Antidiabetic Drugs

Archive for the ‘Diabetes Treatment’ Category

Hypoglycaemia

The most frequent complication of insulin therapy is hypoglycaemia and patients taking insulin need to be educated about its cause, symptoms, and treatment. Most patients can recognise the early warning signs of hypoglycaemia and by taking sugar immediately can prevent more serious symptoms developing. Comatose patients need to be given intravenous glucose or, if this is not practicable, subcutaneous, intramuscular, or intravenous glucagon (although glucose is still required if mere is no response within 10 minutes). Hypoglycaemia can also develop in patients taking oral antidiabetics, notably the sulfonylureas.

Some patients report loss of the warning signs of hypoglycaemia after transferring from animal to human insulin and these patients, if appropriate, may need to be transferred back to animal insulin. However, the most significant factor in loss of hypoglycaemic warning signs may be exposure to hypoglycaemia itself a study found mat total avoidance of hypoglycaemic episodes for 3 weeks while maintaining glycaemic control restored awareness. Loss of hypoglycaemic awareness, which appears to be due to an adaptive conservation of glucose uptake in the brain, is liable to be a particular problem in patients receiving intensive therapy. There is limited data to suggest that caffeine can improve awareness of hypoglycaemia.

Diabetic ketoacidosis

Diabetic ketoacidosis is caused by an absolute or relative lack of insulin and commonly occurs after noncompliance or failure to adjust insulin dosage in the presence of factors such as infection that increase insulin requirements (see Precautions for Insulin). Failure of an insulin pump can be a cause. Also pregnant diabetic women are more prone to development of diabetic ketoacidosis.

Diabetic ketoacidosis is characterised by hyperglycaemia, hyperketonaemia, and acidaemia, with subsequent dehydration and electrolyte abnormalities. Onset may be rapid, or insidious over many days. Initial presenting symptoms such as thirst, polyuria, fatigue, and weight loss are those of any newly presenting type 1 diabetic they then progress to nausea, vomiting, abdominal pain, and impaired consciousness or coma, and, if untreated, death.

Diabetic ketoacidosis is a medical emergency and should be treated immediately with fluid replacement and insulin. Fluid requirements depend on the needs of the individual overvigorous fluid replacement without severe dehydration carries the risk of precipitating cerebral oedema.

Soluble insulin should also be given immediately. Large doses were formerly thought necessary, but lower dose regimens accompanied by adequate hydration have since been shown to be preferable. Insulin resistance in diabetic ketoacidosis is generally exacerbated by hyperosmolarity and other confounding factors, and insulin therapy is therefore most effective when preceded or accompanied by adequate fluid and electrolyte replacement. In the UK, the BNF considers that insulin should preferably be given by intravenous infusion, with the intramuscular route used if facilities for intravenous infusion are not available. However, in the USA some consider that an intravenous bolus followed by subcutaneous injection may be appropriate in certain patients. Intramuscular or subcutaneous injection are not appropriate in patients with hypovolaemic shock, due to poor tissue perfusion. Where the response to insulin is inadequate the intravenous route is generally required and the rate of infusion may be doubled on an hourly basis until an appropriate response is seen. A case report has suggested mat mecasermin may be useful if there is insulin resistance.

When the blood-glucose concentration has fallen to about 12.5 mmol/litre the dose of insulin may be reduced by about half and glucose given intravenously, usually in a strength of 5% with saline although in rare cases a glucose strength of 10% may be necessary. The use of glucose enables insulin to be continued in order to clear ketone bodies without inducing hypoglycaemia. Once glucose concentrations have been controlled and acidosis has completely cleared, subcutaneous injections of insulin can begin but intravenous insulin should not be stopped until subcutaneous dosage has begun.

Total body stores of potassium are depleted in patients with diabetic ketoacidosis. Insulin deficiency appears to be the main initiating factor for hyperkalaemia in diabetic ketoacidosis. Although patients may present with raised, normal, or decreased serum-potassium concentrations, the concentrations will start to fall with the correction of acidosis. Potassium is added to the infusion fluid after initial fluid expansion and once insulin therapy has begun. In hyperkalaemic patients, potassium is given once serum concentrations have fallen to within normal limits. In the rare patient presenting with hypokalaemia potassium replacement should be begun before insulin therapy and the latter withheld until potassium concentrations have risen to normal values.

