Teratogenic Effects of Diabetes and/or Obesity

Author: J.M. Graham
Submitted: Monday 14th of September 2009 09:54:07 AM
Submitted by: egf
Educational levels: qc2, qc3

Abstract

Diabetes mellitus is a metabolic derangement in which carbohydrate utilization is reduced by decreased insulin or resistance to insulin. Type 1 diabetes is juvenile onset (usually less than age 20 years), insulin dependent and associated with normal or wasted body habitus and low to absent plasma insulin. Type 2 diabetes is adult onset (usually greater than age 40 years), non-insulin-dependent, and associated with obesity, and insulin resistance in target tissues resulting in normal to high plasma insulin levels. Type 1 diabetes is immune mediated in genetically susceptible individuals, presumably triggered by a virus. Type 2 diabetes is multifactorial with a strong genetic predisposition. Currently there are at least 17 million affected Americans (roughly 6% of U.S. population). By 2050, 45-50 million Americans will become affected, and one in three children born in 2000 will become diabetic. Nearly half of all Black and Latino children are likely to develop the disease. Among 267,051 pregnancies screened by Kaiser in CA (86.8% of pregnancies), there has been an increase in yearly cumulative incidence of gestational diabetes mellitus (GDM). GDM increased from 5.1% in 1991 to 7.4% in 1997, leveling off at 6.9% through 2000. Compared with 1991, women screened in 2000 slightly older and more likely to be African American, Asian, Hispanic, or other (51.4% versus 37.3%). Increases in GDM probably reflect increases in the prevalence of diabetes and obesity. Elevations in 1st trimester maternal HbA1c are strongly associated with increased risks for major malformations (normal HbA1c < 8%). Screening for GDM is done at 24-28 weeks with a 50 gm glucose load (glucose >140 mg/dl in 80% of women with gestational diabetes). Further confirmation is done via a 100 gm oral glucose tolerance test (fasting glucose 105 mg/dl; 1 hr 190 mg/dl; 2 hr 165 mg/dl; 3 hr 140 mg/dl). HbA1c levels above 12 were associated with a 40% risk for malformations (RR =13) among 303 insulin-requiring diabetics. There is a 2 to 4-fold increased risk for diabetic embryopathy with poor early control (cardiac malformations, CNS malformations, renal and urinary tract anomalies, and skeletal anomalies) The increased risk for major anomalies that are fatal or require surgery is especially high (7-10-fold). There is also a risk for diabetic fetopathy, if there is poor later control (macrosomia, neonatal hypoglycemia, polycythemia and hyperbilirubinemia, hypocalcemia and hypomagnesemia, and cardiomyopathy). One unusual and highly suggestive pattern associated with diabetic embryopathy is hallucal polydactyly with tibial hemimelia and distinctive proximal placement of the extra hallux. An epidemiologic study of 15,675 malformed children in Spain revealed high risk for preaxial polydactyly of the feet in infants of diabetic mothers (OR 24.60, P=0.0004). Other distinctive defects include congenital microcolon with microgastria, holoprosencephaly, caudal regression, situs inversus, femoral hypoplasia-unusual facies, and the combination of aural, cardiac, vertebral, and CNS defects. Among 4,180 consecutive pregnancies complicated by GDM diagnosed after 20 weeks gestation, offspring with diabetes-related malformations had significantly-elevated fasting glucose and HbA1c levels. It is recommended that diabetics achieve good glycemic control prior to conception and throughout pregnancy, but good control does not guarantee that malformations will not occur. Some studies suggest that preconception multivitamin supplements reduce risk for malformations. For women with poor control, prenatal diagnosis through expanded AFP, fetal ultrasound, and echocardiography may be of benefit. Compared to normal-weight women, obese women have an increased risk of infertility and pregnancy complications. The most consistently described pregnancy complications are hypertensive disorders, gestational diabetes mellitus, thromboembolic events, and cesarean section. Fetal and neonatal complications may include congenital malformations, macrosomia, and shoulder dystocia. Obesity represents an imbalance between energy intake from food and energy output expended as physical and metabolic activity. The health effects of body weight are expressed as the body mass index (BMI), which is defined as weight in kilograms divided by the square of the height in meters). Overweight is defined as BMI 25, and obesity as BMI 30. According to the National Center for Health Statistics (2004), in 1999–2000 64% of the U.S. population aged 20–74 was overweight, and almost half of the overweight group was obese. The prevalence of overweight (52%) and obesity (26%) among women aged 20–34 years (the age group most likely to become pregnant) was somewhat lower, but prevalences of overweight and obesity were comparable to the overall population in women aged 35–44. Obesity in the general population appears to be increasing. The literature suggests that women with a body mass index (BMI) > 30 have approximately double the risk of having a child with a neural tube defect (NTD) compared to normal-weight women, and the increased risk associated with higher maternal body weight does not appear to be modified by folic acid supplementation.

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J.M. Graham. Teratogenic Effects of Diabetes and/or Obesity. EUROGENE portal. September 2009. online: http://eurogene.open.ac.uk/content/teratogenic-effects-diabetes-andor-obesity

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