Gestational Diabetes During and After Pregnancy

16. The Diabetic Intrauterine Environment: Short and Long-Term Consequences

Dana Dabelea 

(1)

Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, 13001 East 17th Avenue, Campus Box B-119, Aurora, CO 80045, USA

Dana Dabelea

Email: Dana.Dabelea@ucdenver.edu

Abstract

Fetal life is one of the critical periods when an exposure may have lifelong effects through biological programming. Intrauterine exposure to an excess of fuels, such as hyperglycemia, leads to greater birth weight and an increased risk of obesity, impaired glucose tolerance, and type 2 diabetes. These effects are not limited to children of women diagnosed with diabetes. In addition to hyperglycemia, alterations in other maternal fuels or derangement in placental transport of fuels may be involved in fetal overgrowth. Obesity is a major risk factor for diabetes and studies have shown an independent association of maternal obesity with excessive fetal growth and adiposity. Several mechanisms that are not mutually exclusive may explain these associations, including: genetic predisposition, shared familial socioeconomic and lifestyle factors, and specific intrauterine effects. Future research should further characterize the specific intrauterine mediators of short and long-term consequences, and provide better understanding of the biological bases of fetal programming. Such studies could ultimately lead to the development of strategies for early life prevention of future chronic disorders.

16.1 Introduction

Diabetes during pregnancy is a growing problem worldwide. Type 2 diabetes is increasing at an alarming rate1 and is occurring in younger individuals more often than previously,2 resulting in more women being diagnosed with type 2 diabetes during their reproductive years. In addition, gestational diabetes (GDM) has also been shown to be increasing among all racial/ethnic groups in several studies in the United States.34 The observed increase probably reflects the well-documented obesity epidemic.5

The hypothesis of fetal over-nutrition or fuel mediated teratogenesis proposed in the 1950s by Pederson6 postulates that intrauterine exposure of the fetus of women with diabetes in pregnancy to hyperglycemia causes permanent fetal changes, leading to malformations, greater birth weight, and an increased risk of developing type 2 diabetes and obesity in later life. In the 1980s this hypothesis was broadened to include the possibility that other fuels, such as free fatty acids (FFA), ketone bodies, and amino acids also increased fetal growth.7 More recently, it has been suggested that fetal over-nutrition may also occur in nondiabetic but obese pregnancies.8 The notion that inadequate “nutrition” at critical periods of development in fetal life is a key determinant of childhood and adult health has important implications.911 Animal studies have demonstrated that the metabolic imprinting caused by the diabetic intrauterine environment can be transmitted across generations.1213 It has been suggested that a “vicious cycle” results, explaining at least in part the increases in type 2 and GDM seen over the past several decades.

This chapter reviews the evidence on the effect of intrauterine over-nutrition on fetal growth, metabolic imprinting, and offspring risk of obesity and type 2 diabetes later in life. Possible mechanisms for these effects are reviewed, and the clinical and public health implications are discussed.

16.2 Intrauterine Over-Nutrition and Fetal Growth

Fetal over-nutrition has generally been inferred indirectly from measures such as maternal prepregnancy weight, height, weight gain during pregnancy, and infant birth weight. Maternal metabolism has seldom been assessed and most studies to date have focused on maternal hyperglycemia and diabetes.

16.2.1 Maternal Diabetes and Obesity and Fetal Growth

Infants of diabetic mothers display excess fetal growth, often resulting in large-for-gestational age (LGA) or macrosomia,14,15 consequently increasing the risk for cesarean delivery and traumatic birth injury.15

It is thought that excessive fetal growth and other metabolic changes related to intrauterine exposure to diabetes can lead to increased adiposity in the offspring. There is evidence that increased adiposity is present at birth in infants of mothers with GDM. Catalano et al16 studied a group of 195 infants born to mothers with GDM and 220 infants of mothers with normal glucose tolerance, and found that fat mass, but not birth weight or fat-free mass, was 20% higher in the infants exposed to diabetes in utero. Maternal fasting glucose level measured during the oral glucose tolerance test was the strongest correlate of infant adiposity, further supporting the hypothesis that the degree of hyperglycemia determines the metabolic effect on the neonate. The results of this study suggest that, even in the absence of LGA or macrosomia, the exposure to the diabetic intrauterine milieu causes alterations in fetal growth patterns that likely predispose these infants to overweight and obesity later in life.

Much less is known about whether and how fetal programming is driven by exposure in utero to maternal obesity in the absence of diabetes. Maternal height and “frame size,” regarded as markers of lifelong nutritional status, are important determinants of fetal growth.17 Birth weight was shown to increase linearly with increasing prepregnancy body mass index (BMI) and with increasing weight gain during pregnancy.1819 Vohr et al found that maternal prepregnancy weight, and weight gain during pregnancy were significant predictors not only of macrosomia, but also of neonatal adiposity (based on skinfold assessment) among both infants of mothers with GDM and control infants.20 Moreover, these patterns of adiposity present at birth persisted at age 1 year.21 More recently, increased maternal pregravid weight and estimated insulin resistance were shown to explain most of the variance in birth weight (48%) and fat mass at birth (46%).22 In a Canadian study23 mother’s prepregnancy weight, weight gain during pregnancy, and parity were stronger correlates of birth weight percentile than plasma glucose levels.

