ARTICLE PEDIATRICS Volume 138, number 1, July 2016:e20154434 Survival and Major Morbidity of Extremely Preterm Infants: A Population-Based Study James G. Anderson, MD, a Rebecca J. Baer, MPH, b J. Colin Partridge, MD, MPH, a Miriam Kuppermann, PhD, MPH, c Linda S. Franck, RN, PhD, d Larry Rand, MD, c Laura L. Jelliffe-Pawlowski, PhD, MS, e Elizabeth E. Rogers, MD a abstract OBJECTIVES: To assess the rates of mortality and major morbidity among extremely preterm infants born in California and to examine the rates of neonatal interventions and timing of death at each gestational age. METHODS: A retrospective cohort study of all California live births from 2007 through 2011 linked to vital statistics and hospital discharge records, whose best-estimated gestational age at birth was 22 through 28 weeks. Major morbidities were based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Survival beyond the first calendar day of life and procedure codes were used to assess attempted resuscitation after birth. RESULTS: A total of 6009 infants born at 22 through 28 weeks’ gestation were included. Survival to 1 year for all live births ranged from 6% at 22 weeks to 94% at 28 weeks. Seventy-three percent of deaths occurred within the first week of life. Major morbidity was present in 80% of all infants, and multiple major morbidities were present in 66% of 22- and 23-week infants. Rates of resuscitation at 22, 23, and 24 weeks were 21%, 64%, and 93%, respectively. Survival after resuscitation was 31%, 42%, and 64% among 22-, 23-, and 24-week infants, respectively. Improved survival was associated with increased birth weight, female sex, and cesarean delivery (P < .01) for resuscitated 22-, 23-, and 24-week infants. CONCLUSIONS: In a population-based study of extreme prematurity, infants ≤24 weeks’ gestation are at highest risk of death or major morbidity. These data can help inform recommendations and decision-making for extremely preterm births. Departments of a Pediatrics, c Obstetrics, Gynecology, and Reproductive Sciences, and e Epidemiology and Biostatistics, and d School of Nursing, University of California San Francisco, San Francisco, California; and b Department of Pediatrics, University of California San Diego, La Jolla, California Dr Anderson was responsible for study conception and design, analysis and interpretation of data, and drafting and revising the article for critically important intellectual content; he had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Baer, Partridge, Kuppermann, Franck, Rand, Jelliffe-Pawlowski, and Rogers were responsible for study conception and design, analysis and interpretation of data, and drafting and revising the article for critically important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. DOI: 10.1542/peds.2015-4434 Accepted for publication Apr 11, 2016 To cite: Anderson JG, Baer RJ, Partridge JC, et al. Survival and Major Morbidity of Extremely Preterm Infants: A Population-Based Study. Pediatrics. 2016;138(1):e20154434 WHAT’S KNOWN ON THIS SUBJECT: Extremely preterm infants (22–28 weeks’ gestation) are at high risk of death and morbidity. In recent years, more infants born at 22 to 24 weeks’ gestation are being resuscitated instead of receiving comfort care only. WHAT THIS STUDY ADDS: In our population-based study, extremely preterm infants remain at risk for death and major morbidity, with 22- to 25-week gestation infants being at highest risk. We report rates of resuscitation and timing of death for 22- to 28-week gestation infants. by guest on January 31, 2021 www.aappublications.org/news Downloaded from
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ARTICLEPEDIATRICS Volume 138 , number 1 , July 2016 :e 20154434
Survival and Major Morbidity of Extremely Preterm Infants: A Population-Based StudyJames G. Anderson, MD, a Rebecca J. Baer, MPH, b J. Colin Partridge, MD, MPH, a Miriam Kuppermann, PhD, MPH, c Linda S. Franck, RN, PhD, d Larry Rand, MD, c Laura L. Jelliffe-Pawlowski, PhD, MS, e Elizabeth E. Rogers, MDa
abstractOBJECTIVES: To assess the rates of mortality and major morbidity among extremely preterm
infants born in California and to examine the rates of neonatal interventions and timing of
death at each gestational age.
METHODS: A retrospective cohort study of all California live births from 2007 through 2011
linked to vital statistics and hospital discharge records, whose best-estimated gestational
age at birth was 22 through 28 weeks. Major morbidities were based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Survival beyond the
first calendar day of life and procedure codes were used to assess attempted resuscitation
after birth.
RESULTS: A total of 6009 infants born at 22 through 28 weeks’ gestation were included.
Survival to 1 year for all live births ranged from 6% at 22 weeks to 94% at 28 weeks.