Intravenous bicarbonate is now generally reserved for patients with severe acidaemia a common practice is to give isotonic bicarbonate to those with a pH of less man 7.0 with the aim of raising the pH to 7.1.

Phosphate concentrations are affected in a similar manner to potassium concentrations in the ketoacidotic state, but there is less agreement on the need for routine doses of phosphate. Phosphate concentrations should be monitored and phosphate given if clinically significant hypophospha-taemia occurs.

The precipitating cause of diabetic ketoacidosis should also be identified and managed appropriately.

Hyperosmolar hyperglycaemic state

Hyperosmolar hyperglycaemic state or hyperosmolar hyperglycaemic nonketotic coma (HONK) occurs mainly in elderly patients with type 2 diabetes and though much

less common man diabetic ketoacidosis it carries a higher mortality. Patients may present in coma with severe hyperglycaemia but with minimal ketosis dehydration and renal impairment are common. Treatment is similar to mat of diabetic ketoacidosis, although potassium requirements are lower and large amounts of fluid and less insulin may be required some suggest the use of hypotonic fluid if necessary. There is an increased likelihood of thrombotic events, so prophylactic anticoagulation should be considered.

Pregnant women with diabetes are much more prone to diabetic ketoacidosis due to the combination of insulin resistance and accelerated catabolism of pregnancy. Initiating factors are the same as those for any person with diabetes and include vomiting, infections, failure of insulin administration or failure to meet increasing insulin requirements. Ketoacidosis in pregnancy must be treated with the utmost urgency as fetal loss occurs in almost 50% of cases. Patients are best managed on a medical intensive care unit along conventional lines but with close fetal monitoring. Adequate fluid and potassium replacement is essential in conjunction with intravenous insulin infusion, adjusted to achieve a smooth reduction of plasma glucose concentration. Initial rehydration should be with normal saline; this should be changed to 10% dextrose, once the blood glucose is less than 10 mmol/L and continued until the patient is free of ketones.

The use of corticosteroids in premature labour before 34 weeks of gestation to accelerate fetal lung maturation may dramatically increase insulin resistance. Similarly, the use of intravenous β sympathomimetic agents to treat premature uterine contractions will cause severe hyperglycaemia and ketoacidosis unless appropriately anticipated. Careful glucose monitoring should always accompany this form of treatment and aggressive intravenous insulin treatment must be started if necessary.

Dramatic changes in insulin sensitivity may occur in insulin-dependent diabetics at the time of delivery. Once active labour has started, insulin requirements fall. After delivery, once the placenta and its hormonal products have been removed, there is a further rapid reduction in insulin requirement. Indeed, immediately after delivery, insulin requirements may fall below pre-pregnancy values.

During labour the simplest scheme is to use a constant infusion of 10% glucose at a rate of 1 L every 8 hours. An independent insulin infusion of human soluble insulin, initially at 1 unit/h, is also given; this is subsequently adjusted on the basis of hourly bedside blood glucose. This system may be used irrespective of the last subcutaneous insulin dose, but where induction of labour or caesarean section is planned it is best started at breakfast time after a bedtime injection of isophane insulin. As soon as the infant is delivered, the insulin infusion must be reduced or, in women with gestational diabetes, stopped altogether. The glucose infusion is continued until the next meal in patients who had vaginal deliveries or until a normal diet is resumed in those delivered by caesarean section. The pre-pregnancy insulin doses should be resumed at this time and adjusted according to the blood sugar levels. An additional 40-50 g carbohydrate, relative to the pre-pregnancy dietary intake, is generally recommended during lactation. Women should also be warned about the potential risk of hypoglycaemia whilst feeding, especially in the middle of the night. They may need advice on appropriate snacks or fluids that contain carbohydrate. Oral hypoglycaemic agents, where they were being used before pregnancy, are probably best avoided. Small quantities of sulphonylureas are secreted into breast milk and therefore can theoretically induce hypoglycaemia in the infant. This is probably of significance only with the longer acting sulphonylureas such as chlorpropamide. Metformin is not recommended for use in lactation. However, there is no evidence of harm for the infant from the small amount of metformin that is secreted into breast milk. Infant exposure to metformin can be minimised by breastfeeding just before taking the dose and by avoiding feeding for at least 2-3 hours after taking the dose. It has been suggested that prophylactic antibiotics should be given after operative deliveries to offset the increased risk of wound infection in women with diabetes.

