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Metabolic and Metabolic and Stress Components Stress Components
of Neonatal of Neonatal Outcome Outcome
Josephine Carlos-RabocaJosephine Carlos-RabocaSection Chief, Section Chief,
Endocrinology Diabetes and Endocrinology Diabetes and MetabolismMetabolism
Makati Medical CenterMakati Medical Center
Metabolic and Stress Components of Metabolic and Stress Components of Neonatal OutcomeNeonatal Outcome
Josephine Carlos-Raboca, Josephine Carlos-Raboca, MD,FPCP, FPSEMMD,FPCP, FPSEM
Makati Medical CenterMakati Medical Center
Cradle to cradleCradle to cradle
Health begins in the womb Health begins in the womb Mother to baby to mother to Mother to baby to mother to
babybaby It comes in several full It comes in several full
circlescircles
OutlineOutline
Fetal ProgrammingFetal Programming Neonatal OutcomesNeonatal Outcomes Metabolic Components-Nutrition as major Metabolic Components-Nutrition as major
determinantdeterminant > Glucose and Diabetes> Glucose and Diabetes > Lipids> Lipids > Maternal Weight Gain > Maternal Weight Gain Stress in UteroStress in Utero Modifying OutcomesModifying Outcomes
Fetal ProgrammingFetal Programming
Fetal stage is a time of plasticityFetal stage is a time of plasticity Environment that nurtures fetal Environment that nurtures fetal
development is largely dictated by development is largely dictated by the mother the mother
Development is modified by exposure Development is modified by exposure to nutrition, stress and other factors to nutrition, stress and other factors in utero influenced by genetic make in utero influenced by genetic make upup
Lifelong changes of adult diseaseLifelong changes of adult disease
Nutrition and Neonatal Nutrition and Neonatal OutcomeOutcome
Undernutrition - small for Undernutrition - small for gestational age gestational age
Overnutrition - large for Overnutrition - large for gestational agegestational age
glucoseglucose lipidslipids amino acids amino acids
Mechanism of Mechanism of ProgrammingProgramming
Fetal programming
Genetic predisposition
CVD, INSULIN RESISTANCE
Environmental factors
Thrifty Gene/ Barker’s Thrifty Gene/ Barker’s Hypothesis/Fetal Origin Hypothesis/Fetal Origin
TheoryTheory Growth in utero has profound effects Growth in utero has profound effects
on adult healthon adult health Undernutrition has permanent Undernutrition has permanent
effectseffects Small for gestational age at risk for Small for gestational age at risk for
diabetes mellitus type 2, diabetes mellitus type 2, hypertension, coronary artery hypertension, coronary artery disease disease
Death rates from CVD according to Death rates from CVD according to birth weight modified from Barker birth weight modified from Barker
1996 (n=15726)1996 (n=15726)Birth Birth weight(kg)weight(kg)
Standardized Standardized mortality mortality ratioratio
Number of Number of deathsdeaths
<2.52.5 100100 5757
2.952.95 8181 137137
3.413.41 8080 298298
3.863.86 7474 289289
4.314.31 5555 103103
>4.31>4.31 6565 5757
totaltotal 7474 941941
DUTCH FAMINE COHORT DUTCH FAMINE COHORT STUDIESSTUDIES
malnutrition of daily caloric consumption malnutrition of daily caloric consumption <1000<1000
increased adiposity in later life in female increased adiposity in later life in female offspringoffspring
Earlier onset of CAD (HR 1.9 47 y vs 50 y)Earlier onset of CAD (HR 1.9 47 y vs 50 y) Early gestation exposure was associated with Early gestation exposure was associated with
an excess in dyslipidemia, more obesity in an excess in dyslipidemia, more obesity in women, higher CAD and breast cancer women, higher CAD and breast cancer
Mid and late gestation raised 2 hour Mid and late gestation raised 2 hour glucose concentrations and insulin glucose concentrations and insulin concentrationsconcentrations
Association Of Low Birth Weight and Association Of Low Birth Weight and Diabetes Mellitus 2 in Young Filipino Diabetes Mellitus 2 in Young Filipino
AdultsAdults 81 young diabetics vs 82 control, 18-37 years 81 young diabetics vs 82 control, 18-37 years
old old LBW <2500g (13% vs 2%) OR %>%LBW <2500g (13% vs 2%) OR %>% Low birth weight < 2500g, adult obesity and a Low birth weight < 2500g, adult obesity and a
