Chapter Thirty-Five. Diabetes mellitus and other metabolic disorders in pregnancy
Introduction
Pregnancy in some endocrine disorders is rare and management is sometimes based on limited observation and clinical judgement rather than on evidence-based criteria (Hague 2001). However, diabetes mellitus is by far the most common of these diseases and much progress has been made in its management. Normal metabolism is discussed in Chapter 23 and readers may wish to remind themselves of normal carbohydrate utilisation.
Diabetes mellitus
Diabetes mellitus is a group of disorders characterised by impaired carbohydrate utilisation caused by an absolute or relative deficiency of insulin production by the endocrine pancreas. A total of 180 000 000 people worldwide have diabetes and this figure will double by 2030 (WHO 2008). The changes in uncontrolled diabetes are a rise in blood glucose (normal range 3–5 mmol/L) and increases in glycogen breakdown (gluconeogenesis), fatty acid oxidation, ketone production and urea formation. There is also a reduced production of glycogen, lipid and protein in cells of tissue such as muscle and adipose tissue that are normally dependent on insulin (Brook & Marshall 2001).
Pathophysiology
The inability of the tissues to receive enough glucose results in inhibition of glycolytic enzymes and activation of the enzymes involved in gluconeogenesis (Bewley 2004). This results in more blood glucose than can be utilised. Excessive glucose passes into the renal filtrate and glycosuria occurs. Glucose is osmotically active and pulls water after it, resulting in polyuria and dehydration. Thirst increases to try to maintain adequate body fluids (Brook & Marshall 2001).
The body tries to mobilise energy from fats and proteins. Urea, produced as a by-product of amino acid metabolism, is excreted in the urine. Fatty acid release always results in ketogenesis but in the diabetic person excess ketones are produced and excreted in the urine, and on the breath. The ketones in the blood cause metabolic acidosis and lowering of pH (Bewley 2004, Brook & Marshall 2001). The buffer systems attempt to correct this and become exhausted. Other metabolic processes are disturbed and all body systems are affected. If untreated, acidosis leads to shock, coma and death (Tortora & Grabowski 2000).
Diabetes mellitus in pregnancy
Diabetes mellitus in pregnancy includes type 1 or insulin-dependent diabetes (IDDM). Recently, more pregnant women were found to have type 2 or non-insulin-dependent diabetes (NIDDM) (Feig & Palda 2002). Gestational diabetes (GDM) is diagnosed if diabetes develops for the first time in pregnancy.
Aetiology
Type 1 diabetes mellitus (IDDM)
This is rare before 9 months and peaks at 12 years of age and there is an almost total lack of insulin production. Hyperglycaemia, polyuria and ketosis are present at onset and insulin treatment is necessary. There are differences between populations both within and between countries. IDDM accounts for about 10% of diabetes in the developed countries. It is thought to be more prevalent amongst white people than amongst non-white people and the incidence is highest in Finland and lowest in Japan. There is a seasonal variation in the onset of IDDM, with more new cases in the northern hemisphere being reported in autumn and winter.
The Coxsackie virus B4 (CB4) may be implicated in the onset of type 1 diabetes (Saunders 2002). This common childhood infection causes a high fever, sore throat and headache which lasts for about 3 days. The CB4 virus may destroy pancreatic islet cells and trigger an autoimmune response in genetically susceptible children. There is a long period of subclinical diabetes as β cells are progressively destroyed and islet cell antibodies have been found years before the onset of clinical signs. There is evidence that α-cell function is impaired, leading to excess glucagon, which exacerbates hyperglycaemia. Autoantibodies have been found in most people with juvenile-onset diabetes.
Type 1 diabetes mellitus is subdivided into two distinct types. IDDM type 1 A develops in childhood and is thought to be due to a genetic–environment interaction. There is a link with the human leucocyte antigen HLA-DR4. The predisposing gene is carried on chromosome 6. About 12% of newly diagnosed diabetics of this type have a first-degree relative with the disease. IDDM type 1B tends to occur later in life, between the ages of 30 and 50 years, and is probably an autoimmune disorder linked to HLA-DR3 (Anastassios 2008).