Seventy-three percent of deaths occurred within the first week of life. Major morbidity
was present in 80% of all infants, and multiple major morbidities were present in 66% of
22- and 23-week infants. Rates of resuscitation at 22, 23, and 24 weeks were 21%, 64%,
and 93%, respectively. Survival after resuscitation was 31%, 42%, and 64% among 22-, 23-,
and 24-week infants, respectively. Improved survival was associated with increased birth
weight, female sex, and cesarean delivery (P < .01) for resuscitated 22-, 23-, and 24-week
infants.
CONCLUSIONS: In a population-based study of extreme prematurity, infants ≤24 weeks’
gestation are at highest risk of death or major morbidity. These data can help inform
recommendations and decision-making for extremely preterm births.
Departments of aPediatrics, cObstetrics, Gynecology, and Reproductive Sciences, and eEpidemiology and
Biostatistics, and dSchool of Nursing, University of California San Francisco, San Francisco, California; and bDepartment of Pediatrics, University of California San Diego, La Jolla, California
Dr Anderson was responsible for study conception and design, analysis and interpretation of
data, and drafting and revising the article for critically important intellectual content; he had full
access to all of the data in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Baer, Partridge, Kuppermann, Franck, Rand, Jelliffe-Pawlowski,
and Rogers were responsible for study conception and design, analysis and interpretation of
data, and drafting and revising the article for critically important intellectual content. All authors
approved the fi nal manuscript as submitted and agree to be accountable for all aspects of the
work.
DOI: 10.1542/peds.2015-4434
Accepted for publication Apr 11, 2016
To cite: Anderson JG, Baer RJ, Partridge JC, et al. Survival
and Major Morbidity of Extremely Preterm Infants: A
a Resuscitation attempted = “Survived 1 calendar day or less AND received any ventilation/intubation or cardiopulmonary resuscitation [CPR]” or “Survived past 1 calendar day.”
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ANDERSON et al 6
TABL
E 4
Per
inat
al a
nd
Mat
ern
al D
emog
rap
hic
Ch
arac
teri
stic
s Am
ong
Su
rviv
ors
and
Non
surv
ivor
s fo
r W
hom
Res
usc
itat
ion
Was
Att
emp
ted
Ch
arac
teri
stic
Ges
tati
on a
t B
irth
, wk
22 (
n =
93)
23 (
n =
385
)24
(n
= 7
11)
22 t
o 24
(n
= 1
189)
Su
rviv
ors
(n
= 2
9)
Non
surv
ivor
s (n
= 6
4)
P
Su
rviv
ors
(n
= 1
62)
Non
surv
ivor
s (n
= 2
23)
P
Su
rviv
ors
(n
= 4
58)
Non
surv
ivor
s (n
= 2
53)
PS
urv
ivor
s (n
= 6
49)
Non
surv
ivor
s (n
= 5
40)
P
Bir
th w
eigh
t, g
a
M
ean
529.
552
7.5
.004
611.
758
0.6
.001
685.
063
3.3
<.0
0166
2.7
599.
0<
.001
S
D85
.110
6.8
94.2
88.9
119.
410
9.9
117.
410
7.4
Mal
eb17
(58
.6)
29 (
45.3
).2
3477
(47
.5)
132
(59.
2).0
2321
0 (4
5.9)
154
(60.
9)<
.001
304
(56.
8)31
5 (5
8.3)
<.0
01
Sin
glet
on b
irth
b26
(89
.7)
46 (
71.9
).0
5813
4 (8
2.7)
176
(78.
9).3
5436
9 (8
0.6)
206
(81.
4).7
8152
9 (8
1.5)
428
(79.
3).3
30
Ces
area
n d
eliv
eryb
13 (
44.8
)18
(28
.1)
.114
85 (
52.5
)11
8 (5
2.9)
.931
318
(69.
4)16
9 (6
6.8)
.469
416
(64.
1)30
5 (5
6.5)
.007
No
pre
nat
al v
isit
sb2
(6.9
)2
(3.1
).4
069
(5.6
)12
(5.
4).9
4113
(2.
8)10
(4.
0).4
2124
(3.
7)24
(4.
4).5
15
Hyp
erte
nsi
onb
2 (6
.9)
2 (3
.1)
.406
6 (3
.7)
9 (4
.0)
.868
54 (
11.8
)24
(9.
5).3
4762
(9.
6)35
(6.
5).0
54
Dia
bet
es m
ellit
usb
2 (6
.9)
3 (4
.7)
.662
10 (
6.2)
19 (
8.5)
.389
58 (
12.7
)16
(6.
3).0
0870
(10
.8)
38 (
7.0)
.025
Ch
orio
amn
ion
itis
b5
(17.
