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Hyperglycemia and Adverse Pregnancy Outcomes Aghaei Meybodi HR, MD Assistant Professor of Endocrinology and Hyperglycemia and Adverse Pregnancy Outcomes Aghaei Meybodi HR, MD Assistant Professor of Endocrinology and Metabolic Diseases Endocrine and Metabolism Research Institute Tehran University of Medical Sciences 16 th June 2010 Zanjan

Agenda • Overview • Adverse Outcome of GDM (HAPO Study) • Pre-GDM - Maternal Agenda • Overview • Adverse Outcome of GDM (HAPO Study) • Pre-GDM - Maternal outcomes - Fetal outcomes • Summary 3

Overall Prevalence of Pregnancy Complicated by DM • Pre-GDM 0. 81% in 1999 1. Overall Prevalence of Pregnancy Complicated by DM • Pre-GDM 0. 81% in 1999 1. 82% in 2005 • The prevalence of GDM remained constant at about 7. 5% during the same interval Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999 -2005. Diabetes Care 2008; 31: 899 4

Gestational Diabetes Mellitus • “glucose intolerance with onset or first recognition during pregnancy” ; Gestational Diabetes Mellitus • “glucose intolerance with onset or first recognition during pregnancy” ; whether or not insulin is used for treatment or hyperglycemia persists after pregnancy • Criteria for the diagnosis were initially established more than 40 years ago • With minor modifications, remain in use today O’sullivan JB, Mahan CM. Criteria for oral glucose tolerance test in pregnancy. Diabetes 1964; 13: 278– 285 5

Recommendations on Diagnostic Criteria for GDM The Review of Diabetic Studies 2008; 5: 194 Recommendations on Diagnostic Criteria for GDM The Review of Diabetic Studies 2008; 5: 194 -202 6

International Association of Diabetes and Pregnancy Study Groups (IADPSG) • Was formed in 1998; International Association of Diabetes and Pregnancy Study Groups (IADPSG) • Was formed in 1998; 225 conferees from 40 countries. • The principal objectives of IADPSG are to foster an international approach to enhancing the quality of care, facilitating research, and advancing education in the field of diabetes in pregnancy. Diabetes Care 2010; 33(3): 676 -82 7

Hyperglycemia and Adverse Pregnancy Outcome ( HAPO) study • 25, 505 pregnant women at Hyperglycemia and Adverse Pregnancy Outcome ( HAPO) study • 25, 505 pregnant women at 15 centers in nine countries • Primary outcomes were birth weight above the 90 th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90 th percentile. • Secondary outcomes were delivery before 37 wks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. N Engl J Med 2008; 358: 1991 -2002 8

Primary outcomes N Engl J Med 2008; 358: 1991 -2002 9 Primary outcomes N Engl J Med 2008; 358: 1991 -2002 9

Adjusted Odds Ratios for Associations between Maternal Glycemia as a Continuous Variable and Primary Adjusted Odds Ratios for Associations between Maternal Glycemia as a Continuous Variable and Primary and Secondary Perinatal Outcomes. * N Engl J Med 2008; 358: 1991 -2002 10

Key Messages • The frequency of birth weight, C-peptide, or percent infant body fat Key Messages • The frequency of birth weight, C-peptide, or percent infant body fat >90 th percentile was approximately twofold greater when any of the glucose values were greater than or equal to the threshold • The frequency of preeclampsia was twofold higher when one or more glucose values met or exceeded threshold, and frequencies of preterm delivery and primary cesarean section were >45% higher Diabetes Care 2010; 33(3): 676 -82 11

Adverse Pregnancy Outcomes in Women with Pre-GDM • Prospective series from Sweden • 5089 Adverse Pregnancy Outcomes in Women with Pre-GDM • Prospective series from Sweden • 5089 singleton pregnancies in women with type 1 diabetes • 1. 2 million singleton pregnancies in the general obstetrical population • From 1991 and 2003 Persson M, Norman M, Hanson, U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: A large, population-based study. Diabetes Care 2009; 32: 2005. 12

