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aDepartment of Pediatric Newborn Medicine, and Departments of gChanning Division of Network Medicine, Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; bHarvard Medical School, Harvard University, Boston, Massachusetts; cDepartment of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; dDepartment of Clinical Research, OpenBiome, Somerville, Massachusetts; eDepartment of Pediatrics, University of Rochester Medical Center, Rochester, New York; fDepartment of Research, Community
To cite: Lee AC, Panchal P, Folger L, et al. Diagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review. Pediatrics. 2017;140(4):e20171423
CONTEXT: An estimated 15 million neonates are born preterm annually. However, in low- and middle-income countries, the dating of pregnancy is frequently unreliable or unknown.OBJECTIVE: To conduct a systematic literature review and meta-analysis to determine the diagnostic accuracy of neonatal assessments to estimate gestational age (GA).DATA SOURCES: PubMed, Embase, Cochrane, Web of Science, POPLINE, and World Health Organization library databases.STUDY SELECTION: Studies of live-born infants in which researchers compared neonatal signs or assessments for GA estimation with a reference standard.DATA EXTRACTION: Two independent reviewers extracted data on study population, design, bias, reference standard, test methods, accuracy, agreement, validity, correlation, and interrater reliability.RESULTS: Four thousand nine hundred and fifty-six studies were screened and 78 included. We identified 18 newborn assessments for GA estimation (ranging 4 to 23 signs). Compared with ultrasound, the Dubowitz score dated 95% of pregnancies within ±2.6 weeks (n = 7 studies), while the Ballard score overestimated GA (0.4 weeks) and dated pregnancies within ±3.8 weeks (n = 9). Compared with last menstrual period, the Dubowitz score dated 95% of pregnancies within ± 2.9 weeks (n = 6 studies) and the Ballard score, ±4.2 weeks (n = 5). Assessments with fewer signs tended to be less accurate. A few studies showed a tendency for newborn assessments to overestimate GA in preterm infants and underestimate GA in growth-restricted infants.LIMITATIONS: Poor study quality and few studies with early ultrasound-based reference.CONCLUSIONS: Efforts in low- and middle-income countries should focus on improving dating in pregnancy through ultrasound and improving validity in growth-restricted populations. Where ultrasound is not possible, increased efforts are needed to develop simpler yet specific approaches for newborn assessment through new combinations of existing parameters, new signs, or technology.
Diagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic ReviewAnne CC Lee, MD, MPH, a, b Pratik Panchal, MD, MPH, c, d Lian Folger, BA, a Hilary Whelan, MD, e Rachel Whelan, MPH, BA, f Bernard Rosner, PhD, b, g Hannah Blencowe, MRCPCH, MBChB, Msc, h, i Joy E. Lawn, MBBS, PhDh, i
abstract
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
PEDIATRICS Volume 140, number 6, December 2017:e20171423 Review ARticle by guest on March 30, 2019www.aappublications.org/newsDownloaded from
Of the estimated 14.9 million annual preterm births, 13.6 million (91%) occur in low- and middle-income countries (LMIC) .1, 2 Preterm birth is the leading cause of mortality in children less than 5 years of age globally, accounting for 1 million neonatal deaths annually, almost all of which are in LMIC.3 In these settings, early recognition of the preterm infant may facilitate the timely delivery of life-saving interventions, such as continuous positive airway pressure or kangaroo mother care.
Ultrasound dating in early pregnancy is the most accurate method currently available to assess gestational age (GA) and is a standard of care in high-income countries. In LMIC, pregnancy dating is challenging, and GA of the infant is frequently unknown or inaccurate. Maternal recall of last menstrual period (LMP) is often unavailable or unreliable, particularly in populations with high rates of maternal illiteracy.4, 5 The shortage of health care providers in LMIC, currently estimated at 7.9 million, 6 contributes to poor coverage of antenatal care. In sub-Saharan Africa and Southeast Asia, fewer than one-third of mothers in households in the poorest quintile receive at least 1 antenatal care visit.7 Furthermore, the timing of the first visit for antenatal care is late, occurring typically late in the second trimester.8, 9 Moreover, access to ultrasonography is low, with <7% of pregnant women having access to ultrasound in rural sub-Saharan Africa.4 Traditional sonography in late pregnancy is notably inaccurate for determining GA (±4 weeks).10, 11
Clinical assessment of newborn maturity has long been used as a proxy to estimate GA after birth (Table 1). In 1966, Farr et al12 defined a classification for the development of external physical characteristics in the newborn. In 1968, Amiel-Tison13 described the assessment of neonatal neurologic maturation. Dubowitz et al14 developed a score for GA based
on a combination of neurologic and physical signs, which dated pregnancies within 5 days of LMP in their original study. Since then, several simplified clinical assessments have been described in the literature.15 – 18 The Ballard score19 is one of the most commonly usedand was revised to the New Ballard score in 1991 to improve accuracy for early preterm infants.20
Newborn assessment for GA dating has become less relevant in high-income settings, where ultrasound coverage is high and uncertainty of antenatal pregnancy dating is less common than in LMIC. In LMIC settings without widespread access to early ultrasound dating and where accuracy of LMP recall is highly variable, clinical assessment of the newborn remains the commonest available tool to evaluate GA. Accurate GA is necessary to identify preterm and small-for-gestational-age (SGA) babies and provide them with effective interventions.
The Every Newborn Action Plan was launched in 2014 with the aim to end preventable neonatal deaths and stillbirths by 2030.34 GA measurement was identified as a priority area35 for improving (1) the epidemiology of preterm birth and SGA and (2) the comparability of neonatal mortality estimates through stratification by GA and birth weight.
