Diabetes and Pregnancy

Written by Dr. Furrat Amen

Introduction

Diabetes during pregnancy may be established, Insulin Dependent Diabetes Mellitus (IDDM) or Non Insulin Dependent Diabetes Mellitus, or gestational and both are causes of high prenatal and perinatal mortality and morbidity. It is important to follow the diabetic from pre-conception to after delivery with a view to reducing problems associated with diabetes. The following text represents a discussion of the subject in such a chronological order.

1) Conception Advice

Good diabetic control is necessary, before conception and during the first trimester, to try to reduce the incidence of congenital abnormalities. It is necessary to use contraceptive methods until the patient wishes to conceive, even though some Insulin IDDM patients suffer from infertility. This infertility may be due to a degree of suppression of cyclical pituitary function, in turn due to the stress of undernutrition which causes a rise in prolactin levels.

To achieve good control, it may be necessary to advise them about control using home glucometers, perhaps four times a day, more rigorous insulin regimes, or use of an insulin infusion pump for good control before attempting to get pregnant, and once pregnant. A dietician may also help to maintain dietary control for blood glucose.

Mothers may be told that improved fetal monitoring and good glycaemic control have reduced perinatal mortality to below 2%, 40% of which is caused by congenital abnormalities. Elevated blood glucose around the time of the fourth to sixth weeks of pregnancy coincides with embryogenesis and this may be to blame for the high risk of congenital defects being produced at this time. Termination is rarely recommended: in cases of patients with vascular disease which is severe in nature eg. proliferative retinopathy or severe nephropathy.

2) Test to find affected mothers and risk factors

All pregnant women should be screened for gestational diabetes at 24 to 28 weeks – undetected it is a cause of a two-fivefold increase in perinatal morbidity and mortality. If a universal glucose challenge test is administered a two hour specimen should be taken in preference to a one hour specimen.

In Germany, only 10% of mothers with gestational diabetes are recognised. A routine blood glucose of over 100mg/dl should be an indication for doing a oral glucose tolerance test. Amniotic fluid insulin levels may be used as a indicator for starting insulin therapy – indeed there is a significant increase in the risk of fetal macrosomia and fetal pathology without it.

Risk factors for development of diabetes include: age in excess of 25 years, East Indian origin and glycosuria (1). In Boston, a raised HbA1c in the first trimester was found to be linked to congenital abnormalities (2). Initial levels of HbA1c over 6.1% should indicate the need for fetal echocardiographic imaging to exclude congenital heart disease. However the fetal echocardiography has a sensitivity of only 57% and tends to miss atrial or ventricular communications, especially in horizontally-challenged women. There is no difference in mean HbA1c values or increase in congenital or cardiac anomalies between type I or II diabetic mothers’ babies, nor does the degree of HbA1c elevation correlate with the severity of cardiac lesions (3).

A scheme for managing patients in an antenatal clinic (4)

If abnormal proceed to next line:

Urine glucose every visit

Random plasma glucose on first booking and at 28 weeks

Standard 75g carbohydrate breakfast test

Diet advice – repeat breakfast test if necessary

75g oral GTT

Insulin treatment

Postpartum random plasma glucose or 75g oral GTT

Ambulatory blood glucose values recorded by reflectance meters with memories for time and date of reading may help glycaemic control (5). Serum fructosamine levels show good correlation with levels on glucose tolerance tests and may prove a useful screen for gestational diabetes. It is necessary with such a test to have cut-off values that adjust for gestational age and compensate for rate of glycosylation of serum proteins. Serum fructosamine levels may be measured at four to six week intervals (6). It has also been suggested that a combined blood ketone strip may be helpful for testing urine for ketones at home.

Activin is a dimeric protein synthesised by trophoblasts and decidua. It increases in concentration with gestational age, up to term, in healthy women. 44% of patients with gestational diabetes exhibit a serum activin concentration exceeding one standard deviation above the mean of normal controls of the same gestational age. These levels decrease to normal after treatment with insulin (7).

Ultrasounds demonstrate large for gestational age infants in gestational diabetic mothers. Also the abdominal circumference is significantly larger in the early than the late growth pattern in this group. Femur length, head circumference and growth rates are similar for large-for-gestational age infants and appropriate-for-gestational-age fetuses. Similar measurements and growth rates are apparent for insulin-dependent mothers and hypertensive control subjects.