positive family history of DM 2 were associated positive family history of DM 2 were associated with an increased risk for type 2 DMwith an increased risk for type 2 DM
Obrero, Raboca,Litonjua,. PJIM 2006 Obrero, Raboca,Litonjua,. PJIM 2006 gm%gm%
Summary for Summary for Undernutrition fetal Undernutrition fetal
programmingprogramming Undernutrition in gestation induces Undernutrition in gestation induces
programming of the pancreatic beta programming of the pancreatic beta cell, muscle, liver, adipose tissues and cell, muscle, liver, adipose tissues and neuroendocrine axisneuroendocrine axis
Mismatch of poor prenatal Mismatch of poor prenatal environment and rich postnatal environment and rich postnatal environment leads to maladaptationenvironment leads to maladaptation
Leads to glucose intolerance , obesity Leads to glucose intolerance , obesity and coronary disease in adult lifeand coronary disease in adult life
Nutrient supply > demand
Glucose OversupplyGlucose Oversupply
Maternal hormonal and metabolic Maternal hormonal and metabolic alteration in GDM modify in- utero alteration in GDM modify in- utero environment leading to abnormal environment leading to abnormal fetal growthfetal growth
Impaired fetal development has Impaired fetal development has severe metabolic consequences with severe metabolic consequences with increased risk to develop glucose increased risk to develop glucose intolerance and obesity in intolerance and obesity in adolescence and later lifeadolescence and later life
Pedersen’s TheoryPedersen’s Theory
1950 - maternal glucose leads to 1950 - maternal glucose leads to fetal hyperinsulinemia and fetal fetal hyperinsulinemia and fetal overgrowth Increaseovergrowth Increase
Macrosomia-Macrosomia-PathogenesisPathogenesis
Macrosomic Newborn Macrosomic Newborn (4.2kg)(4.2kg)
www.drsarma.in 26
The Hyperglycemia and The Hyperglycemia and Adverse Pregnancy Adverse Pregnancy Outcome (HAPO)Outcome (HAPO)
Is there a glycemic threshold for maternal Is there a glycemic threshold for maternal
and neonatal adverse effects?and neonatal adverse effects?
very large, international , randomized, very large, international , randomized, observational studyobservational study
To clarify the risks of adverse outcomes To clarify the risks of adverse outcomes associated with various degrees of associated with various degrees of maternal glucose intolerance less severe maternal glucose intolerance less severe than in overt diabetesthan in overt diabetes
MethodsMethods
25,502 pregnant women at 15 centers in 9 25,502 pregnant women at 15 centers in 9 countriescountries
75 g OGTT at 0,1h,2 h test at 24-32 weeks 75 g OGTT at 0,1h,2 h test at 24-32 weeks of gestationof gestation
Data blinded if FPG Data blinded if FPG < < 105 mg/dl(5.8mmol/l)105 mg/dl(5.8mmol/l)
RPG <160 mg/dlRPG <160 mg/dl
2 HPG 2 HPG < < 200 200 mg/dl(11.1mmol/l)mg/dl(11.1mmol/l)
Unblinded if RPG < 45 mg/dl(2.5 mmol/l)Unblinded if RPG < 45 mg/dl(2.5 mmol/l)
OutcomesOutcomes Primary: birth weight >90Primary: birth weight >90thth centile centile primary CSprimary CS clinical neonatal hypoglycemiaclinical neonatal hypoglycemia cord blood serum c-peptide >90cord blood serum c-peptide >90thth
centilecentile Secondary : Premature delivery <37 weeks of Secondary : Premature delivery <37 weeks of
gestation gestation Shoulder dystocia or Shoulder dystocia or birth injurybirth injury
need for intensive neonatal careneed for intensive neonatal care hyperbilirubinemiahyperbilirubinemia pre-eclampsiapre-eclampsia
ResultsResults
Continuous variable analysisContinuous variable analysis Odds ratio calculatedOdds ratio calculated
for 1-SD in birth weight cord for 1-SD in birth weight cord blood blood >90% C- >90% C-peptide>90%peptide>90%
fasting /6.9 mg/dl 1.38 1.55fasting /6.9 mg/dl 1.38 1.55 1h, /30.9 mg/dl 1.46 1.461h, /30.9 mg/dl 1.46 1.46 2 h /23.8 mg/dl 1.38 1.372 h /23.8 mg/dl 1.38 1.37
Glucose categoriesGlucose categories
fastingfasting 1 hour1 hour 2 hour2 hour
<75<75 <105<105 <90<90
75-7975-79 106-132106-132 91-10891-108
80-8480-84 133-155133-155 109-125109-125
85-8985-89 156-171156-171 126-139126-139
90-9490-94 172-193172-193 140-157140-157
95-9995-99 194-211194-211 158-177158-177
