DIABETES MELLITUS AND PREGNANCY Part 2

 

Clinical
Fetal morbidity with diabetes during pregnancy

*Miscarriages

• In all women with preexisting diabetes mellitus, there is a 9-14% rate of miscarriage.
• Current data suggest a strong association between degree of glycemic control prior to pregnancy and miscarriage rate. Suboptimal glycemic control has been shown to double the miscarriage rate in women with diabetes. A correlation also exists between more advanced diabetes and miscarriage rates. Patients with long-standing (>10 y) and poorly controlled (glycohemoglobin exceeding 11%) diabetes have been shown to have a miscarriage rate of up to 44%. Conversely, reports demonstrate a normalization of miscarriage rate with excellent glycemic control.

*Birth defects

• Among the general population, major birth defects occur in 1-2% of the population. In women with overt diabetes and suboptimal glycemic control prior to conception, the likelihood of a structural anomaly is increased 4- to 8-fold.
• Although initial reports demonstrated anomaly rates as high as 18% in women with preexisting diabetes mellitus,6 more recent reports with more aggressive preconception and first trimester management report anomaly rates between 5.1 and 9.8%.7, 8
• Two-thirds of anomalies involve the cardiovascular and central nervous systems. Neural tube defects occur 13-20 times more frequently in diabetic pregnancy. Genitourinary, gastrointestinal, and skeletal anomalies are also more common.
• The fact that no increase in birth defects occurs among the offspring of fathers who are diabetic and women who develop gestational diabetes after the first trimester is notable. This suggests that periconceptional glycemic control is the main determinant of abnormal fetal development in diabetic women.
• When the frequency of congenital anomalies in patients with normal or high first-trimester maternal glycohemoglobin values was compared to the frequency in healthy patients, the rate of anomalies was only 3.4% with glycosylated hemoglobin values (HbA1C) of less than 8.5%, whereas patients with poorer glycemic control in the periconceptional period (HbA1C >8.5%) had a 22.4% rate of malformations. An overall malformation rate of 13.3% was reported in 105 patients with diabetes, but the risk of delivering a malformed infant was comparable to a normal population when the glycosylated hemoglobin (HbA1c ) was less than 7%.9 More recently, in a review of 7 cohort studies, researchers found that patients with a normal glycohemoglobin (0 SD above normal), the absolute risk of an anomaly was 2%. At 2 SD above normal, this risk was 3%, with an odds ratio of 1.2 (1.1- 1.4). As the glycohemoglobin increased so did the risk for malformation in a direct relationship.10
• Because birth defects occur during the critical 3-6 weeks after conception, nutritional and metabolic intervention must be initiated well before pregnancy begins. Clinical trials of intensive metabolic care have demonstrated that malformation rates similar to those in the nondiabetic population can be achieved with meticulous preconceptional glycemic control.11 Subsequent trials comparing a preconceptional intensive metabolic program to standard treatment over 15 years duration have demonstrated lowered perinatal mortality (0% vs 7%) and reduced congenital anomaly rate (14% to 2%). In addition, when the preconceptional counseling program was discontinued, the congenital anomaly rate increased by over 50%.12

* Growth restriction

• Although most fetuses of diabetic mothers exhibit growth acceleration, growth restriction occurs with significant frequency in pregnancies in women with preexisting type 1 diabetes.
• The most import predictor of fetal growth restriction is underlying maternal vascular disease. Specifically, pregnant patients with diabetes-associated retinal or renal vasculopathies and/or chronic hypertension are most at risk for growth restriction.

* Growth acceleration

• Excessive body fat stores, stimulated by excessive glucose delivery during diabetic pregnancy, often extends into childhood and adult life.
• Approximately 30% of fetuses of women with diabetes mellitus in pregnancy are large for gestational age (LGA). In preexisting diabetes mellitus this incidence appears slightly higher, 38%.4
• Maternal obesity, common in type 2 diabetes, appears to significantly accelerate the risk of infants being LGA.