Adverse Pregnancy Outcomes in Women with Pre-GDM General Population Cesarean delivery 46 12 LGA Adverse Pregnancy Outcomes in Women with Pre-GDM General Population Cesarean delivery 46 12 LGA 31 3. 6 13. 7 0. 2 mild 9. 7 2. 0 severe 4. 3 0. 8 Major malformations 4. 7 1. 8 Preterm birth < 37 week 21 5. 1 Respiratory Distress Synd. 1. 0 0. 2 Stillbirth 1. 5 0. 3 Perinatal mortality 20/1000 4. 8/1000 Neonatal death 7/1000 2. 2/1000 Shoulder dystocia Preeclampsia Persson M, Norman M, Hanson, U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: A large, population-based study. Diabetes Care 2009; 32: 2005. 13

Pregnancy Complications • Three major potential fetal/pregnancy complications among women with pre. GDM: - Pregnancy Complications • Three major potential fetal/pregnancy complications among women with pre. GDM: - congenital malformations - spontaneous abortion - macrosomia • Hyperglycemia is probably important determinant the most 14

Congenital Malformations • The overall risk of one or more major anomalies is 6 Congenital Malformations • The overall risk of one or more major anomalies is 6 - 7 percent, which is double the risk in the general obstetric population Greene MF. Spontaneous abortions and major malformations in women with diabetes mellitus. Semin Reprod Endocrinol 1999; 17: 127. • Increasing glucose concentration causes embryopathy in a dose-dependent fashion Fraser RB, Waite SL, Wood KA, Martin KL. Impact of hyperglycemia on early embryo development and embryopathy: in vitro experiments using a mouse model. Hum Reprod 2007; 22: 3059. 15

Spontaneous Abortion • Probably related, in part, to an increased frequency of dysmorphogenesis • Spontaneous Abortion • Probably related, in part, to an increased frequency of dysmorphogenesis • But in the general population, at least onehalf of spontaneous abortions are related to chromosomal abnormalities Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996; 174: 1343. 17

Macrosomia • The most serious potential complication of macrosomia is shoulder dystocia • ↑likelihood Macrosomia • The most serious potential complication of macrosomia is shoulder dystocia • ↑likelihood need of cesarean delivery Boulet SL, et al. J Perinatol 2005; 25: 569. • Macrosomia does not appear to increase the propensity for adult obesity, though existing data are sparse Seidman DS, et al. Acta Obstet Gynecol Scand 1998; 77: 58. 18

Macrosomia • Although is typically considered a late pregnancy problem, the pathogenetic factors appear Macrosomia • Although is typically considered a late pregnancy problem, the pathogenetic factors appear to be present in early pregnancy. • Tight control of maternal blood glucose at conception and in the first trimester has a greater impact on reducing the risk of delivering a macrosomic neonate than late pregnancy glycemic control Rey E, et al. Am J Obstet Gynecol 1999; 181: 202. Gold AE, et al. Diabetes Care 1998; 21: 535. 19

Macrosomia • Episodic hypoglycemia during pregnancy has also been associated with an increased frequency Macrosomia • Episodic hypoglycemia during pregnancy has also been associated with an increased frequency of macrosomia • Presumably due to rebound hyperglycemia Langer O, et al. Am J Obstet Gynecol 1989; 161: 646. 20

Preterm Birth • The reasons are not well-defined • May be related to preeclampsia, Preterm Birth • The reasons are not well-defined • May be related to preeclampsia, worsening nephropathy, macrosomia, and poor glycemic control • Is associated with a higher risk of late fetal death and hyaline membrane disease Sibai BM, et al. Am J Obstet Gynecol 2000; 183: 1520. 21

Perinatal Mortality • Congenital malformations now account for approximately 50 percent of the perinatal Perinatal Mortality • Congenital malformations now account for approximately 50 percent of the perinatal deaths in infants of diabetic mothers Weintrob N, et al. J Diabetes Complications 1996; 10: 294. 22

Neuro-developmental Outcome • Maternal hypoglycemia has not been shown to adversely affect the fetus's Neuro-developmental Outcome • Maternal hypoglycemia has not been shown to adversely affect the fetus's long-term neurodevelopment, but data are sparse. Ter Braak EW, et al. Diabetes Metab Res Rev 2002; 18: 96. 23

