1. Diabetes and Macrosomia Pennington Biomedical Research Center Division of Education

2. PBRC 2009 2 of 35 Gestational Diabetes Mellitus (GDM) Overview Affects 2 to 9 percent of all pregnancies. Associated with maternal and perinatal complications. Long-term adverse health outcomes among infants born to mothers with GDM: – Sustained impairment of glucose tolerance – Subsequent obesity – Impaired intellectual achievement The risk of macrosomia is increased.

3. PBRC 2009 3 of 35 Gestational Diabetes (GDM) Development Related to increased maternal body mass index (BMI). Pre-pregnancy BMI of 30 kg/m 2 or higher is a strong risk factor for the development of GDM. Maternal obesity combined with an excessive weight gain during pregnancy are major risk factors for: – pre-eclampsia – Cesarean section – preterm delivery – fetal macrosomia – fetal death.

4. PBRC 2009 4 of 35 Macrosomia An oversized fetus. Occurs frequently in women with diabetes. Can lead to trauma during birth and a greater chance of a cesarean delivery.cesarean delivery

5. PBRC 2009 5 of 35 Large for Gestational Age babies Birth weight above the 90th percentile, is considered as LGA (large for gestational age).

6. PBRC 2009 6 of 35 Around the World Increasing proportion of infants born with a high birth weight (HBW). In Sweden, HBW infants has risen to more than 20%. A similar pattern occurs in North America and Europe. Researchers have found that – increasing maternal weight – gestational weight gain – gestational diabetes – reduced smoking prevalence among pregnant women may likely explain the increase in proportion of LGA births between 1976 and 1996 in Canada.

7. PBRC 2009 7 of 35 Factors relating to LGA babies Related to the level of glycemic control that the mother achieves. Other factors that contribute to the development of LGA neonates are: – Obesity of the mother – Excessive weight gain in pregnancy

8. Research Maternal diabetes control on infant health at birth and in later life.

9. PBRC 2009 9 of 35 Fetal Growth Spurt and Pregestational Diabetic Pregnancy Researchers assessed the timing of the fetal growth spurt among pre-existing diabetic pregnancies (types 1 and 2) and its relationship with diabetic control. They hoped to find correlations between fetal growth acceleration and factors influencing this occurrence. Wong S, Oats J, Chan F, McIntyre D. Diabetes Care. 2002; 25: 1681-1684

10. PBRC 2009 10 of 35 Fetal Growth Spurt and Pregestational Diabetic Pregnancy In this study of 101 diabetic pregnancies, glucose control was found not to have a direct effect on the incidence of LGA babies. Instead, maternal BMI was shown to have the more direct and greater effect. Pregnancies were separated into two groups: – Diabetic mothers with normal weight babies – Diabetic mothers with LGA babies Wong S, Oats J, Chan F, McIntyre D. Diabetes Care. 2002; 25: 1681-1684

11. PBRC 2009 11 of 35 Fetal Growth Spurt and Pregestational Diabetic Pregnancy The women of the group with LGA babies were shown to have significantly higher pre-pregnancy body weights and BMI’s. There were no differences between the two groups with glucose control in either the first, second, or third trimester. Wong S, Oats J, Chan F, McIntyre D. Diabetes Care. 2002; 25: 1681-1684

12. PBRC 2009 12 of 35 Conclusions Fetal growth acceleration in LGA fetuses of diabetic mothers was shown to begin in the second trimester, from as early as 18 weeks. In this particular study, glucose control did not appear to have any direct effect on the incidence of LGA babies, and such observation might result from the effects of other not yet identified contributing factors. Wong S, Oats J, Chan F, McIntyre D. Diabetes Care. 2002; 25: 1681-1684

13. PBRC 2009 13 of 35 Determinants of Fetal Growth at Different Periods of Pregnancies Complicated by GDM or Impaired Glucose Tolerance (IGT) The aim of this study was to determine what maternal factors had the strongest influence on fetal growth at different periods of pregnancies complicated by an abnormal glucose tolerance test (GTT). The fetal abdominal circumference (AC) is used to describe fetal growth in this study because accelerated growth in the fetal AC in the early 3 rd trimester has been shown to be a good predictor of macrosomia at birth. Schaefer-Graf U et al. Diabetes Care. 2003; 26: 193-198.