The mean diurnal blood glucose concentration in non-diabetic pregnant women is around 5 mmol/L at 30 weeks of gestation. Diabetic women should be aiming for this level of control, attempting to obtain fasting and preprandial values of between 4 and 6 mmol/L and postprandial values of less than 10 mmol/L. This will be reflected in an HbAlc value within the normal non-diabetic range, certainly <7% and preferably close to 6%. It must not be forgotten that there is also a physiological reduction in glycaemic values observed by around 20 weeks of gestation. This reduction in HbAlc levels is due to the increased haematopoiesis and the presence of unglycated red cells in the circulation in pregnancy. Health professionals and women may frequently be unaware of this pattern and may falsely attribute this physiological shift to an improvement in control.

Home blood glucose measurement is an essential routine aspect of self-management and should be performed 4-6 times/day to recognise the need for insulin dose modification. This dosage adjustment can be performed by the medical team, but the patient should be encouraged and helped to gain the confidence to undertake this herself. Continuous blood glucose profiling may be a useful additional tool to assessing and optimising glycaemic control. HbAlc levels should be measured regularly as this provides an objective assessment of glycaemic control. Target values should be the middle of the normal non-diabetic range.

Hypoglycaemia is an inevitable consequence of achieving strict glycaemic control. All women on insulin should therefore be provided with glucagon 1 mg (Lilly) or GlucaGen (Novo-Nordisk) for use in moderate to severe hypoglycaemia and their relatives should be instructed in its use.

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.

A report describes promising results from trials of a combination of the drug troglitazone (Rezulin) and insulin in Type II diabetics. Researchers at St. Michael’s Hospital, Toronto, Canada, administered 200 or 400 mg/day of troglitazone, in addition to insulin, to 539 diabetics to collect data. It was found that the combination therapy was effective in reducing levels of both HbA1c (hemoglobin) and fasting plasma glucose and that use of troglitazone allowed patients to reduce their daily insulin requirements. It was further found that those participants whose baseline HbA1c was 140 percent above the normal range experienced the greatest benefit from the combination therapy, with hemoglobin levels falling by an average of 1.35 percent. Results of the study were presented by Dr. Lawrence Leiter, director of the lipid disorders clinic at St. Michael’s Hospital, Toronto, at the American Diabetes Association’s 59th Annual Scientific Sessions in San Diego.

Postpartum

There is an immediate decrease in maternal insulin requirements following delivery. The main reason for this decrease is loss of the placenta, which functioned to synthesize many steroids and create an insulin-resistant environment throughout pregnancy. Postpartum, it is best to start with approximately one-half of the normal prepregnancy dose of insulin and check blood glucose levels before meals and at bedtime to regain tight control. Breastfeeding should be encouraged in both type 1 and 2 diabetic populations. However, patients should be advised about the risk of hypoglycemia from loss of carbohydrates during breastfeeding, and therefore aim for a target fasting (preprandial) glucose level in the range of 110­-120 mg/dL. It may even be necessary to take an additional carbohydrate snack prior to breastfeeding and maintain a high calcium and fluid intake.

Neonates of diabetic mothers should be carefully and thoroughly assessed. They are at an increased risk for all the complications previously mentioned and listed in Table 8, including hypoglycemia and respiratory distress syndrome, requiring specialized care.

Conclusion

Table 10 provides a summary of monitoring parameters in a pregnant diabetic patient, from preconception through the first, second, and third trimesters. The overall outlook for the pregnant diabetic patient has improved enormously over the last few decades. The most important aspect of diabetic care for the mother is the need to maintain good glycemic control, with the goal of lessening the risk for congenital malformations and other, later fetal complications. If no major complications are present, good glycemic control and careful monitoring can result in a healthy neonate, with minimal long-term health risk to the mother.