100 and more100 and more 212 and more212 and more 178 and more178 and more
Results:Results:
ConclusionsConclusions
Risk of macrosomia, neonatal hypoglycemia Risk of macrosomia, neonatal hypoglycemia and neonatal hyperinsulinemia increase and neonatal hyperinsulinemia increase with blood glucose in a continuum over the with blood glucose in a continuum over the entire range of blood glucose levels entire range of blood glucose levels
Neonatal hyperinsulinemia and large Neonatal hyperinsulinemia and large babies were noted even in blood glucose babies were noted even in blood glucose levels considered normal levels considered normal
Maternal glucose measured at a single Maternal glucose measured at a single point in pregnancy is effective in point in pregnancy is effective in predicting birth outcomepredicting birth outcome
HAPO follow up studyHAPO follow up study Antropometric measures associated with cord Antropometric measures associated with cord
c-peptide were assessed using logistic c-peptide were assessed using logistic regression analysisregression analysis
Adjusted for confoundersAdjusted for confounders Maternal glucose is associated with increasedMaternal glucose is associated with increased
C –peptide and neonatal obesity in a C –peptide and neonatal obesity in a continuous mannercontinuous manner
Confirms Pedersen’s TheoryConfirms Pedersen’s Theory
Diabetes 58; 453-459, 2009Diabetes 58; 453-459, 2009
ConclusionsConclusions
Risk of macrosomia, neonatal Risk of macrosomia, neonatal hypoglycemia and neonatal hypoglycemia and neonatal hyperinsulinemia increase with blood hyperinsulinemia increase with blood glucose in a continuum over the entire glucose in a continuum over the entire range of blood glucose levels with no range of blood glucose levels with no clear cut off levelsclear cut off levels
Neonatal hyperinsulinemia and large Neonatal hyperinsulinemia and large babies were noted even in blood glucose babies were noted even in blood glucose levels considered normal levels considered normal
Weight GainWeight Gain
Excessive weight gain increases Excessive weight gain increases risks:risks:
> Diabetes> Diabetes
> Preecclampsia> Preecclampsia
> Bigger babies> Bigger babies
> C sections> C sections
> Birthing injuries> Birthing injuries
Maternal Fetal Outcomes in Maternal Fetal Outcomes in Asians Raboca et al 2003 Asians Raboca et al 2003 JAFESJAFES
Figure1. Correlation of Birth Weight vs Maternal Weight Gain
R2 = 0.0404
0.00
1000.00
2000.00
3000.00
4000.00
5000.00
6000.00
-80 -60 -40 -20 0 20 40 60 80 100 120
Maternal Weight Gain (Lbs)
BW
Linear (BW)
Linear (BW)
Fetal overgrowth – Frenkel Fetal overgrowth – Frenkel and Metzger 1980and Metzger 1980
nutrients other than glucose led to nutrients other than glucose led to fetal overgrowth as well but fetal overgrowth as well but hyperinsulinemia and glucose hyperinsulinemia and glucose control had primary rolescontrol had primary roles
Fate of Early Lesions in Fate of Early Lesions in Children (FELIC)Children (FELIC)
156 children 1-13 y/o 156 children 1-13 y/o Atherosclerosis progress faster in those Atherosclerosis progress faster in those
whose mothers who were whose mothers who were hypercholesterolemic during pregnancyhypercholesterolemic during pregnancy
Hypothesis: lipid levels exert constitutive Hypothesis: lipid levels exert constitutive changes on gene expression in arterial changes on gene expression in arterial lining and influence later CVDlining and influence later CVD
Napoli, Lancet 1999Napoli, Lancet 1999
Long term outcome of GDM Long term outcome of GDM babiesbabies
Increasing prevalence of obesity and diabetes in Increasing prevalence of obesity and diabetes in childhood and adolescencechildhood and adolescence
1994 Obesity 14%/ overweight 12% in adolescents1994 Obesity 14%/ overweight 12% in adolescents Ogden et al JAMA 2002:288,1728-1732Ogden et al JAMA 2002:288,1728-1732 NHANES 1999-2000 obesity 30.3% in 6-11years NHANES 1999-2000 obesity 30.3% in 6-11years
old.old.Incidence of DM2 among adolescentsIncidence of DM2 among adolescents 1982 5%1982 5% 1999 45%1999 45% Kaufman J Ped Endoc Metab 2002: 15, 737-Kaufman J Ped Endoc Metab 2002: 15, 737-
744.744.