14. PBRC 2009 14 of 35 Determinants of Fetal Growth at Different Periods of Pregnancies Complicated by GDM or Impaired Glucose Tolerance (IGT) Normalizing the macrosomia rate is the primary goal in treating women with pregnancies complicated by GDM. Macrosomia is not only associated with a higher rate of birth injury for the mother and newborn, but it is also associated with higher weight and accumulation of fat in childhood, with a higher rate of obesity in adulthood. Although normalizing maternal glucose levels has reduced neonatal morbidity in GDM, it has not been as effective in regards to macrosomia. Macrosomia rates in mothers with GDM when compared to mothers without GDM still remain elevated even with maternal glucose normalization. Schaefer-Graf U et al. Diabetes Care. 2003; 26: 193-198.

15. PBRC 2009 15 of 35 Because maternal weight, glycemia after therapy, rates of fetal macrosomia, and LGA were not significantly different between GDM and IGT groups, they were analyzed together. Results indicated that in the late 2 nd and early 3 rd trimester, maternal BMI and LGA in a previous pregnancy appear to have the strongest influence on fetal growth. Later in the 3 rd trimester, coincident with the period of maximal growth described in diabetic pregnancies, maternal glycemia predominates. Determinants of Fetal Growth at Different Periods of Pregnancies Complicated by GDM or Impaired Glucose Tolerance (IGT) Schaefer-Graf U et al. Diabetes Care. 2003; 26: 193-198.

16. PBRC 2009 16 of 35 Conclusions Conclusions of this second study were in agreement with the first, stating that maternal BMI has a great effect on the development of LGA babies. However, this study went a step further in finding that both maternal BMI and LGA in a previous pregnancy had the largest influence on fetal growth, and identified the time frame when this effect was predominant. This study also found that maternal glycemia does effect fetal growth, and found the particular time frame when its effects occurred. Schaefer-Graf U et al. Diabetes Care. 2003; 26: 193-198.

17. PBRC 2009 17 of 35 What Degree of Maternal Metabolic Control in Women With Type 1 DM is Associated with Normal Size & Proportions in Full-Term Infants? The aim of this study was to assess the degree of maternal metabolic control in women with Type 1 DM necessary to allow for normal fetal growth and normal neonatal body proportions. In this study, the anthropometric characteristics of 98 full-term singleton infants born to 98 Caucasian women with Type 1 DM were measured. All women were enrolled within 12 weeks of gestation and were later placed in one of three mother-infant pair groups based on the level of glycemic control they were able to maintain over the 2 nd and 3 rd trimesters of pregnancy. Mello G et al. Diabetes Care. 2000; 23: 1494-1498.

18. PBRC 2009 18 of 35 What Degree of Maternal Metabolic Control in Women With Type 1 DM is Associated with Normal Size & Proportions in Full-Term Infants? The three groups were: There was a control group of 1,415 Caucasian mother-infant pairs with full-term singleton pregnancies. Members of the control group had normal glucose challenge test when screened for gestational diabetes. Number of mother-infant pairsCriteria required to be a member Group 137An average daily glucose level during the 2 nd and 3 rd trimester of ≤ 95 mg/dl Group 237An average daily glucose level during the 2 nd trimester of > 95 mg/dl and during the 3 rd trimester of ≤ 95 mg/dl Group 324An average daily glucose level during the 2 nd and 3 rd trimester of > 95 mg/dl Mello G et al. Diabetes Care. 2000; 23: 1494-1498.

19. PBRC 2009 19 of 35 What Degree of Maternal Metabolic Control in Women With Type 1 DM is Associated with Normal Size & Proportions in Full-Term Infants? Infants of diabetic mothers in group 1 of this study were found to be similar to those of the control group in birth weight and in other anthropometric parameters. In contrast, offspring of diabetic mothers of groups 2 and 3 had an increased incidence of LGA, significantly greater means of ponderal index and thoracic circumferences, and significantly smaller cranial/thoracic circumference ratios with respect to the control group. Mello G et al. Diabetes Care. 2000; 23: 1494-1498.

20. PBRC 2009 20 of 35 Conclusions The results of the study indicate that, in diabetic pregnancies, only overall daily glucose values of ≤ 95 mg/dl throughout the second and third trimesters can avoid alterations in fetal growth. Mello G et al. Diabetes Care. 2000; 23: 1494-1498.