In this systematic review, we aim to (1) identify individual neonatal signs and combined clinical scores or assessments that have been used to ascertain GA of newborns; and (2) assess the diagnostic accuracy and reliability of these methods for estimating GA, compared with dating by a reference standard (ie, ultrasound or LMP).
MeThods
search strategy
We conducted a systematic review of the published and gray literature,
initially done in March 2015 and updated in June 2016 (Fig 1). Databases we searched included PubMed, Embase, Cochrane, Web of Science, POPLINE, and the World Health Organization Global Health Libraries and regional databases (Latin American and Carribbean Health Sciences, Index Medicus for the Eastern Mediterranean Region, African Index Medicus). The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42015020499). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, review protocol, and detailed search terms are available in the Supplemental Information.
Inclusion Criteria
There were no language restrictions. Abstracts of non-English articles were translated via Google Translate, and if eligible, the full text was translated to English by fluent speakers. Articles were considered for inclusion if the study met the following criteria: (1) included live-born neonates; (2) compared at least 2 methods of GA estimation, 1 of which was a neonatal clinical assessment, score or individual clinical sign(s); and (3) reported at least 1 statistic assessing correlation, agreement, or validity of GA estimation. Prenatal assessments (eg, symphysis fundal height, ultrasound) and neonatal anthropometrics (eg, foot length) were reviewed separately and will be reported elsewhere.
exclusion Criteria
We excluded studies in which researchers did not provide data describing the correlation, agreement, or validity of neonatal clinical assessment compared with a reference method of pregnancy dating (ie, ultrasound or LMP). We excluded studies from specialized subpopulations (eg, infants of
LEE et al2
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
PEDIATRICS Volume 140, number 6, December 2017 3
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
TABL
e 1
Neon
atal
Ass
essm
ents
/ Sc
orin
g Sy
stem
s by
Lev
el o
f Com
plex
ity
Clin
ical
Sc
orin
g Sy
stem
or
Nam
e
No. o
f cr
iteri
aPh
ysic
al C
rite
ria
Neur
omus
cula
r Cr
iteri
aOt
her
Crite
ria
Refe
renc
e St
anda
rdOr
igin
al R
epor
ted
Accu
racy
or
Corr
elat
ion
with
GA
Stud
y Se
ttin
g an
d Lo
catio
nSa
mpl
e Si
zeYe
ar
Amie
l-Tis
on
et a
l2123
Skin
col
or, s
kin
opac
ity, s
kin
text
ure,
ede
ma,
lanu
go,
skul
l har
dnes
s, e
ar fo
rm,
ear
firm
ness
, gen
itals
, br
east
siz
e, n
ippl
e fo
rmat
ion,
pla
ntar
cre
ases
Retu
rn to
flex
ion
of fo
rear
ms,
sc
arf s
ign,
pop
litea
l ang
le, f
oot
dors
iflex
ion,
rig
htin
g re
actio
n,
rais
e to
sit,
bac
k to
lyin
g, fi
nger
gr
asp
and
resp
onse
to tr
actio
n,
nonn
utri
tive
suck
ing,
cro
ssed
ex
tens
ion,
vis
ion
fix a
nd tr
ack
—BO
ECo
rrel
atio
n of
indi
vidu
al
sign
s in
man
uscr
ipt
Port
-Roy
al-B
aude
locq
ue
Hosp
ital;
Pari
s, F
ranc
e39
719
99
Fere
su e
t al22
22Ed
ema,
ski
n te
xtur
e, s
kin
colo
r, sk
in o
paci
ty, l
anug
o,
plan
tar
crea
ses,
nip
ple
form
atio
n, b
reas
t siz
e,
ear
form
, ear
firm
ness
, ge
nita
ls
Post
ure,
squ
are
win
dow
, do
rsifl
exio
n of
foot
, arm
rec
oil,
leg
reco
il, p
oplit
eal a
ngle
, he
el-to
-ear
, sca
rf s
ign,
hea
d la
g,
vent
ral s
uspe
nsio
n
Birt
h w
eigh
t (B
W)
LMP
Corr
elat
ion
of in
divi
dual
si
gns
in m
anus
crip
tM
ater
nity
uni
t, Ha
rare
Ce
ntra
l Hos
pita
l; Ha
rare
, Zi
mba
bwe
364
2002
Dubo
witz
et
al14
21Ed
ema,
ski
n te
xtur
e, s
kin
colo
r, sk
in o
paci
ty, l
anug
o,
plan
tar
crea
ses,
nip
ple
form
atio
n, b
reas
t siz
e,
ear
form
, ear
firm
ness
, ge
nita
ls
Post
ure,
squ
are
win
dow
, ank
le
dors
iflex
ion,
arm
rec
oil,
leg
reco
il, p
oplit
eal a
ngle
, hee
l to
ear,
scar
f sig
n, h
ead
lag,
ven
tral
su
spen
sion
—LM
P95
% C
I: ±
2.0
wk
NICU
, Jes
sop
Hosp
ital
for
Wom
en; S
heffi
eld,
En
glan
d
167
1970
Dubo
witz
and
Fa
rr (
from
Ni
colo
poul
os
et a
l23)
17Sk
in te
xtur
e, s
kin
colo
r, sk
in
opac
ity, l
anug
o, p
lant
ar
crea
ses,
nip
ple
form
atio
n,
brea
st s
ize,
ear
form
, ear
fir
mne
ss
Post
ure,
squ
are
win
dow
, do
rsifl
exio
n of
foot
, pop
litea
l an
gle,
hee
l-to-
ear,
scar
f sig
n,
head
lag,
ven
tral
sus
pens
ion
—LM
Pr
= 0.