2)13
(20
.3)
.728
39 (
24.1
)45
(20
.2)
.361
94 (
20.5
)37
(14
.6)
.052
138
(21.
3)95
(17
.6)
.112
Rac
e/et
hn
icit
yb
W
hit
e, n
on-H
isp
anic
6 (2
0.7)
4 (6
.3)
.037
27 (
16.7
)34
(15
.3)
.706
87 (
19.0
)41
(16
.2)
.354
120
(18.
5)79
(14
.6)
.076
H
isp
anic
16 (
55.2
)33
(51
.6)
.747
92 (
56.8
)13
5 (6
0.5)
.461
235
(51.
3)13
7 (5
4.2)
.468
343
(52.
9)30
5 (5
6.5)
.211
B
lack
1 (3
.5)
12 (
18.8
).0
4918
(11
.1)
12 (
5.4)
.038
45 (
9.8)
30 (
11.9
).3
9864
(9.
9)54
(10
.0)
.937
As
ian
4 (1
3.8)
7 (1
0.9)
.693
12 (
7.4)
21 (
9.4)
.487
53 (
11.6
)28
(11
.1)
.839
69 (
10.6
)56
(10
.4)
.884
O
ther
2 (6
.9)
8 (1
2.5)
.419
13 (
8.0)
21 (
9.4)
.635
38 (
8.3)
17 (
6.7)
.451
53 (
8.2)
46 (
8.5)
.827
Mat
ern
al a
ge, y
b
<
183
(10.
3)3
(4.7
).3
048
(4.9
)14
(6.
3).5
7616
(3.
5)15
(5.
9).1
2827
(4.
2)32
(5.
9).1
63
18
–34
17 (
58.6
)54
(84
.4)
.007
123
(75.
9)17
4 (7
8.0)
.628
334
(72.
9)18
8 (7
4.3)
.690
474
(73.
0)41
6 (7
7.0)
.113
>
349
(31.
0)7
(10.
9).0
1731
(19
.1)
35 (
15.7
).3
7710
8 (2
3.6)
50 (
19.8
).2
4114
8 (2
2.8)
92 (
17.0
).0
14
Mat
ern
al e
du
cati
on, y
b
<
1213
(44
.8)
19 (
29.7
).1
5554
(33
.3)
80 (
35.9
).6
0512
1 (2
6.4)
80 (
31.6
).1
4018
8 (2
9.0)
179
(33.
2).1
20
12
5 (1
7.2)
18 (
28.1
).2
6043
(26
.5)
59 (
26.5
).9
8510
8 (2
3.6)
61 (
24.1
).8
7415
6 (2
4.0)
138
(25.
6).5
46
>
129
(31.
0)22
(34
.4)
.752
58 (
35.8
)73
(32
.7)
.531
211
(46.
1)99
(39
.1)
.074
278
(42.
8)19
4 (3
5.9)
.015
Insu
ran
ce s
tatu
sb
P
riva
te in
sura
nce
11 (
37.9
)20
(31
.3)
.527
60 (
37.0
)88
(39
.5)
.629
196
(42.
8)10
0 (3
9.5)
.397
267
(41.
1)20
8 (3
8.5)
.358
M
edi-C
al16
(55
.2)
42 (
65.6
).3
3588
(54
.3)
116
(52.
0).6
5521
9 (4
7.8)
137
(54.
2).1
0632
3 (4
9.8)
295
(54.
6).0
95
O
ther
2 (6
.9)
2 (3
.1)
.406
14 (
8.6)
19 (
8.5)
.996
43 (
9.4)
16 (
6.3)
.156
59 (
9.1)
37 (
6.9)
.158
Bir
th h
osp
ital
NIC
U le
velb
N
o N
ICU
4 (1
3.8)
9 (1
4.1)
.972
28 (
17.3
)49
(22
.0)
.256
85 (
18.6
)47
(18
.6)
.995
117
(18.
0)10
5 (1
9.4)
.533
In
term
edia
te1
(3.5
)3
(4.7
).7
8512
(7.
4)9
(4.0
).1
5013
(2.
8)11
(4.
4).2
8626
(4.
0)23
(4.
3).8
27
C
omm
un
ity
20 (
69.0
)41
(64
.1)
.645
101
(62.
4)13
8 (6
1.9)
.927
254
(55.
5)15
0 (5
9.3)
.324
375
(57.