21. PBRC 2009 21 of 35 Evaluation of Body Composition of LGA Infants of Women with GDM compared with Women with Normal Glucose Tolerance Levels The purpose of this study was to determine whether or not there is a difference in body composition in the LGA infants of women with GDM compared with the LGA infants of women with normal glucose tolerance levels. The researchers also wanted to identify factors associated with the different levels of fat mass in these infants if a difference in body composition was found. Durnwald C, Huston-Presley L, Amini S, Catalano P. Am J Obstet Gynecol 2004; 191: 804-8

22. PBRC 2009 22 of 35 Evaluation of Body Composition of LGA Infants of Women with GDM compared with Women with Normal Glucose Tolerance Levels Fifty cases of women with gestational diabetes and 52 cases of women with normal glucose tolerance levels were evaluated in the study. Researchers found that infants born in the two groups did have similar birth weights. Infants born to mothers with gestational diabetes did, in fact, have increased fat mass and percent body fat, with decreased lean body mass, when compared to infants of mothers with normal glucose tolerance levels. Durnwald C, Huston-Presley L, Amini S, Catalano P. Am J Obstet Gynecol 2004; 191: 804-8

23. PBRC 2009 23 of 35 Conclusions Results of the study indicated that LGA infants of mothers with gestational diabetes mellitus have increased fat mass and decreased lean body mass when compared with infants of mothers with normal glucose tolerance levels. Factors were also identified which are believed to affect the level of fat mass an infant has. Researchers indicated that in gestational diabetes, gestational age, and fasting value of the oral glucose tolerance test was shown to correlate best with the fat mass observed. Durnwald C, Huston-Presley L, Amini S, Catalano P. Am J Obstet Gynecol 2004; 191: 804-8

24. PBRC 2009 24 of 35 Growth and Fatness at Three to Six Years of Age of Children Born Small- or Large-for Gestational Age The objective of this study was to determine whether or not there are differences in growth and fatness in early childhood as associated with birth weight status. Children 3 to 6 years of age who were born small-for-gestational age (SGA) or large-for-gestational age (LGA) were compared with those who were born appropriate-for-gestational age. Hediger M et al. Pediatrics. 1999; 104(3).

25. PBRC 2009 25 of 35 Growth and Fatness at Three to Six Years of Age of Children Born Small- or Large-for Gestational Age From the third National Health and Nutrition Examination survey, 3,192 US-born non-Hispanic white, non-Hispanic black, and Mexican-American children were included in the study. The children were categorized, and growth outcome was assessed by birth weight-for-gestational age status. The growth outcomes considered in these analyses were body weight (kg), height (cm), head circumference (cm), mid-upper arm circumference (MUAC; cm), and triceps and subscapular skinfold thicknesses (mm). Hediger M et al. Pediatrics. 1999; 104(3).

26. PBRC 2009 26 of 35 Growth and Fatness at Three to Six Years of Age of Children Born Small- or Large-for Gestational Age The study found that SGA children remain significantly shorter and lighter throughout early childhood. The children do not seem to catch up from 36 to 83 months of age. On the other hand, LGA infants remain longer and heavier throughout 83 months of age, but, unlike children born SGA, LGA children have a tendency to accumulate fat in early childhood. This indicates that early childhood may be a particularly sensitive period in which there are increases in variation in levels of fatness associated with size at birth. If this is so, then one could conclude that intrauterine growth is associated with size in early childhood. Hediger M et al. Pediatrics. 1999; 104(3).

27. PBRC 2009 27 of 35 Conclusions Further research is needed to confirm that LGA children may be at risk for accumulating excess fat at an early age. This study suggests that birth weight status and gestational age may be useful in assembling a prognostic risk profile for children, with LGA infants being placed in a category of “highest risk.” Hediger M et al. Pediatrics. 1999; 104(3).

28. PBRC 2009 28 of 35 Maternal and Fetal Outcomes if Gestational Impaired Glucose Tolerance is Not Treated The purpose of this study was to evaluate whether there is increased maternal or neonatal morbidity in connection with impaired glucose tolerance (IGT) during pregnancy when the condition is not treated. The 213 study participants were from a defined geographic area in Sweden, and the study period was from 1997-2001. Ostlund I et al. Diabetes Care. 2003; 26(7): 2107-2111.

