Infants of Diabetic Mothers Jennifer Bromley Newborn Nursery Presentation 3.25.2011

Introduction Diabetes = most common medical complication of pregnancy 4% of pregnant women in the US 88% gestational 12% pregestational Prenatal complications: Preeclampsia Prematurity Stillbirth Congenital anomalies LGA/macrosomia Neonatal complications: Hypoglycemia Hyperbilirubinemeia Hypocalcemia Polycythemia RDS Longer-term outcomes Gestational = glucose intolerance that appears during pregnancy pregestational: 35% type 1, 65% type 2 Prenatal, neonatal and even further reaching complications to the fetus

Prenatal Management Treatment: self-glucose monitoring, diet + exercise, insulin, oral anti-hyperglycemic agents Antenatal testing: twice weekly non-stress tests with amniotic fluid index starting at 32 weeks gestation Single third trimester ultrasound to screen for macrosomia Scheduled C/S if the estimated fetal weight > 4500g Elective induction of labor… …for medically controlled GDM at 39 weeks …for diet controlled GDM at 40 weeks Lower rates of macrosomia and LGA infants Lower rates of shoulder dystocia Lower C/S rates Treatment goals fasting glucose <90, 1h postprandial <120 Women with GDM higher risk for developing preeclampsia, due, in part, to insulin resistance Higher risk of stillbirth: fetuses of women with GDM are at higher risk of IUFD, mostly related to poor glycemic control, and higher risk for patients requiring medical interventions above just diet control.

Diabetic Embryopathy Hyperglycemia in the 6-7 weeks of gestation Yolk sac failure  Spontaneous abortions Major fetal malformations Other teratogens may also be linked to hyperglycemia including ketones, and reduced levels of arachidonic acid with overproduction of oxygen radicals that leaves to abnormalities in prostaglandin metabolism Disrupting the vascularization of developing tissues

Diabetic Fetopathy Intermittent maternal hyperglycemia  Fetal hyperglycemia  Premature maturation of fetal pancreatic islets Hypertrophy of beta cells  Hyperinsulinemia Fetal hyperinsulinemia  Stimulates glycogen storage in the liver Increased activity of hepatic enzymes of lipid synthesis “Fatty liver” Increased hepatic enzymes for lipid synthesis  Elevated metabolic rate  Increased oxygen demand  Fetal hypoxemia Study in which amniotic fluid insulin concentrations in women with type 1 DM were higher with macrosomic fetuses than with those appropriate for gestational age. Another study demonstrated increased levels of C-peptide in cord blood samples of infants with mothers who were diabetic compared to control infants of nondiabetic mothers; Elevated cord blood c-peptide levels were associated with neonatal hypoglycemia and macrosomia but not hyaline membrane disease.

Fetal Growth Excessive nutrients  Increased fetal growth (particularly of insulin-sensitive tissues – liver, muscle, cardiac muscle, subQ fat) and macrosomia After 24 weeks gestation, hyperglycemia causes disproportionally increased abdominal circumference due to fat deposition and visceromegaly, while the head growth remains normal Excessive nutrients because mom’s DM is poorly controlled

Neonatal Effects Congenital anomalies Prematurity Perinatal asphyxia Respiratory Distress Syndrome Metabolic

Neonatal Effects: Congenital Anomalies A large case-control study showed the relative risk for major malformations in infants of mothers with type 1 DM versus the risk in infants of nondiabetic mothers: 7.9 Another case-control study showed increased prevalence of birth defects in infants of mothers with pregestational and gestational DM Congenital malformations account for 50% of perinatal deaths to diabetic mothers Risk of perinatal death can be significantly reduced by good glycemic control during pregnancy

Neonatal Effects: Congenital Anomalies 2/3 of the anomalies involve cardiac or CNS Anencephaly and spina bifida occur 13-20x more frequently in infants of diabetic mothers GU, GI, and skeletal anomalies also occur at increased rates Small left colon syndrome: transient inability to pass meconium that resolves spontaneously Unique to infants of diabetic mothers Caudal regression syndrome 200x more common in infants of diabetic mothers Caudal regression syndrome aka caudal agenesis, sacral dysgenesis, caudal dysplasia sequence

Neonatal Effects: Premature Delivery Spontaneous premature labor occurs more frequently in diabetic pregnancies Poor glycemic control is associated with a high rate of UTIs Maternal preeclampsia, which also occurs more commonly in diabetic pregnancies, also contributes to premature delivery

Neonatal Effects: Perinatal Asphyxia Increased risk of… fetal heart rate abnormalities during labor Low Apgar scores Intrauterine death As many as 27% of infants born to diabetic mothers had perinatal asphyxia Hypothesis: maternal vascular disease, manifested by nephropathy, contributes to fetal hypoxia and subsequent perinatal asphyxia