8)32
9 (6
0.9)
.272
R
egio
nal
4 (1
3.8)
11 (
17.2
).6
8021
(13
.0)
27 (
12.1
).8
0210
6 (2
3.1)
45 (
17.8
).0
9513
1 (2
0.2)
83 (
15.4
).0
31
Dat
a ar
e p
rese
nte
d a
s n
(%
) u
nle
ss o
ther
wis
e in
dic
ated
.a
Cal
cula
ted
by
usi
ng
t te
st.
b C
alcu
late
d b
y u
sin
g χ2
test
.
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PEDIATRICS Volume 138 , number 1 , July 2016
than population-based data from
Sweden5 and multicenter data from
Japan.9
In our OSHPD cohort, more
than two-thirds of all infants
who survived to 1 year of
age had major morbidity. For
every 1-week decrease in
gestational age from 28 weeks,
the percentage of infants with
≥2 major morbidities increased.
IVH, PVL, BPD, NEC, sepsis, and
ROP have all been associated
with neurodevelopmental
impairment.26–30 Other studies
have shown higher rates of cerebral
palsy, cognitive impairment, and
behavioral problems among those
born at very early gestations, 31–34
thus putting extremely preterm
infants with major neonatal
morbidities at high risk for
significant impairment later in life.
The rates of attempted
resuscitation at 22 to 24 weeks in
our study were similar to several
publications from the same time
period. EPICure2 reported on the
proportion of live born infants for
whom stabilization was withheld
at birth.1 NRN considered infants
to have received active treatment if
they received certain interventions:
surfactant therapy, tracheal
intubation, ventilator support,
parenteral nutrition, epinephrine,
or chest compressions.11 CPQCC
categorized infants as having
received intensive care if they
were mechanically ventilated.13
Most other published studies on
mortality of extremely preterm
infants have not reported whether
resuscitative measures or active
treatment were attempted or
withheld, 5, 9 and thus they were
not suitable for direct comparison.
There was a slightly higher rate of
resuscitation or active treatment
at 23 weeks in EPICure2 and NRN
(83% and 72%, respectively)
compared with CPQCC and OSHPD
7
TABLE 5 Perinatal and Maternal Demographic Characteristics Among Survivors and Nonsurvivors for Whom Resuscitation Was Attempted
Data are presented as n (%) unless otherwise indicated.a Calculated by using t test.b Calculated by using χ2 test.
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ANDERSON et al
(both 65%), but the ranges of
attempted resuscitation or active
treatment at 22 weeks (21%–27%)
and 24 weeks (93%–97%) were
relatively similar in all 4 studies.
When comparing survival after
resuscitation, the California OSHPD
and CPQCC data both showed
a higher percentage of 22- to
25-week infants surviving after
resuscitation (28%–32% at 22
weeks, 42%–43% at 23 weeks,
64% at 24 weeks, and 80%–81%
at 25 weeks) compared with the
EPICure2 (7%, 23%, 42%, and
67%) and NRN (23%, 33%, 57%,
and 72%) data. The differences in
survival may reflect the variations
in the definitions of resuscitation
or active treatment in each study,
or variations in resuscitative and
neonatal practice at the individual,
hospital, or regional level.
The NRN study reported significant
between-hospital variation in
treatment initiation of extremely
preterm infants, which accounted
for a large portion of the variation
in hospital survival.11 It is possible
that the differences in resuscitation
practices and mortality may
extend beyond hospital variability
and may represent regional
variability. Previous studies have
explored or proposed individual
decision-making in resuscitation of
extremely preterm infants, 35, 36
whereas other studies have
examined more “macro” differences
in resuscitation practice and
subsequent outcomes at the
hospital or country level.37–39
Population-based studies and
analyses are needed to gain a better
understanding of the determinants
of, and extent to, which regional
practice variations underlie these
mortality rate differences.
Differences in perinatal
characteristics and maternal
demographic characteristics
between resuscitated survivors and
nonsurvivors, such as increased
birth weight and female sex,
demonstrate favorable predictors
for survival, as previously described
by Tyson et al.12 However, in the
present study, singleton birth was
not associated with a statistically
significant increase in survival.
The majority of extremely preterm
births in our cohort occurred in
hospitals with a community-level
NICU, which conferred no survival
benefit, whereas an increase in
survival was seen in infants born
at a hospital with a regional-level
NICU, which has been reported
in other studies.20, 40 In addition,
several sociodemographic factors
were associated with survival after
resuscitation, including white,
non-Hispanic mothers, maternal
age >34 years, maternal education
>12 years, and private insurance.
Maternal race, education, and
income have all been previously
reported as important factors in
neonatal outcomes, 41–44 but further
studies are needed to examine how
these factors may affect survival.
