01 Ehrenkranz Impact of Growth on Neonatal … of Growth on Neonatal Outcomes ... Yale Estimated...

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Impact of Growth on Neonatal Outcomes

Richard A. Ehrenkranz, MDProfessor of Pediatrics

Yale University School of Medicine

Disclosure StatementsRichard A. Ehrenkranz, MD

I have no relevant financial relationships to disclose or conflicts of interest to resolve.

I will not discuss any unapproved or off-label, experimental or investigational use of a product, drug, or device.

Objectives● To discuss curves used to monitor postnatal

growth of preterm infants, especially extremely preterm (EPT) infants

● To review the data that: postnatal growth reflects the adequacy of nutrient postnatal growth reflects the adequacy of nutrient

intake growth correlates with neurodevelopmental

outcomes

● To recommend the implementation of feeding guidelines

Plotting Serial Anthropometric Measurements on Growth Curves

• Provide an assessment of nutritional status

• Permit comparisons with established norms

• Identify alterations in growth patterns Symmetric vs asymmetric Growth along a percentile vs

faltering Growth below the 10th percentile

• Assess response to interventions

Nutritional Management of Preterm Infants: Current Recommendations

To provide nutrients to approximate the rate of growth and composition of weight gain f l f t f thfor a normal fetus of the same postmenstrual age and to maintain normal concentrations of nutrients in blood and tissue.

AAP CON. Pediatric Nutrition Handbook, 6th ed. 2009; p.79.

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Growth Curves and Postnatal Growth of Preterm Infants

Controversy exists over feasibility and appropriateness of achieving AAPCON goalgoal.

Descriptive curves based upon:Intrauterine growth dataPostnatal growth data

3000

3500

4000

4500

s)

Yale Estimated Fetal Weight Growth Curve

0

500

1000

1500

2000

2500

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Fet

al W

eig

ht

(gra

ms

Gestational Age

3rd %

50th %

97th %

IU Growth from Live Births at 26-42 Weeks’ Gestation

Lubchenco. Pediatr 1966; 37: 403-408

IU Growth from Live Births at 25-44 Weeks’ Gestation

Mean + 2 sd

Usher, McLean. J Pediatr. 1969; 74:901-910

A New Growth Chart for Preterm Infants

Fenton. BMC Pediatrics, 2003.

New IU Growth Curves Based on US Data

Olsen. Pediatrics, 2010.

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Limitations of Intrauterine Growth Curves for Monitoring Postnatal Growth

Curves represent cross-sectional data derived from newborns, not serial measures over time

Preterm infants may not be “normal”

Gestational age dating is imprecise

Curves maybe population specific, and not generalizable

Postnatal Weight Changes in Low Birth Weight Infants

Shaffer. Pediatrics 1987; 702-705

Longitudinal Growth of VLBW Infants

1500

1750

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ram

s)

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901

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1 1

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Postnatal Age (Days)

1 14 28 42 56 70 84 98

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ght

(gr

NICHD Growth Observational Study, 1999

Ehrenkranz. Pediatr 1999

Longitudinal Growth of VLBW InfantsLongitudinal Growth of VLBW Infants

40

45

50

cm)

501 601 701 801 901 1001 1101

1201 1301

1401

Postnatal Age (Weeks)

1 2 3 4 5 6 7 8 9 11 13 15 17

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35

Leng

th (

c

NICHD Growth Observational Study, 1999NICHD Growth Observational Study, 1999


Longitudinal Growth of VLBW InfantsLongitudinal Growth of VLBW Infants

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35

renc

e (c

m)

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Postnatal Age (Weeks)

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d C

ircum

fer



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Postnatal Growth of VLBW Infants vs Expected Intrauterine Growth

1500

2000

ram

s)

50th 10th

Postmenstrual Age (Weeks)

Intrauterine growth24-25 weeks26-27 weeks28-29 weeks

24 28 32 36

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1000

Wei

ght

(gr

•

•

•



Postnatal Weight Gain After Very Preterm Birth: A UK Population Study

Postnatal growth of 2577 infants < 32 wks GA plotted on UK-WHO growth charts. (Cole. ADC/RCPCH Abst. 2011.)

Embleton, et al. Pediatrics 2001; 107:270-3.