For most women with diabetes, pregnancy can be brought to term with a normal vaginal delivery if there has been good control of glucose levels. Women with poor diabetic control, especially with nephropathy, hypertension, growth-retarded fetuses and some macrosomic fetuses, may need to be delivered earlier. Although many regimens have been suggested for attaining glucose control during labor and delivery, including subcutaneous insulin, control of plasma glucose is easier when insulin is administered as a continuous infusion for women with type 1 and type 2 diabetes. Usually, the patient is hospitalized the day prior to induction of labor and is given her usual diet and insulin dose. The morning after, breakfast and insulin are withheld, and baseline glucose is measured. An intravenous infusion is initiated with dextrose 5% or 10% in water at 125 cc/hr, using an infusion pump. A separate insulin infusion (1 U/10 mL) should also be initiated at the same time. Table 9 provides a guide for the insulin dose to be administered initially, based on the capillary glucose level.

During labor, the glucose level and insulin doses should be monitored and adjusted hourly to maintain a normal glucose level of 70­-120 mg/dL. For spontaneous labor, the same procedure is followed. However, if the patient has taken an intermediate-acting insulin in the previous 12 hours, the insulin requirements may be less. Patients with fever, infection, or other complications require higher doses, as do obese patients with type 2 diabetes who have required greater than 100 units of insulin/day prepartum. For patients in whom perinatal complications and/or poor diabetic control necessitates a cesarean section, the breakfast meal and the morning insulin dose are omitted. During surgery, separate dextrose and insulin infusions, as mentioned above, should be utilized and continued until the patient has bowel sounds and is able to eat without vomiting.

Shoulder dystocia is a main concern for these fetuses and is a major reason for cesarean section. The incidence of shoulder dystocia is directly related to fetal size, with a 10% incidence if the fetus weighs more than 4.5 kg.Various maneuvers exist in dealing with this problem. Planned cesarean delivery may be a good strategy for diabetic pregnant women with estimated fetal weights greater than 4.25 kg.

Maternal Complications, Management, and Monitoring

In the second trimester, continued insulin/insulin-resistance-glycemic-control-improves-outcomes”>glycemic control is still the goal. Office visits are usually every two weeks, with HbA1c checked every 4­-6 weeks. Monthly assessments of renal function, to monitor for neuropathy, and ophthalmologic exams, to check for retinopathy, should be performed in this trimester. Insulin requirements also increase during the second trimester due to the increased production of pregnancy-related hormones — estrogen, progesterone, placental lactogen and prolactin — all of which increase insulin resistance. Insulin doses may be increased on average by 50 units, but there is a wide dosage range adjustment. Monitoring of urine ketones and monitoring for signs and symptoms of diabetic ketoacidosis (DKA) should continue during this period. DKA is most common between 20 and 36 weeks gestation because insulin resistance is now a major factor. Dietary intake and weight should also be monitored continually during each visit. The standard recommendation is to increase caloric intake by 200-­300 kcal per day. However, diet should be adjusted to keep the weight gain close to the ideal for the prepregnancy BMI.

In the third trimester, after 32 weeks the physician visits should again be weekly. Monthly renal function tests should begin and another ophthalmologic exam should be performed. Insulin requirements usually peak about three weeks prior to delivery and then drop. Careful home monitoring of blood glucose is necessary to maintain good glycemic control. At this time, monitoring for preeclampsia becomes important, along with checking for edema, hypertension, and proteinuria. The reported rate of preeclampsia ranges from 9% to 66% in women with diabetes mellitus; the highest rate is in women with prepregnancy diabetic nephropathy. The risk factors identified for preeclampsia are nulliparity, chronic hypertension, duration of diabetes, retinopathy, microalbuminuria prior to pregnancy, nephropathy, and poor glycemic control early in pregnancy. In a study by Hiilesmaa et al., 683 women with type 1 diabetes and 854 without diabetes were followed for the duration of pregnancy. Preeclampsia developed in 12.8% of the women with diabetes (excluding those with nephropathy prior to pregnancy) and in 2.7% of the control women (OR 2.5; 95% CI 3.3-8.4). The adjusted odds ratio for preeclampsia were 1.6 (95% CI 1.3-2.0) for each 1% increment in the HbA1c value at 4­-14 weeks gestation and 0.6 (95% CI 0.5-0.8) for each 1% decrement achieved during the first half of pregnancy. Changes in glycemic control in the latter part of pregnancy did not significantly alter the risk of preeclampsia. Though this is a problem that becomes evident only in the second and third trimester of pregnancy, achieving normoglycemia in the first trimester is still the best method for preventing this complication.