Since maternal obesity during pregnancy is a state of insulin resistance,24 it can be hypothesized that, during gestation, obese women make available increased amounts of nutrients to the fetus, resulting in increased fetal growth, especially in adipose tissue. In support of this hypothesis, Brown et al25 have described independent associations between maternal waist/hip ratio and infant’s birth weight and ponderal index. Maternal central obesity was shown to be associated with metabolic changes that may influence fetal growth, including insulin resistance, hyperinsulinemia, dyslipidemia, and elevated blood glucose levels.26 Insulin, which is influenced by maternal nutritional and metabolic status, is an important regulator of fetal growth.27 Maternal insulin resistance and hyperinsulinemia in pregnancies complicated by obesity and diabetes may increase the transfer of nutrients from mother to offspring in order to meet maximal (although not optimal) fetal requirements, even at the expense of maternal health.17

16.2.2 Maternal Glucose Supply and Fetal Growth

Maternal hyperglycemia, extreme enough to be recognized as GDM, is a clear risk factor for macrosomia. However, most macrosomic infants are not born to mothers diagnosed with GDM, but to mothers with obesity without recognized glucose intolerance.2830 Health care providers disagree about several aspects of GDM, including criteria for diagnosis, associated perinatal and maternal morbidity and optimal therapeutic strategies.3136 The current approach in the United States consists of determining plasma glucose levels 1 h after a 50-g oral glucose load in a nonfasting state at 24–28 weeks’ gestation, followed by a diagnostic 3-h 100-g glucose load only in women with an abnormal screening test. However, women with lesser degrees of glucose intolerance, who exhibit an abnormal glucose screening test but do not meet diagnostic criteria for GDM may also be at risk for delivering a macrosomic infant.37,38

Several recent studies suggest that the relation between glycemia during pregnancy and infant body size is linear. A retrospective study conducted on 143 infants of nondiabetic mothers in Rhode Island showed a linear relationship between the 50-g glucose screen and infant BMI (r = 0.24, p = 0.007).20 Similarly, in a different study of 6,854 consecutive pregnant women screened for GDM, increasing glucose concentration at screening was associated with higher prevalence of macrosomia.39 In a large community-based study in Mysore, South India, maternal fasting glucose at 30-weeks of gestation was positively associated with infant birth weight (79 g increase per 1 mmol/L higher glucose), ponderal index, and head circumference even among mothers who did not fulfill the Carpenter-Coustan criteria for GDM diagnosis.40 There were similar findings in a study of 917 nondiabetic women in Scotland, in which birth weight, length, head circumference, and skinfolds were positively related to maternal fasting plasma glucose concentrations measured in the third trimester of pregnancy.41

Since maternal fuel supply across a population is a continuum, the relationship between glycemia and offspring size at birth should be present across the entire distribution of maternal glucose concentrations. As discussed in the chapter by Steering Committee for the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, HAPO was a major international effort including over 20,000 pregnant women that specifically tested and confirmed the hypothesis that maternal glucose levels during pregnancy show a linear association with adverse pregnancy outcomes (including birth weight), thus indicating the need to reconsider current GDM diagnostic criteria.42 In HAPO, an increase in the fasting glucose levels at 24–32 weeks of gestation of 1 SD (30.9 mg/dL) was associated with 1.38-fold higher odds (95% CI=1.32–1.44) for neonatal macrosomia (birth weight above the 90th percentile) and 1.55-fold higher odds (95% CI = 1.47–1.64) for neonatal hyperinsulinemia (cord blood C-peptide above the 90th percentile).

The timing of excessive nutrient delivery to the fetus may also be a critical component in the fetal accretion of fat. Among women with pre-existing diabetes, suboptimal glycemic control in the first trimester of pregnancy is a stronger predictor of neonatal macrosomia than is suboptimal control in the third trimester.43 There is also evidence that glucose transfer by placental GLUT 1 transporters may be programmed early in pregnancy.4446 Aberrancies of glucose metabolism in GDM women have only been examined in the late second and third trimester of pregnancy. There are, in fact, no studies that examine whether hyperglycemia occurs early in obese pregnant women. Such early nutrient excess could possibly program placental transfer of substrates much sooner than previously appreciated.

16.2.3 Maternal Lipid Supply and Fetal Growth

Although unrecognized maternal hyperglycemia is likely to be an important contributor to excess fetal growth, especially in obese pregnancies, descriptive evidence suggests that alterations in maternal lipid metabolism47 may also be an important mechanism and contribute substantially to “fuel mediated teratogenesis.”7

FFA and triglycerides have been shown to be increased in mothers of obese neonates,48 and due to the limited de novo lipogenic capacity of the fetus, most precursors for fetal fat accretion are supplied by transplacental transfer of maternal substrates derived from lipids.4748 In the late second trimester, coincident with the increasing insulin resistance of pregnancy, women shift from fat storage to accelerated lipolysis so that FFA and glycerol can be used for maternal energy needs, sparing glucose as a fuel for the fetus. However, nonesterified fatty acids can be transferred across the placenta, which may occur directly, or secondarily, by hydrolysis of triglycerides.