878
Alex
andr
a M
ater
nity
Ho
spita
l; At
hens
, Gre
ece
710
1976
Finn
strö
m24
12Br
east
siz
e, n
ippl
e fo
rmat
ion,
sk
in o
paci
ty, s
calp
hai
r, ha
ir-fo
rehe
ad b
orde
r, ey
ebro
ws,
ear
car
tilag
e,
finge
rnai
ls, x
ipho
id
proc
ess,
ext
erna
l gen
italia
, pl
anta
r sk
in c
reas
es,
pupi
llary
mem
bran
e
——
LMP
r =
0.84
for
5 ex
tern
al
char
acte
rist
ics
Univ
ersi
ty H
ospi
tal;
Umea
, Sw
eden
174
1972
Balla
rd e
t al19
12Sk
in c
olor
, lan
ugo,
pla
ntar
cr
ease
s, b
reas
t siz
e, e
ar
firm
ness
, gen
itals
Post
ure,
squ
are
win
dow
(w
rist
), ar
m r
ecoi
l, po
plite
al a
ngle
, sca
rf
sign
, hee
l-to-
ear
—LM
P an
d cl
inic
al
data
r =
0.85
2NI
CU, C
inci
nnat
i Gen
eral
Ho
spita
l; Ci
ncin
nati,
Ohi
o25
219
79
Balla
rd e
t al
(Ne
w
Balla
rd
scor
e)20
12Sk
in, l
anug
o, p
lant
ar c
reas
e,
brea
st m
atur
ity, e
ye a
nd/
or e
ar, g
enita
ls
Post
ure,
squ
are
win
dow
(w
rist
), ar
m r
ecoi
l, po
plite
al a
ngle
, sca
rf
sign
, hee
l-to-
ear
—BO
Er
= 0.
97NI
CUs
and
nurs
erie
s;
Cinc
inna
ti, O
hio
530
1991
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
LEE et al4
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
Clin
ical
Sc
orin
g Sy
stem
or
Nam
e
No. o
f cr
iteri
aPh
ysic
al C
rite
ria
Neur
omus
cula
r Cr
iteri
aOt
her
Crite
ria
Refe
renc
e St
anda
rdOr
igin
al R
epor
ted
Accu
racy
or
Corr
elat
ion
with
GA
Stud
y Se
ttin
g an
d Lo
catio
nSa
mpl
e Si
zeYe
ar
Farr
2510
—Sp
onta
neou
s m
otor
act
ivity
, re
actio
n of
pup
ils to
ligh
t, ra
te
of s
ucki
ng, c
losu
re o
f mou
th
whe
n su
ckin
g, s
trip
ping
act
ion
of th
e to
ngue
, res
ista
nce
agai
nst
pass
ive
mov
emen
t, re
coil
of
fore
arm
s, p
lant
ar g
rasp
, pitc
h of
cr
y, in
tens
ity o
f cry
—LM
PAc
cura
te ±
1 w
k: 6
1%Ab
erde
en, S
cotla
nd82
1968
Tunç
er e
t al26
8Sk
in te
xtur
e, e
ar fo
rm,
firm
ness
, bre
ast s
ize
and
nipp
le fo
rmat
ion,
pla
ntar
cr
ease
s, fa
cial
app
eara
nce
Post
ure,
arm
rec
oil,
scar
f sig
n—
LMP
r =
0.94
5Ha
cett
epe
Univ
ersi
ty, N
ICU;
An
kara
, Tur
key
100
1981
Ereg
ie17
8Sk
in te
xtur
e, e
ar fo
rm, b
reas
t si
ze, g
enita
liaPo
stur
e, s
carf
sig
nHe
ad
circ
umfe
renc
e,
mid
-arm
ci
rcum
fere
nce
Dubo
witz
Accu
rate
±2
wk:
92%
Univ
ersi
ty te
achi
ng
hosp
itals
; Ben
in, N
iger
ia26
219
91
Capu
rro
et a
l157
Skin
text
ure,
nip
ple
form
atio
n, e
ar fo
rm,
brea
st s
ize,
pla
ntar
cr
ease
s
Scar
f sig
n, h
ead
lag
—LM
Pr
= 0.
9M
onte
vide
o, U
rugu
ay11
519
78
Kollé
e et
al27
7Sk
in c
olor
, ski
n te
xtur
e,
plan
tar
crea
ses,
bre
ast
size
, ear
firm
ness
, nai
l le
ngth
—AV
CLNS
95%
CI:
±19
.9 d
Ca
thol
ic U
nive
rsity
; Ni
jmeg
en, N
ethe
rlan
ds22
919
85
Klim
ek e
t al28
6La
nugo
, pla
ntar
cre
ases
, br
east
siz
ePo
stur
e, a
ngle
fore
arm
to a
rm,
pulli
ng a
n el
bow
to th
e bo
dy—
Balla
rdr
= 0.
72Te
rtia
ry c
are
hosp
itals
; Po
land
800
2000
Sim
plifi
ed
Dubo
witz
(f
rom
Alla
n et
al29
)
6Br
east
siz
e, s
kin
text
ure,
ear
be
ndin
g (s
ubst
itute
d fr
om
ear
firm
ness
bec
ause
so
me
Abor
igin
al b
abie
s ha
ve le
ss e
ar c
artil
age)
Squa
re w
indo
w, p
oplit
eal a
ngle
, sc
arf s
ign
—Ul
tras
ound
Mea
n di
ffere
nce:
0.4
wk
(95%
LOA
: −2.
