Diabetes and pregnancy

Pregnancy in women with diabetes poses a challenge with potential adverse consequences for both mother and fetus. There is also evidence that children born to a diabetic mother are at increased risk of future obesity and diabetes. As maternal diabetes is hazardous for the fetus with an increased risk of major congenital malformations and metabolic and developmental problems, diabetic patients should be closely supervised during pregnancy and preferably attend a combined diabetic/obstetric clinic. Women with type 1 diabetes who are of reproductive age should be asked about future plans for conception and advised to attempt to normalize their HbA1c levels prior to conception to avoid the risk of congenital malformations (most commonly sacral agenesis).

There is now little excess mortality among diabetic mothers. Perinatal mortality among diabetic pregnancies approaches that for non-diabetic pregnancy, but still remains above that for the general population largely because of stillbirth, congenital malformation and the respiratory distress syndrome that affects infants born prematurely. Other neonatal problems include jaundice, hypoglycemia and polycythemia. Fetal macrosomia leads to problems with delivery (dystocia).

Uncontrolled diabetes may cause fetal loss as a result of early spontaneous miscarriage. The congenital malformation rate of 4-10% remains three to five times greater than that in the general population with malformations involving the heart and central nervous system being potentially lethal. Diabetic malformations are likely to be caused by both genetic and environmental factors with glucose being the most likely major teratogen through an unidentified mechanism. The increase in congenital abnormalities is related to the HbA]c level in early pregnancy hence the importance of pre-pregnancy counseling.

Maternal hyperglycemia in diabetic pregnancy is thought to be the major stimulus for the consequent fetal hyperinsulinemia and resultant abnormal fetal growth. The frequency of large-for-gestational-age infants in diabetes is approximately twice as high as in non-diabetic pregnancies. Such infants are at increased risk of emergency cesarean section, birth trauma and birth asphyxia. There is also an unexplained excess of late stillbirths in diabetic pregnancies. The combined diabetic/obstetric clinic should be staffed by a dia-betologist with an interest in obstetrics, an obstetrician with an interest in diabetes, a diabetes specialist nurse, a midwife and a dietician. The mother with type 1 diabetes will need to attend at frequent intervals, usually every 1-2 weeks. An early ultrasound scan is recommended to identify gestational age and search for gross congenital abnormalities. Type 1 diabetic patients who are pregnant need to monitor their blood glucose levels intensively. Frequent adjustments of insulin doses based on the results are undertaken usually on the recommendation of the diabetologist. There is a physiologic decrease in insulin sensitivity between the second and third trimesters of pregnancy, so insulin dose requirements usually increase gradually throughout the second trimester. Appetite is also less affected by the nausea of early pregnancy, so food intake rises. Existing retinopathy may worsen during pregnancy or new retinopathy appear, hence detailed retinal screening is mandatory during the pregnancy. Pregnant mothers with diabetic nephropathy are a high-risk group. Pregnancy may worsen renal function, occasionally irreversibly. A successful outcome of pregnancy is likely when serum creatinine is less than 175 |imol/l and diastolic blood pressure is less than 90mmHg before conception. Fewer than half the pregnancies are successful when creatinine exceeds 250 |imol/l. Diabetic women who have had a renal or combined renal-pancreatic transplant have had successfully completed pregnancies.

A repeat ultrasound scan should be performed at 18-20 weeks' gestation and regularly after 26 weeks to assess fetal growth and liquor volume. Most specialist centers advocate delivery at 38 weeks, although some may allow women with uncomplicated diabetes to go into spontaneous labor. Respiratory distress syndrome is a major cause of neonatal morbidity and mortality in diabetic pregnancies. It is difficult to predict its occurrence. Pre-eclampsia is also more common in diabetic pregnancy. The mother's diabetes is best managed by continuous intravenous insulin infusion during labor or cesarean section. Following delivery, insulin requirements fall promptly to normal pre-pregnancy levels. The neonates of the diabetic mother may exhibit several abnormalities. These include macrosomia, congenital malformations, hypoglycemia owing to fetal hyperinsulinemia, polycythemia, respiratory distress syndrome, transient hypertrophic cardiomyopathy, hypocalcemia, hypomagnesemia and jaundice. All require skilled assessment and management by the neonatal team.

An increasing number of pregnant patients with type 2 diabetes are being encountered. Many are undi-agnosed during the critical stages of organogenesis and have the same high risk of congenital abnormalities as patients with poorly controlled type 1 diabetes. Pregnancies of women with type 2 diabetes may be at even more risk than those with type 1 diabetes owing to poor glycemic control in early pregnancy, obesity, greater age and increased parity.