Evidence exists that excess maternal obesity may increase lipid availability, modulate delivery of lipid substrates to the fetus, and be an important determinant of excess fetal growth. In a study of pregnant Italian women with various degrees of glucose intolerance, presence of the metabolic syndrome in mid-pregnancy predicted neonatal macrosomia independent of glucose tolerance status.49 Other authors found an association between maternal serum triglyceride levels at 24–32 weeks of gestation and macrosomia among nondiabetic women with positive screening tests,5052 independent of maternal prepregnancy BMI, weight gain during pregnancy, and mid-pregnancy plasma glucose levels.51 These observations suggest that maternal triglyceride concentrations in mid-pregnancy may have important predictive value for fetal overgrowth in nondiabetic pregnancies; however, these findings may be limited to women with positive diabetic screening tests. Increased available lipid substrate due to hydrolysis of maternal triglycerides may be used directly as an energy source for the fetus.53 Alternatively, triglycerides may be used for maternal fat oxidation and glycerol production for maternal gluconeogenesis, preserving glucose for preferential use by the fetal-placental unit.47

16.2.4 Maternal Insulin Resistance and Inflammation and Fetal Growth

Human pregnancy is an insulin-resistant condition,54 which facilitates the transfer of nutrients from mother to fetus.55 The insulin resistance of normal pregnancy that occurs in the second and third trimester is thought to be mediated by placental hormones and is a physiological adaptation that ensures that maternal glucose is adequately delivered to the fetus.56 In early pregnancy, peripheral sensitivity to insulin and glucose is similar to pregravid levels but may already be high if the woman is very obese.55,5759 Recent data suggest that the degree to which insulin resistance is present in late gestation is primarily dependent on pregravid obesity and only secondarily mediated through placental hormones.60 With increased insulin resistance, glucose uptake and suppression of hepatic glucose production are decreased resulting in increased circulating concentrations of fuels and increased fuel availability to the fetus.

Although there is abundant evidence concerning the effects of obesity on metabolic pathways in nonpregnant individuals, such information is sparse with respect to pregnancy. In nonpregnant subjects, obesity is a recognized state of low-grade inflammation.6162 Limited data suggest that similar inflammatory implications of obesity may exist during pregnancy. In a recent study of 47 normoglycemic pregnant women, Ramsay et al63 demonstrated microvascular endothelial dysfunction, metabolic abnormalities (fasting hyperinsulinemia, hypertriglyceridemia and low HDL-cholesterol), and low-grade inflammation (elevated C-reactive protein (CRP) and interleukin-6 (IL-6)), in obese vs. lean pregnant women. These comprehensive data demonstrate that, as in nonpregnant obese individuals, obesity in pregnancy is associated not only with marked hyperinsulinemia (without necessarily glucose dysregulation) and dyslipidemia, but also impaired endothelial function, higher blood pressure, and inflammatory up-regulation. In a different study of 180 pregnant women, higher maternal CRP levels correlated strongly with prepregnancy maternal obesity, but not with GDM presence.61 These data suggest a model in which prepregnant obesity mediates a state of mild systemic inflammation present throughout pregnancy, with possible metabolic consequences, including greater insulin resistance and glucose intolerance in late gestation. Such a state may also have fetal programming implications, as suggested by several lines of evidence.64 For example, altered maternal vascular function may dysregulate nutrient flow to the fetus65A proinflammatory state may be associated with future cardiovascular disease in the offspring.66 Rats injected with IL-6 throughout pregnancy had offspring with greater body fat and increased insulin resistance.67 Of note, the dysregulation of several metabolic pathways by pregestational obesity described above may be independent of maternal fuels, including maternal diabetes.

16.3 Long-Term Consequences of Intrauterine Exposure to Maternal Diabetes and Obesity

The infant of the diabetic mother eventually becomes the child, the adolescent, and the adult offspring of the diabetic mother. The legacy of the diabetic intrauterine environment, acquired during gestation, cannot be ignored. It is widely recognized now that the effects of the diabetic intrauterine environment extend beyond those apparent at birth.68 Importantly, these effects are independent of birth weight,2469,70 and appear to be similar regardless of mother’s type of diabetes.71,72

16.3.1 Childhood Growth and Risk for Obesity

The role of exposure to diabetes in utero on infant and childhood growth, later obesity, and type 2 diabetes has been prospectively examined in two studies: the Pima Indian Study and the Diabetes in Pregnancy Study at Northwestern University in Chicago. The offspring of Pima Indian women with pre-existent type 2 diabetes and GDM were larger for gestational age at birth, and, at every age, they were heavier for height than the offspring of prediabetic or nondiabetic women.7375 Even in normal birth weight offspring of diabetic pregnancies, childhood obesity was still more common than among offspring of nondiabetic pregnancies.69

Researchers at The Diabetes in Pregnancy Center at Northwestern University have reported excessive growth in offspring of women with diabetes during pregnancy.76 By age 8 years the children were, on average, 30% heavier than expected for their height. In this study, amniotic fluid insulin was collected at 32–38 weeks of gestation. At the age of 6 years there was a significant positive association between the amniotic fluid insulin and childhood obesity, as estimated by the symmetry index. The insulin concentrations in 6-year-old children who had a symmetry index of less than 1.0 (86.1 pmol/L) or between 1.0 and 1.2 (69.9 pmol/L) were only half of what was measured in the more obese children with a symmetry index greater than 1.2 (140.5 pmol/L, p < 0.05 for each comparison). Thus, a direct correlation between an objective measure of the altered diabetic intrauterine environment and the degree of obesity in children and adolescents was demonstrated in this study.

