Diabetes in Pregnancy

Diabetes mellitus is a metabolic (chemistry) disorder characterized by hyperglycemia (high blood sugar) and other signs, as distinct from a single illness or condition.

The World Health Organization recognizes three main forms of diabetes:

Type 1 is usually due to autoimmune destruction of the pancreatic beta cells which produce insulin.

Type 2 is characterized by tissue-wide insulin resistance and varies widely; it sometimes progresses to loss of beta cell function.

gestational diabetes (occurring during pregnancy), which have similar signs, symptoms, and consequences, but different causes and population distributions. Gestational diabetes is similar to type 2 diabetes, in that it involves insulin resistance; the hormones of pregnancy cause insulin resistance in those women genetically predisposed to developing this condition. Gestational diabetes typically resolves with delivery.

Ultimately, all forms are due to the beta cells of the pancreas being unable to produce sufficient insulin to prevent hyperglycemia.

Types 1 and 2 are incurable chronic conditions, but have been treatable since insulin became medically available in 1921, and today are usually managed with a combination of dietary treatment, tablets (in type 2) and, frequently, insulin supplementation.

Diabetes can cause many complications.

Acute complications (hypoglycemia, ketoacidosis or nonketotic hyperosmolar coma) may occur if the disease is not adequately controlled.

 Serious long-term complications include:

cardiovascular disease (doubled risk),

chronic renal failure (diabetic nephropathy is the main cause of dialysis in developed world adults),

retinal damage (which can lead to blindness and is the most significant cause of adult blindness in the non-elderly in the developed world), nerve damage (of several kinds), and

microvascular damage, which may cause poor healing. Poor healing of wounds, particularly of the feet, can lead to gangrene which can require amputation — the leading cause of non-traumatic amputation in adults in the developed world. Adequate treatment of diabetes, as well as increased emphasis on blood pressure control and lifestyle factors (such as not smoking and keeping a healthy body weight), may improve the risk profile of most aforementioned complications.

The first case report of gestational diabetes mellitus appeared in 1824, with a description of a mother with thirst, polyuria and glycosuria and the death of a macrosomic infant from shoulder impaction. Before the introduction of insulin in 1921, few women with type 1 diabetes became pregnant; those who survived childhood were generally underweight, amenorrhoeic and infertile. In those who did conceive, the maternal mortality rate was approximately 40% (mainly because of ketoacidosis) and fetal and neonatal survival was less than 50%.

Insulin has led to a dramatic improvement in maternal survival.

Diabetes complicates approximately four per 1000 pregnancies, making it the most common pre-existing medical disorder in pregnancy.

Change in eating pattern (hyperemesis in early pregnancy)

Increase in insulin dose requirements at 18-28 weeks' gestation

Greater importance of tight glucose control (ideally HbA1c <6.1%)

Increased risk of severe hypoglycaemia

Risk of deterioration in pre-existing retinopathy

Risk of deterioration of established nephropathy

Lower renal threshold for glycosuria

Control in type 1 diabetes is achieved by matching insulin dose with food intake and the changing insulin sensitivity. In early pregnancy, morning sickness may disrupt normal eating, and changes in timing or dose of insulin may be required; for women on a basal bolus-type regimen, this is relatively simple. Access to telephone advice from the diabetes team is important over this most critical phase of pregnancy.

Insulin dose requirements change in pregnancy as a consequence of the physiological increase in insulin resistance. The extent of increase is determined by placental function and varies in successive pregnancies in any one woman. A five year, single centre, observational study has shown that the average increase in insulin requirement is 40%, with a wide range from no change to a higher than threefold increase.⁰²⁰¹

Figure 1 shows the average time course of this change.

Figure 1. Data on 107 singleton pregnancies (showing means with standard deviations), from Taylor et al.⁰²⁰¹ Average insulin dose does not change until around 18 weeks' gestation and then increases steadily until around 28 weeks' gestation. The average fall in insulin dose of 5% between weeks 34 and 38 conceals wide individual variation.

One consequence of achieving near normoglycaemia is that asymptomatic hypoglycaemia will occur more frequently, and this will lead to unawareness of hypoglycaemia. Women must be advised that they are at greater risk than usual of severe, unannounced hypoglycaemia and be specifically counselled about the importance of testing blood glucose concentrations before driving. Ideally a spouse or partner should be provided with a glucagon kit and trained in its use.