Type 2 diabetes mellitus (NIDDM)
This is four times as common as IDDM and its incidence is increasing globally (WHO 2008). The onset is usually in later life in obese people. NIDDM occurs in pregnancy more frequently as women delay conception (Hague 2001). It varies with ethnicity, suggesting a genetic–environment interaction (Feig & Palda 2002). A form of NIDDM called maturity-onset diabetes of the young (MODY) is caused by an autosomal dominant gene. Sufferers are usually of normal weight and under 25 years of age.
Amyloid deposits associated with islet cell destruction are seen in about 25% of cases, usually correlating with the person’s age and severity of disease. The ratio of α to β cells is normal and there is no reduction of insulin in the blood, but in obese people insulin has a decreased ability to influence cellular uptake of glucose. This is perhaps due to increased circulating free fatty acids, although reaction of other substances has also been proposed (Anastassios 2008). There is increased insulin resistance because of decreased numbers of cellular insulin receptors.
The incidence of NIDDM in pregnancy is difficult to assess as some women taking insulin may have type 2 diabetes, especially in susceptible populations such as East-Asian women. Many women may be undiagnosed prior to pregnancy. Pregnant women with type 2 diabetes are likely to be obese and to suffer hypertension and hyperlipidaemia. Screening women before pregnancy or early in the first trimester of pregnancy might help to differentiate between women with NIDDM and those with gestational diabetes (Feig & Palda 2002) but the dangers are the same.
Gestational diabetes mellitus (GDM)
Women with impaired glucose tolerance may develop diabetes in stressful situations. In pregnancy this is called gestational diabetes; these women may well go on to develop type 2 diabetes in later life, particularly if obese (Metzger et al 2007). GDM occurs in 2% of all pregnancies, mostly in the third trimester. Following delivery, glucose metabolism may return to normal.
Population differences in the incidence of GDM
Studies have been conducted into the incidence of gestational diabetes between different ethnic groups. There was found to be an increased risk in women of lower socioeconomic class, older women, obese women and those with infertility (Modder 2006). In Great Britain, 49% of women are from ‘black, Asian and other minority groups’; 9% are type 1 diabetic (Modder 2006).
Shelley-Jones et al (1993) in Australia compared the physiology of 15 women with normal glucose tolerance, 16 Caucasian women with GDM and 19 Asian-born women with GDM. They found that:
• Caucasian women, unlike the Asian women, were obese compared to the control group of women.
• Both groups of women with GDM had a similar abnormal insulin response to a glucose load.
• Fasting serum triglycerides were increased in all women with GDM. Asian women had significantly lower serum cholesterol levels than the Caucasian women, with or without GDM.
They concluded that it is difficult to know whether the differences in obesity and serum cholesterol ‘reflect a dietary difference or a major difference in lipid metabolism’.
Glucose tolerance test
The glucose tolerance test (GTT) can be used to confirm the presence of diabetes. Fasting blood and urine specimens are taken, then a 75 g glucose drink is given. Venous blood samples are then taken at intervals. Normally, blood glucose rises but returns to normal (3–5 mmol/L) within 2 h. The following abnormalities occur in glucose impairment (Porterfield & White 2007):
• A fasting plasma glucose >7 mmol/L.
• A blood glucose level >10 mmol/L after 2 h.
• If the 2 h blood glucose level is between 7 and 10 mmol/L, glucose tolerance is impaired.
General pathological effects of diabetes mellitus
The metabolic changes and physiological effects of diabetes mellitus are profound (Fig. 35.1). Seventy years ago young diabetics usually died within 2 years of onset. The identification of insulin by Banting and Best led to survival, but the acute and long-term effects of diabetes mellitus became apparent. Deaths from cardiovascular disease and renal disease are much more common than in the general population. Acute complications include hypoglycaemia and diabetic ketoacidosis. Pregnant women who have had IDDM for more than 10 years are significantly more at risk of associated cardiovascular, ophthalmic, renal and neuropathic problems, and in general diabetic women are at risk of a poor pregnancy outcome, particularly if diabetic control has been less than ideal (Hague 2001, Stenhouse 2007).