Not all studies have shown as clear an association between exposure to GDM and childhood adiposity. Gillman et al77 reported on obesity and overweight among 9–14-year-old offspring of mothers with GDM, with all data collected by questionnaire. In this study, exposure to GDM while in utero was also associated with a 40% increased odds of being overweight as an adolescent; however these odds were attenuated when further adjustments were made for birth weight (odds ratio 1.3, 95% confidence interval 0.9–1.9) and maternal BMI (odds ratio 1.2, 95% confidence interval 0.8–1.7). While these results suggest that any increase in childhood obesity associated with prenatal exposure to gestational diabetes is not independent of birth weight and maternal obesity, there are important limitations to this study. All data were collected by questionnaire, and self-reported weight may be inaccurate. In addition, only about half of the mothers with children agreed to have the study contact their children, and of the eligible children only 68% of the girls and 58% of the boys completed the questionnaires, for an overall response rate of approximately 34%.

Similarly, In a retrospective chart review study, Whitaker et al found no difference in overweight (≥85th percentile for weight) for children ages 5–10 according to maternal GDM status.78 The inconsistency in these results may be partly explained by differences in exposure prevalence across populations studied, as the Pima Indians are a population with extremely high rates of obesity and diabetes, including during pregnancy. Further studies are needed to evaluate the effect of intrauterine diabetes exposure on fetal and childhood growth among different ethnic groups.

16.3.2 Abnormal Glucose Tolerance and Risk for Type 2 Diabetes

For more than 30 years, Pima Indian women have had routine oral glucose tolerance tests approximately every 2 years as well as during pregnancy.75 Women who had diabetes before or during pregnancy were termed diabetic mothers; those who developed diabetes only after pregnancy were termed prediabetic mothers. By age 5–9 and 10–14 years, type 2 diabetes was present almost exclusively among the offspring of diabetic women. In all age groups there was significantly more diabetes in the offspring of diabetic women than in those of prediabetic and nondiabetic women, and there were much smaller differences in diabetes prevalence between offspring of prediabetic and nondiabetic women.79

The comparison between offspring of diabetic and prediabetic women is an attempt to control for any potential confounding effect of a genetic predisposition to obesity and diabetes on the relationship between exposure to the maternal diabetic environment and obesity and diabetes in the offspring. The ideal way to approach this question is to examine sibling pairs in which one sibling is born before and one is born after the onset of their mother’s diabetes.80 Using this design, the prevalence of type 2 diabetes was compared in Pima Indian siblings born before and after their mother developed diabetes.80 There were 19 nuclear families with sibling pairs (n = 28 pairs) discordant for both type 2 diabetes and exposure to a pregnancy complicated by diabetes. In 21 of the 28 sib-pairs, the sibling who developed type 2 diabetes was born after the mother’s diagnosis of diabetes and in only 7 of the 28 pairs was the sibling with type 2 diabetes born before (odds ratio 3.0, p < 0.01). In contrast, among 84 siblings and 39 sib-pairs from 24 families of diabetic fathers, the risk for type 2 diabetes was similar in the sib-pairs born before and after father’s diagnosis of diabetes. Since siblings born before and after a diabetic pregnancy are believed to carry a similar risk of inheriting the same susceptibility genes, the excess risk associated with maternal diabetes likely reflects the effect of intrauterine exposure associated with or directly due to hyperglycemia and/or other fuel alterations of a diabetic pregnancy.

Recently, the SEARCH Case–Control Study provided novel evidence that intrauterine exposure to maternal diabetes and obesity are important determinants of type 2 diabetes in youth of other racial/ethnic groups (non-Hispanic white, Hispanic and African American). In this study, youth with type 2 diabetes were more likely to have been exposed to maternal diabetes or obesity in utero than were nondiabetic controls (p < 0.0001 for each). After adjusting for offspring age, sex and race/ethnicity, exposure to maternal diabetes (OR = 5.7; 95% CI = 2.4–13.4) and exposure to maternal prepregnancy obesity (2.8; 95% CI = 1.5–5.2) were independently associated with type 2 diabetes in the offspring. Adjustment for other perinatal and socio-economic factors did not alter these associations.81