Retinopathy deteriorates whenever blood glucose control is suddenly tightened, as shown by several large randomised studies. In pregnancy, the extent of deterioration is strongly related to the degree of retinopathy present just before pregnancy. If retinopathy is not present on digital imaging according to the national standards for England, then it is highly unlikely that clinically significant change will occur during pregnancy.^{9001, 9601} Rechecking at 28 weeks' gestation is all that is required. However, if moderate background changes are present, over half of women will develop proliferative retinopathy,⁹⁵⁰¹ and full retinal screening is required at booking, 16-20 weeks, and 28 weeks.

If diabetic nephropathy is already established and serum creatinine is raised, there is an increased risk of permanent loss of renal function.⁹⁶⁰²

The increased risks of diabetes in pregnancy are:-

congenital malformation

fetal macrosomia (large baby) 

Polyhydramnios

pre-eclampsia 

premature labour

miscarriage and intrauterine death

 

 

Miscarriage is more common with diabetes.⁰⁷⁰¹

Perinatal mortality is increased in association with diabetes.^{9701, 9702, 0301, 0401, 0604}

In the study of Casson et al ⁹⁷⁰¹ there was a five-fold increase in stillbirth rate.

Diabetes is associated with an increased risk of major and minor fetal abnormality.^{9401, 0501, 9702}

Figure 2. The risk of all congenital malformations is increased above the background population rate of 2%, even in women with type 1 diabetes with normal HbA1c concentrations. The risk increases sharply with increasingly poor blood glucose control. (After Taylor and Davison, BMJ  2007;334:742-745 ). Even women with type 1 diabetes with normal HbA1c concentrations have intermittent, marked hyperglycaemia, and this may explain the difficulty of completely minimising the risk.

Hyperglycaemia exerts its teratogenic effects during the period of organogenesis—the first 42 days of pregnancy—and pregnancy is invariably confirmed when much of this time has elapsed. This, together with delays in seeking advice from a nurse or doctor, means that frequently no effective advice to modify risk of congenital malformations can be given during the pregnancy. Diabetes confers a significant increase in risk of early spontaneous fetal loss, often as a consequence of non-viable, severe malformation.⁹⁴⁰¹

Table 1 . Congenital anomalies seen in infants of diabetic mothers

Prepregnancy care from specialised multidisciplinary clinics, involving optimisation of blood glucose control and prescription of folic acid, could considerably decrease the observed rates of congenital malformation. Regrettably, however, even energetic local programmes may have only modest impact⁹⁹⁰¹ although improvements are possible.⁰⁶⁰¹

Macrosomia (birth weight >4000 g) occurs in about a fifth of pregnancies in women with type 1 diabetes—twice the incidence for England—with the associated risk of an increased risk of birth injury to such babies. Shoulder dystocia occurs in about 8% of births to diabetic mothers (with risk of Erb's palsy), compared with 3% to the background population as shown by large, well conducted observational studies. Associated with macrosomia is the greater risk of more severe trauma to the mother, with potential future problems of poor pelvic floor function. Serial monitoring of fetal growth and size by ultrasonography is essential to allow judicious planning of delivery.

Macrosomia might also be a factor influencing timing of delivery, although there is little evidence to support this.^{Cochrane 2007}

Polyhydramnios occurs in about 15% of diabetic pregnancies and is again related to glycaemia: polyhydramnios generally reduces as diabetic control improves. The excess fluid is thought to be caused by fetal osmotic diuresis secondary to hyperglycaemia.

Pre-eclampsia is four times more likely to occur in women with type 1 diabetes than in women without diabetes,⁰⁶⁰² and even more likely in the presence of nephropathy (if proteinuria has been established before pregnancy). A large observational study has demonstrated that poor blood glucose control before pregnancy does not in itself increase the likelihood of pre-eclampsia, although persistent poor control during pregnancy does increase the risk (odds ratio 1.65 for each 1% increase in HbA1c).⁰⁶⁰³

Preterm labour occurs in up to 20% of diabetic pregnancies.⁹⁷⁰⁴ Ritodrine, which has become the conventional tocolytic in the UK, produces hyperglycaemia and, particularly when used in combination with antenatal steroids, can make glycaemic control difficult to maintain. A sliding scale involving high doses of insulin is usually required. It may be that treatments other than sympathomimetics are more appropriate choices for tocolysis because of fewer effects on glycaemic control. Guidelines from the RCOG recommend that "The use of antenatal corticosteroids in pregnancies complicated by maternal diabetes mellitus is recommended, but a significant reduction in rates of RDS has not been demonstrated. If commenced, inpatient supervision by an experienced diabetic/obstetric team is essential to regulate diabetic control.