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| Figure 35.1 Diabetes mellitus. (A) Metabolic changes. (B) Physiological effects. (From Hinchliff S M, Montague S E 1990, with permission.) |
Hypoglycaemia
Hypoglycaemia occurs in 90% of IDDM sufferers and is also known as insulin shock or insulin reaction. Diabetic patients aim to prevent hypoglycaemia by diet and insulin administration. The balance of insulin versus available glucose becomes unbalanced and blood levels of glucose fall, brain cells are depleted of nutrients and loss of consciousness results in coma (Porterfield & White 2007, Tortora & Grabowski 2000).
Symptoms and treatment
Hypoglycaemia causes the secretion of glucagon, adrenaline (epinephrine) and growth hormone which in turn causes tachycardia, palpitations, tremors, pallor and anxiety. Other symptoms include headaches, dizziness, irritability, confusion, visual disturbances, hunger and convulsions. Coma will occur if not treated with oral or intravenous glucose (Porterfield & White 2007, Tortora & Grabowski 2000).
Diabetic ketoacidosis
Glucose is not available for cell metabolism because there is a deficit of insulin, thus the body breaks down fatty acids causing ketoacidosis. It is a serious condition because, as fatty particles are mobilised round the transport system, fatty deposits are left behind in the blood vessels causing atherosclerosis with consequent cardiovascular problems. There is an increase in hormones such as catecholamines, glucagon, cortisol and growth hormone antagonising the effect of insulin. Liver glucose production increases and peripheral glucose usage decreases. The most likely precipitating causes are interruption of insulin administration, infection and trauma (Porterfield & White 2007, Tortora & Grabowski 2000).
Symptoms and treatment
Polyuria, polydipsia and dehydration will occur because of osmotic diuresis. Coma is rare. Sodium, magnesium and phosphorus deficits may occur but the most severe electrolyte disturbance is potassium deficiency. Hyperventilation may occur to compensate for the acidosis with postural dizziness, anorexia, nausea and abdominal pain. Both glucose and ketones will be present in the urine. There may be a smell of acetone on the breath. Treatment will aim to decrease blood glucose levels by continual administration of low-dose insulin and maintaining normal electrolyte levels.
Long-term complications
• Diabetic neuropathy with sensory deficits.
• Microvascular disease with thickening of capillary basement membrane appears to be directly linked to the duration of the disease and blood glucose levels. Retinopathy causes blood vessel changes, leading to loss of sight. Nephropathy may result in end-stage renal disease.
• Atherosclerosis appears at a younger age and progresses more rapidly in the diabetic, leading to hypertension, coronary artery disease and stroke. This is unrelated to the severity of diabetes and may occur with only impaired glucose tolerance. Peripheral vascular disease, leading to gangrene and amputation, may result due to the abnormal level of glucose in the tissues.
• Infection is more common as pathogens utilise the increased tissue glucose to multiply and the function of phagocytic white cells is impaired.
• Pre-eclampsia will develop in about 13% of pregnant women (Evers et al 2004, Porterfield & White 2007).
Effects of diabetes on pregnancy
Pregnancy changes glucose metabolism creating a diabetogenic effect. Women with carbohydrate intolerance may not show signs or symptoms of diabetes, but there is a significant increase in fetal and maternal morbidity (Modder 2006). A comparison was made between women who tested negative on one glucose loading test and those with one positive result. There were 14 036 women in the study and those with an elevated glucose level were more inclined to have babies weighing >4000 g, have a caesarean section, pre-eclampsia and admission of the baby to a neonatal unit (McLaughlin et al 2006). Diabetes becomes more difficult to control in pregnancy although immediately after delivery women return to their pre-pregnancy needs.
Fetal problems
These include:
• The incidence of fetal malformations is higher in women with poor diabetic control as is first trimester abortions. Congenital anomalies of the nervous, cardiovascular, renal and skeletal systems may occur but are difficult to diagnose on ultrasound (Galindo et al 2006).
• Fetal macrosomia (i.e. birth weight >4500 g or >95th centile) is increasingly correlated with maternal obesity due to poor diabetic control in the second and third trimesters. This is not a simple relationship between blood glucose levels and fetal size, as both protein and triglyceride metabolisms have been implicated in excessive fetal growth (Clausen et al 2005, Ehrenberg et al 2004).