Association of Intrauterine Association of Intrauterine exposure to maternal diabetes exposure to maternal diabetes and obesity with T2DM and and obesity with T2DM and
obesity in youthobesity in youth 10-22 years old 10-22 years old Dm 2 <20 years of ageDm 2 <20 years of age 79 diabetic youth vs 190 non diabetic 79 diabetic youth vs 190 non diabetic
controlcontrol Exposure to diabetes and obesity Exposure to diabetes and obesity
recalled by biological motherrecalled by biological mother Adjusted for offspring age, sex, ethnicityAdjusted for offspring age, sex, ethnicity
Dabalea et al Diabetes Care 31; 1422-Dabalea et al Diabetes Care 31; 1422-1426,20081426,2008
Factors associated with Factors associated with hypertension and DM2 in hypertension and DM2 in
childhoodchildhood
Longitudinal cohort study in American Pima Longitudinal cohort study in American Pima IndiansIndians
Birth Weight Birth Weight
large for gestationl agelarge for gestationl age
small for gestational agesmall for gestational age
Exposure to diabetes in utero Exposure to diabetes in utero
Obesity Obesity
Pettitt et al Am J Epid Pettitt et al Am J Epid 1994:140:123-131.1994:140:123-131.
GDM may lead to GDM may lead to Dysregulation of Dysregulation of
Adipoinsular Axis in Adipoinsular Axis in offspringoffspring cross sectional study of 116 Polynesian, cross sectional study of 116 Polynesian,
South Asian women in New ZealandSouth Asian women in New Zealand Leptin levels are increased with Leptin levels are increased with
increased birth weight in offspring of increased birth weight in offspring of mothers with GDM mothers with GDM
Leads to leptin resistance, obesity and Leads to leptin resistance, obesity and DM2DM2
Simmons et al Diabetes Care 225:1539-1544, Simmons et al Diabetes Care 225:1539-1544, 2002.2002.
Stress and Neonatal Stress and Neonatal OutcomeOutcome
Altered ACTH and cortisol response to Altered ACTH and cortisol response to acute social and pharmacologic damageacute social and pharmacologic damage
Altered HPA-axis feedback sensitivityAltered HPA-axis feedback sensitivity LBW asso with elevated basal cortisol LBW asso with elevated basal cortisol
concentrations and increased concentrations and increased adrenocortical responsiveness to ACTH adrenocortical responsiveness to ACTH at adult ageat adult age
Altered setpoint resulting in an increased Altered setpoint resulting in an increased activity and secretion of glucocorticoids activity and secretion of glucocorticoids asso with insulin resistanceasso with insulin resistance
What can we do to What can we do to prevent cycle?prevent cycle?
obesityobesity
insulin resistance insulin resistance
(GDM)(GDM)
GDGDMM
ObesityObesityDM2DM2 CVDCVD
Australian Carbohydrate Australian Carbohydrate Intolerance Study Intolerance Study
(ACHOIS(ACHOIS))490 women with GDM at 24-34 weeks 490 women with GDM at 24-34 weeks
gestationgestation
randomized to intervention treatment randomized to intervention treatment (dietary advice, blood glucose monitoring (dietary advice, blood glucose monitoring and insulin treatment) and insulin treatment)
510 randomized to routine care.510 randomized to routine care.