Fetal Complications

During pregnancy, complications result from the increased flux of glucose from mother to fetus and from the resulting fetal hyperinsulinemia. Table 8 lists the various medical problems most often encountered in infants of diabetic mothers.

All diabetic women, even under strict glycemic control, experience higher blood glucose concentrations than nondiabetic women, leading to a higher glucose concentration gradient between the maternal and fetal arterial blood. The fetal response to the increased glucose load is increased secretion of insulin from the fetal pancreas. Due to the increase in insulin in the fetal circulation, the fetus converts glucose to fat for storage in adipocytes, increases its metabolic rate and becomes hypoxemic, and alters insulin receptor function. The conversion of glucose to fat is a major contributing factor to the development of macrosomia. Most organs are affected, with the exception being the brain. One study, by Enzi et al., determined that the body fat mass increased by 20% in infants of insulin-dependent diabetic mothers compared to 12% in controls. However, not all infants become macrosomic. If the diabetes is very severe with vascular involvement, the uterine blood flow will be impaired, resulting in decreased oxygen transfer from mother to fetus, and intrauterine growth retardation. If the hypoxemia is extremely severe, with subsequent development of acidosis and increased cardiac output, there is also an increased risk of late fetal death.

Uncontrolled diabetes in the mother also leads to cardiovascular pathophysiology. Ventricular septal hypertrophy may occur, resulting in cardiomyopathy with clinical symptoms of congestive heart failure. If the fetus survives, the septal hypertrophy appears to resolve over a period of several months. There are two hypotheses for the cardiac pathophysiology, according to Morriss et al. In one hypothesis, the septal hypertrophy is a direct consequence of fetal hyperinsulinemia acting on the myocardial insulin receptors. In the second hypothesis, the increased cardiac output, cardiac workload, and cardiac blood flow needed to counteract the hypoxemic effects indirectly cause the hypertrophy.

Respiratory-related disorders associated with an increased incidence in infants of diabetic mothers are pulmonary hypertension and idiopathic respiratory distress syndrome (IRDS). The mechanism for pulmonary hypertension occurring is still unknown; however, fetal hypoxemia resulting from an increased fetal metabolic rate is thought to be a causal factor. In the 1960s and 1970s the rate of IRDS complicating the pregnancy of diabetic mothers was in the range of 20%. However, by the 1990s, the incidence had dropped to about 1.6%, due to better glycemic control. Mechanisms for the development of respiratory distress syndrome are believed to be deficient and delayed surfactant secretion in the lungs. Parker et al. conducted a study which indicated that endocrine immaturity, leading to decreased levels of prolactin, estrone, estradiol, estriol, and cortisol, may be the cause of the decreased and delayed phospholipid synthesis and secretion. This study, of the 28 infants of women with diabetes that were studied, found that plasma glucose levels were highest in the women whose neonates developed the respiratory distress syndrome. Also, an inverse correlation was found between maternal glucose levels and lecithin-sphingomyelin ratios (surfactant concentrations) in the amniotic fluid, (r = 0.50, p = 0.05), indicating that this phenomenon is related to the extent of diabetic control during pregnancy. Some diabetic mothers are administered corticosteroids to induce lung maturity, and in these cases, close monitoring of glucose levels and insulin is required due to increased insulin requirement with steroid usage.