16.3.3 Insulin Resistance, Secretion, and Cardiovascular Abnormalities

Several studies performed in newborns of diabetic mothers have shown an enhanced insulin secretion to a glycemic stimulus.82 Consistent with these findings, Van Assche83 and Heding84 described hyperplasia of the beta cells in newborns of diabetic mothers. Conversely, impaired insulin secretion has also been proposed as a possible mechanism. Among Pima Indian adults the acute insulin response to infused glucose was 40% lower in individuals whose mothers had diabetes during pregnancy than in those whose mothers developed diabetes after the birth of the subject.85

Animal studies have shown that exposure to diabetes in utero can induce cardiovascular dysfunction in adult offspring.86 Few human studies have examined cardiovascular risk factors in offspring of diabetic pregnancies. By 10–14 years, offspring of diabetic pregnancies enrolled in the Diabetes in Pregnancy follow-up study at Northwestern University had significantly higher systolic and mean arterial blood pressure than offspring of nondiabetic pregnancies.76 Higher concentrations of markers of endothelial dysfunction (ICAM-1, VCAM-1, E-selectin), as well as increased cholesterol-to-HDL ratio were reported among offspring of mothers with type 1 diabetes compared with offspring of nondiabetic pregnancies, independent of current BMI.87 Recently, the Pima Indian investigators have shown that, independent of adiposity, 7–11-year-old offspring exposed to maternal diabetes during pregnancy have significantly higher systolic blood pressure than offspring of mothers who did not develop type 2 diabetes until after the index pregnancy.88 These data suggest that in utero exposure to diabetes confers risks for the development of cardiovascular disease later in life that are independent of adiposity and may be in addition to genetic predisposition to diabetes or cardiovascular disease.

16.4 Clinical and Public Health Implications

The hypothesis of fuel-mediated teratogenesis suggests that excess fetal growth caused by maternal fuel abnormalities also results in adult disease in the offspring, and so interventions to reduce the transmission of obesity, cardiovascular disease, and type 2 diabetes would logically focus on normalizing maternal metabolism and fuel delivery to the infant.

There is evidence that hyperglycemia increases fetal growth and also may induce other metabolic changes which are associated with adult chronic disease. However, there is little information available regarding the optimal level of glycemic control needed to prevent metabolic changes in the offspring. Intensive treatment in women with GDM reduced birth weight and incidence of macrosomia in infants born to mothers who participated in the intervention compared to women who received routine care.89 However, more evidence is needed to determine optimal glucose levels during pregnancy that would prevent long-term metabolic disturbances in the offspring.

While excess glucose stimulates fetal insulin production and results in increased fetal growth and adiposity, fetal growth appears to be increased even in nondiabetic obese pregnancies. It is therefore likely that, in addition to hyperglycemia, alterations in other maternal fuels or derangement in placental transport of fuels are also involved in fetal overgrowth. In addition, maternal obesity and weight gain during pregnancy contribute to fetal overgrowth, and adjustment for maternal obesity attenuates some of the effect of exposure to intrauterine diabetes on obesity and type 2 diabetes risk in the offspring.

There is also a need to evaluate the effects of exposure to maternal hyperglycemia and obesity on fetal growth, adiposity and insulin resistance in an ethnically diverse population. For example, biologic mechanisms may differ across racial/ethnic groups – either absolutely or relatively. In addition, the prevalence of different risk factors will likely differ by racial/ethnic group, such that even if the mechanisms are similar, the attributable fractions for specific risk factors will differ according to race/ethnicity, and this may drive strategies for prevention.

Much more information is needed to determine the most effective strategies to address the risk of chronic metabolic diseases in the infant of the diabetic mother. However, it is increasingly clear that public health efforts to prevent type 2 diabetes should focus on not only adult lifestyle risk factors such as obesity and sedentary lifestyle, but also on prenatal exposure to diabetes and obesity in utero. Reduced obesity in women of reproductive age and prevention of excessive weight gain during pregnancy may not only lessen the risk of GDM in the mother, but will likely also reduce the risk of excess fetal growth, future obesity and type 2 diabetes in the offspring.

References

1.

Hussain A, Claussen B, Ramachandran A, Williams R. Prevention of type 2 diabetes: a review. Diabetes Res Clin Pract. 2007;76:317-326.PubMedCrossRef

2.

Dabelea D, Pettitt DJ, Jones KL, Arslanian SA. Type 2 diabetes mellitus in minority children and adolescents. An emerging problem. Endocrinol Metab Clin North Am. 1999;28(9):709-729.

3.

Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diab Care. 2005;28:579-584.CrossRef

4.

Ferrarra A, Kahn HS, Quesenberry CP, Riley C, Hedderson MM. An increase in the incidence of gestational diabetes mellitus: Northern California, 1991–2000. Obstet Gynecol. 2004; 103:526-533.CrossRef

5.

Sobngwi E, Boudou P, Mauvais-Jarvis F. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet. 2003;361:1861-1865.PubMedCrossRef

6.

Pedersen J. Weight and lenght at birth in infants of diabetic mothers. Acta Endocrinol. 1954;16:330-342.PubMed

7.

Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes. 1980;29:1023-1035.

8.

Whitaker RC, Dietz WH. Role of the prenatal environment in the development of obesity. J Pediatr. 1998;132:768-776.PubMedCrossRef

9.