8 to
1.9
)Pr
ivat
e Ho
spita
ls; N
orth
ern
Terr
itory
, Aus
tral
ia98
2009
Nara
yana
n
et a
l305
Skin
col
or, e
ar fo
rm, p
lant
ar
skin
cre
ase,
bre
ast
form
atio
n, s
kin
text
ure
—AV
CLLM
P95
% C
I: ±
11 d
Kala
wat
i Sar
an C
hild
ren’
s Ho
spita
l; Ne
w D
elhi
, In
dia
356
1982
Robi
nson
31 (
from
Se
rfon
tein
and
Ja
rosz
ewic
z32)
5—
Pupi
l rea
ctio
n, tr
actio
n, g
labe
llar
tap,
nec
k ri
ghtin
g, h
ead
turn
ing
—Du
bow
itz95
CI:
±1
wk;
r =
0.8
5So
uth
Afri
ca73
1966
Park
in e
t al16
4Sk
in te
xtur
e, b
reas
t siz
e,
edem
a, p
lant
ar s
kin
crea
ses,
nai
l len
gth,
nai
l te
xtur
e, e
ar fi
rmne
ss, s
kull
hard
ness
, lan
ugo
hair,
ge
nita
lia
——
LMP
95 C
I: ±
18.1
dUn
iver
sity
hos
pita
l; Ne
wca
stle
, Eng
land
392
1976
TABL
e 1
Cont
inue
d
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
diabetic mothers), editorials or reviews without original data, individual case reports, and duplicate studies.
data extraction
All articles were reviewed independently by 2 researchers and extracted into a standard Excel file. Differences were resolved by a third independent reviewer. The study characteristics extracted are listed in Supplemental Information 2 .
study Quality Assessment
Two independent reviewers graded the methodological quality of the studies of diagnostic accuracy using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS–2)36 tool, modified for the context of this review (Supplemental Information, “Study Quality Assessment” section). Individual studies were evaluated for limitations and biases in the following domains: patient selection, test method, reference standard, and patient flow and timing. Studies with a reference standard GA of ultrasonography or best obstetric estimate (BOE) (including ultrasound confirmation of dating) were graded as highest quality. Though LMP may be considered gold standard in high-resource settings (where rates of literacy and early antenatal care are high), in LMIC, LMP recall is considered less reliable because of low literacy rates and late presentation to antenatal care.11, 37 Additionally, we assessed the generalizability of study results to LMIC.
statistical Analysis
Stata 13 (StataCorp, College Station, TX) and R (R Foundation for Statistical Computing, Vienna, Austria) were used for analyses. The definition of preterm birth was a live birth <37 weeks’ gestation. Studies were grouped by method of newborn assessment and reference standard. Simple descriptive statistics were
used to report ranges and medians. The mean individual-level differences between 2 methods of GA assessment were pooled using the Stata metan command, which provided the pooled mean-difference estimate and 95% confidence interval (CI). The variance and SD around the pooled estimate were calculated using the following formula38:
Variance pooled =
∑ i=1 k ( n i − 1 ) S i 2 _______________ ∑ i=1 k ( n i − 1)
For studies in which researchers reported the percent of test measures within ±1 to 2 weeks of a reference, percentages were logit transformed and SEs were calculated. Meta-analysis was conducted with a random effects model. The Higgins I2 statistic was calculated to assess heterogeneity. For reports of diagnostic accuracy, forest plots were generated in R to summarize diagnostic accuracy across studies. Because pooling of sensitivity and specificity separately fails to account for the interrelatedness of the measures, hierarchical bivariate models are recommended for meta-analysis.39 These were analyzed by using MetaDisc 1.4 and RStudio (Mada package). Hierarchal summary receiver operating characteristic curves were generated.
Subgroup analyses were conducted by assessment method, reference standard type, and country income level. Correlation coefficients were not pooled, given that in many studies type of coefficient (ie, Spearman or Pearson) was not indicated, and furthermore, methods for pooling Spearman correlation coefficients have not been well described.38
ResuLTs
Neonatal Clinical Assessments
We identified 3862 titles, and 66 articles were included, some
PEDIATRICS Volume 140, number 6, December 2017 5
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
Clin
ical
Sc
orin
g Sy
stem
or
Nam
e
No. o
f cr
iteri
aPh
ysic
al C
rite
ria
Neur
omus
cula
r Cr
iteri
aOt
her
Crite
ria
Refe
renc
e St
anda
rdOr
igin
al R
epor
ted
Accu
racy
or
Corr
elat
ion
with
GA
Stud
y Se
ttin
g an
d Lo
catio
nSa
mpl
e Si
zeYe
ar
Bhag
wat
et
al18
(fr
om
Bind
usha
et
al33
)
4Sk
in te
xtur
e, b
reas
t siz
e, e
ar
firm
ness
, gen
italia
)—
—LM
PM
ean
diffe
renc
e: −
0.58
wk;
r
= 0.
91M
edic
al C
olle
ge;
Thir
uvan
anth
apur
am,
Kera
la, I
ndia
1000
; GA
28–3
7 w
k
2014
LOA,
lim
its o
f agr
eem
ent;
NS, n
ot s
tate
d; —
, not
app
licab
le.
