfeed. Conversely, if the condition is undiagnosed or inadequately treated then there are the risks of severe dehydration and electrolyte disturbances, which may lead to maternal seizures or oligohydramnios.

Intranasal DDAVP, the synthetic analogue of ADH, is safe to use in pregnancy (53), and is the treatment of choice for cranial or transient DI (especially, as it has 75 times less oxytocic action than arginine vasopressin, which could stimulate uterine activity), and is relatively resistant to vasopressinase. For nephrogenic DI, chlorpropamide is usually avoided in pregnancy because of the risk of fetal hypoglycaemia, and a thiazide diuretic or carbamazepine are alternatives, although there is an increased teratogenicity risk with the latter (54). Serum electrolytes and plasma osmolality should be monitored closely, to ensure adequate treatment, whilst avoiding water retention and hyponatraemia.