Neonatal Complications • Morbidity associated with preterm birth • Macrosomia increases the risk of Neonatal Complications • Morbidity associated with preterm birth • Macrosomia increases the risk of birth injury (brachial plexus injury) • Morbidity associated with growth restriction (in women with vascular or renal disease) • Polycythemia • Hyperbilirubinemia • Cardiomyopathy • Hypoglycemia and other metabolic abnormalities • Respiratory problems • Congenital anomalies and their management 24

Fetal Effects • Diabetic embryopathy (birth defects and spontaneous abortions) occurs in the sixth Fetal Effects • Diabetic embryopathy (birth defects and spontaneous abortions) occurs in the sixth to seventh weeks of gestation • Diabetic fetopathy (predominantly macrosomia and fetal hyperinsulinemia) occurs in the second and third trimesters Buchanan TA, Kitzmiller JL. Metabolic interactions of diabetes and pregnancy. Annu Rev Med 1994; 45: 245. 25

Diabetic Embryopathy • Mostly related to the degree of hyperglycemia Greene MF, et al. Diabetic Embryopathy • Mostly related to the degree of hyperglycemia Greene MF, et al. Teratology 1989; 39: 225. 26

Diabetic Fetopathy • Pedersen hypothesis: intermittent maternal hyperglycemia causes fetal hyperglycemia premature maturation and Diabetic Fetopathy • Pedersen hypothesis: intermittent maternal hyperglycemia causes fetal hyperglycemia premature maturation and hypertrophy of fetal beta cells and resultant hyperinsulinemia Pedersen J. Acta Endocrinol (Copenh) 1954; 16: 330. 27

Diabetic Fetopathy • Amniotic fluid insulin concentrations in women with T 1 DM were Diabetic Fetopathy • Amniotic fluid insulin concentrations in women with T 1 DM were higher with macrosomic fetuses than with those appropriate for gestational age (34 vs 13 m. U/L) Fraser RB. Diabet Med 1999; 16: 568. • Higher C-peptide in cord blood of infants with diabetic mothers compared to control infants of nondiabetic mothers. • Elevated cord blood c-peptide were associated with neonatal hypoglycemia and macrosomia, but not hyaline membrane disease. Sosenko IR, et al. N Engl J Med 1979; 301: 859. 28

Fetal Growth • is similar in diabetic and nondiabetic women during the first and Fetal Growth • is similar in diabetic and nondiabetic women during the first and early second trimesters. • After 24 weeks gestation, hyperglycemia results in disproportionally increased abdominal circumference secondary to fat deposition and visceromegaly, while head growth remains normal. Reece EA, et al. Am J Perinatol 1990; 7: 18. 29

Fetal Hypoxemia Chronic fetal hyperinsulinemia Accumulation of glycogen in the liver ↑ activity of Fetal Hypoxemia Chronic fetal hyperinsulinemia Accumulation of glycogen in the liver ↑ activity of hepatic enzymes involved in lipid synthesis Accumulation of fat ↑ metabolic rate Mc. Cormick KL, et al. Diabetes 1979; 28: 1064. 30

Fetal Hypoxemia Fetal hypoxemia ↑Erythropoietin synthesis Polycythemia Promotes catecholamine production HTN and cardiac hypertrophy Fetal Hypoxemia Fetal hypoxemia ↑Erythropoietin synthesis Polycythemia Promotes catecholamine production HTN and cardiac hypertrophy 20 to 30 percent of stillbirth seen in poorly controlled diabetic pregnancy Widness JA, et al. Diabetologia 1990; 33: 378. Kitzmiller JL. Diabetes Care 1993; 16 Suppl 3: 107. 31

Polycythemia May lead to hyperviscosity syndrome ↑ incidence of renal vein thrombosis Hct should Polycythemia May lead to hyperviscosity syndrome ↑ incidence of renal vein thrombosis Hct should be measured within 12 hours of birth 32

Congenital Anomalies • account for approximately 50 percent of the perinatal deaths in IDMs Congenital Anomalies • account for approximately 50 percent of the perinatal deaths in IDMs Weintrob N, et al. J Diabetes Complications 1996; 10: 294. • Two-thirds of the anomalies in IDMs involve the cardiovascular (8. 5 per 100 live births) or central nervous system (5. 3 per 100 live births) Becerra JE, et al. Pediatrics 1990; 85: 1. 33