• Polyhydramnios.
• Traumatic delivery due to macrosomia (Jevitt 2008).
• Stillbirth.
• Neonatal asphyxia and respiratory distress syndrome.
• Hyperviscosity syndrome.
Effect of pregnancy on the diabetes
Pregnancy with additional fetal requirements places large demands on maternal metabolism, particularly in the last trimester. This changes to allow more efficient storage of nutrients while minimising catabolism of protein stores. There is progressive insulin resistance caused by oestrogens and progestins decreasing insulin efficiency. Normally, the β cells increase the amount of insulin they release in the presence of insulin resistance but glucose metabolism in diabetic pregnant women becomes unstable and more insulin will be needed to achieve metabolic control (Porterfield & White 2007).
Diabetic nephropathy
This is present in 5% of pregnant women with diabetes and increases perinatal risk and the incidence of pre-eclampsia. There is evidence to suggest that angiotensin-converting enzyme inhibitors are teratogenic; these drugs may have been taken pre-pregnancy to aid kidney function and as a hypotensive (BNF 2007, Landon 2007). Although in non-pregnant women a protein-restricted diet to aid kidney function would be commenced, this is generally avoided in pregnancy because of fetal nutritional needs.
Diabetic retinopathy
Pregnancy may temporarily increase the progression of retinopathy (Kaaja & Loukovaara 2007). It has been associated with poor control of blood glucose and blood pressure, albuminuria and poor perinatal outcome (Lauszus et al 2000). Ophthalmologic examination and evaluation should be carried out at regular intervals and the Valsalva manoeuvre avoided in labour to prevent possible retinal haemorrhage. Pregnant women who have proliferative retinopathy with neovascularisation (new blood vessel growth) risk loss of vision; this can be treated by laser photocoagulation.
Care in pregnancy
Preconception advice
Pregnancy should be discussed with the diabetic woman prior to conception (Hague 2001). Adequate blood glucose control prior to conception helps to reduce fetal loss due to early abortion, congenital abnormalities, fetal macrosomia, polyhydramnios and stillbirth. Research has shown that diabetic women whose blood sugar is well controlled around conception and during pregnancy have outcomes approaching the incidence of the non-diabetic population (Sacks 2006). Folic acid 5 mg daily should be taken preconceptually and blood glucose levels monitored (Modder 2006, Stenhouse 2007).
Management during pregnancy
Health professionals should collaborate with the diabetic woman in her care during pregnancy. The involvement of the diabetic team, the obstetrician and the midwife is essential. The woman should be booked for care and delivery in a consultant unit with neonatal facilities and is usually seen at least every 2 weeks (Hague 2001).
Diabetic control
The management of diabetes before and during pregnancy requires control of blood sugar and prevention of ketosis. Hypoglycaemia may be a particular problem in the first trimester particularly where excessive vomiting occurs. Dietary intake and insulin dosage should be monitored with blood glucose levels by self-assessment at home. Self-monitoring of ketoacidosis should also take place and if positive the woman should be admitted for stabilisation with IV insulin (NICE 2008). Ketoacidosis may present in pregnancy with normal glucose levels and is an emergency situation as the fetus has a greatly increased mortality rate (Wallace & Matthews 2004). Pregnancy alters the renal threshold for glucose, and therefore urinary glucose levels are unhelpful.
Glycaemic control
NICE (2008) targets for plasma glucose levels are 3.5–5.9 mmol/L in the fasting state and <7.8 mmol/L after a meal. They suggest that, to monitor hypoglycaemia, plasma levels should be taken before bedtime as well. Women must be told about the risk of nausea and vomiting likely to occur in the first trimester and how glucose metabolism is changed by the presence of the fetus. The added awareness will assist them in reporting abnormalities to their doctor. The effect of the pregnancy on lifestyle, including the implications of maintaining a demanding job and the possible need for medical leave, should be discussed.
Glycosylated haemoglobin
Glycosylated haemoglobin (HbA 1c
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