Women should attend a specialist diabetic clinic as soon as their pregnancy is confirmed. This clinic should include an obstetrician with a special interest in diabetic pregnancy, a diabetologist, a dietician and a diabetes specialist midwife or nurse as part of a multidisciplinary approach. A record must be made of prepregnancy insulin requirements, as this information has often been forgotten in the postpartum period when it is required. Nausea and vomiting can make management of blood glucose concentrations difficult and women often need support and frequent antenatal visits throughout the first trimester. Women with persistent vomiting must be admitted to hospital. Hypoglycaemia can be a serious problem and affects up to 70% of women. It is not detrimental to the fetus but pregnant women are often less aware of its presence. There were three cases attributed to diabetes in the last Report on Confidential Enquiries into Maternal Deaths (2000-02).^CEMACH All three were attributed to hypoglycaemia. For this reason, all partners of pregnant women with diabetes should be given a glucagon kit and taught how to use it.

Proteinuria detected on routine testing warrants a 24-hour urine collection and tests of renal function.

An early ultrasound examination is indicated to confirm fetal viability (there is an increased risk of miscarriage⁰⁷⁰¹) and to determine gestational age.

Chromosomal abnormalities are not increased in diabetic pregnancies. Antenatal screening should be, nevertheless be offered. If the triple test is used a different reference range is required, because alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotrophin levels are all lower in pregnant women with diabetes compared with pregnant women without diabetes. Nuchal translucency scanning can also be performed but has not been validated independently in diabetic pregnancy. There may be a relationship between increased translucency and gestational diabetes.⁰⁵⁰²

The risk of other congenital abnormalities is increased (Table 1). All women should be offered an anomaly scan at around 20 weeks of gestation as well as more detailed cardiac scans at 20 and 32 weeks of gestation.

Fundoscopy should also be performed in pregnant women with diabetes. Those with longer duration diabetes and more advanced forms of retinopathy are at greatest risk of disease progression during pregnancy; these women should be referred to an ophthalmologist.

All women with diabetic nephropathy should have a 24-hour urine collection for baseline measurements of proteinuria and creatinine clearance (ideally prepregnancy). Risks of nephropathy include renal failure, superimposed pre-eclampsia, fetal-growth restriction, stillbirth and preterm delivery.

Diabetic ketoacidosis, which is rare in pregnancy, is usually preceded by a gradual onset of polyuria and drowsiness. Presenting symptoms and signs include dehydration, tachypnoea, hypotension, deep sighing respirations and ketotic smell. Rehydration and correction of hyperglycaemia and electrolyte imbalance are reuired. Potential causes, such as infection, should be investigated. Nausea and vomiting can predispose to ketoacidosis, even with near normal blood glucose levels. The fetus is at risk of sudden intrauterine death. A compromised fetus may improve with correction in the mother's metabolic abnormality.

Hypoglycaemia can produce rapid onset of loss of consciousness and is best treated with intramuscular glucagon, as this avoids the extreme hyperglycaemia that may occur with intravenous dextrose. If dextrose is be administered, 20% should be given into a vein without force.

Women should be monitored regularly in an antenatal diabetic clinic throughout pregnancy,. They should be seen at least every two weeks until 34 weeks of gestation and then weekly until delivery. Glycaemic control should be monitored by patient records; blood glucose should be measured two or three times weekly prior to meals and snacks (i.e. six times each day). More frequent measurements should be advised when control is poor. Memory meters can be useful to monitor the correlation between meter readings and patient records. A random blood glucose level taken at the clinic visit can also provide information about control and accuracy of the patient's measurements.

Glycosylated haemoglobin (HbAlc) levels can give an indication of medium- to long-term glycaemic control; although some argue that indiscriminate use of these diagnostic indicators should be avoided as they are expensive and have not been shown to improve outcome.

Fetal macrosomia is related to maternal postprandial glucose levels (one-hour postprandial sugar levels being the most sensitive indicator). Therefore, one aim of treatment of diabetes in pregnancy is to reduce postprandial hyperglycaemia; this can be achieved through a combination of a diet low in simple carbohydrates and insulin therapy.