* Fetal obesity

• Macrosomia is typically defined as a birthweight above the 90th percentile for gestational age or greater than 4000 grams. In pregnant diabetic women, macrosomia occurs in 15-45% of cases, a 3-fold increase from normoglycemic controls.
• Newborns with macrosomia experience excessive rates of neonatal morbidity, as illustrated by a study by Hunter et al in 1993, which compared the neonatal morbidity among infants of 230 women with insulin-dependent diabetes and infants of 460 women without diabetes. The infants of diabetic mothers (IDMs) had 5-fold higher rates of severe hypoglycemia, a 4-fold increase in macrosomia, and a doubled increase in neonatal jaundice.13
• Birth injury, including shoulder dystocia and brachial plexus trauma, are more common among infants of diabetic mothers, and macrosomic fetuses are at the highest risk.
• The macrosomic fetus in diabetic pregnancy develops a unique pattern of overgrowth, involving central deposition of subcutaneous fat in the abdominal and interscapular areas. Skeletal growth is largely unaffected. Neonates of diabetic mothers have a larger shoulder and extremity circumference, a decreased head-to-shoulder ratio, significantly higher body fat and thicker upper extremity skin folds compared to nondiabetic control infants of similar weights. Since fetal head size is not increased during poorly controlled diabetic pregnancy but shoulder and abdominal girth can be markedly augmented, the risk of injury to the fetus after delivery of the head (eg Erb palsy) is significantly increased.
• When serial ultrasound examination findings from diabetic fetuses are plotted, the growth velocity of the abdominal circumference is often well above the growth centiles seen in nondiabetic fetuses and is higher than the fetal head and femur centiles. The accelerated growth of the abdominal circumference begins to rise significantly above normal after 24 weeks.

* Metabolic syndrome

• The adverse downstream effects of abnormal maternal metabolism on the offspring have been documented well into puberty. Glucose intolerance and higher serum insulin levels are more frequent in children of diabetic mothers as compared to normal controls. By age 10-16 years, offspring of diabetic pregnancy have a 19.3% rate of impaired glucose intolerance.14
• The childhood metabolic syndrome includes childhood obesity, hypertension, dyslipidemia, and glucose intolerance. A growing body of literature supports a relationship between intrauterine exposure to maternal diabetes and risk of a metabolic syndrome later in life.15, 16
• Fetuses of diabetic women that are born large for gestational age appear to be at the greatest risk.16

* Role of glucosa level

• Excess nutrient delivery to the fetus causes macrosomia and truncal fat deposition, but whether fasting or peak glucose values are more correlated with fetal overgrowth is less clear.
  Data from the Diabetes in Early Pregnancy project indicate that fetal birthweight correlates best with second- and third-trimester postprandial blood sugar levels and not with fasting or mean glucose levels.17
• More recent data from the ACHOIS trial demonstrated a positive relationship between severity of maternal fasting hyperglycemia and risk of shoulder dystocia, with a 1 mmol increase in fasting glucose leading to a relative risk for shoulder dystocia of 2.09 (1.03- 4.25).18
• When postprandial glucose values average 120 mg/dL or less, approximately 20% of infants can be expected to be macrosomic. When postprandial levels range as high as 160 mg/dL, macrosomia rates can reach 35%.
• In addition, there appears to be a role for excessive fetal insulin levels in mediating accelerated fetal growth. In the study by Simmons et al which compared umbilical cord sera in infants of diabetic mothers newborns and controls, the heavier, fatter babies from diabetic pregnancies were also hyperinsulinemic.19

* Role of maternal obesity

• Maternal obesity has a strong and independent effect on fetal macrosomia. Birthweight is largely determined by maternal factors other than hyperglycemia, with the most significant influences being gestational age at delivery, prepregnancy maternal body mass index (BMI), maternal height, pregnancy weight gain, the presence of hypertension, and cigarette smoking.
• When women who are very obese (weight >300 lb) were compared to women of normal weight, the obese women had more than double the risk of macrosomia compared to the women who were of normal weight. This may explain the failure of glycemic control to completely prevent fetal macrosomia in several series.

Perinatal morbidity and birth injury

* Perinatal mortality

• In diabetic pregnancy, perinatal mortality has decreased 30-fold since the discovery of insulin in 1922 and intensive obstetrical and infant care in the 1970s. Nevertheless, the current perinatal mortality rates among women who are diabetic remain approximately twice those observed in the nondiabetic population.
• Congenital malformations, respiratory distress syndrome (RDS), and extreme prematurity account for most perinatal deaths in contemporary diabetic pregnancies.

To be continue..............