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Newborn Screening of Premature Infants: Clinical Trial Data Suggests Gestational Age and Chronological Age are Key to Interpretation
D. CHACE, R. CLARK, A. SPITZER, A. KELLEHER, PEDIATRIX MEDICAL GROUP, SUNRISE, FL
Objectives
To describe the influence that gestational age and chronological age have on amino acid and acylcarnitine profiles in an at risk population of premature infants.
Patient Samples
Premature Infants Studied
Collection Times (Days <1,7,24,42)
Metabolic Disorders Confirmed
The Numbers
995 3,579
4 0
The Analyses
Amino Acid Profile (NL 102, butyl esters)
Acylcarnitine Profile (Pre 85, butyl esters)
179,500 data points (3,579 x 50 metabolites)
Study Details
Gestational Ages of Premature Infants 23 – 31 weeks
3 Groups
Group 1: 23 to 26 weeks (n = 293)
Group 2: 27 to 28 weeks (n = 277)
Group 3: 29 to 31 weeks (n = 425)
Median Birth Weight
1057 grams (644–1514 g)
Study performed at 23 sites in 17 states 1 Central lab performed all tests
PE Genetics
Interpretation of results Pediatrix Analytical
Samples collected using NBS consensus protocols State data shared from all abnormal results.
Received 15/17 state alert values
Nutrition
Parenteral (IV) Nutrition 2 Hours (median, initiated)
Dextrose, Amino Acids
24 Hours Lipids
33% of patients Carnitine
Increased use with Decreased gestational age
Major Source of Nutrition < 7 days
Enteral Nutrition > 24 Hours (median, initiated)
Human Breast Milk, Formulas Day 7
% Enteral > Parenteral Highest % AA and Lipids
Day 42 All Enteral Max nutrition
Study Results
March of Dimes®
Amino-Acids and Ratios
-4
-2
0
2
4
6
8
10
Arg
Day
=1A
rg D
ay=7
Arg
Day
=28
Arg
Day
=42
His D
ay=1
His D
ay=7
His D
ay=2
8Hi
s Day
=42
Leu_
Ile D
ay=1
Leu_
Ile D
ay=7
Leu_
Ile D
ay=2
8Le
u_Ile
Day
=42
Met
Da
y=1
Met
Da
y=7
Met
Da
y=28
Met
Da
y=42
Phe
Day
=1Ph
e D
ay=7
Phe
Day
=28
Phe
Day
=42
Val
Da
y=1
Val
Da
y=7
Val
Da
y=28
Val
Da
y=42
Ala
Day
=1A
la D
ay=7
Ala
Day
=28
Ala
Day
=42
Asp
Day
=1A
sp D
ay=7
Asp
Day
=28
Asp
Day
=42
Cit
119
Day
=1C
it 11
9 D
ay=7
Cit
119
Day
=28
Cit
119
Day
=42
Glu
Day
=1G
lu D
ay=7
Glu
Day
=28
Glu
Day
=42
Gly
56
Day
=1G
ly 5
6 D
ay=7
Gly
56
Day
=28
Gly
56
Day
=42
Orn
Day
=1O
rn D
ay=7
Orn
Day
=28
Orn
Day
=42
Ser D
ay=1
Ser D
ay=7
Ser D
ay=2
8Se
r Day
=42
Tyr D
ay=1
Tyr D
ay=7
Tyr D
ay=2
8Ty
r Day
=42
Cit
119
_Arg
Day
=1C
it 11
9 _A
rg D
ay=7
Cit
119
_Arg
Day
=28
Cit
119
_Arg
Day
=42
Cit_
Phe
119
Day
=1C
it_Ph
e 11
9 D
ay=7
Cit_
Phe
119
Day
=28
Cit_
Phe
119
Day
=42
Gly
56_
Ala
Day
=1G
ly 5
6_A
la D
ay=7
Gly
56_
Ala
Day
=28
Gly
56_
Ala
Day
=42
Leu_
Ala
Day
=1Le
u_A
la D
ay=7
Leu_
Ala
Day
=28
Leu_
Ala
Day
=42
Leu_
Phe
Day
=1Le
u_Ph
e D
ay=7
Leu_
Phe
Day
=28
Leu_
Phe
Day
=42
Met
_Phe
Day
=1M
et_P
he D
ay=7
Met
_Phe
Day
=28
Met
_Phe
Day
=42
Phe_
Tyr D
ay=1
Phe_
Tyr D
ay=7
Phe_
Tyr D
ay=2
8Ph
e_Ty
r Day
=42
Tyr_
Leu
Day
=1Ty
r_Le
u D
ay=7
Tyr_
Leu
Day
=28
Tyr_
Leu
Day
=42
Val
_Phe
Day
=1V
al_P
he D
ay=7
Val
_Phe
Day
=28
Val
_Phe
Day
=42
Med
ian
(10-
90th
) Z s
core
Day (1-42)
Quick Peak
Amino Acid Example: Leu+Ile
0.0
50.0
100.0
150.0
200.0
250.0
300.0
1 1 7 28 42 1 7 28 42 1 7 28 42
Quantiles90 Quantiles10 Median
23 to 26 weeks 27 to 28 weeks 29 to 31 weeks Term
From NBS Data
Primarily TPN Primarily Enteral
Days
All Acylcarnitines
-4-202468
10121416
FreeCN
Day=1
C2 D
ay=1
C3 D
ay=1
