Metabolic and Stress Components of Neonatal Outcome

1. Metabolic and Stress Components of Neonatal Outcome Josephine Carlos-Raboca, MD,FPCP, FPSEM Makati Medical Center

3. Cradle to cradle • Health begins in the womb • Mother to baby to mother to baby • It comes in several full circles

4. Outline • Fetal Programming • Neonatal Outcomes • Metabolic Components-Nutrition as major determinant > Glucose and Diabetes > Lipids > Maternal Weight Gain • Stress in Utero • Modifying Outcomes

6. Fetal Programming • Fetal stage is a time of plasticity • Environment that nurtures fetal development is largely dictated by the mother • Development is modified by exposure to nutrition, stress and other factors in utero influenced by genetic make up • Lifelong changes of adult disease

7. Neonatal Outcomes • Neonatal fat mass/ neonatal weight • Large babies – childhood obesity, adult obesity, DM2 • Small for gestational age – cardiovascular disease, metabolic syndrome

8. Neonatal Outcomes and Adult Health • Endocrine: obesity, diabetes mellitus, altered cortisol production, dyslipidemia • Immune: antibody formation, cytokine production • Cardiovascular: hypertension, coronary artery disease

9. Nutrition and Neonatal Outcome Undernutrition - small for gestational age Overnutrition - large for gestational age • glucose • lipids • amino acids

11. Thrifty Gene/ Barker’s Hypothesis/Fetal Origin Theory • Growth in utero has profound effects on adult health • Undernutrition has permanent effects • Small for gestational age at risk for diabetes mellitus type 2, hypertension, coronary artery disease

12. Death rates from CVD according to birth weight modified from Barker 1996 (n=15726)

13. malnutrition of daily caloric consumption <1000 increased adiposity in later life in female offspring Earlier onset of CAD (HR 1.9 47 y vs 50 y) Early gestation exposure was associated with an excess in dyslipidemia, more obesity in women, higher CAD and breast cancer Mid and late gestation raised 2 hour glucose concentrations and insulin concentrations DUTCH FAMINE COHORT STUDIES

14. Association Of Low Birth Weight and Diabetes Mellitus 2 in Young Filipino Adults • 81 young diabetics vs 82 control, 18-37 years old • LBW <2500g (13% vs 2%) OR 5.5 • Low birth weight < 2500g, adult obesity and a positive family history of DM 2 were associated with an increased risk for type 2 DM Obrero, Raboca,Litonjua,. PJIM 2006

17. Summary for Undernutrition fetal programming • Undernutrition in gestation induces programming of the pancreatic beta cell, muscle, liver, adipose tissues and neuroendocrine axis • Mismatch of poor prenatal environment and rich postnatal environment leads to maladaptation • Leads to glucose intolerance , obesity and coronary disease in adult life

18. Nutrientsupply > demand

19. Pedersen’s Theory • 1950 - increased maternal glucose leads to fetal hyperinsulinemia and fetal overgrowth

20. Macrosomia-Pathogenesis

21. Macrosomic Newborn (4.2kg) www.drsarma.in 22

22. Glucose Oversupply • Maternal hormonal and metabolic alteration in GDM modify in- utero environment leading to abnormal fetal growth • Impaired fetal development has severe metabolic consequences with increased risk to develop glucose intolerance and obesity in adolescence and later life

23. Is there a glycemic threshold for maternal and neonatal adverse effects? very large, international , randomized, observational study To clarify the risks of adverse outcomes associated with various degrees of maternal glucose intolerance less severe than in overt diabetes The Hyperglycemia and Adverse Pregnancy Outcome (HAPO)

24. Methods • 25,502 pregnant women at 15 centers in 9 countries • 75 g OGTT at 0,1h,2 h test at 24-32 weeks of gestation • Data blinded if FPG < 105 mg/dl(5.8mmol/l) RPG <160 mg/dl 2 HPG < 200 mg/dl(11.1mmol/l) • Unblinded if RPG < 45 mg/dl(2.5 mmol/l)