Cardiomyopathy In one retrospective study: • About half of IDMs with T 1 DM Cardiomyopathy In one retrospective study: • About half of IDMs with T 1 DM developed hypertrophic cardiomyopathy, and 20 % had congenital heart disease • One-quarter of IDMs with T 2 DM developed hypertrophic cardiomyopathy, and ≈ 6 % had CHD • ≈ < 2 % of infant mothers with GDM developed hypertrophic cardiomyopathy or CHD Ullmo S, et al. Eur Heart J 2007; 28: 1319. 34

Cardiomyopathy • Usually transient and concentrations normalize resolves as insulin • Symptomatic infants typically Cardiomyopathy • Usually transient and concentrations normalize resolves as insulin • Symptomatic infants typically recover after two to three weeks of supportive care • Echocardiographic findings resolve within 6 to 12 months Way GL, et al. J Pediatr 1979; 95: 1020. 35

Metabolic Complications • Hypoglycemia • Hypocalcemia • Hypomagnesemia 36 Metabolic Complications • Hypoglycemia • Hypocalcemia • Hypomagnesemia 36

Hypoglycemia • Occurs frequently in IDMs (27 % in one large Cordero L, et Hypoglycemia • Occurs frequently in IDMs (27 % in one large Cordero L, et al. Arch Pediatr Adolesc Med 1998; 152: 249. series) • Most common in macrosomic infants • Typically occurs in the first few hours after birth • related to persistent hyperinsulinemia in the newborn after interruption of the intrauterine glucose supply from the mother 37

Hypocalcemia • Occurs in 10 - 50 % of IDMs • Typically occurs between Hypocalcemia • Occurs in 10 - 50 % of IDMs • Typically occurs between 24 to 72 hours after birth • Often is associated with hyperphosphatemia • Is related to the severity and duration of maternal diabetes • Is thought to be caused by the lower PTH concentrations after birth in IDMs compared to normal infants • In term IDMs usually is asymptomatic and resolves without treatment Mimouni F, et al. Am J Dis Child 1986; 140: 798. Tsang RC, et al. J Pediatr 1975; 86: 399. 38

Hypomagnesemia • Occurs in up to 40 percent of IDMs within the first three Hypomagnesemia • Occurs in up to 40 percent of IDMs within the first three days after birth • The mechanism is thought to be maternal hypomagnesemia caused by increased urinary loss secondary to diabetes. • Prematurity may be a contributing factor • Usually transient and asymptomatic Tsang RC, et al. J Pediatr 1976; 89: 115. Freitag JJ, et al. J Clin Invest 1979; 64: 1238. 39

Hyper-bilirubinemia • In 11 to 29 percent of IDMs • Macrosomia, polycythemia and prematurity Hyper-bilirubinemia • In 11 to 29 percent of IDMs • Macrosomia, polycythemia and prematurity are contributing factors • Mechanism is thought to be increased hemolysis • Excess hemolysis may result from glycosylation of RBC membranes Peevy KJ, et al. Pediatrics 1980; 66: 417. Stevenson DK, et al. J Pediatr 1981; 98: 822. 40

Risk of developing T 1 DM Proband with T 1 DM Father Mother Both Risk of developing T 1 DM Proband with T 1 DM Father Mother Both Parents Pregnancy < 25 years Pregnancy ≥ 25 years Risk 1 in 17 1 in 25 1 in 100 10 – 25 % * These risks are doubled if the affected parent developed diabetes before age 11 ADA. www. diabetes. org/diabetes-basics/genetics-of-diabetes. html. Last accessed 2 May 2010 41

Risk of developing T 2 DM Proband with T 2 DM One Parent* Dx Risk of developing T 2 DM Proband with T 2 DM One Parent* Dx before 50 years Dx after 50 years Both Parents Risk 1 in 7 1 in 13 1 in 2 * Mother brings greater risk ADA. www. diabetes. org/diabetes-basics/genetics-of-diabetes. html. Last accessed 2 May 2010 42