Increased concentrations of serum bilirubin concentrations, usually in the immediate neonatal time period, are also encountered in the infants of diabetic mothers. The mechanism of this pathophysiological state appears to be related to an increased concentration of carboxyhemoglobin, increased rate of heme catabolism, and increased hemolysis in these neonates.

Other pathophysiological complications seen in these pregnancies are hypocalcemia, hypomagnesemia, and increased thrombosis and abnormal clotting. These problems do not appear to be linked to the increased glucose load and subsequent increased insulin concentrations. The hypocalcemia and the related hypomagnesemia appear to be related to diminished parathyroid hormone response in these infants. Abnormalities in clotting mechanism are not yet clearly defined; however, abnormalities in platelet aggregation and fibrinolysis have been suggested by Morriss et al.

Fetal Monitoring

Antenatal obstetric surveillance is a critical aspect of monitoring and managing these fetal complications. Alpha-fetoprotein, ultrasound scanning, and biophysical fetal monitoring comprise the basic components of obstetric surveillance. Maternal serum a-fetoprotein should be determined at 16-­18 week gestation, and if the maternal level is abnormal, the a-fetoprotein in the amniotic fluid should be measured, at about 21-­22 weeks, to check for neural-tube defects. Complete ultrasound scanning, starting from early pregnancy, is part of obstetric surveillance. Scanning can also assist in examining for congenital anomalies, most often at 18­-22 weeks gestation, when detailed structure can be assessed. From late second trimester onward, fetal growth can be assessed and is helpful in identifying asymmetric growth acceleration. If macrosomia is suspected, the fetal weight estimates may assist in deciding on mode of delivery. Fetal echocardiography, to determine fetal cardiac physiology, and amniocentesis, to determine fetal pulmonary function, are useful if HbA1c values were abnormally high at earlier prenatal visits. If maternal glucose is adequately controlled prior to conception and in the first trimester, both of these tests are not required.

Biophysical monitoring, including fetal breathing moments and rates, baseline heart rate, and body movements, and external fetal heart rate monitoring, with nonstress tests should be assessed at about 32 weeks, with twice weekly monitoring starting at 36 weeks gestation. Earlier nonstress tests can be conducted in women with complications such as hypertension, preterm labor, infection, developmental defects, premature rupture of membranes, intrauterine growth retardation, and hydramnios. In a study by Devoe et al., fetal bimonthly biophysical studies from 30­-38 weeks in 18 normal and 18 well-controlled insulin-dependent diabetic pregnancies were compared. The fetuses of the diabetic mothers had higher mean incidences of fetal breathing movement, fetal heart rates, and fetal breathing rates, but lower fetal movements and fetal heart rate acceleration counts than the controls throughout the study. This study illustrates that even with good maternal glycemic control, the fetuses of diabetic women behaved differently from fetuses of nondiabetic women, proving that careful monitoring is required.

Maternal Complications, Management, and Monitoring

The main goal in caring for a pregnant diabetic patient in the first trimester is maintenance of near-perfect insulin/insulin-resistance-glycemic-control-improves-outcomes”>glycemic control, which should have been achieved prior to conception. Weekly (or at least every two weeks) physician visits are necessary in the earlier part of the pregnancy. Patients should perform home blood glucose monitoring at least four times a day, with three before meals and one before bedtime. Hemoglobin A1c levels should also be checked every 4­-6 weeks during this period. Insulin requirements should be individualized and insulin given accordingly. There is no clear standard on how many daily injections should be given or what the ratio should be between the regular and intermediate-acting insulin. Each patient’s dose will be individualized based on the results of the blood glucose monitoring and HbA1c levels.

In a study by Schuster et al., 93 women were followed during pregnancy to assess the efficacy of using premixed insulin (70% NPH/30% Regular) by injectable pen versus the traditional self-mixed insulin administered by syringe. The women were enrolled into four different groups: 1) self-mixed/ syringe, 2) premixed/syringe, 3) self-mixed/pen, and 4) premixed/ pen. The study found a significant difference (p = 0.03) of fewer cesarean deliveries for failure to progress to labor in the women in the premixed pen group. However, no significant differences were noted in glucose control, compliance, cost, incidence of infections, or infant macrosomia. Therefore, tight glycemic control by close monitoring and individualized dosing, using a variety of dosing and administration techniques, will result in a positive outcome.