Those women with type 2 diabetes treated with oral hypoglycaemic agents are usually converted to insulin. However, there is growing evidence for the use of metformin in pregnancy, especially as it is now being used for the treatment of women with polycystic ovary syndrome, in whom it may decrease the rate of first-trimester miscarriage.⁰²⁰² There has also been some interest in the use of oral hypoglycaemic medications later in pregnancy for gestational diabetes.⁰⁰⁰²

A diet high in complex carbohydrates is recommended; fat worsens insulin resistance and the total number of calories is also important. Many women will need to increase the frequency of both insulin injections and blood glucose monitoring to improve their control. The woman's usual insulin regimen should not be changed if she has good diabetic control. Those with poor control should be changed to four injections per day with three pre-meal injections of short-acting insulin and one of intermediate-acting (or occasionally longacting) insulin at bedtime. Continuous subcutaneous insulin via a pump may enhance control in some women.

Recombinant human insulin analogues, lispro and aspart, are absorbed rapidly and achieve a faster peak insulin level, which mimics the physiological first phase of insulin release more closely than regular human insulin. Significantly lower postprandial glucose levels have been achieved in non-pregnant diabetics.⁹⁷⁰³

Both conventional human insulin and recombinant analogues produce minimal maternal antibody response, thereby minimising insulin transfer to the fetus. A retrospective analysis of 76 women with type 1 diabetes concluded that pregnancies managed with recombinant human insulin analogues have similar outcomes to those of similar diabetic populations.⁰³⁰² Although rapid insulin analogues have not yet been licensed for use in pregnancy in the UK, there does not appear to be any reason why women who become pregnant while using them should not continue with this regimen.

The recently introduced long acting insulin analogue glargine is one of the most important advances in diabetes management as it minimises the risk of hypoglycaemia despite tight control.⁰⁰⁰¹ There appear to be no safety problems in pregnancy.⁰⁷⁰¹ Given that swings of blood glucose are known to be deleterious, any safety problems specific to glargine are outweighed by the beneficial effects on overall control. Like most insulins, glargine is not licensed specifically for use in pregnancy, and individuals must be advised about risks and benefits. There is no single insulin regimen that suits all patients in pregnancy.

Serial ultrasound scans, should be performed every four weeks until 32 weeks of gestation and fortnightly thereafter. They provide information about fetal growth and the presence of polyhydramnios and macrosomia. The abdominal circumference at 28-29 weeks of gestation has been shown to be predictive of subsequent macrosomia. Excess growth apparent at this gestation highlights the need for optimisation of glucose control and close surveillance during the third trimester. Macrosomic babies, however, can be born to mothers with apparently excellent glycaemic control. Maternal obesity is also a risk factor for macrosomia.

The fetal biophysical profile has been shown to be of value for monitoring fetal wellbeing in diabetic pregnancies⁸⁸⁰¹ and is thought by some to be the single most useful means of assessing fetal wellbeing in late pregnancy in diabetic women.⁹⁹⁰¹

Uterine artery blood flow is not affected by diabetic glycaemic control, nephropathy or vasculopathy. If there is increased impedance to flow, this is predictive of increased risk of preeclampsia and/or intrauterine growth restriction, as in women without diabetes.

Fetal Doppler measurements are of limited value in pregnancies complicated by maternal diabetes mellitus as this condition does not produce the redistribution of fetal blood flow that occurs in cases of intrauterine growth restriction. Metabolic abnormalities may, however, produce acidaemia without hypoxia and the diabetic fetus may be compromised while recording apparently normal fetal Doppler measurements. These may be, therefore, be misleading.

A plan for delivery should be formulated at 36 weeks of gestation, or earlier in pregnancies with marked asymmetric macrosomia because of the greatly increased risk of shoulder dystocia even with premature deliveries after 34 weeks.

In women with good diabetic control and an uncomplicated pregnancy it should be possible to reach 39 completed weeks of gestation. Beyond this time there is little evidence of benefit and some evidence of harm. Poorly controlled diabetes may require earlier delivery but this will increase the risk of neonatal complications, particularly respiratory distress syndrome and jaundice. The mode of delivery is dependent upon a number of factors including parental choice, past obstetric history, estimates of fetal weight, prediction of asymmetrical macrosomia and fetal wellbeing. Spontaneous vaginal delivery should be the method of choice for all women with diabetes, wherever possible. Caesarean section rates in excess of 40%, however, are still quoted.⁰⁴⁰²

