Metabolic and Stress Components of Neonatal Outcome

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Metabolic and Stress Components of Neonatal
Outcome

• Josephine Carlos-Raboca
• Section Chief,
• Endocrinology Diabetes and Metabolism
• Makati Medical Center

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Metabolic and Stress Components of Neonatal
Outcome

• Josephine Carlos-Raboca, MD,FPCP, FPSEM
• Makati Medical Center

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Cradle to cradle

• Health begins in the womb
• Mother to baby to mother to baby
• It comes in several full circles

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Outline

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

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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

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Nutrition and Neonatal Outcome

• Undernutrition - small for gestational age
• Overnutrition - large for gestational age
• glucose
• lipids
• amino acids

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Mechanism of Programming
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Thrifty Gene/ Barkers 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

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Death rates from CVD according to birth weight
modified from Barker 1996 (n15726)
Birth weight(kg) Standardized mortality ratio Number of deaths
lt2.5 100 57
2.95 81 137
3.41 80 298
3.86 74 289
4.31 55 103
gt4.31 65 57
total 74 941
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DUTCH FAMINE COHORT STUDIES

• malnutrition of daily caloric consumption lt1000
• 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

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Association Of Low Birth Weight and Diabetes
Mellitus 2 in Young Filipino Adults

• 81 young diabetics vs 82 control, 18-37 years
  old
• LBW lt2500g (13 vs 2) OR gt
• Low birth weight lt 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 gm

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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

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Men exposed Control sibling Women exposes Control sibling



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Neonatal Outcomes

• Neonatal fat mass/ neonatal weight
• Large babies childhood obesity, adult obesity
• Small for gestational age cardiovascular
  disease, metabolic syndrome
• Diabetes mellitus

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Maternal and Neonatal Risks

• Maternal
• Preecclampsia
• Cesarian delivery
• Future DM2

• Neonate Macrosomia
  Respiratory Distress
  Hypoglycemia Hyperbiliruinemia
  Future
  obesity/DM2

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Nutrient supply gt demand
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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

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Metabolic Adaptations during Pregnancy

• Primarily influenced by placental hormones,
  especially late in gestation.
• These hormones affect both glucose and lipid
  metabolism to ensure ample fetal fuel supply and
  nutrients always.
• There is a switch from carbohydrate to fat
  utilization that is facilitated by both insulin
  resistance and increased plasma concentration of
  lipolytic hormones
• Butte, NF. Carbohydrate and lipid metabolism in
  pregnancy normal compared with gestational
  diabetes mellitus. Am J Clin Nutr 2000 711256S.
  

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Pedersens Theory

• 1950 - maternal glucose leads to fetal
  hyperinsulinemia and fetal overgrowth Increase

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Macrosomia-Pathogenesis
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Macrosomic Newborn (4.2kg)
www.drsarma.in
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The Hyperglycemia and Adverse Pregnancy Outcome
(HAPO)

• 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

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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 lt 105 mg/dl(5.8mmol/l)
• RPG lt160 mg/dl
• 2 HPG lt 200
  mg/dl(11.1mmol/l)
• Unblinded if RPG lt 45 mg/dl(2.5 mmol/l)

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Outcomes

• Primary birth weight gt90th centile
• primary CS
• clinical neonatal hypoglycemia
• cord blood serum c-peptide gt90th
  centile
• Secondary Premature delivery lt37 weeks of
  gestation Shoulder dystocia or
  birth injury
• need for intensive neonatal
  care
• hyperbilirubinemia
• pre-eclampsia

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Results

• Continuous variable analysis
• Odds ratio calculated
• for 1-SD in birth
  weight cord blood
  gt90 C-peptidegt90
• 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

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Glucose categories
fasting 1 hour 2 hour
lt75 lt105 lt90
75-79 106-132 91-108
80-84 133-155 109-125
85-89 156-171 126-139
90-94 172-193 140-157
95-99 194-211 158-177
100 and more 212 and more 178 and more
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Results
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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

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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 Pedersens Theory
• Diabetes 58 453-459,
  2009

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Maternal Morbidity

• Hypertension Insulin Resistance
• Preeclampsia and Eclampsia
• Cesarean delivery Pre term labour
• Polyhydramnios fluid gt 2000 ml
• Post-partum uterine atony
• Abruptio placenta

www.drsarma.in
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• The Hyperglycemia and Adverse Pregnancy Outcome
  (HAPO) study reported in this issue of the
  Journal is an elegantly designed, very large,
  international study that answers previous
  questions by clearly demonstrating that there is
  a continuum of risk, without clear thresholds,
  between carbohydrate intolerance in pregnancy and
  adverse pregnancy outcomes.

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Conclusions

• Risk of macrosomia, neonatal hypoglycemia and
  neonatal hyperinsulinemia increase with blood
  glucose in a continuum over the entire range of
  blood glucose levels with no clear cut off levels
• Neonatal hyperinsulinemia and large babies were
  noted even in blood glucose levels considered
  normal

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Premature Birth

• Dyslipidemia( total chol gt220 and TG gt140) was
  associated with spontaneous premature birth
• Catov, Ame J of
  Epid 2007

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Weight Gain

• Excessive weight gain increases risks
• gt Diabetes
• gt Preecclampsia
• gt Bigger babies
• gt C sections
• gt Birthing injuries

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Maternal Fetal Outcomes in Asians Raboca et al
2003 JAFES
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Fetal overgrowth Frenkel and Metzger 1980

• nutrients other than glucose led to fetal
  overgrowth as well but hyperinsulinemia and
  glucose control had primary roles

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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

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Long term outcome of GDM babies

• Increasing prevalence of obesity and diabetes in
  childhood and adolescence
• 1994 Obesity 14/ overweight 12 in adolescents
• Ogden et al JAMA
  2002288,1728-1732
• NHANES 1999-2000 obesity 30.3 in 6-11years old.
• Incidence of DM2 among adolescents
• 1982 5
• 1999 45
• Kaufman J Ped Endoc Metab 2002
  15, 737-744.