25. Outcomes • Primary: birth weight >90th centile primary CS clinical neonatal hypoglycemia cord blood serum c-peptide >90th centile • Secondary : Premature delivery <37 weeks of gestation Shoulder dystocia or birth injury need for intensive neonatal care hyperbilirubinemia pre-eclampsia

26. Results • Continuous variable analysis • Odds ratio calculated for 1-SD in birth weight cord blood >90% C-peptide>90% • fasting /6.9 mg/dl 1.38 1.55 • 1h, /30.9 mg/dl 1.46 1.46 • 2 h /23.8 mg/dl 1.38 1.37

27. Glucose categories

28. Results:

29. Conclusions • Risk of macrosomia, neonatal hypoglycemia and neonatal hyperinsulinemia increase with blood glucose in a continuum over the entire range of blood glucose levels • Neonatal hyperinsulinemia and large babies were noted even in blood glucose levels considered normal • Maternal glucose measured at a single point in pregnancy is effective in predicting birth outcome

30. HAPO follow up study • Antropometric measures associated with cord c-peptide were assessed using logistic regression analysis • Adjusted for confounders • Maternal glucose is associated with increased C –peptide and neonatal obesity in a continuous manner • Confirms Pedersen’s Theory Diabetes 58; 453-459, 2009

31. Maternal Weight Gain • Excessive weight gain increases risks: > Diabetes > Preecclampsia > Bigger babies > C sections > Birthing injuries

32. Maternal Fetal Outcomes in Asians Raboca et al 2003 JAFES

33. Fetal overgrowth – Frenkel and Metzger 1980 • nutrients other than glucose led to fetal overgrowth as well but hyperinsulinemia and glucose control had primary roles

36. Fate of Early Lesions in Children (FELIC) 156 children 1-13 y/o Atherosclerosis progress faster in those whose mothers who were hypercholesterolemic during pregnancy Hypothesis: lipid levels exert constitutive changes on gene expression in arterial lining and influence later CVD Napoli, Lancet 1999

38. Stress and endocrine system • Altered ACTH and cortisol response to acute social and pharmacologic damage • Altered HPA-axis feedback sensitivity • LBW asso with elevated basal cortisol concentrations and increased adrenocortical responsiveness to ACTH at adult age • Increased sympathetic activity

39. Stress and Immune System • Altered cytokine production- Increased IL 4 over interferon gamma • Increased susceptibility to autoimmune diseases and infection

41. What can we do to prevent cycle? insulin resistance (GDM) obesity Obesity DM2 GDM CVD

42. Australian Carbohydrate Intolerance Study (ACHOIS)NEJM 2005,353;2477-86 Women 24-34 weeks gestation with GDM 490 randomized to intervention treatment (dietary advice, blood glucose monitoring and insulin treatment) 510 randomized to routine care. Primary outcome – serious perinatal complications

43. Results Intervention group vs routine care • Perinatal complications was significantly lower 1% vs 4% p = 0.01 • More infant admissions to neonatal nursery 71% vs 61% p=0.01 • Higher induced labor rate 39% vs 29% p=<0.001 • Similar cesarean delivery 31% vs 32%

45. Conclusions • Treatment of gestational diabetes reduces perinatal morbidity and may also improve the woman’s health related quality of life.

46. A Multicenter Randomized Trial of Treatment for Mild Gestational DiabetesNICHD-MFMU • 958 pregnant women • 100 gm OGTT 24-31 weeks of gestation • 485 randomized to treatment • 473 to control group Landon et al NEJM October 2009

47. A Multicenter Randomized Trial of Treatment for Mild Gestational DiabetesNICHD-MFMU • Primary outcome: stillbirth or perinatal death and neonatal complications as hyperbilirubinemia hyperinsulinemia and birth trauma • Secondary outcomeslarge for gestational age, small for gestational age, respiratory distress syndrome,admission to neonatal intensive care unit

48. Perinatal and Neonatal Outcomes • No significant difference between the treatment group and control group in the frequency of the primary outcomes • No perinatal death in both groups.

49. Secondary outcomes • Significant reductions in LGA in treatment group • No significant difference in SGA

50. MFMU secondary outcomes