RCT: Aggressive Nutritional Support in VLBW Infants

Intervention Control(n=64) (n=61)

Protein 0.5 g/kg/d (d1) 0.5 g/kg/d (d3)to 3.5 g/kg/d to 2.5 g/kg/d

Lipid 0.5 g/kg/d (d2) 0.5 g/kg/d (d5)to 3.5 g/kg/d to 2.0 g/kg/d

Enteral 0.5 mL/hr (d1) started when daily, rarely d/c stable

Wilson, et al. Arch Dis Child. 1997; 77;F4-F11.

RCT: Aggressive Nutritional Support in VLBW Infants

Intervention Control(n=64) (n=61)

Age regain BW 9 d 12 d* NEC 8 % 7 %Bacteremia 50 % 66 %CoNS bacteremia 44 % 56 %At d/c or death:

Body wt < 10th% 59 % 82 %*Length < 10th% 56 % 74 %HC < 10th% 14 % 30 %

[* p<0.05]

Wilson, et al. Arch Dis Child. 1997; 77:F4-F11.

RCT of Aggressive Nutritional Support in VLBW Infants

Wilson, Arch Dis Child 1997

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Early & Aggressive Nutrition Strategy in VLBW Infants: Historical Control Study

Aggressive Conventional(n=117) (n=65)

Protein 1.5 g/kg/d (hrs) 0.5 g/kg/d (d3)to 4.0 g/kg/d to 3.0 g/kg/d

Lipid 0 5 g/kg/d (24 hrs) 0 5 g/kg/d (d3-4)Lipid 0.5 g/kg/d (24 hrs) 0.5 g/kg/d (d3-4)to 3.5 g/kg/d to 3.0 g/kg/d

Enteral 10 mL/kg/d HM or started when PF (d1), by 10 stable; mL/kg/d x 7 d, then advanced per15-20 mL/kg/d to team.180 mL/kg/d.

Dinerstein, et al. J Perinatolog 2006; 26:436-442.

Early and Aggressive Nutritional Strategy (Parenteral & Enteral) Decreases Growth

Failure in VBLW Infants

Dinerstein, et al. J Perinatology 2006; 26: 436-442.

Early & Aggressive Nutrition Strategy in VLBW Infants: Historical Control Study

Aggressive Conventional(n=117) (n=65)

Age regain BW 10 d 12 d* Age to full EN 15 d 20 d*NEC 2 % 3 %L t t i 26 % 23 %Late-onset sepsis 26 % 23 %At 40 wks PMA:Body wt < 10th% 53 % 77 %*Body wt (median) 2.95 kg 2.70 kg*Length (mean) 46.6 cm 45.6 cm*HC (mean) 35.2 cm 34.3 cm*[* p<0.01]

Dinerstein, et al. J Perinatology. 2006;26:436-442.

Neurodevelopmental Outcomes at 18-22 mos by Weight Gain Quartile

40%

50%

60%

ents

wit

h

me

MDI <70 PDI <70 Impairment

0%

10%

20%

30%

12.0 (2.1) 15.6 (0.8) 17.8 (0.8) 21.2 (2)

Weight Gain Groups (grams/kg/day)

Per

cen

t o

f P

ati

Ou

tco

m

Ehrenkranz. Pediatrics 2006:117:1253-61

Cerebral Palsy at 18-22 mos by Weight Gain Quartile

20%

25%

wit

h O

utc

om

e

0%

5%

10%

15%

12.0 (2.1) 15.6 (0.8) 17.8 (0.8) 21.2 (2)

Weight Gain Groups (grams/kg/day)

Per

cen

t o

f P

atie

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w


Growth Outcomes at 18-22 mos by Weight Gain Quartile


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Early Provision of Parenteral AA in ELBW Infants: Growth Outcomes at 36 wks PMA

Early

n=182

Late

n=836

OR (95% CI)

p-value

Weight (gms) 1958 ± 383 1819 ± 320 <0.0001

Wt <10th %tile 127 (82%) 681 (95%) 4.2 (2.4-7.5)

Wt <5th %tile 108 (70%) 605 (85%) 2.1 (1.4-3.2)

Length 41.7 ± 2.7 41.0 ± 2.3 0.0108

HC 30.9 ± 1.8 30.3 ± 1.6 <0.0001

Poindexter et al. J Pediatr 2006; 148:300-305

Head Circumference at 18-22 mos CA

* P < 0.05 Poindexter et al. J Pediatr 2006; 148:300-305

Neurodevelopment at 18-22 mos CA

Early

(n=182)

Late

(n=836)

Adjusted OR

(95% CI)

# Evaluated 154 (85%) 712 (85%)

Bayley MDI<70 33% 32% 0.9 (0.6-1.4)