29. PBRC 2009 29 of 35 Maternal and Fetal Outcomes if Gestational Impaired Glucose Tolerance is Not Treated The diagnostic criteria for gestational diabetes in this area was limited to the criteria used for diabetes. Because of this, 213 women, who were identified with IGT during pregnancy, were not diagnosed or treated. Researchers collected the data on the maternal and fetal outcomes for each subject. For each research subject used in the study, four control subjects were taken from the same delivery department. Ostlund I et al. Diabetes Care. 2003; 26(7): 2107-2111.

30. PBRC 2009 30 of 35 Maternal and Fetal Outcomes if Gestational Impaired Glucose Tolerance is Not Treated The researchers found that the proportion of women who underwent cesarean section was significantly higher in the research subjects than in the control subjects and was independently associated with IGT. They also found that the proportion of infants who were LGA was independently and significantly associated with untreated IGT during pregnancy. Admission to a neonatal intensive care unit for 2 days or longer was also more common for infants of mothers with untreated IGT during pregnancy. Overall, 71.3% of the children in the IGT group and 87.3% of the children in the control group had no neonatal complications. Ostlund I et al. Diabetes Care. 2003; 26(7): 2107-2111.

31. PBRC 2009 31 of 35 Conclusions The researchers concluded that there is an increased independent association between cesarean section rate, prematurity, LGA, and macrosomic infants born to mothers with untreated IGT. Although most of the children were healthy in this study, there was still increased morbidity in the group of children born to mothers with untreated IGT. Researchers call for further investigations on this topic. Ostlund I et al. Diabetes Care. 2003; 26(7): 2107-2111.

32. Division of Education Phillip Brantley, PhD, Director Pennington Biomedical Research Center Claude Bouchard, PhD, Executive Director. Heli J Roy, PhD, RD Reviewed by: Beth Kalicki Edited : October 2009

33. About Our Company The Pennington Biomedical Research Center is a world-renowned nutrition research center. Mission: To promote healthier lives through research and education in nutrition and preventive medicine. The Pennington Center has several research areas, including: Clinical Obesity Research Experimental Obesity Functional Foods Health and Performance Enhancement Nutrition and Chronic Diseases Nutrition and the Brain Dementia, Alzheimer’s and healthy aging Diet, exercise, weight loss and weight loss maintenance The research fostered in these areas can have a profound impact on healthy living and on the prevention of common chronic diseases, such as heart disease, cancer, diabetes, hypertension and osteoporosis. The Division of Education provides education and information to the scientific community and the public about research findings, training programs and research areas, and coordinates educational events for the public on various health issues. We invite people of all ages and backgrounds to participate in the exciting research studies being conducted at the Pennington Center in Baton Rouge, Louisiana. If you would like to take part, visit the clinical trials web page at www.pbrc.edu or call (225) 763-3000. PBRC 2009 33 of 35

34. PBRC 2009 34 of 35 References Wong S, Oats J, Chan F, McIntyre D. Fetal growth spurt and pre-gestational diabetic pregnancy. Diabetes Care. 2002; 25: 1681-1684. Crowther C, Hiller J, Moss J, McPhee A, Jeffries W, Robinson J. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. NEJM. 2005; 352(24): 2477-2486. Schaefer-Graf U et al. Determinants of fetal growth at different periods of pregnancies complicated by gestational diabetes mellitus or impaired glucose tolerance. Diabetes Care. 2003; 26: 193-198. Mello G et al. What degree of maternal metabolic control in women with type 1 diabetes is associated with normal body size and proportions in full-term infants? Diabetes Care. 2000; 23: 1494-1498.

35. PBRC 2009 35 of 35 References Durnwald C, Huston-Presley L, Amini S, Catalano P. Evaluation of body composition of large-for-gestational age infants of women with gestational diabetes mellitus compared with women with normal glucose tolerance levels. American Journal of Obstetrics and Gynecology. 2004; 191: 804-8. Hediger M et al. Growth and fatness at three to six years of age of children born small- or large-for-gestational age. Pediatrics. 1999; 104(3). Ostlund I et al. Maternal and fetal outcomes if gestational impaired glucose tolerance is not treated. Diabetes Care. 2003; 26(7): 2107-2111. http://www.umm.edu/ency/article/002248.htm Copyright 2009 PBRC # PPT30