TABL
e 1
Cont
inue
d
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reporting on more than one scoring system (22 articles reported on the Dubowitz score, 31 on the Original and/or New Ballard score, and 25 on other clinical scores)(Fig 1). Basic study characteristics of all included studies are in Supplemental Table 10. The studies were published between 1968 and 2016, with fewer than half from LMIC. Most studies (n = 62) were conducted in health facilities, with 19 conducted in NICUs
on preterm and/or low birth weight (LBW) populations. For the reference standard, there were 31 studies in which researchers had ultrasound-based dating, 42 in which they used LMP, and 3 in which researchers used dating based on another neonatal assessment.
The overall QUADAS–2 summary is in Supplemental Fig 6. In general, the quality of the studies was relatively
low. In over half of the studies, there was a high risk of bias related to patient selection, test method, or reference standard.
Neonatal Clinical Assessments or Scores
We identified 18 different neonatal assessments or scoring systems (combining >1 individual clinical sign) for GA determination (Table 1). Twelve were developed in high-income countries (HICs) and 7 in LMIC (4 in Africa, 2 in Asia, 1 in Turkey). The reference standard from which the scores were derived was ultrasound/BOE in only 2 studies. The most complex score, Amiel-Tison, 21 has 23 criteria, including a large number of neurologic signs. The simplest score, the Parkin, 16 includes only 4 external physical criteria. One simplified score was developed in Nigeria (Eregie17) and includes physical anthropometrics (head circumference and midarm circumference).
Individual External Physical Criteria and Signs
Table 2 shows 12 studies in which researchers reported the correlation of individual external physical criteria with GA. Correlation coefficients were generally higher for comparisons with an LMP reference, for which median correlation coefficients ranged from 0.60 to 0.75 for most signs. Three studies used an ultrasound or BOE GA reference, and lower correlations were reported in 2 of these studies, neither of which included early preterm infants.21, 40 The physical characteristics with the highest median correlation were breast size, plantar skin creases, ear firmness, and skin texture.
Individual Neuromuscular Signs
In 10 studies, researchers reported the correlation of individual neuromuscular criteria with GA (Table 2). The median correlation
LEE et al6
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
FIGuRe 1Neonatal clinical assessment: flow diagram. Diagram of the screening process to identify studies for inclusion in neonatal assessment review; adapted from the PRISMA (Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009 Jul 21;6(7):e1000097). *Note: Several papers reported on>1 score.
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
PEDIATRICS Volume 140, number 6, December 2017 7
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
TABL
e 2
Corr
elat
ion
of In
divi
dual
Phy
sica
l or
Neur
omus
cula
r Cr
iteri
a W
ith G
A
Amie
l-Ti
son
et
al21
Lee
et a
l40Ba
llard
et
al (
New
Ba
llard
)20
Park
in e
t al
16Du
bow
itz
and
Farr
(N
icol
opou
los
et a
l23)
Ragh
u et
al
41Fe
resu
et
al22
Dubo
witz
an
d Fa
rr
(Sun
joh
et
al42
)
Finn
strö
m24
Balla
rd e
t al
19Tu
nçer
et
al26
Nara
yana
n et
al30
Sum
mar
y Ac
ross
Al
l Stu
dies
, M
edia
n (M
inim
um,
Max
imum
)
N (s
ampl
e si
ze)
397
710
530
392
710
160
364
358
174
252
220
356
Stud
y Se
ttin
g an
d Lo
catio
nTe
rtia
ry
Hosp
ital;
Pari
s,
Fran
ce
Com
mun
ity,
Sylh
et,
Bang
lade
sh
NICU
s an
d nu
rser
ies;
Ci
ncin
nati,
Oh
io
Univ
ersi
ty
Hosp
ital;
New
cast
le,
Engl
and
Mat
erni
ty
Hosp
ital;
Athe
ns,
Gree
ce
Univ
ersi
ty
hosp
ital;
Lusa
ka,
Zam
bia
Mat
erni
ty
unit;
Ha
rare
, Zi
mba
bwe
Tert
iary
Ho
spita
l; Ya
ound
e,
Cam
eroo
n
Univ
ersi
ty
hosp
ital;
Umea
, Sw
eden
NICU
an
dnur
sery
; Ci
ncin
nati,
Oh
io
NICU
; Ank
ara,
Tu
rkey
Child
ren’
s Ho
spita
l; Ne
w D
elhi
, In
dia
—
GA r
ange
incl
uded
37–4
1 w
k34
–42
wk
20–4
4 w
k25
.2–4
5.2
wk
28–4
4 w
kNS
24–4
5 w
k25
–44
wk
32.1
–34
wk
26–4
4 w
k,
760–
5460
g
27–4
1 w
k26
–44.
4 w
k—
Refe
renc
e st
anda
rdBO
EUl
tras
ound
BOE
LMP
LMP
LMP
LMP
LMP
LMP
LMP
LMP
LMP
—Ph
ysic
al c
rite
ria
Sk
in c
olor
0.19
0.05
—0.
780.
760.
520.
450.
80.
480.
84—
0.74
0.63
(0.
05, 0
.84)
Ea
r fo
rm0.
110.
020.
73—
0.76
0.64
0.57
0.72
0.41
0.84
0.62
—0.
63 (
0.02
, 0.8
4)
Ear
firm
ness
0.18
0.03
—0.
780.
760.
650.
530.
72—
——
0.85
0.69
(0.
03, 0
.85)
Pl
anta
r sk
in
crea
ses
0.34
0.02
0.72
0.76
0.77
0.56
0.64
0.76
0.65
0.79
0.64
0.87
0.69
, (0.
02, 0
.87)
Br
east
siz
e0.
