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