Barker DJ, Fall CH. Fetal and infant origins of cardiovascular disease. Arch Dis Child. 1993;68:797-799.PubMedCrossRef

10.

Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life [see comments]. Lancet. 1993;341:938-941.PubMedCrossRef

11.

Barker DJ. In utero programming of chronic disease. Clin Sci (Colch ). 1998;95:115-128.CrossRef

12.

Aerts L, Sodoyez-Goffaux F, Sodoyez JC, Malaisse WJ, Van Assche FA. The diabetic intrauterine milieu has a long-lasting effect on insulin secretion by B cells and on insulin uptake by target tissues. Am J Obstet Gynecol. 1988;159:1287-1292.PubMedCrossRef

13.

Gauguier D, Nelson I, Bernard C. Higher maternal than paternal inheritance of diabetes in GK rats. Diabetes. 1994;43:220-224.PubMedCrossRef

14.

Lampl M, Jeanty P. Exposure to maternal diabetes is associated with altered fetal growth patterns: A hypothesis regarding metabolic allocation to growth under hyperglycemic-hypoxemic conditions. Am J Hum Biol. 2004;6:237-263.CrossRef

15.

Jansson T, Cetin I, Powell TL. Placental transport and metabolism in fetal overgrowth — a workshop report. Placenta. 2006;27(suppl A):S109-S113.

16.

Catalano PM, Thomas A, Huston-Presley L, Amini SB. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am J Obstet Gynecol. 2003;189:1698-1704.PubMedCrossRef

17.

Perry IJ, Lumey LH. In: Kuh D, Ben-Shlomo Y, eds. A Life Course Approach to Chronic Disease Epidemiology. Oxford: Oxford University Press; 2004:345.

18.

Luke B. Nutritional influences on fetal growth. Clin Obstet Gynecol. 1994;37:538-549.PubMedCrossRef

19.

Abrams BF, Berman CA. Nutrition during pregnancy and lactation. Prim Care. 1993;20:585-597.PubMed

20.

Vohr BR, McGarvey ST, Coll CG. Effects of maternal gestational diabetes and adiposity on neonatal adiposity and blood pressure. Diabetes Care. 1995;18:467-475.PubMedCrossRef

21.

Vohr BR, McGarvey ST. Growth patterns of large-for-gestational-age and appropriate-for-gestational-age infants of gestational diabetic mothers and control mothers at age 1 year. Diabetes Care. 1997;20:1066-1072.PubMedCrossRef

22.

Catalano PM, Kirwan JP. Maternal factors that determine neonatal size and body fat. Curr Diab Rep. 2001;1:71-77.PubMedCrossRef

23.

Ouzilleau C, Roy MA, Leblanc L, Carpentier A, Maheux P. An observational study comparing 2-hour 75-g oral glucose tolerance with fasting plasma glucose in pregnant women: both poorly predictive of birth weight. CMAJ. 2003;168:403-409.PubMedCentralPubMed

24.

Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. J Nutr. 2003; 133:1674S–1683S.

25.

Brown JE, Potter JD, Jacobs DR Jr. Maternal waist-to-hip ratio as a predictor of newborn size: results of the Diana Project. Epidemiology. 1996;7:62-66.PubMedCrossRef

26.

McKeigue PM, Pierpoint T, Ferrie JE, Marmot MG. Relationship of glucose intolerance and hyperinsulinaemia to body fat pattern in South Asians and Europeans. Diabetologia. 1992; 35:785-791.PubMed

27.

Fowden AL. The role of insulin in prenatal growth. J Dev Physiol. 1989;12:173-182.PubMed

28.

Langer O, Conway DL. Level of glycemia and perinatal outcome in pregestational diabetes. J Matern Fetal Med. 2000;9:35-41.PubMed

29.

Langer O. Fetal macrosomia: etiologic factors. Clin Obstet Gynecol. 2000;43:283-297.PubMedCrossRef

30.

Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol. 2005;192:989-997.PubMedCrossRef

31.

Ratner RE. Clinical review 47: gestational diabetes mellitus: after three international workshops do we know how to diagnose and manage it yet? J Clin Endocrinol Metab. 1993;77:1-4.PubMedCrossRef

32.

Jarrett RJ. Gestational diabetes: a non-entity? Brit Med J. 1993;306:37-38.PubMedCrossRef

33.

Buchanan TA, Kjos SL. Gestational diabetes: risk or myth? J Clin Endocrinol Metab. 1999;84:1854-1857.PubMedCrossRef

34.

Kjos SL, Buchanan TA. Gestational diabetes mellitus. N Engl J Med. 1999;341:1749-1756.PubMedCrossRef

35.

Dornhorst A, Chan SP. The elusive diagnosis of gestational diabetes. Diabet Med. 1998;15:7-10.PubMedCrossRef

36.

Ferrara A, Hedderson MM, Quesenberry CP, Selby JV. Prevalence of gestational diabetes mellitus detected by the national diabetes data group or the carpenter and coustan plasma glucose thresholds. Diabetes Care. 2002;25:1625-1630.PubMedCrossRef

37.