25—
0.8
0.75
0.76
0.66
0.57
0.76
0.62
0.89
0.66
0.81
0.75
(0.
25, 0
.89)
Ni
pple
form
atio
n0.
190.
14—
—0.
720.
620.
550.
750.
68—
——
0.62
(0.
14, 0
.75)
Sk
in te
xtur
e0.
280.
140.
750.
720.
770.
590.
570.
8—
—0.
650.
770.
69 (
0.14
, 0.8
0)
Geni
talia
0.17
0.02
0.82
0.66
0.65
0.36
0.62
0.63
0.43
0.67
——
0.63
(0.
02, 0
.82)
La
nugo
hai
r0.
2−
0.01
0.81
0.62
0.73
0.55
0.49
0.71
—0.
77—
—0.
62 (
−0.
01, 0
.81)
Ed
ema
0.16
——
0.59
0.64
0.67
0.22
0.41
——
——
0.50
(0.
16, 0
.67)
Sk
in o
paci
ty0.
090.
02—
—0.
720.
220.
350.
70.
48—
——
0.35
(0.
02, 0
.72)
Na
il te
xtur
e—
——
0.57
——
——
——
——
0.57
(0.
57, 0
.57)
Na
il le
ngth
——
—0.
51—
——
——
——
—0.
51 (
0.51
, 0.5
1)
Faci
al
appe
aran
ce—
——
——
——
——
—0.
77—
0.77
(0.
77, 0
.77)
Sk
ull h
ardn
ess
0.15
——
——
——
——
——
—0.
15 (
0.15
, 0.1
5)Ne
urom
uscu
lar
crite
ria
——
——
——
——
——
——
—
Po
stur
e—
0.12
0.82
0.75
0.72
0.31
0.65
0.76
—0.
690.
48—
0.69
(0.
12, 0
.82)
Sq
uare
win
dow
——
0.79
0.21
0.73
0.58
0.64
0.69
—0.
7—
0.69
(0.
21, 0
.79)
Sc
arf s
ign
0.23
0.08
0.82
0.67
0.72
0.51
0.63
0.72
—0.
710.
41—
0.65
(0.
08, 0
.82)
Po
plite
al a
ngle
0.23
0.05
0.74
0.48
0.76
0.39
0.63
0.7
—0.
77—
—0.
63 (
0.05
, 0.7
7)
Arm
rec
oil
0.19
0.07
0.71
0.62
0.65
0.29
0.55
0.56
—0.
610.
36—
0.56
(0.
07, 0
.71)
He
el to
ear
—0.
040.
810.
510.
760.
50.
590.
66—
0.72
——
0.63
(0.
04, 0
.81)
Le
g re
coil
——
—0.
590.
550.
30.
470.
52—
——
—0.
52 (
0.30
, 0.5
9)
Vent
ral
susp
ensi
on—
——
0.59
0.72
0.42
0.7
0.71
——
——
0.70
(0.
42, 0
.72)
He
ad la
g—
——
0.47
0.71
0.36
0.59
0.65
——
——
0.59
(0.
36, 0
.71)
An
kle
dors
iflex
ion
0.21
——
0.37
0.74
0.47
0.59
0.66
——
——
0.53
(0.
21, 0
.74)
No
nnut
ritiv
e su
ckin
g re
flex
0.24
——
——
——
——
——
—0.
24 (
0.24
, 0.2
4)
Cr
osse
d ex
tens
ion
0.16
——
——
——
——
——
—0.
16 (
0.16
, 0.1
6)
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coefficients ranged from 0.52 to 0.70 in the studies using an LMP reference standard GA. Of the 3 studies that used an ultrasound-based reference standard GA, correlation coefficients were again lower in the same 2 studies as they were for physical criteria.21, 40 The signs with the highest median correlation coefficients were ventral suspension, square window, and posture.
Validity of Neonatal Clinical Scores of GA
Studies in which researchers reported on the validity or agreement of neonatal assessments with a reference standard are shown in Table 3 (Dubowitz), Table 4 (Ballard), and Supplemental Table 12 (other assessments).
Dubowitz Score
There were 26 studies in which researchers validated the Dubowitz score (11 ultrasound/BOE; 19 LMP reference). Ten studies were from LMIC. In most studies, the neonatal assessment was performed by physicians or nurses.
Ultrasound or BOE Reference Standard
In 2 studies, researchers reported the correlation of GA dating by Dubowitz score and BOE (r = 0.73 and 0.90, respectively). In 7 studies, researchers reported a mean difference in GA between Dubowitz and ultrasound-based dating, ranging from −2.2 weeks (underestimation) to +0.7 weeks (overestimation). The pooled mean difference was not statistically different from the null hypothesis (ie, difference = 0), indicating no evidence of overall systematic bias (Table 5, Supplemental Fig 7). The precision of the estimate is reflected in the SD of the mean difference, which, at the individual study level, ranged from 0.52 to 1.94 weeks. The pooled SD across the studies was 1.3 weeks, indicating that 95% of the differences in GA (Dubowitz score–ultrasound
dating) fell within ±2.6 weeks (n = 7 studies). In the studies in which researchers reported on the percent agreement within weeks (n = 3), the Dubowitz GA fell within 1 week of ultrasound dates in 53% of infants (pooled estimate, 95% CI: 47% to 71%), and within 2 weeks in 59% of newborns (pooled estimate, 95% CI: 41% to 74%). Researchers in 1 study reported on the diagnostic accuracy of the Dubowitz score to identify preterm infants compared to ultrasound-based dating (sensitivity 61%, specificity 99%).50 Among studies done in LMIC, there was no significant bias compared with ultrasound dating, and the precision of GA dating by the Dubowitz score was similar to HICs (Supplemental Table 11).