Neonatal Effects: Macrosomia Macrosomia = birth weight > 4000g More likely to have hyperbilirubinemia, hypoglycemia, acidosis, respiratory distress, shoulder dystocia, and brachial plexus injuries Infants usually appear large and plethoric with excessive fat accumulation in the abdominal and scapular regions and visceromegaly Occurrence is 4 times higher in infants born to diabetic mothers Other end of the spectrum: mothers with vasculopathy causing intrauterine growth restriction

Neonatal Effects: Respiratory Distress Syndrome Hypothesis: hyperinsulinemia may cause delayed maturation of surfactant synthesis by interfering with the glucocorticoids normally responsible for induction of lung maturation To ensure lung maturity, can preform an amniocentesis and look at the lechitin to sphingomyelin ratio which is >2 in mature lungs DDX of respiratory distress in infants of diabetic mothers: pneumonia, hypertrophic cardiomyopathy, transient tachypnea of the newborn In contrast, fetal lung maturation may occur early in diabetic pregnancies complicated by vasculopathy Transient tachypnea of the newborn: aka retained fetal lung fluid; occurs 2-3 times more commonly in IDMs than normal infants; may be related to decreased fluid clearance in the diabetic fetal lung although frequent cesarean delivery is a contributing factor as well

Neonatal Effects: Metabolic Hypoglycemia Blood glucose <40 mg/dL Occurs in as many as 1/3 of all infants of diabetic mothers Within the first few hours after birth Hyperinsulinemic state typically lasts 2-4 days Hypocalcemia Total calcium < 7 mg/dL or ionized calcium < 4 mg/dL Occurs in 10-50% of infants of diabetic mothers Usually bottoms out between 24-72 hours after birth Higher serum ionized Ca++ in utero can suppress fetal parathyroid glands Hypomagnesemia Magnesium < 1.5 mg/dL Occurs in 40% of infants of diabetic mothers in the first 3 days of life Maternal hypomagnesimia caused by increased urinary loss secondary to diabetes Fix Mg before you can fix Ca HYPOGLYCEMIA: Tight glucose control does not eliminate this risk – still 14% of infants were hypoglycemic in mothers who had tight glycemic control during pregnancy. Even premature or SGA infants of diabetic moms are at risk: glycogen stores are decreased and hyperinsulinemia decreases the ability to mobilize hepatic glycogen Potentiating factor is depressed response to hypoglycemia of counter regulatory hormones (glucagon and catecholamines) HYPOCALCEMIA Usually asymptomatic and resolves without treatment so routine screening is not recommended BUT worry about infants with jitteriness, lethargy, apnea, tachypnea, seizures Hypomagnesemia: usually asx and not usually treated; hypomageneemia can decrease both PTH secretion and PTH responsiveness so if the baby has BOTH hypoCa and hypoMg, the Ca may not correct until the Mg is corrected

Neonatal Effects: Other Complications Polycythemia and hyperviscosity syndrome 13-33% of infants of diabetic mothers Chronic fetal hypoxemia  increased erythropoietin Hyperbilirubinemia 11-29% of infants of diabetic mothers Increased hemolysis secondary to glycosylation of erythrocyte membranes Hypertrophic cardiomyopathy Transient, resolves as insulin concentrations normalize Polycythemia  hyperviscosity syndrome including vascular sludging, ischemia, and infarction of vital organs (increased risk of renal vein thrombosis)

Neurodevelopmental Outcome Poorly controlled diabetes may result in developmental abnormalities Studies of 3 and 6-9 year olds have showed cognitive and developmental differences between children of diabetic mothers and their peers Head circumference at 3 years old negatively correlated with HbA1c during pregnancy Smaller head circumference associated with poorer intellectual performance Psychomotor development at six to nine years of age correlated with maternal ketone concentrations during the second and third trimesters IUGR and malformations also contribute to developmental Delay

Long-term Metabolic Risk Inheritance of pregestational diabetes is genetically linked Children of diabetic mothers are more likely to be diabetic and more likely to be obese Intrauterine exposure to hyperglycemia and hyperinsulinemia may affect the development of adipose tissue and pancreatic beta cells, leading to future obesity and altered glucose metabolism A number of studies have found that wile macrosomia may resolve within the first year of life, obesity reoccurs in childhood at increased rates in children of diabetic mothers

Conclusion Tight maternal glycemic control is associated with improved outcomes in infants of diabetic mothers Regardless of glycemic control, these infants are at higher risks for birth defects, abnormal growth, metabolic complications and even neurodevelopmental delay as compared to their peers of non-diabetic mothers.