B l PDI<70 17% 19% 1 1 (0 6 1 9)Bayley PDI<70 17% 19% 1.1 (0.6-1.9)

Cerebral Palsy (any)

17% 14% 0.6 (0.4-1.0)

Hearing Disability 3% 3% 1.1 (0.4-3.3)*

Blindness (L or R) 0% 1% (p=0.224)*

NDI 32% 35% 1.0 (0.6-1.5)

*Unadjusted Poindexter et al. J Pediatr 2006; 148:300-305

First-Wk Protein Intake Are Associated with 18-mos CA Developmental Outcomes in ELBW Infants

[Stephens. Pediatrics. 2009]

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1 2 3 4 5 6 7Day of Life

mea

n g/

kg

124 infants born 2000-2001. Wk #1 mean protein intake = 1.8 g/kg/day

First-Wk Protein Intakes Are Associated with 18-mos CA Developmental Outcomes in ELBW Infants

[Stephens. Pediatrics. 2009]

Regression analyses controlling for BW, gender, IVH, BPD, NEC and maternal education demonstrated:

Each 1 gm/kg/d increase in protein intake: ▪ 8.2-point increase in MDI

A t d f 17% f th i i MDI▪ Accounted for 17% of the variance in MDI

Each 10 kcal/kg/d increase in energy intake:▪ 4.6-point increase in MDI ▪ Accounted for 18% of the variance in MDI

Intrauterine, Early Neonatal, and Postdischarge Growth & Neurodevelopmental Outcome at 5.4 Yrs in Extremely Preterm Infants After Intensive

Nutritional Support►Franz, et al. Pediatrics 2009; 123:e101-e109● Study Design: 219 (83%) of 263 surviving VLBW

infants born between July 1996-June 1999 were evaluated at about 5 yrs of age with:

1) standardized neuroexam2) Kaufmann Assessment Battery for Children3) Gross Motor Function Classification Scale

● All infants received “intensive early nutritional support” that included initiation of parenteral protein (2 g/kg/d) on day 1 and enteral feeds (~16 mL/kg/d) on day 1. Parenteral protein was increased to 3 g/kg/d; enteral feeds by ~ 16 mL/kg /d.

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Contribution of Perinatal Risk Factors on Mental Processing Composite from

Multiple Linear Regression Models

Parameter (in weight model) Partial R2 P-value

IVH > 3 vs < 3 0.213 < 0.001

Duration of MV, > 7 vs < 7 d 0.113 < 0.001Measure of weight gain

SDS t bi th0.035

0 005SDS at birth∆SDS (D/C – birth)∆SDS (F/U – D/C)

0.0050.0470.884

PVL, yes vs no 0.020 0.029Highest maternal education,

lowest vs higher sch deg 0.016 0.009Total R2 of model 0.396

Franz. Pediatrics 2009; 123:e101-e109

Infant Growth Before & After Term:Effects on Neurodevelopment in Preterm Infants

► Belfort, et al. Pediatrics 2011; 128:e899-e906● Design: Observational study of 613 infants < 33 wks GA

born between 4/01-10/05; participants of DINO (DHA for Improvement of Neurodevelopmental Outcome) Trial

1) Anthropometrics at term, 4, 12, & 18 mos CA2) Bayley Scales of Infant Development-II at 18 mos CA2) Bayley Scales of Infant Development-II at 18 mos CA

● Findings:1) Between 1 wk-term, greater wt gain → higher BSID scores 2) Between 1 wk-term w/ BW < 1250 g, stronger associations w/MDI & PDI

3) Between term - 4 mos, greater wt gain & linear growth→ higher PDI scores

4) Between 4 – 12 mos, no growth associations with BSID

Infant Growth Before & After Term: Effects on Neurodevelopment in Preterm Infants

Belfort. Pediatr 2011; 128:e899-e906.

Neonatal Caloric Intake Influences Preterm Infant Head Growth

● AGA infants calorically deprived (< 85 kcal/kg/d) for > 4 wks (SGA infants for > 2 wks) had HC growth -1 to -2 SD below standard HC growth curves at 12 mos CA; AGA infants also had motor developmental delay at 12 mos CAdelay at 12 mos CA.

Georgieff, J Pediatr 1985; 107:581-587

● Early high-energy nutrient intake (> 95 kcal/kg/d) between postnatal days 2-10 by VLBW, SGA infants promoted catch-up HC growth & significantly higher DQ/IQ scores from 6 mos to adulthood, when compared to SGA infants w/o catch-up HC growth.