Since insulin requirements fluctuate in early pregnancy, the patient, family, and physician must watch for signs and symptoms of hypoglycemia, which may occur without warning. Patients should be warned about the dangers of missing meals and instructed in the use of glucagon. The patient must also be instructed on how to change the insulin dosage as needed based on the results of the blood glucose test results. For the patient on a twice-daily regimen, the morning short-acting regular insulin should be adjusted on the before-lunch test result and the morning intermediate-acting NPH insulin dose on the before-dinner meal test. Evening short-acting regular insulin should be adjusted on the bedtime test and the evening intermediate-acting insulin on the before-breakfast test. Keep in mind that the adjustment is always 24 hours behind.

Achieving good glycemic control is further complicated in early pregnancy by nausea and vomiting (morning sickness). Good glycemic control is of particular importance, since morning sickness increases the risk of ketoacidosis and fetal loss. Patients are advised to manage nausea initially by changing dietary habits, such as eating dry crackers or toast before rising, eating frequent small meals and snacks, drinking liquids between meals rather than with meals, and avoiding caffeine and foods that are spicy or have a high fat content. If the nausea is severe, antinausea medications should be utilized. Table 5 lists the antiemetics that have been used in managing hyperemesis gravidarum. Vomiting that is severe may require patients to be hospitalized for intravenous nutrition, especially if ketonuria is present, or to be put on home IV therapy.

Diabetic ketoacidosis (DKA) is another complication that can occur in early and late pregnancy. DKA is associated with a fetal mortality of about 35%. It is a condition characterized by insulin deficiency, hyperglycemia, and acidosis. This is considered a true medical emergency, for both the mother and the fetus. The presenting signs and symptoms of DKA are vomiting, polydipsia, polyuria, weakness, abdominal pain, weight loss, hyperventilation, dry mucous membranes, tachycardia, hypotension, disorientation, and coma. Factors that predispose a pregnant diabetic woman to ketoacidosis are listed in Table 6. Pregnant diabetic patients can develop DKA at a lower glucose level than that seen in a nonpregnant diabetic patient. For the manifestations of diabetic ketoacidosis to develop, the glucose level is at least 300 to 350 mg/dL in a nonpregnant diabetic patient, while in the pregnant diabetic patient, the signs and symptoms leading to diabetic ketoacidosis have been observed with glucose levels as low as 200 mg/dL.

Pregnant patients with diabetic ketoacidosis should be admitted to an intensive care unit and appropriate management initiated. Management goals of a pregnant DKA patient are maternal stabilization, hydration, and reversal of hyperglycemia and metabolic acidosis. Attainment of these goals will also result in decreased fetal hypoxemia, acidosis, and hypokalemia. If the pH is less than 7.0, management consists of fluid replacement, insulin administration, potassium replacement, and bicarbonate replacement. Table 7 lists some specific measures to acutely manage diabetic ketoacidosis in pregnancy.

Fetal Complications

In the first trimester the main complication for the fetus is the development of congenital mal-formations due the hyperglycemic states of the mother. All abnormalities occur during the first eight weeks of pregnancy; therefore, glucose control must start prior to pregnancy. In a study by Fuhrmann et al., the authors followed 292 diabetic women who began strict metabolic control after 8 weeks gestation and 128 diabetic women who began intensive treatment before conception. In the first group there were 22 infants with congenital malformations versus one malformation in the second group (p <0.01). The same authors also reported studying 56 women who were normoglycemic in the early weeks of gestation versus 144 pregnant diabetic patients who were only seen after eight weeks of pregnancy, with no preconceptional metabolic control. They report one infant with a fatal heart malformation in the normoglycemic women versus nine congenital malformations (three fatal, three severe, and three minor) in the women who were not normoglycemic in the initial weeks of pregnancy. These studies clearly indicate the need for achieving and maintaining glucose control in the initial stages of pregnancy to decrease the incidence of congenital malformations.