C3D
C C
8OH D
ay=1
C4 D
ay=1
C4_O
H Day=1
C4D
C D
ay=1
C5 D
ay=1
C5_O
H Day=1
C5_1 D
ay=1
C5D
C C
10_OH D
ay=1
C6 D
ay=1
C6D
C D
ay=1
C6_O
H Day=1
C8 D
ay=1
C8_1 D
ay=1
C10 D
ay=1
C10_1 D
ay=1
C10_2 D
ay=1
C12 D
ay=1
C12_1 D
ay=1
C12_O
H Day=1
C12D
C D
ay=1
C14 D
ay=1
C14_1 D
ay=1
C14_2 D
ay=1
C14_O
H Day=1
C16 D
ay=1
C16_1 D
ay=1
C16_O
H Day=1
C18 D
ay=1
C18_1 D
ay=1
C18_2 D
ay=1
C18_O
H Day=1
C18_1_O
H Da
y=1
Med
ian
(10-
90th
%) Z
scor
e
Day (1-42)
Quick Peak
Acylcarnitines (OA)Example: Isovaleryl Carnitine
0
0.2
0.4
0.6
0.8
1
1.2
1 1 7 28 42 1 7 28 42 1 7 28 42
Quantiles90 Quantiles10 Median
23 to 26 weeks
27 to 28 weeks
29 to 31 weeks
Term
From NBS Data Primarily TPN
Primarily Enteral
Days
Acylcarnitines (FA)Example: Linoleyl Carnitine
00.20.40.60.8
11.21.41.61.8
1 1 7 28 42 1 7 28 42 1 7 28 42
Quantiles90 Quantiles10 Median
23 to 26 weeks
27 to 28 weeks
29 to 31 weeks
Term
From NBS Data
Primarily TPN
Primarily Enteral
Days
Generalized Findings (AA and AC)
MS/MS Study (AC and AA) 214 alerts (21.5% based on standard NBS interpretation protocols)
29% from Group 1 • 17% from Group 2 (all days)
12% Day 1 • 2% Day 28 (all groups)
Highest rate of abnormal results were on day 7 from Group 1
State NBS Screening (all tests) 461 alerts% (21.5% based on standard NBS interpretation protocols)
Premature Infants had most abnormal results: 64% versus 36% term
T4/TSH and CAH: highest percentage of abnormal results.
MS/MS: 8.9% and 2.6% for AC and AA, abnormal results respectively
Study and State NBS results were similar in terms of abnormal % and metabolite elevations (harmonization)?
Key Amino Acid Findings
Phe Higher in the 23-26 week group 1 than other groups.
Above median at day 1 (62 µM). Median day 7 (55 µM).
Well below median days 28-42 (38 µM).
Phe/Tyr ratio above median day 7 and below median days 28-42. Tyrosine below median day 7, above median day 1
Citrulline Increased with time for all groups (At days 28-42, 40% greater than day 1 and 7). Lowest on day 7.
Interesting note (Citrulline not contained in protein or amino acid solution in TPN) Made in small intestine, potential marker of gut health (low in unhealthy or abnormal GI tract )
Key Acylcarnitine Findings
Organic acid acylcarnitines higher in group 1(C5,C5:1,C4DC,C5OH, C5DC) compared to group 2 and 3.
Most ACs higher on day 0 than decrease through day 7. More variable pattern days 28-42.
Linoleic Acid Significant increase by day 7. Return to normal levels days 28-42 Due to Intralipid in TPN. Direct correlation between intralipid C18:2 content and C18:2 acylcarnitine)
Free Carnitine
Supplemented patients with L-carnitine showed highest FC on day 7 (40 µM versus 18µM) Higher FC on day 1 compared to normal. Lower FC on day 7 for non supplemented patients).
Summary
21 % of infants had an abnormal alert value
0% could be explained by TPN contamination with amino acids.
Cutoff values inappropriate for premature infants (median values 1 SD above and below medians) Normative values must correct for time and gestational age.
Must also correct for illness and nutritional support
The most premature infants metabolically different that most mature premature infants.
Organic acid acylcarnitines, branched chain amino acids, long chain acylcarnitines highest on day 7. All feed into beta oxidation pathway
Elevating more toxic metabolites