3) Changes and Treatments in Pregnancy

In a study of 731diabetic women in Kuwait - 22% were found to be established diabetics. 570 women were found to have diabetes during pregnancy - 43% were gestational diabetics and the remainder, 57%, were classified as having impaired glucose tolerance. Unexplained intrauterine death is eighteen times more likely in established diabetics compared with controls, and thirteen times as likely in gestational diabetics. Established type II diabetics tend to be treated with oral hypoglycaemic drugs before pregnancy and insulin during pregnancy (9).

During pregnancy there is a rise in the level of insulin and a concurrent fall of action at the hepatic level. This causes a state of insulin resistance. The increase in human placental lactogen, oestrogen, progesterone and cortisol conspires to create ,in some pregnant women, a state of impaired glucose tolerance, or gestational diabetes, whereby there is a decrease in the peripheral action of insulin. Women who were previously diabetic have poorer control when pregnant. IDDM mothers will require twice the amount of insulin used before pregnancy (this rapidly declines after pregnancy). The earlier insulin is needed in such mothers, the greater the fluctuations are in blood sugar levels during a day.

Hyperglycaemia of the mother causes hyperglycaemia of the fetus. This is responded to by the fetus by an increase in insulin secretion. This is thought to be the reason behind much of the pathology which is seen e.g. placental insufficiency, pre-eclampsia, macrosomia, fetal intra-uterine death, malformation, hypertrophic cardiomyopathy, and delay in fetal lung maturity.

Established diabetes seems constant in studies as being 2 to 3 per 1000 pregnancies in USA. Gestational diabetes estimates vary. Established diabetics have ten times normal risk of developing pre-eclampsia – gestational diabetics have four times the risk. Hypertension may be treated by hydralazine or methyldopa – not angiotensin converting enzyme inhibitors which affect fetal renal development and function.

Both also run a higher chance of delivering by Caesarean section. Forty percent of established diabetics had primary Caesarean sections and twenty-two percent had repeat sections – a total of sixty-two percent – five times normal. Gestational diabetics have twice the normal Caesarean section rate (9). Anomalies have been increased in incidence in diabetic animal models that have been given alcohol. Rats made diabetic using streptozocin before mating show retardation of skeletal development is also potentiated by alcohol.

Norbert Freinkel has proposed the theory of “fuel-mediated teratogenesis” – whereby the fuel that the conceptus receives from the diabetic mother is important in the abnormalities found commonly in babies. Altering the ‘fuel’ at different times in the pregnancy is assumed to have differing effects eg. teratogenic in early pregnancy, CNS disturbance in the middle trimester, and metabolic disturbances in the last trimester.

Dietary therapy (and possibly insulin therapy) may be helpful in reducing such abnormalities in gestational diabetics. Some gestational diabetics will require insulin in addition to dietary control to achieve the goal of 60-120mg/dl, with a daily mean of 85-90mg/dl during pregnancy and before conception. Two week follow-ups may help with the detection of complications or indeed their treatment. A weight gain of 22 to 26 pounds should be aimed for. Certainly if the mother is obese weight reduction is not a priority during pregnancy – indeed an additional 300kcal are required daily – amounting to some 1800-2500 calories per day.

It is also necessary to bear in mind that calcium, folic acid, iron, and sodium are needed in the diet. Snacks and regular meals help to combat ketosis and overnight hypoglycaemia. This asymptomatic nocturnal hypoglycaemia is common in insulin requiring diabetic women and occurs in conjunction with an increased cortisol. In IDDM patients 24 hour mean cortisol values are significantly lower post partum compared to the second trimester. This is also the case for NIDDM and no consistent differences exist between the two groups. Peak cortisol concentration during gestation maintains a circadian rhythm for type I and II diabetics and this does not change with progression of pregnancy. There is however no significant difference between mean cortisol in IDDM patients and controls (10). Therefore cortisol levels probably do not explain the difference between controls and diabetic glycaemic rises and carbohydrate intolerance. It is possible to say, however, that in insulin treated diabetic women – hypoglycaemia induces a rise in plasma cortisol levels. A close association between the diabetic and obstetric specialists may offer better care for the diabetic mother.They may teach the father to administer a single 1mg subcutaneous injection of glucagon, to a hypoglycaemic wife, to raise blood glucose enough for further oral nutrition. It is a good idea also to periodically check blood glucose at 1.00AM and 3.00AM in asymptomatic insulin treated diabetics.

