Type 1 diabetes and pregnancy

Planning for pregnancy

The most important aim is to achieve the best possible glycaemic control before pregnancy. 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.1 2 3^{w1 w2} 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,2^w3 although a “planned pregnancy” rate of 84% among diabetic women across the Netherlands has been reported.^w4 A modest rise in planned pregnancy rates has been reported in one United Kingdom centre.4^w5 An approach that raises awareness in the general population may be needed to promote further behaviour change in the UK.

For women with established diabetic nephropathy the chance of successful pregnancy diminishes sharply as serum creatinine increases (80% chance if 125-180 µmol/l; 75% chance if 180-220 µmol/l; and 60% chance if >220 µmol/l).^w6 The higher the prepregnancy creatinine concentrations, the higher the risk of permanent loss of renal function. When albuminuria is established in a woman with type 1 diabetes, the implications for timing of pregnancy should be explained to her. Diabetic nephropathy will inevitably advance, and renal function will decline over a period of months or years. Once the creatinine concentration has increased, the chance of successful pregnancy decreases.

How does pregnancy affect diabetes?

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.5 Figure 1⇓ shows the average time course of this change, which is helpful for advising what is to be expected from each clinic visit. Box 1 summarises the effects of pregnancy on diabetes.

Fig 1 Data on 107 singleton pregnancies (showing means with standard deviations), from Taylor et al.5 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

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One consequence of achieving near normoglycaemia is that asymptomatic hypoglycaemia will occur more frequently, and this will lead to unawareness of hypoglycaemia.^w7 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.6^w8 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,7 then it is highly unlikely that clinically significant change will occur during pregnancy.^w9-w11 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,^w11 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.^w12

How does diabetes affect the pregnancy?

The most profound potential effect is the increased risk of congenital malformations. The recent UK Confidential Enquiry into Maternal and Child Health survey showed a threefold excess of cardiac and neural tube anomalies.8 Figure 2⇓ shows that very poor control of blood glucose leads to over 25% risk of malformation but that improved prepregnancy glucose control can decrease this almost to background levels.^w13-w15 Even women with type 1 diabetes with normal HbA_1c concentrations have intermittent, marked hyperglycaemia, and this may explain the difficulty of completely minimising the risk.^{w16 w17}

Fig 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 HbA_1c concentrations. The risk increases sharply with increasingly poor blood glucose control. Data from Rosenn et al^w13

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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.^w13

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 have only modest impact at best,1 4 and data from countries round the world suggest that achieving change is very difficult.2 3^{w1 w18} Many patient information leaflets about pregnancy do not make clear the risks of pregnancy in diabetes. It is now routine practice to advise women to take 5 mg of folic acid daily before conception and for the first 12 weeks of pregnancy. No direct evidence supports this advice; the consensus to offer such advice ^{w19 w20} was extrapolated from information that increased folic acid intake is more effective in preventing malformations in other conditions of high risk of neural tube defects.^w21

Macrosomia (birth weight >4000 g) occurs in about a fifth of pregnancies in women with type 1 diabetes—twice the incidence for England^w22—with the important corollary 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.2^w4 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.

Delivery at about 38 weeks' gestation is advised for women with diabetes to minimise the risk of unexplained late fetal death. The timing and mode of delivery should be determined on an individual basis based on best possible assessments of risk to mother and baby. Macrosomia might also be a factor influencing timing of delivery, although little evidence supports this.^w23 In recent published series, delivery before 37 weeks occurred in about a third of women with type 1 diabetes, with preterm caesarean section being the greatest single contributor.5 8^w24

Pre-eclampsia is four times more likely to occur in women with type 1 diabetes than in women without diabetes,9 and even more likely in the presence of nephropathy (if albuminuria or microalbumuria has been established before pregnancy).^w25 A large observational study has shown 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 HbA_1c).^w5

Box 2 summarises the effects of diabetes on pregnancy.

How should drug treatment be managed?

The use of the recently introduced long acting insulin analogue glargine is one of the most important recent advances in diabetes management as it minimises the risk of hypoglycaemia despite tight control.10 Two case series totalling 174 individuals have shown no safety problems in pregnancy.^{w26 w27} 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 in pregnancy.

If a patient is taking antihypertensive treatment such as an angiotensin converting enzyme inhibitor before pregnancy, then this should be tailed-off as soon as possible because of the risk of congenital malformations.^w28 Methyldopa should be substituted providing that continuing treatment is required.

Treatment with high dose steroids may be required to mature the fetal lung if delivery is necessary before 34 weeks' gestation, for asthma, or for hyperemesis gravidarum. If treatment is indicated, the inevitable and predictable increase in insulin resistance requires a prospective increase in insulin dosage. In practice, an increase of 40% at the time of the first dose will prevent loss of control.^w29 The increased dose of insulin is required until 24 hours after the last steroid dose. This will prevent the gross hyperglycaemia otherwise precipitated and is extremely unlikely to cause hypoglycaemia.

Management of mother and baby around delivery

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. The risk does not correlate with HbA_1c during pregnancy.1 5 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.5 Hence, maternal blood glucose concentrations of 4-8 mmol/l should be achieved using glucose and insulin infusion.1 As soon as the cord is cut, the rate of insulin infusion should be halved 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.

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^{w30 w31}). 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. To avoid this “empty arms syndrome” 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.

Conclusions

If Julie (see Scenario box) had contacted her diabetes team before going ahead with her plans to conceive and if blood glucose control had been optimised, the risk of congenital malformation would have been much reduced. Care from the combined obstetric and diabetes team during pregnancy indeed allowed early detection of problems. The induction of labour at 38 weeks avoided the potential risk of unexplained late fetal death. Good blood glucose control during labour minimised the chance of neonatal hypoglycaemia, and separation of mother and baby after delivery was avoided.