Primary outcome – serious perinatal Primary outcome – serious perinatal complications complications
NEJM 2005,353;2477-86 NEJM 2005,353;2477-86
Australian Carbohydrate Australian Carbohydrate Intolerance Study Intolerance Study
(ACHOIS(ACHOIS))NEJM 2005,353;2477-86NEJM 2005,353;2477-86
Women 24-34 weeks gestation with Women 24-34 weeks gestation with GDM 490 randomized to GDM 490 randomized to intervention treatment (dietary intervention treatment (dietary advice, blood glucose monitoring advice, blood glucose monitoring and insulin treatment) and insulin treatment)
510 randomized to routine care.510 randomized to routine care.
Primary outcome – serious perinatal Primary outcome – serious perinatal complicationscomplications
ResultsResults
Intervention group vs routine careIntervention group vs routine care Perinatal complications was significantly Perinatal complications was significantly
lower lower 1% vs 4% p = 0.011% vs 4% p = 0.01 More infant admissions to neonatal More infant admissions to neonatal
nurserynursery 71% vs 61% p=0.0171% vs 61% p=0.01 Higher induced labor rateHigher induced labor rate 39% vs 29% p=<0.00139% vs 29% p=<0.001 Similar cesarean deliverySimilar cesarean delivery 31% vs 32%31% vs 32%
ResultsResults
At 3 months post partumAt 3 months post partum
lower rates of depression, higher lower rates of depression, higher scores for quality of life consistent scores for quality of life consistent with improved health status in with improved health status in intervention group vs routine careintervention group vs routine care
ConclusionsConclusions
Treatment of gestational diabetes Treatment of gestational diabetes reduces perinatal morbidity and may reduces perinatal morbidity and may also improve the woman’s health also improve the woman’s health related quality of life.related quality of life.
A Multicenter Randomized Trial of A Multicenter Randomized Trial of Treatment for Mild Gestational Treatment for Mild Gestational
DiabetesDiabetesNICHD-MFMUNICHD-MFMU
958 pregnant women958 pregnant women 100 gm OGTT 24-31 weeks of gestation100 gm OGTT 24-31 weeks of gestation 485 randomized to treatment485 randomized to treatment 473 to control group473 to control group
Landon et al NEJM Landon et al NEJM October 2009October 2009
A Multicenter Randomized Trial of A Multicenter Randomized Trial of Treatment for Mild Gestational Treatment for Mild Gestational
DiabetesDiabetesNICHD-MFMUNICHD-MFMU
Primary outcome: stillbirth or Primary outcome: stillbirth or perinatal death and neonatal perinatal death and neonatal complications as hyperbilirubinemia complications as hyperbilirubinemia hyperinsulinemia and birth traumahyperinsulinemia and birth trauma
Secondary outcomesSecondary outcomeslarge for gestational age, small for large for gestational age, small for gestational age, respiratory distress gestational age, respiratory distress syndrome,admission to neonatal syndrome,admission to neonatal intensive care unitintensive care unit
Perinatal and Neonatal Perinatal and Neonatal OutcomesOutcomes
No significant difference between No significant difference between the treatment group and control the treatment group and control group in the frequency of the group in the frequency of the primary outcomesprimary outcomes
No perinatal death in both groups.No perinatal death in both groups.
Secondary outcomesSecondary outcomes
Significant reductions in LGA in Significant reductions in LGA in treatment grouptreatment group
No significant difference in SGANo significant difference in SGA
MFMU secondary MFMU secondary outcomesoutcomesTreatment Treatment grpgrp
Routine careRoutine care
Mean birth Mean birth weightweight
3302 g3302 g 3408 g3408 g
Neonatal fat Neonatal fat massmass
427 g427 g 464 g464 g
LGALGA 7.1%7.1% 14.5%14.5%
BW>4000gBW>4000g 5.9%5.9% 14.3%14.3%
Conclusions MFMU Conclusions MFMU StudyStudy
Although treatment of mild Although treatment of mild gestational diabetes mellitus did not gestational diabetes mellitus did not significantly reduce the frequency of significantly reduce the frequency of a composite outcome that included a composite outcome that included stillbirth or perinatal death and stillbirth or perinatal death and several neonatal complications, it did several neonatal complications, it did reduce the risks of fetal overgrowth reduce the risks of fetal overgrowth shoulder dystocia, cesarian delivery shoulder dystocia, cesarian delivery and hypertensive disordersand hypertensive disorders
RecommendationsRecommendations Daily consumption 0f 8-12 fruit and vegetable Daily consumption 0f 8-12 fruit and vegetable
servings, 3 low fat dairy servings, 5-9 0z of protein servings, 3 low fat dairy servings, 5-9 0z of protein rich foods, 6-10 whole grain servings and 3-7 tsp of rich foods, 6-10 whole grain servings and 3-7 tsp of healthy fat as olive oil canola oil or nuts.healthy fat as olive oil canola oil or nuts.