Sermer M, Naylor CD, Gare DJ. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes. The Toronto Tri-Hospital Gestational Diabetes Project. Am J Obstet Gynecol. 1995;173:146-156.PubMedCrossRef

38.

Leikin EL, Jenkins JH, Pomerantz GA, Klein L. Abnormal glucose screening tests in pregnancy: a risk factor for fetal macrosomia. Obstet Gynecol. 1987;69:570-573.PubMed

39.

Yogev Y, Langer O, Xenakis EM, Rosenn B. The association between glucose challenge test, obesity and pregnancy outcome in 6390 non-diabetic women. J Matern Fetal Neonatal Med. 2005;17:29-34.PubMedCrossRef

40.

Hill JC, Krishnaveni GV, Annamma I, Leary SD, Fall CH. Glucose tolerance in pregnancy in South India: relationships to neonatal anthropometry. Acta Obstet Gynecol Scand. 2005;84:159-165.PubMed

41.

Farmer G, Russell G, Hamilton-Nicol DR. The influence of maternal glucose metabolism on fetal growth, development and morbidity in 917 singleton pregnancies in nondiabetic women. Diabetologia. 1988;31:134-141.PubMedCrossRef

42.

The HAPOStudy Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. New Engl J Med. 2008;358:1991-2002.CrossRef

43.

Rey E, Attie C, Bonin A. The effects of first-trimester diabetes control on the incidence of macrosomia. Am J Obstet Gynecol. 1999;181:202-206.PubMedCrossRef

44.

Illsley NP. Glucose transporters in the human placenta. Placenta. 2000;21:14-22.PubMedCrossRef

45.

Illsley NP. Placental glucose transport in diabetic pregnancy. Clin Obstet Gynecol. 2000;43:116-126.PubMedCrossRef

46.

Gaither K, Quraishi AN, Illsley NP. Diabetes alters the expression and activity of the human placental GLUT1 glucose transporter. J Clin Endocrinol Metab. 1999;84:695-701.PubMedCrossRef

47.

Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000;71:1256S-1261S.PubMed

48.

Di Cianni G, Miccoli R, Volpe L. Maternal triglyceride levels and newborn weight in pregnant women with normal glucose tolerance. Diabet Med. 2005;22:21-25.PubMedCrossRef

49.

Bo S, Menato G, Gallo ML. Mild gestational hyperglycemia, the metabolic syndrome and adverse neonatal outcomes. Acta Obstet Gynecol Scand. 2004;83:335-340.PubMed

50.

Nolan CJ, Proietto J. The feto-placental glucose steal phenomenon is a major cause of maternal metabolic adaptation during late pregnancy in the rat. Diabetologia. 1994;37:976-984.PubMedCrossRef

51.

Kitajima M, Oka S, Yasuhi I, Fukuda M, Rii Y, Ishimaru T. Maternal serum triglyceride at 24–32 weeks’ gestation and newborn weight in nondiabetic women with positive diabetic screens. Obstet Gynecol. 2001;97:776-780.PubMedCrossRef

52.

Knopp RH, Magee MS, Walden CE, Bonet B, Benedetti TJ. Prediction of infant birth weight by GDM screening tests. Importance of plasma triglyceride. Diabetes Care. 1992;15:1605-1613.PubMedCrossRef

53.

Peterson CM, Jovanovic-Peterson L, Mills JL. The Diabetes in Early Pregnancy Study: changes in cholesterol, triglycerides, body weight, and blood pressure. The National Institute of Child Health and Human Development–the Diabetes in Early Pregnancy Study. Am J Obstet Gynecol. 1992;166:513-518.PubMedCrossRef

54.

Catalano PM, Vargo KM, Bernstein IM, Amini SB. Incidence and risk factors associated with abnormal postpartum glucose tolerance in women with gestational diabetes. Am J Obstet Gynecol. 1991;165:914-919.PubMedCrossRef

55.

Cousins L. Insulin sensitivity in pregnancy. Diabetes. 1991;40(suppl 2):39-43.PubMedCrossRef

56.

Barbour LA. New concepts in insulin resistance of pregnancy and gestational diabetes: long-term implications for mother and offspring. J Obstet Gynaecol. 2003;23:545-549.PubMedCrossRef

57.

Catalano PM, Tyzbir ED, Wolfe RR, Roman NM, Amini SB, Sims EA. Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant women. Am J Obstet Gynecol. 1992;167:913-919.PubMedCrossRef

58.

Catalano PM, Tyzbir ED, Wolfe RR. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol. 1993;264:E60-E67.PubMed

59.

Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol. 1991; 165:1667-1672.PubMedCrossRef

60.

Kirwan JP, Hauguel-De MS, Lepercq J. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51:2207-2213.PubMedCrossRef

61.

Ford ES. Body mass index, diabetes, and C-reactive protein among U.S. adults. Diabetes Care. 1999;22:1971-1977.PubMedCrossRef

62.

Yudkin JS. Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent? Diab Care. 1999;22(suppl 3):C25-C30.

63.