In 4 studies, there was evidence of greater bias of Dubowitz scoring among preterm infants (Supplemental Table 12). In 4 studies, researchers reported that the Dubowitz score systematically overestimated GA in preterm infants by up to 2.6 weeks48 – 50 and more so among early preterm infants.46, 48 – 50
LMP Reference Standard
The correlation of GA determined by Dubowitz scoring and LMP GA was reported in 14 studies and was generally high, ranging from 0.41 to 0.94 (median = 0.89). The pooled mean difference was 0.65 weeks (n = 6, 95% CI: 0.01 to 1.30), in dicating a systematic overestimation com-pared with LMP-based GA (Table 5, Supplemental Fig 7). 95% of the differences fell within ±2.9 weeks of the mean. The GA determined by Dubowitz assessment fell within 1 week of LMP dates in 59% of newborns (n = 4, 95% CI: 41% to 74%) and within 2 weeks in 87% (n = 6, 95% CI: 71% to 95%). Researchers in 1 study reported on the diagnostic accuracy of the Dubowitz score to identify preterm infants (sensitivity 81.5%, specificity 98.6%).41 Among LMIC studies (n = 2), there was a
LEE et al8
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
Amie
l-Ti
son
et
al21
Lee
et a
l40Ba
llard
et
al (
New
Ba
llard
)20
Park
in e
t al
16Du
bow
itz
and
Farr
(N
icol
opou
los
et a
l23)
Ragh
u et
al
41Fe
resu
et
al22
Dubo
witz
an
d Fa
rr
(Sun
joh
et
al42
)
Finn
strö
m24
Balla
rd e
t al
19Tu
nçer
et
al26
Nara
yana
n et
al30
Sum
mar
y Ac
ross
Al
l Stu
dies
, M
edia
n (M
inim
um,
Max
imum
)
Visi
on: fi
x an
d tr
ack
0.1
——
——
——
——
——
—0.
10 (
0.10
, 0.1
0)
Ri
ghtin
g re
actio
n0.
07—
——
——
——
——
——
0.07
(0.
07, 0
.07)
Ra
ise
to s
it0.
15—
——
——
——
——
——
0.15
(0.
15, 0
.15)
Ba
ck to
lyin
g0.
03—
——
——
——
——
——
0.03
(0.
03, 0
.03)
Fi
nger
gra
sp a
nd
resp
onse
to
trac
tion
0.11
——
——
——
——
——
—0.
11 (
0.11
, 0.1
1)
NS, n
ot s
tate
d; —
, not
app
licab
le.
TABL
e 2
Cont
inue
d
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
PEDIATRICS Volume 140, number 6, December 2017 9
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
TABL
e 3
Agre
emen
t and
Val
idity
of t
he D
ubow
itz S
core
Auth
orYe
arSt
udy
Sett
ing
and
Loca
tion
GA o
f Coh
ort
Sam
ple
Size
Asse
ssm
ent
Vers
ion
(Tot
al,
Phys
ical
or
Exte
rnal
, Ne
urol
ogic
)
Agre
emen
tVa
lidity
Corr
elat
ion
Coef
ficie
nt
(R)
With
Re
fere
nce
GA
Mea
n Di
ffere
nce
(wk)
SD o
f the
M
ean
Diffe
renc
e (w
k)
Blan
d-Al
tman
95
% L
OA
±1.
96 S
D (L
L, U
L)
(wk)
Perc
ent
With
in 1
w
k
Perc
ent
With
in 2
w
k
Sens
itivi
ty
Pret
erm
<3
7 w
k (%
) (9
5%
CI)
Spec
ifici
ty
Pret
erm
<3
7 w
k (%
) (9
5%
CI)
<37
wk
PPV
<37
wk
NPV
Ultr
asou
nd
HICs
Alla
n et
al29
2009
Tert
iary
Hos
pita
ls;
Nort
hern
Ter
rito
ry,
Aust
ralia
29.6
–41.
7 w
k98
Tota
l—
0.10
1.10
(−2.
3, 2
.0)
——
——
——
Robe
rts
et
al43
1979
Univ
ersi
ty H
ospi
tal;
Card
iff,
Wal
esNS
118
Tota
l—
——
—68
.689
.8—
——
—
Vik
et a
l4419
97Tr
ondh
eim
and
Ber
gen,
No
rway
All G
As97
0To
tal
—−
0.20
1.12
(−2.
3, 2
.1)
——
——
——
Awou
st a
nd
Levi
4519
82Un
iver
sity
Hos
pita
l; Br
usse
ls, B
elgi
umNS
130
Tota
l—
0.50
1.04
——
——
——
—
Sand
ers
et
al46
1991
NICU
; Bal
timor
e, M
D<1
500
g, >
20
wk
110
Tota
l0.
733.
00—
—18
.239
.1—
——
—
War
iyar
et
al47
1997
New
cast
le, U
K32
–42
wk
347
Tota
l—
0.71
1.17
(−1.
57, 3
.0)
——
——
——
<30
wk
105
Tota
l—
2.86
2.48
(−2.
0, 7
.71)
Robi
llard
et
al48
1992
NICU
; Gua
dalu
pe, F
renc
h W
est I
ndie
s<2
500
g38
4To
tal
—0.
641.
94—
61.0
82.0
——
——
Shuk
la
et a
l4919
87Un
iver
sity
hos
pita
ls; N
ew
York
, NY
Pret
erm
<38
w
k, A
GA25
Tota
l0.