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Association of Intrauterine exposure to maternal
diabetes and obesity with T2DM and obesity in
youth

• 10-22 years old
• Dm 2 lt20 years of age
• 79 diabetic youth vs 190 non diabetic control
• Exposure to diabetes and obesity recalled by
  biological mother
• Adjusted for offspring age, sex, ethnicity
• Dabalea et al Diabetes
  Care 31 1422-1426,2008

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Factors associated with hypertension and DM2 in
childhood

• Longitudinal cohort study in American Pima
  Indians
• Birth Weight
• large for gestationl age
• small for gestational age
• Exposure to diabetes in utero
• Obesity
• Pettitt et al Am J Epid
  1994140123-131.

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GDM may lead to Dysregulation of Adipoinsular
Axis in offspring

• cross sectional study of 116 Polynesian, South
  Asian women in New Zealand
• Leptin levels are increased with increased birth
  weight in offspring of mothers with GDM
• Leads to leptin resistance, obesity and DM2
• Simmons et al Diabetes Care
  2251539-1544, 2002.

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Stress and Neonatal Outcome

• 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
• Altered setpoint resulting in an increased
  activity and secretion of glucocorticoids asso
  with insulin resistance

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What can we do to prevent cycle?
insulin resistance (GDM)
obesity
Obesity
GDM
DM2
CVD
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Australian Carbohydrate Intolerance Study
(ACHOIS)

• 490 women with GDM at 24-34 weeks gestation
• randomized to intervention treatment (dietary
  advice, blood glucose monitoring and insulin
  treatment)
• 510 randomized to routine care.
• Primary outcome serious perinatal complications
  
• NEJM
  2005,3532477-86

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Australian Carbohydrate Intolerance Study
(ACHOIS)NEJM 2005,3532477-86

• 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

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Protocol

• 16-30 weeks gestation
• 50 gm GCT gt7.8 mmol/l
• 75 gm OGTT at 24-28 weeks
• FBS 7.8 mmol/l
• 2nd hour between 7.8 to 11 mmol/l

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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 p0.01
• Higher induced labor rate
• 39 vs 29 plt0.001
• Similar cesarean delivery
• 31 vs 32

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Results

• At 3 months post partum
• lower rates of depression, higher scores for
  quality of life consistent with improved health
  status in intervention group vs routine care

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Conclusions

• Treatment of gestational diabetes reduces
  perinatal morbidity and may also improve the
  womans health related quality of life.

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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

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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

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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.

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Secondary outcomes

• Significant reductions in LGA in treatment group
• No significant difference in SGA

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MFMU secondary outcomes
Treatment grp Routine care
Mean birth weight 3302 g 3408 g
Neonatal fat mass 427 g 464 g
LGA 7.1 14.5
BWgt4000g 5.9 14.3

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Conclusions MFMU Study

• Although treatment of mild gestational diabetes
  mellitus did not significantly reduce the
  frequency of a composite outcome that included
  stillbirth or perinatal death and several
  neonatal complications, it did reduce the risks
  of fetal overgrowth shoulder dystocia, cesarian
  delivery and hypertensive disorders

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Recommendations

• Daily consumption 0f 8-12 fruit and vegetable
  servings, 3 low fat dairy servings, 5-9 0z of
  protein rich foods, 6-10 whole grain servings and
  3-7 tsp of healthy fat as olive oil canola oil or
  nuts.
• Eating regular meals and small healthy snacks
  between meals
• Fat portion of less than 30 0f caloric intake
• Decrease intake of sweets and sweetened drinks
• Use of food diary to monitor nutritional adequacy
  and portion size
• Limiting caloric intake to 10 to 300 extra
  calories per day beyond prepregnancy caloric
  needs
• 30minute exercise on most days after consulting
  with healthcare provider regarding how to start
  an exercise program

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Recommended weight gain for prepregnancy BMI

• Underweightlt18.5 kg/m2
• Normal weight 18.5-24.9 kg/m2
• Overweight 25-29.9 kg/m2
• Obesegt30kg/m2

• 28-40lbs
• 25-35 lbs
• 15-25lbs
• 11-20 lbs

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Conclusions

• Fetal Programming occurs early in utero.
• This is determined by genes, nutrition, stress
  and maternal health.
• Undernutrition mainly measured by small for
  gestation age leads to organ programming adapted
  to poor environment referred to as a thrifty
  gene. Exposed to rich nutrtition post natally
  leads to maladaptation, obesity, coronary artery
  disease and diabetes mellitus type 2.
• This has been shown by Barker and in the Dutch
  Famine Cohort Studies.

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Conclusions

• Similarly, overnutrition mainly studied in
  gestational diabetes also leads to fetal
  programming that leads to obesity and diabetes
  mellitus type 2 in adult life in a different
  mechanism.
• LGA has been shown to result from GDM in the
  major study , HAPO

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Conclusions

• Stress in utero can come in many forms from
  infection, trauma, psychosocial stress to
  mother, and even nutritional stress.
• Stress induces changes in the hypothalamic
  adrenal axis either by setting a different
  setpoint or altered sensitivity causing higher
  glucocorticoid production, obesity and metabolic
  problems in adult life.

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Conclusions

• Preventive health therefore starts early from
  prepregnancy to pregnancy with emphasis on proper
  nutrition, adequate weight gain and stress
  control.

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• Thank You

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