Ramsay JE, Ferrell WR, Crawford L, Wallace AM, Greer IA, Sattar N. Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. J Clin Endocrinol Metab. 2002;87:4231-4237.PubMedCrossRef

64.

Retnakaran R, Hanley AJ, Raif N, Connelly PW, Sermer M, Zinman B. C-reactive protein and gestational diabetes: the central role of maternal obesity. J Clin Endocrinol Metab. 2003; 88:3507-3512.PubMedCrossRef

65.

Ramsay JE, Stewart F, Greer IA, Sattar N. Microvascular dysfunction: a link between pre-eclampsia and maternal coronary heart disease. BJOG. 2003;110:1029-1031.PubMedCrossRef

66.

Forsen T, Eriksson JG, Tuomilehto J, Teramo K, Osmond C, Barker DJ. Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. Brit Med J. 1997;315:837-840.PubMedCrossRef

67.

Dahlgreen J, Nilsson C, Jennische E, et al. Prenatal cytokine exposure results in obesity and gender-specific programming. Am J Physiol Endocrinol Metab. 2001;281:E326–E334.

68.

Pettitt DJ, Knowler WC. Diabetes and obesity in the Pima Indians: a crossgenerational vicious cycle. J Obesity Weight Regul. 1988;7:61-65.

69.

Pettitt DJ, Knowler WC, Bennett PH, Aleck KA, Baird HR. Obesity in offspring of diabetic Pima Indian women despite normal birth weight. Diabetes Care. 1987;10:76-80.PubMedCrossRef

70.

Harder T, Kohlhoff R, Dorner G, Rohde W, Plagemann A. Perinatal ‘programming’ of insulin resistance in childhood: critical impact of neonatal insulin and low birth weight in a risk population. Diabet Med. 2001;18:634-639.PubMedCrossRef

71.

Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers: Relationship to fetal hyperinsulinism. Diabetes Care. 1995; 18:611-617.PubMedCrossRef

72.

Weiss PA, Scholz HS, Haas J, Tamussino KF, Seissler J, Borkenstein MH. Long-term follow-up of infants of mothers with type 1 diabetes: evidence for hereditary and nonhereditary transmission of diabetes and precursors. Diabetes Care. 2000;23:905-911.PubMedCrossRef

73.

Pettitt DJ, Nelson RG, Saad MF, Bennett PH, Knowler WC. Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes Care. 1993;16:310-314.PubMedCrossRef

74.

Pettitt DJ, Baird HR, Aleck KA, Bennett PH, Knowler WC. Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. New Engl J Med. 1983;308:242-245.PubMedCrossRef

75.

Pettitt DJ, Bennett PH, Knowler WC, Baird HR, Aleck KA. Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring Diabetes. 1985;34(suppl 2):119-122.

76.

Silverman BL, Rizzo T, Green OC. Long-term prospective evaluation of offspring of diabetic mothers. Diabetes. 1991;40(suppl 2):121-125.PubMedCrossRef

77.

Gillman MW, Rifas-Shiman S, Berkey CS, Field AE, Colditz GA. Maternal gestational diabetes, birth weight, and adolescent obesity. Pediatrics. 2003;111:e221-e226.PubMedCrossRef

78.

Whitaker RC, Pepe MS, Seidel KD, Wright JA, Knopp RH. Gestational diabetes and the risk of offspring obesity. Pediatrics. 1998;101:E 91-E 97.

79.

Dabelea D, Pettitt DJ. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility. J Pediatr Endocrinol Metab. 2001;14:1085-1091.PubMed

80.

Dabelea D, Hanson RL, Lindsay RS. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49:2208-2211.PubMedCrossRef

81.

Dabelea D, Mayer-Davis EJ, Lamichhane AP. Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH Case-Control Study. Diab Care. 2008;31:1422-1426.CrossRef

82.

Pildes RS, Hart RJ, Warrner R, Cornblath M. Plasma insulin response during oral glucose tolerance tests in newborns of normal and gestational diabetic mothers. Pediatrics. 1969;44:76-83.PubMed

83.

Van Assche FA, Gepts W. The cytological composition of the foetal endocrine pancreas in normal and pathological conditions. Diabetologia. 1971;7:434-444.PubMedCrossRef

84.

Heding LG, Persson B, Stangenberg M. B-cell function in newborn infants of diabetic mothers. Diabetologia. 1980;19:427-432.PubMedCrossRef

85.

Gautier JF, Wilson C, Weyer C. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes. 2001;50:1828-1833.PubMedCrossRef

86.

Holemans K, Gerber RT, Meurrens K, De Clerck F, Poston L, Van Assche FA. Streptozotocin diabetes in the pregnant rat induces cardiovascular dysfunction in adult offspring. Diabetologia. 1999;42:81-89.PubMedCrossRef

87.

Manderson JG, Mullan B, Patterson CC, Hadden DR, Traub AI, McCance DR. Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy. Diabetologia. 2002;45:991-996.PubMedCrossRef

88.

Bunt JC, Tataranni PA, Salbe AD. Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children. J Clin Endocrinol Metab. 2005;90:3225-3229.PubMedCentralPubMedCrossRef

89.

Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477-2486.PubMedCrossRef



If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!