Several factors must be considered when selecting an insulin regimen. Any regimen must be able to take account of the substantial changes in insulin sensitivity that may increase daily doses of insulin several fold as pregnancy progresses. Regular home blood glucose measurements are essential not only to meet the day-to-day variations in blood glucose concentrations but also to keep up with increasing insulin requirements. These should be undertaken with a home blood glucose meter with a memory (a useful check of compliance). With this degree of surveillance and the patient’s almost invariably higher motivation, it is possible to achieve sufficiently good control with most insulin regimens that entail two or more injections of a mixture of insulins. However, the use of multiple injections (‘basal bolus regimens’) has become common practice. Substantial changes in strategy are best initiated pre-pregnancy.
Choice of insulin regimens
It is preferable to use human insulin in diabetic pregnancy, although a very small minority of patients who are still using animal insulins, because of hypoglycaemic unawareness, maybe reluctant to change. Porcine insulin is probably acceptable but bovine insulin is best avoided as it can produce significant levels of insulin antibodies that freely cross the placenta. These have been implicated as a cause of infant morbidity possibly affecting β-cell function of the fetus and influencing neonatal insulin secretion. Whilst the current insulin analogues possess theoretically attractive properties for pregnancy, none are licensed for use in pregnancy. Some of the short-acting analogues are being used more widely, seemingly without problems.
Once daily insulin regimens
These would seldom be appropriate in pregnant mothers with diabetes established before pregnancy, but single daily injections of an intermediate-duration insulin before breakfast maybe very effective in some women with type 2 or mild gestational diabetes. Such individuals can usually produce sufficient insulin in a fasting state overnight to maintain normoglycaemia and thus an intermediate insulin, e.g., an isophane, such as Humulin I (Lilly), Insulatard (Novo-Nordisk) would be suitable. Additional short-acting or soluble insulin, e.g., Actrapid (Novo-Nordisk) or Humulin S (Lilly) may be added later as a fast-acting component to counter postprandial hyperglycaemia. The use of such regimens significantly reduces the incidence of fetal macrosomia in women with gestational diabetes when compared with treatment by diet alone.
The newer short-acting insulin analogues insulin lispro (Humalog (Lilly)) and insulin aspart (Novorapid (Novo-Nordisk)) have rapid absorption characteristics that provide a peak insulin concentration more rapidly than obtained with human insulin. This results in lower postprandial plasma glucose concentrations. This is therapeutically attractive in the context of the increased insulin resistance associated with pregnancy. However, it is unknown whether these analogue insulins are teratogenic. Maternally derived insulin can only cross the placenta if antibody bound. In clinical trials with insulin lispro, there has been no observed increase in antibody response. This means little insulin transfer from mother to fetus and thus no likely increased risk for congenital malformations. A multicentre, multinational study in 500 pregnancies exposed to insulin lispro (Humalog) during organogenesis showed no increase in malformation rates.
Anxieties have been expressed that the use of insulin lispro during pregnancies complicated by diabetes may accelerate retinopa-thy through its influence on the IGF-1 (insulin-like growth factor 1) system. This seems unlikely as insulin lispro binds to the IGF-1 receptor with an affinity of only about 1/1000 that of IGF-1 and with an affinity of only about 1.5 times human insulin. Insulin aspart (Novorapid) has only 69% IGF-1 activity that of human insulin. Whilst remaining unlicensed for use in pregnancy these analogues are being used increasingly in some centres.
Twice daily combinations of short- and intermediate-acting insulins
This type of regimen is still fairly widely used outside pregnancy -although diminishing in preference to basal prandial regimens -and is perfectly capable of providing adequate control during pregnancy as well. The usual combinations are a soluble insulin with an isophane insulin. Pre-mixed formulations of these insulins should be avoided in pregnancy as they do not afford sufficient flexibility. It is preferable to change women using these to free-mixing their insulins during the preconception period. The ability to change the proportion of short- to intermediate-acting insulin is important because as pregnancy progresses, the required balance between the two may change with increasing insulin resistance. Frequently it is found that hyperglycaemia before breakfast cannot be resolved by increasing the evening dose of isophane insulin without incurring frequent hypoglycaemia during the night, partly as a result of continued glucose usage in the fetoplacental unit. The general solution to this is to divide the evening injection, taking the short-acting insulin with the evening meal and the intermediate insulin at bedtime. Similarly, as gestation progresses, the proportion of short-acting insulin required may increase, reflecting increased insulin resistance, and to control postprandial hyperglycaemia in the afternoon it often becomes necessary to abandon the morning dose of intermediate insulin in preference to an additional lunch-time injection of short-acting insulin. From 36-week onwards, there is a tendency for the fasting blood glucose concentration to fall, which may require reduction or even omission of the evening injection of intermediate insulin. Sudden dramatic falls in insulin requirements at this time should alert the clinicians to the possibility of placental insufficiency sufficient to threaten the pregnancy.
Multiple daily insulin injections
Many younger patients with diabetes already employ such regimens, using pen-type insulin delivery devices. It is a particularly satisfactory means of achieving excellent metabolic control which is readily understood by the patient and can easily be altered to cope with variations in diet and activity. Generally, a short-acting insulin is administered with each of the main meals of the day and an isophane is given at bedtime. Close self-monitoring is essential for this type of regimen, but this will not differ from what is required for pregnancy anyway. Unfortunately, glargine insulin (Lantus (Sanofi-Aventis)), whilst commonly used in both type 1 and type 2 diabetes, is unlicensed for pregnancy and in view of theoretical considerations is not being recommended for use in pregnancy. It has a sixfold higher binding affinity for IGF-1 receptors, and experimental studies suggest an increased mitogenicity on tumour cell lines at high dosage. Until large-scale studies have demonstrated that placental transfer of glargine insulin is similar to the transfer of human insulin, and there is no increased risk to the fetus, this agent is not recommended. Its use is perhaps only justified where severe hypoglycaemia has been a problem, and there must be full discussion of the safety issues with the patient. Furthermore, this means that patients established on glargine insulin have to be switched back to an isophane basal insulin in the preconception period, or immediately an unplanned pregnancy is detected. Detimir insulin (Levemir (Novo-Nordisk)), another long-acting insulin analogue, does not have increased IGF-1 activity, so may eventually prove to be an attractive long-acting insulin alternative, but again is currently unlicensed for use in pregnancy.
Continuous subcutaneous insulin infusion
Open-loop subcutaneous insulin infusion with miniature pumps can achieve near-normal glycaemic control in appropriately selected patients. However, multiple injection regimens remain a simpler solution that can achieve very similar results and continuous subcutaneous insulin infusion is potentially more dangerous in pregnancy. Severe hypoglycaemia is a significant risk and the rapid development of ketoacidosis may occur in the event of pump failure. This option should be considered very carefully and probably only undertaken in centres with extensive pump experience.