Gestational diabetes mellitus (GDM) is glucose intolerance first recognized during pregnancy. Occasionally type 1 or type 2 diabetes presents in pregnancy. There is a lack of agreed diagnostic criteria for GDM, but this should not detract from the detrimental impact of maternal hyperglycemia on the pregnancy and the future health of the mother and child. The American Diabetes Association recommends immediate glucose testing for those women deemed to be at high risk of GDM (marked obesity, previous history of GDM, glycosuria or strong family history of diabetes). A fasting plasma glucose > 126mg/dl (7mmol/l) or a random plasma glucose > 200mg/dl (11mmol/l) meets the threshold for diagnosis of GDM and should be confirmed on a subsequent day. High-risk women not found to have GDM at initial screening and average-risk women should be screened between 24 and 26 weeks of gestation by either a one-step approach using a 100 g oral glucose tolerance test (OGTT) or a two-step approach. The two-step approach involves measuring the plasma glucose 1 h after a 50 g oral glucose load and performing a 100 g OGTT test on those women who exceed the glucose threshold 1h after the 50 g oral glucose load. A glucose threshold value of

> 140 mg/dl (7.8mg/dl) identifies around 80% of women with GDM. Diagnostic criteria for the 100 g OGTT are as follows: >95 mg/dl (5.3 mmol/l) fasting,

> 180 mg/dl (10 mmol/l) at 1 h, > 155 mg/dl (8.6 mmol/l) at 2h and > 140 mg/dl (7.8 mmol/l) at 3 h. Two or more of the plasma glucose values must be met or exceeded to make the diagnosis of GDM. In many other countries, such testing methods are not used and there is a reliance on the 75 g OGTT as recommended by the WHO. GDM is associated with high parity, obesity, increased maternal age and membership of ethnic groups with a high background incidence of type 2 diabetes. GDM most commonly occurs after the middle of the second trimester and can be detected by appropriate screening tests, especially in those at high risk. Perinatal morbidity in GDM increases with increasing maternal hyper-glycemia. Much of the pregnancy-related morbidity of GDM is associated with delivering a large-for-gestational-age infant. Women with GDM consistently have increased Cesarian section rates, although this may be reduced by intensive management of maternal hyperglycemia. Sequential ultrasound estimations of fetal growth and abdominal circumference help to identify features of inappropriate fetal growth and inform decisions about the need for intensive blood glucose control. The majority of mothers with GDM can be managed by diet alone. Input from a dietician is mandatory. Care recommendations from Diabetes UK state that blood glucose monitoring should be performed and if pre-prandial levels exceed 6.0 mmol/l (108 mg/dl) insulin treatment should be considered. Insulin dose should be adjusted to achieve pre-prandial levels of 4.0-6.0mmol/l (72-108mg/dl).

Many studies have indicated the advantage of controlling post-prandial plasma glucose levels to achieve a good outcome. The American Diabetes Association recommends that insulin therapy should be considered if, on two or more occasions within a 1-2 week interval, dietary management does not maintain fasting plasma glucose below 5.8mmol/l (105mg/dl) and/or the 2-hour post-prandial glucose below 6.7mmol/l (120mg/dl).

There has long been controversy over the importance of treating GDM. A large NIH-funded multinational study (the Hyperglycemia and Adverse Pregnancy Outcome Study, HAPO) which aims to define the glycemic thresholds during a 75 g OGTT that are associated with an adverse pregnancy outcome should help resolve this dilemma. Recently, a large Australian study examined whether treatment of women with gestational diabetes reduced the risk of perinatal complications. The rate of serious perinatal complications was found to be significantly lower among the infants of the women in the actively treated group with the conclusion that treatment of GDM did indeed reduce serious perinatal morbidity and may also improve the woman's health-related quality of life. On the basis of this research, this view was supported by an editorial in the New England Journal of Medicine, although undoubtedly several issues remain, not least of which is the blood glucose level that should trigger active intervention.

The importance of GDM to the mother is that it identifies her as having a metabolic susceptibility for the subsequent development of type 2 diabetes. There is a variable rate of progression to diabetes, with up to 50% of women from ethnic minority groups progressing to diabetes within 5 years of a GDM pregnancy, although this is lower in Caucasian women. There is also an increased risk of cardiovascular disease and such women need to be advised about the benefit of weight loss, exercise and smoking cessation. All women with GDM should have an OGTT 6 weeks after delivery and the results interpreted according to WHO or ADA criteria.

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