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Diabetes-induced Embryopathy—Is Prevention Feasible?
complications.
32
Therefore, weight control during pregnancy has been
Figure 3: Diagrammatic Illustration of Mitogen-activated Protein
the primary focus of prevention efforts.
Kinase Pathways in Diabetic Embryopathy
The guidelines of the Institute of Medicine (IOM) on this matter (see Table
1) favor limiting weight gain during pregnancy rather than losing weight,
Maternal hyperglycemia
and state that gestational weight gain goals be modified according to
pre-pregnancy body mass index to produce better maternal and infant
outcomes.
33
The available evidence suggests that pregnancy weight gain
Oxidative stress
within the IOM’s recommended ranges is associated with the best outcome
for both mothers and infants.
34,35
? MKK4
Exercise
It is generally accepted that exercise during pregnancy can prevent and limit
adverse maternal and fetal morbidities and provide long-term benefit
through reduction of maternal weight gain during pregnancy. However,
ERK JNK
there is insufficient evidence to recommend or offer advice against enrolling
diabetic pregnant women in specific exercise programs.
36
p66Shc
Nutritional Supplementation
Over the past decade, our group and others have extensively
Cell proliferation
?
studied the ability of nutritional supplements, particularly antioxidants, to Cell survival
Apoptosis
prevent diabetes-induced birth defects. In animal models, lipoic acid, a
naturally occurring scavenger of free radicals, has been shown to reduce
the malformation rate in diabetic pregnancies by as much as 10–25%.
37,38
Malformation
In an exploratory clinical study of non-pregnant diabetic individuals,
Embryo
lipoic acid lowered the plasma lipid hydroperoxides, demonstrating a
decrease in oxidative stress. This effect was even seen in patients with
MKK4 = mitogen-activated protein kinase kinase 4; ERK = extracellular signal-regulated kinases; J
NK = c-Jun N-terminal kinases.
high glucose levels.
39
Figure 4: Length of Hospital Stay by Type of Birth Defect
Vitamin C is another potent antioxidant and scavenger of free radicals,
20
and has been shown to reduce the rates of embryonic malformations and
18
embryo resorption.
40
Ergothioneine, another naturally occurring antioxidant,
15.9
16
significantly reduced embryonic malformation rates when administered to
14
pregnant diabetic rats.
41
12
10
Arachadonic acid (AA) and vitamin E, two potent antioxidants, have been
8.8
8
shown to prevent membrane lipid peroxidation and may also be able to
6
prevent diabetic embryopathies.
42,43
Both in vitro and in vivo experimental 4.4
studies have demonstrated that AA administration significantly reduces
Stays per 100,000 people
4
2.3
hyperglycemia-induced aberrant membrane lipid metabolism, suggesting a
2
protective effect.
44
We and others also have shown that pregnant diabetic
0
1997 1998 1999 2000 2001 2002 2003 2004
rats fed a diet supplemented with vitamin E have higher serum vitamin E
Cardiac and circulatory Digestive Genital and urinary Nervous system
levels and lower embryonic malformation and resorption rates than non-
Source: Agency for Healthcare Research and Quality.
vitamin-E-supplemented diabetic rats.
45–47
Table 1: Institute of Medicine Recommended Total Weight Gain in
Both n-acetylcysteine (NAC), a cysteine progenitor, and folic acid, a
Pregnant Women by Pre-pregnancy Body Mass Index (in kg/m
2
)*
methionine/cysteine precursor, increase glutathione synthesis. In
experimental models, supplementation with NAC reduced the development
Weight-for-height Category Recommended Total Gain (kg)
Low (BMI <19.8) 12.5–18
of peripheral neuropathy and embryopathy in diabetic rats.
48,49
Dietary
Normal (BMI 19.8–26) 11.5–16
supplementation with folic acid prevents NTDs in non-diabetic experimental
High (BMI >26–29)
a
7–11.5
and clinical models
50
and reduces embryonic malformation rates in animal
BMI = body mass index. * Adolescents and black women should strive for gains at the upper end of the
models and cell cultures.
51
recommended range. Short women (<1.57cm) should strive for gains at the lower end of the range. ª The
recommended target weight gain for obese women (BMI >29) is ≥6. Adapted from reference 4.
Conclusions in embryos generated by maternal diabetes is likely to increase. Although
Along with the rising prevalence of diabetes, particularly type 2 diabetes, tight glycemic control can prevent the problems caused by hyperglycemia,
and obesity in the US population, the risk for developmental abnormalities in practice euglycemia is often difficult to achieve, particularly in a pregnant
US OBSTETRICS & GYNECOLOGY 43
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