Pre-existing diabetic nephropathy can get worse during pregnancy, especially if a decrease in glomerular filtration rate precedes conception. This may lead to intrauterine growth retardation. This means an earlier delivery – probably before 36wks. Proliferative retinopathy also worsen during pregnancy but usually gets better after – although there have been isolated cases where progression has continued after birth despite treatment with laser coagulation. Ladies with coronary artery disease have a high incidence of MI and such an event is associated with higher maternal and fetal death – although not necessarily so. Urinary tract infections are raised in diabetic mothers – especially in IDDM mothers with vascular complications.

There are many chemical changes that occur in pregnancy: surfactant-associated protein (SAP-35) is a glycoprotein in lung alveoli. It organises surfactant phospholipid structurally and controls its secretion and production. It increased by cAMP and epidermal growth factor at the time when type II epithelial cells differentiate. Its RNA and synthesis is inhibited by growth factor and insulin, while glucocorticoids increase and inhibit production of SAP-35. The high insulin level in fetuses of diabetic mothers stop the type II cell from differentiating and slow synthesis of surfactant phospholipid. SAP-35 may be detected in amniotic fluid of diabetics. Better glycaemic control decreases the risk of hyaline membrane disease for the fetus and normalises SAP-35 levels in amniotic fluid. Hyaline membrane disease may also be associated with the preterm deliveries, Caesarean, and asphyxia that are more common amongst this group.

Using radioimmunoassay, an increase of beta endorphin can be found in gestational and established diabetics and this increase is related to gestation. The rise is larger for established diabetics. Insulin in this group increases beta-endorphins. The course gestational diabetes takes may be influenced by beta endorphins inhibiting insulin secretion. Other chemical changes include women with a family history of diabetes showing a higher plasma calcitonin level in the third trimester.

Autoantibodies have an increased incidence in diabetic pregnant women and thyroid antibodies in particular are related to hypothyroidism, and predispose to a high chance of postpartum thyroiditis. Such thyroid antibodies may influence the nutritional disposition of the infant. The gestational age of the infants is also lower if the mother has a positive thyroid stimulating antibody level.

4) Labour and birth

The aim should be for vaginal delivery (4). Good control of diabetes can reduce the incidence of macrosomia, the rate of Caesarean section and neonatal mortality (2). Complications include premature rupture of membranes, and polyhydramnios. Hypoglycaemia may ensue after birth because of persistant hyperinsulinaemia and no continuing high glucose load from the mother. The rate of birth trauma between IDDM and control groups is not significantly different – vaginal delivery being the main risk factor for both groups. The most common trauma seen is brachial plexus injury, facial nerve injury, and cephalohaematoma.

Gestational diabetics are more likely to have high birthweight babies (greater than 4000g) (RR = 2.1), whilst established diabetics have neonates with either high (RR = 1.7) or low (less than 2500g) (RR = 3.2) birthweights (9). A birthweight of over 3600g may indicative of shoulder dystocia and therefore a policy of Caesarean for infants over 4000g should be implemented to reduce perinatal mortality and morbidity (2). Other problems arise eg. anaemia, polycythaemia, bacterial infections, congenital anomalies, birth trauma, preterm delivery, and respiratory distress. In developing nations, despite having a comparable prevalence of gestational diabetes to Western women, higher complication rates are likely due to poor glycaemic control.

5) Post partum

It appears that perinatal death, hypoglycaemia of the newborn, and macrosomia are directly dependent on the degree of glucose control in pregnancy. Macrosomia is also significantly associated with maternal obesity – higher values for glucose tolerance test also may indicate macrosomia. Neonates also suffer from hyperbilirrubinaemia, and hypocalaemia more commonly. Breast feeding should be encouraged – this may reduce the small chance of the baby developing IDDM. Perinatal mortality for babies of mothers with nephropathy has been steadily decreasing, but unfortunately morbidity remains high. Infants of established diabetic mothers have eight times the risk of death in the first eight weeks, and five times the risk in the first year, of non-diabetic mothers. Babies of established diabetic mothers have eight times the risk of congenital malformation. With gestational mothers the risk is twice that of normal mothers’ babies but this may be due to chance – metabolic derangements of gestational diabetes, in general, do not begin until the second or third trimester after organogenesis is complete and so there should be no increased risk (9).