Brandt, J Pediatr 2003; 142:463-468

HC (m+sd) of AGA preterm infants compared with SGA HC catch-up group (CU) & group w/o HC catch-up (no-CU) from 35 wks PMA to adulthood. (Brandt, J Pediatr 2003; 142:463-468)

DQ/IQ (m+sd) of AGA preterm infants compared with SGA HC catch-up group (CU) & group w/o HC catcup (no-CU) from 6 mos to adulthood. (Brandt, J Pediatr 2003; 142:463-468)

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Improving Head Growth in Preterm Infants: A RCT

►Objectives: To explore the relationships between early nutrition, postnatal head growth, quantitative brain MRI, and developmental outcome during the 1st yr of life among infants born < 29 wks gestation.

►Methods: Infants were randomized to hyperalimented or standard parenteral and enteral nutrition. Growth was monitored from birth to 36 wks PMA.

Primary outcome: OFC at 36 wks PMA.Secondary outcomes: Quantitative MRI at 40 wks

PMA; Bayley Scales at 3 & 9 mos post-term

Tan. Arch Dis Child Fetal Neonatal Ed, 2008

RCT: Improving Head Growth in Preterm Infants < 29 wks’ GA

Hyperalimented(n=68)

Control(n=74)

PN compositionEnergy (kcal/kg/d)

Glucose (g/kg/d)

Protein (g/kg/d)

11716.3

4

9313.5

3Protein (g/kg/d)

Fat (g/kg/d)

44

33

Age PN initiated < 24 hrs < 24 hrs

PN advancement Stepwise from 1 g/kg/d P & F to 4 gm/kg/d by d7

Stepwise from 1 g/kg/d P & F to 3 gm/kg/d by d5

Enteral Nutrition EBM, preferably w/in 48 hrs;

↑ by 6-12 mL/d

EBM, preferably w/in 48 hrs;

↑ by 6-12 mL/dTan. Arch Dis Child Fetal Neonatal Ed, 2008

Clinical, Nutritional & Growth Outcomes of All Survivors

Intervention (n=55)

Control(n=59)

Days to regain BW 10.3 (6.1)* 13.9 (6.3)***

Median days on PN 17 (12) 12 (12)

Median days to FEN 19 (11) 15 (11)

Median # sepsis evts/pt 2 (2) 1 (2)

@Oxygen @ 36 wks PMA 40 36

NEC 6 6Energy intake @ 4 wks 2766 (233) 2621 (191)**Protein intake @ 4 wks 73 (7) 64 (5)***

OFC @ 36 wks (cm) 31.1 (1.5) 31.4 (1.3)

Length @ 36 wks (cm) 42.9 (2.3) 42.4 (2.1)

Weight @ 36 wks (g) 2136 (345) 2090 (293)

*Mean (sd); **p<0.01; ***p<0.001


Results: 80% of the infants in the Intervention group vs 97.8% of infants in the Control group were still in overall energy and protein deficit after 4 wks. Therefore, pooled data were used in these scatter plots.


Improving Head Growth in Preterm Infants: Results

● After pooling the study groups, significant correlations existed between:▪ Energy intake & energy deficit during the first 28 d

and:▫ TBV @ 40 wks PMA@▫ MDI & PDI @ 3 mos post-term,

but not 9 mos post-term▪ Anthropometrics @ 36 wks PMA and TBV & CBV

@ 40 wks PMA

▪ Weight @ 36 wks PMA and both mental and motor outcomes during year 1


Poor Linear Growth Velocity & 2 Yr Neurodevelopmental Outcomes in VLBW Infants

Cognitive scores at 24 mos CA: Not associated with WZ at any time points Associated with HCZ at birth and at 4 and 24 mos CA Associated with LZ at 4 and 12 mos CA

Ramel. Neonatology 2012; 1o2:19-24.