Obestity • Macrosomia resolved by one year of age • Obesity recurred in childhood, Obestity • Macrosomia resolved by one year of age • Obesity recurred in childhood, resulting in a greater BMI in IDMs than controls (24. 6 versus 20. 9 kg/m 2) Silverman BL, et al. Diabetes Care 1998; 21 Suppl 2: B 142. 43

Maternal Issues • Two large prospective studies of women with T 1 DM, DCCT Maternal Issues • Two large prospective studies of women with T 1 DM, DCCT and the EURODIAB Prospective Complications Study (PCS), concluded that pregnancy development was not of a early risk factor for nephropathy, retinopathy, or neuropathy after adjusting for confounders such as age, duration of diabetes, and A 1 C Diabetes Care 2000; 23: 1084. Diabet Med 2005; 22: 1503. 44

Diabetic retinopathy • Diabetic retinopathy worsens in some women during pregnancy, although it is Diabetic retinopathy • Diabetic retinopathy worsens in some women during pregnancy, although it is not likely to develop de novo • The likelihood of retinopathy being present is related to the duration of diabetes and to the degree of glycemic control Star J, et al. Clin Perinatol 1998; 25: 887. 45

Diabetic retinopathy • Strict glycemic control, though is clearly beneficial to the developing fetus, Diabetic retinopathy • Strict glycemic control, though is clearly beneficial to the developing fetus, has been associated with worsening retinopathy, with a particular increase in the formation of soft exudates Chew EY, et al. The Diabetes in Early Pregnancy Study. Diabetes Care 1995; 18: 631. • Is related to the baseline level of retinal disease and, in part, to the acute reduction of chronic hyperglycemia Arch Ophthalmol 1998; 116: 874. 46

Diabetic retinopathy • After pregnancy, milder forms retinopathy typically regress of diabetic Serup L, Diabetic retinopathy • After pregnancy, milder forms retinopathy typically regress of diabetic Serup L, et al. Acta Endocrinol (Copenh) 1986; 22: 122. • Some women with severe forms of diabetic retinopathy may show persistence or progression • Therefore, treatment during pregnancy should be considered and close follow-up postpartum is warranted. Chan WC, et al. Eye 2004; 18: 826. 47

Diabetic Nephropathy • Pregnancy does not appear to increase the risk of dialysis and Diabetic Nephropathy • Pregnancy does not appear to increase the risk of dialysis and diabetic nephropathy if neither was present before conception Miodovnik M, et al. Am J Obstet Gynecol 1996; 174: 1180. • GFR declines during pregnancy in about one-third of women with diabetic nephropathy, while another one-third do not have the normal pregnancy-induced rise; even if strict glycemic control is maintained Jovanovic R. Am J Obstet Gynecol 1984; 149: 617. 48

Diabetic Nephropathy • Women with overt proteinuria at baseline, urinary protein excretion can rise Diabetic Nephropathy • Women with overt proteinuria at baseline, urinary protein excretion can rise dramatically as pregnancy progresses • After delivery, protein excretion decreases in most women • Pregnancy is not associated with permanent worsening of renal function in the majority of diabetic women in the absence of uncontrolled HTN or a baseline serum Cr >1. 5 mg/d. L Kitzmiller JL, et al. Am J Obstet Gynecol 1981; 141: 741. 49

Diabetic Nephropathy Renal function in women with Cr > 1. 4 mg/dl at the Diabetic Nephropathy Renal function in women with Cr > 1. 4 mg/dl at the onset of pregnancy • Remained stable in 27 % • Transiently worsened in 27 % • Permanently declined in 45 % Irfan S, et al. J Coll Physicians Surg Pak 2004; 14: 75. 50

Hypertension - Preeclampsia • The prevalence of preeclampsia in diabetics with and without vascular Hypertension - Preeclampsia • The prevalence of preeclampsia in diabetics with and without vascular disease was 17 and 8 percent, respectively • 5 to 8 percent in non-diabetic pregnancies Acker, DB, Barss, VA. Obstetrical complications. In: Diabetes Complication edition, Brown, FM, Hare, JW (Eds), Wiley-Liss, New York 1995. p. 153. Pregnancy, 2 nd 51

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