Eating regular meals and small healthy snacks Eating regular meals and small healthy snacks between mealsbetween meals
Fat portion of less than 30% 0f caloric intakeFat portion of less than 30% 0f caloric intake Decrease intake of sweets and sweetened drinksDecrease intake of sweets and sweetened drinks Use of food diary to monitor nutritional adequacy Use of food diary to monitor nutritional adequacy
and portion sizeand portion size Limiting caloric intake to 10 to 300 extra calories per Limiting caloric intake to 10 to 300 extra calories per
day beyond prepregnancy caloric needs day beyond prepregnancy caloric needs 30minute exercise on most days after consulting with 30minute exercise on most days after consulting with
healthcare provider regarding how to start an healthcare provider regarding how to start an exercise programexercise program
Recommended weight gain Recommended weight gain for prepregnancy BMIfor prepregnancy BMI
Underweight<18.5 Underweight<18.5 kg/m2kg/m2
Normal weight Normal weight 18.5-24.9 kg/m218.5-24.9 kg/m2
Overweight 25-Overweight 25-29.9 kg/m229.9 kg/m2
ObeseObese>>30kg/m230kg/m2
28-40lbs28-40lbs
25-35 lbs25-35 lbs
15-25lbs15-25lbs
11-20 lbs11-20 lbs
ConclusionsConclusions Fetal Programming occurs early in utero.Fetal Programming occurs early in utero. This is determined by genes, nutrition, This is determined by genes, nutrition,
stress and maternal health.stress and maternal health. Undernutrition mainly measured by small Undernutrition mainly measured by small
for gestation age leads to organ for gestation age leads to organ programming adapted to poor environment programming adapted to poor environment referred to as a thrifty gene. Exposed to referred to as a thrifty gene. Exposed to rich nutrtition post natally leads to rich nutrtition post natally leads to maladaptation, obesity, coronary artery maladaptation, obesity, coronary artery disease and diabetes mellitus type 2.disease and diabetes mellitus type 2.
This has been shown by Barker and in the This has been shown by Barker and in the Dutch Famine Cohort Studies.Dutch Famine Cohort Studies.
ConclusionsConclusions
Similarly, overnutrition mainly Similarly, overnutrition mainly studied in gestational diabetes also studied in gestational diabetes also leads to fetal programming that leads to fetal programming that leads to obesity and diabetes leads to obesity and diabetes mellitus type 2 in adult life in a mellitus type 2 in adult life in a different mechanism.different mechanism.
LGA has been shown to result from LGA has been shown to result from GDM in the major study , HAPOGDM in the major study , HAPO
ConclusionsConclusions
Stress in utero can come in many forms Stress in utero can come in many forms from infection, trauma, psychosocial from infection, trauma, psychosocial stress to mother, and even nutritional stress to mother, and even nutritional stress.stress.
Stress induces changes in the Stress induces changes in the hypothalamic adrenal axis either by hypothalamic adrenal axis either by setting a different setpoint or altered setting a different setpoint or altered sensitivity causing higher glucocorticoid sensitivity causing higher glucocorticoid production, obesity and metabolic production, obesity and metabolic problems in adult life.problems in adult life.
ConclusionsConclusions
Preventive health therefore starts Preventive health therefore starts early from prepregnancy to early from prepregnancy to pregnancy with emphasis on proper pregnancy with emphasis on proper nutrition, adequate weight gain and nutrition, adequate weight gain and stress control.stress control.
Thank YouThank You