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Objectives● To discuss curves used to monitor postnatal

growth of preterm infants, especially extremely preterm (EPT) infants

● To review the data that: postnatal growth reflects the adequacy of nutrient

intake growth correlates with neurodevelopmental

outcomes

● To recommend the implementation of feeding guidelines

Implement Feeding Guidelines to Minimize Interruption of Antenatal Nutritional Support

● Feeding guidelines should include:

▪ “Consensus” early PN and EN evidence-based strategies (ie, potentially better practices)p )

▪ Standardized plan to manage “feeding intolerance”

▪ Strategy to maintain steady rate of postnatal growth, adjusting nutritional support if growth parameters not met

Stages of Nutritional Support After Birth of Extremely Preterm Infants

● Initiation

● Transition to full enteral nutrition (FEN)

● Maintenance of steady growth rate on FEN in the NICU

● Post-Discharge nutrition

Stages of Nutritional Support: Initiation

● Target GIR ~ 6 mg glucose/kg/min● Early initiation of parenteral AA

▪ Start within hrs of birth▪ Provide as a “To Deliver” amount

1 / / ( )▪ 1.5 g/kg/d (minimum)

● Total Fluid for first 24 hrs to provide 80-100 mL/kg/d

▪ 50 mL/kg/d of a “starter” (“vanilla”, off-hrs”) PN

▪ 30-50 mL/kg/d of glucose, minimal electrolyte soln

Off-Hours TPN

● Glucose 10 mg/dL (D10W)

● Protein (amino acids) 6.0 g/dL

● Minimal electrolytes

● Ca++ 100 mg/dL

● No vitamins, minerals, lipids

● @ 50mL/kg/d: GIR is 3.5 mg/kg/min, protein delivered is 3.0 g/kg/d, & energy delivered is 23 kcal/kg/d

Stages of Nutritional Support: Transition to Full Enteral Nutrition

● Optimize parenteral nutrition (PN)▪ Increase protein intake to ~ 4 g/kg/d

◦ Daily increases of 0.5-1.0 g/kg/d▪ Increase GIR to ~ 10 mg/kg/min during first week of lifeduring first week of life

▪ Initiate IFE within 24 hrs of birth◦ Start with at least 0.5 g/kg/d ◦ ↑by 0.5-1.0 g/kg/d to ~ 3.0 g/kg/d

▪ Increase % Total Daily Fluids (TDF) as PN over 1st 3-4 days of life

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Stages of Nutritional Support: Transition to Full Enteral Nutrition

● Initiate Minimal Enteral Nutrition [(MEN); trophic feeds, gi stim feeds]

▪ Start within first 24 - 96 hrs of age▫ Colostrum, if possible

▪ Select duration of MEN▪ Select duration of MEN▫ 24 hrs vs several days

▪ Select volume of MEN▫ ~ 10% total daily fld intake (~ 12 mL/kg/d)

▪ Select rate of advancement to FEN▫ ~12 mL/kg/d▫ Fortify HM @ ~ 100 mL/kg/d

Stages of Nutritional Support: Maintenance of Growth on FEN

● Monitor growth▪ Weight gain ~20 gm/kg/d (over 5-7 days)

▪ Length ~ 1 cm/wk

▪ HC ~ 1 cm/wk

● Identify causes of decreased rates of growth▪ Energy needs > energy intake

◦ Fluid restriction (eg, BPD)

◦ Malabsorption◦ ↓ intake during transition to nipple feedings

▪ ↓ protein content of fortified MOM (or DM)

● Maintain adequate energy & protein intakes▪ Energy intake ~ 120 kcal/kg/d (minimum)

▪ Protein intake : ~ 4.0 gm/kg/d < 30 wks PMA [P/E=3.3]~ 3.5 gm/kg/d > 30- 36 wks PMA [P/E=2.9]

Stages of Nutritional Support:Post-Discharge Nutrition

● Special nutritional requirements persist after D/C

▪ Fortified HM

▪ Nutrient-enriched post-D/C formula

● Monitor growth with WHO growth curves from term CA to 24 mos CA

Implementation of Feeding Guidelines Leads to Improved Outcomes, including:

▪ BW regained sooner

▪ FEN achieved sooner (reduced need for PN)

▪ Cumulative energy & protein deficits reduced

Decreased rates of late onset infection & NEC▪ Decreased rates of late-onset infection & NEC

▪ Improved anthropometrics at 36 wks PMA and at discharge (eg, fewer infants < 10th %tile

▪ Mediation of severity of illness

▪ Reduction of hospital stay

Summary and Conclusions● Extrauterine growth restriction (EUGR) may be

unavoidable for many EPT infants.

● Since postnatal growth reflects nutrient adequacy, growth must be monitored.

● Implementation of evidence-based feeding guidelines leads to improved outcomes.

● Postnatal growth is correlated with growth and neurodevelopmental outcomes in early childhood.

01 Ehrenkranz Impact of Growth on Neonatal … of Growth on Neonatal Outcomes ... Yale Estimated...

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