A major strength of this research
is that it is a large population-
based study with mortality and
major morbidity outcomes up to
1 year of age. We demonstrated
that linked statewide statistics (by
using discharge diagnoses, birth
certificates, and death records) may
be used to construct meaningful
population-based outcome data
on extremely preterm infants.
There are some limitations to
using statewide data, however.
The most recent linked data we
can access are through 2011. Also,
we are reliant on ICD-9-CM coding
for diagnoses and procedures. In
extrapolating whether extremely
preterm infants received life-
sustaining interventions after birth,
we were reliant on a limited number
of procedure codes. Considering
that extremely preterm infants
who do not receive life-sustaining
interventions after birth typically
die within the first day of life, 1, 11 it
seemed reasonable to deduce that
infants who survived beyond the
first calendar day of life did receive
resuscitation or life-sustaining
interventions, regardless of ICD-
9-CM procedure code for ventilation,
intubation, or cardiopulmonary
resuscitation. Unfortunately, our
data file was unable to adequately
capture antenatal steroid exposure,
which has been shown to be highly
associated with increased survival in
this population.3, 12, 13 An additional
limitation of the OSHPD data is
that approximately one-half of
the 22- to 28-week births did not
have linked birth certificate and
hospital discharge records, and
were not included in the study
cohort. Although reasons for this
absence are not clear given that the
linkage was completed by OSHPD
staff, considering that our study’s
resuscitation rates and survival
numbers are similar to other
recently published studies, 1, 11, 13 we
do not believe that the observed
findings are biased toward those
with linked data versus not. Other
morbidities are not consistently
coded, such as ROP stage, thus
likely underestimating morbidity.
In contrast, discharge codes may
overestimate culture-positive sepsis
by including infants treated for
culture-negative clinical suspicion
of infection. To minimize these
effects, we reported data for infants
with >1 morbidity. Finally, our
study does not capture long-term
neurodevelopmental outcomes.
Because the major morbidities
described here all have been
associated with neurodevelopmental
impairment, we suspect that high
rates of long-term impairment exist,
particularly in infants of lower
gestational age.
Future population-based
studies are needed to examine
neurodevelopmental and other
outcomes beyond year 1. Multicenter
studies of long-term outcomes in
the United States34, 45 and Japan9
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PEDIATRICS Volume 138 , number 1 , July 2016
have relied on large, within-country
academic medical centers. Given that
many extremely preterm infants are
being cared for in community-level
NICUs, these multicenter studies may
not adequately reflect the full range
of hospital practices and patient
populations. Large, population-based
studies of neurodevelopmental
outcomes in survivors of extreme
prematurity have been conducted in
the United Kingdom (EPICure), 32, 46
Sweden (EXPRESS - Extremely
Preterm Infants Study in Sweden), 47
Australia (VICS - Victorian Infant
Collaborative Study), 48 and France
(EPIPAGE - Etude Epidémiologique
sur les Petits Ages Gestationnels ).31
However, there are no population-
based studies that have assessed
the long-term neurodevelopmental
outcomes of extreme prematurity in
the United States, which has a health
care delivery system different from
those in Western Europe, Australia,
and Japan.
CONCLUSIONS
Our study provides population-based
evidence of survival and timing of
death for extremely preterm infants
in the first year of life. At the lowest
gestational ages (ie, 22 and 23
weeks), less than one-half of infants
survive after attempted resuscitation,
with two-thirds of survivors having
>1 major morbidity. These findings
can inform recommendations for the
care of extremely preterm infants.
9
ABBREVIATIONS
BPD: bronchopulmonary
dysplasia
CPQCC: California Perinatal
Quality Care
Collaborative
ICD-9-CM: International Classi-fication of Diseases, Ninth Revision, Clinical Modification
IVH: intraventricular hemorrhage
NEC: necrotizing enterocolitis
NRN: Neonatal Research Network
OSHPD: Office of Statewide
Health Planning and
Development
PVL: periventricular
leukomalacia
ROP: retinopathy of prematurity
Address correspondence to James G. Anderson, MD, Department of Pediatrics, University of California San Francisco, 550 16th St, 5th Floor, San Francisco, CA
FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.
FUNDING: Funded in part by the UCSF Preterm Birth Initiative.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.
REFERENCES
1. Costeloe KL, Hennessy EM, Haider S,
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S. Franck, Larry Rand, Laura L. Jelliffe-Pawlowski and Elizabeth E. RogersJames G. Anderson, Rebecca J. Baer, J. Colin Partridge, Miriam Kuppermann, Linda
Population-Based StudySurvival and Major Morbidity of Extremely Preterm Infants: A
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Population-Based StudySurvival and Major Morbidity of Extremely Preterm Infants: A
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