The risk of neonatal hypoglycaemia is increased in the presence of maternal diabetes, as the maternal hyperglycaemia triggers excessive rates of insulin synthesis by the fetal pancreas. Normoglycaemia is important because high glucose levels prior to delivery predispose to neonatal hypoglycaemia. Adequate analgesia is also vital since pain stimulates catecholamine release, leading to glycogenolysis and hyperglycaemia. There is an increased incidence of fetal distress in labour and continuous monitoring of the fetal heart rate is recommended. Experienced midwifery and obstetric staff should monitor the labour and be alert to slow progress. The risk does not correlate with HbA1c during pregnancy.^{9901, 0201} However, controlling maternal blood glucose over the few hours before delivery is critical to minimise the risk of neonatal hypoglycaemia as blood glucose concentrations higher than 8 mmol/l will almost inevitably be associated with neonatal hypoglycaemia.⁰²⁰¹ Hence, maternal blood glucose concentrations of 4-8 mmol/l should be achieved using glucose and insulin infusion.⁹⁹⁰¹

The rate of insulin infusion should be halved immediately after delivery as insulin sensitivity returns to normal within minutes of shut-down of the uteroplacental circulation. Subcutaneous insulin administration can be resumed as soon as the mother is able to eat.

Following delivery, breastfeeding should be encouraged. Insulin requirements fall to prepregnancy levels within the first 24 hours after delivery. In those with continuing diabetes, it is usual to resume prepregnancy insulin doses. However, a slightly reduced dose of two-thirds the prepregnancy levels may be indicated if the woman plans to breastfeed. There is much less need for tight diabetic control postpartum compared with pregnancy and it is important to avoid hypoglycaemia.

All women should be seen for a six-week postnatal check at the hospital. With regard to contraception, modern low-dose combined oral contraceptives are generally considered safe for those with type 1 diabetes. Other options include the progesterone-only pill or the Mirena (Schering Health) intrauterine system.

If the baby's blood glucose is checked as a routine precaution too early in life, then low concentrations are certain to be observed (5% of babies of non-diabetic women have a blood glucose concentration of less than 1.7 mmol/l within two hours of birth). When faced with maternal diabetes, inexperienced staff tend to check the neonate's blood glucose, with the consequence that the baby will be unnecessarily admitted to a special care unit and the mother left alone on the ward after nine months of hard struggle with diabetes. It is critical to promote early feeding, with a check of blood glucose only just before the second feed. This will decrease the current separation rate (one in three cases)—two thirds of separations are potentially avoidable. If hypoglycaemia is suspected, however, then glucose concentrations should be checked.

Neonatal complications are increased in association with maternal diabetes:

Metabolic

Hypoglycaemia

Hypocalcaermia

Hypomagnesaemia

Lung

Respiratory Distress Syndrome

Transient tachypnoea of the newborn

 

• Cardiovascular

  Cardiomyopathy

  Cardiac septal hypertrophy

Liver

Jaundice

Kernicterus

Renal

Renal vein thrombosis

Haematological

Polycythaemia

All are related directly or indirectly to hyperinsulinaemia. Respiratory distress syndrome appears to be secondary to suppression of surfactant production by type-2 alveolar cells in the lung caused by excess insulin.

Polycythaemia is probably due to increased hepatic erythropoeisis; this can lead to jaundice and increased blood viscosity and is a risk factor for thrombosis (most notably renal vein thrombosis). Insulin suppresses microsomal enzymes and this immaturity inhibits the ability of the liver to conjugate bilirubin, hence the risk of kernicterus is increased.

The most important aim is to achieve the best possible glycaemic control before pregnancy. Tight glycaemic control is statistically associated with a reduced incidence of congenital malformations.

Over the past two decades intensive efforts to offer individual education about this have not resulted in higher prepregnancy counselling rates or even in presentation before the critical 42 day period of organogenesis.^{9901, 0301, 0401} The St Vincent declaration, a joint declaration by all European governments on preventing the problems of diabetes, outlined an aim of achieving similar outcomes of pregnancy in diabetic and non-diabetic women. This aim has not been met in most countries,^{9701, 0301} although a "planned pregnancy" rate of 84% among diabetic women across the Netherlands has been reported.⁰⁴⁰² A modest rise in planned pregnancy rates has been reported in one United Kingdom centre.⁰⁶⁰¹

Other general advice, for example about smoking and alcohol, should not be forgotten. Folic acid should be taken periconceptually (5 mg/day).

Sources: - Taylor, R and Davison, JM BMJ  2007;334:742-745

DISCLAIMER

The aim of this web site is to provide a general guide and it is not intended as a substitute for a consultation with an appropriate specialist in respect of individual care and treatment.