Thirty to fifty percent of infants born to IDDM mothers have hypocalcaemia, which may be caused by magnesium deficiency that prevents parathyroid hormone response to the neonatal fall in calcium. Magnesium loss is probably due to increased urinary losses. Preterm birth and perinatal asphyxia are also risk factors for neonatal hypocalcaemia. Maternal magnesium deficiency may cause fetal-neonatal magnesium deficiency which may result in secondary hypoparathyroidism and consequent hypocalcaemia. Strict control of glucose (fasting less than 4.4mmol/l / 1.5 hour post-prandial 6.6mmol/l) is associated with a significantly lower rate of hypocalcaemia in infants when compared with customary control (fasting less than 5.5mmol/l / 1.5 hour post-prandial 7.7mmol/l). Lowest infant serum calcium concentration correlates well with maternal HbA1c at delivery, lowest magnesium concentration, and gestational age (11)

Bone mineral content in mother and baby may be measured by photon absorptiometry. A significant decrease in this content is found in infants born to diabetic mothers and the content is correlates inversely with the mean first trimester maternal capillary blood glucose level (no correlation exists with cord serum vitamin D levels, maternal glycosylated haemoglobin, infant gestational age or infant birthweight).

After birth, gestational diabetic mothers have a 20:1 risk of developing type II diabetes (5). With increasing age these women are more likely to develop overt diabetes when not pregnant. Risks of diabetes continuing are increased by early glucosuria found in pregnancy, obesity, heredity from first-degree relatives, and age in excess of thirty years. For retrospective diagnosis of gestational diabetes in women with macrosomic babies, it is possible to measure the level of insulin in cord blood.

6) Future developments

Immunotherapy, using corticosteroids, cyclosporin-A and anti-thymocyte globulin, is being tested as a solution to IDDM. Trials so far have shown major adverse side-effects eg. nephrotoxicity with cyclosporin-A, but this may be overcome with maintainance of the drug at a safe level in the blood. A type of lymphocytic choriomeningitis virus has been tested in mice, with the effect of invading T-lymphocytes of the mice, predisposed to become diabetic, in particular the T helper cells which destroy beta islet-cells of the pancreas – this could be evaluated in humans with a view to eliminating IDDM.

Insulin therapy may be made easier if insulin is specially formulated for oral or intranasal use. Closed-loop delivery systems would have the ability to administer insulin depending upon the prevailing blood glucose level. Biochemical targeting may become available using new drugs to inhibit chronic complications. Islet cell transplants and pancreatic transplantation may become a successful reality. Finally and most attractive of all could be the ability to harness the gene for making insulin, present in every somatic cell, to make insulin according to blood glucose levels – stimulus-secretion coupling.

Five-Point Conclusion

• Pregnancy is an insulin resistant state.

• Pregnant women should be screened for gestational diabetes at 24-28 weeks gestation.

• Good glycaemic control is necessary before and throughout pregnancy for all types of diabetes.

• Aim for vaginal delivery.

• Gestational diabetics have high birth weight babies, whilst IDDM mothers have high or low birth weight babies.

Bibliography

1) Bassaw B, et al; Diabetes in pregnancy. (Int J Gynaecol Obstet, 1995 Jul)

2) Hollander P, et al; Diabetes in pregnancy. No longer a barrier to successful outcome. (Postgrad Med, 1985 Feb)

3) Shields LE, et al; The prognostic value of hemoglobin A1c in predicting fetal heart disease in diabetic pregnancies. (Obstet Gynecol, 1993 Jun)

4) Hadden DR; The management of diabetes in pregnancy. (Postgrad Med J, 1996 Sep)

5) Scientific rationale for management of diabetes in pregnancy. Recent approaches with innovative computer-based technology. (Langer O; Diabetes Care, 1988 Nov-Dec)

6) Serum fructosamine: a screening test for diabetes in pregnancy. (Roberts AB; Am J Obstet Gynecol, 1986 May)

7) Petraglia F, et al; Abnormal concentration of maternal serum activin-A in gestational diseases. (J Clin Endocrinol Metab, 1995 Feb)

8) Johnstone FD, et al; The effect of established and gestational diabetes on pregnancy outcome. (Br J Obstet Gynaecol, 1990 Nov)

9) Heckbert SR, et al; Diabetes in pregnancy: maternal and infant outcome. (Paediatr Perinat Epidemiol, 1988 Oct)

10) Cousins L, et al; Circadian rhythm and diurnal excursion of plasma cortisol in diabetic pregnant women. (Am JObstet Gynecol, 1986 Dec)

11) Demarini S, et al; Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. (Obstet Gynecol, 1994 Jun)

12) Mimouni F, et al; High spontaneous premature labor rate in insulin-dependent diabetic pregnant women: an association with poor glycemic control and urogenital infection. (Obstet Gynecol, 1988 Aug)