90—
——
—48
.0—
——
—
L
MIC
Moo
re
et a
l5020
15Re
fuge
e cl
inic
s; T
hai-
Mya
nmar
bor
der
All G
As25
0To
tal
—2.
57a
1.04
a(0
.49,
4.
65)a
——
6199
——
Rose
nber
g
et a
l5120
09Sp
ecia
l Car
e Nu
rser
y;
Dhak
a, B
angl
ades
h≤
33 w
k35
5To
tal
—0.
560.
52(−
1.57
, 0.
47)
——
——
——
Karu
nase
kera
et
al52
2002
Teac
hing
Hos
pita
l; Ra
gam
a,
Sri L
anka
35–4
2 w
k20
0To
tal
—−
2.18
1.43
——
——
——
—Ex
tern
al—
−0.
452.
39—
——
——
——
LMP
HI
Cs
Ba
llard
et
al19
1979
NICU
and
nur
sery
; Ci
ncin
nati,
OH
NS22
4To
tal
0.85
——
——
——
——
—
Capu
rro
et
al15
1978
Tert
iary
car
e ce
nter
; M
onte
vide
o, U
rugu
ayNS
115
Tota
l0.
91—
——
——
——
——
Mitc
hell53
1979
New
born
nur
sery
, ; Lo
ndon
, En
glan
dNS
20To
tal
0.41
——
——
——
——
—
Nico
lopo
ulos
et
al23
1976
Mat
erni
ty H
ospi
tal a
nd
clin
ics;
Ath
ens,
Gre
ece
28–4
4 w
k71
0To
tal
0.91
——
——
——
——
—Ex
tern
al0.
88—
——
——
——
——
Corr
ecte
d ne
urol
ogic
0.85
——
——
——
——
—
Robe
rts
et
al43
1979
Univ
ersi
ty H
ospi
tal;
Card
iff,
Wal
esNS
118
Tota
l—
——
—67
.879
.6—
——
—
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LEE et al10
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
Auth
orYe
arSt
udy
Sett
ing
and
Loca
tion
GA o
f Coh
ort
Sam
ple
Size
Asse
ssm
ent
Vers
ion
(Tot
al,
Phys
ical
or
Exte
rnal
, Ne
urol
ogic
)
Agre
emen
tVa
lidity
Corr
elat
ion
Coef
ficie
nt
(R)
With
Re
fere
nce
GA
Mea
n Di
ffere
nce
(wk)
SD o
f the
M
ean
Diffe
renc
e (w
k)
Blan
d-Al
tman
95
% L
OA
±1.
96 S
D (L
L, U
L)
(wk)
Perc
ent
With
in 1
w
k
Perc
ent
With
in 2
w
k
Sens
itivi
ty
Pret
erm
<3
7 w
k (%
) (9
5%
CI)
Spec
ifici
ty
Pret
erm
<3
7 w
k (%
) (9
5%
CI)
<37
wk
PPV
<37
wk
NPV
Vogt
et a
l5419
81Te
rtia
ry c
are
cent
er;
Norw
ayAl
l GAs
242
Tota
l—
——
——
90b
——
——
Vik
et a
l4419
97Tr
ondh
eim
and
Ber
gen,
No
rway
All G
As97
0To
tal
—−
0.40
1.43
(−3.
2, 2
.4)
——
——
——
Latis
et a
l5519
81Ne
onat
al u
nit;
Mila
no, I
taly
27–4
2 w
k92
Tota
l—
0.44
1.62
——
80.7
——
——
Dubo
witz
et
al14
1970
New
born
and
Spe
cial
Car
e Nu
rser
ies;
She
ffiel
d,
Engl
and
All G
As16
7To
tal
0.93
——
——
95.0
——
——
Exte
rnal
0.91
——
——
——
——
—Ne
urol
ogic
0.89
——
——
——
——
—
Al
lan
et a
l2920
09Te
rtia
ry H
ospi
tals
; No
rthe
rn T
erri
tory
, Au
stra
lia
29.6
–41.
7 w
k56
Tota
l—
0.30
0.92
(−1.
5, 2
.1)
——
——
——
Hert
z
et a
l5619
78Ge
nera
l Hos
pita
l; Cl
evel
and,
OH
All G
As12
6To
tal
0.86
——
——
——
——
—
Sand
ers
et
al46
1991
NICU
; Bal
timor
e, M
D<1
500
g, >
20
wk
110
Tota
l0.
682.
802.
1—
23.6
46.3
——
——
LM
IC
Fe
resu
et
al22
2002
Mat
erni
ty u
nit;
Hara
re,
Zim
babw
eAl
l GAs
364
Tota
l0.
81—
——
——
——
——
Exte
rnal
0.77
——
——
——
——
—Ne
urol
ogic
0.79
——
——
——
——
—
Su
njoh
et
al42
2004
Tert
iary
Hos
pita
ls;
Yaou
nde,
Cam
eroo
n25
–44
wk
358
Tota
l0.
940.
501.
31—
—93
.0—
——
—
Tunç
er
et a
l2619
81Un
iver
sity
Hos
pita
l; An
kara
, Tu
rkey
27–4
1 w
k12
0To
tal
0.88
——
——
——
——
—
Cevi
t et a
l5719
98Te
rtia
ry c
are
cent
er; S
ivas
, Tu
rkey
28–3
8 w
k;
<250
0 g
91To
tal
0.85
0.30
——
60.4
98.9
——
——
Jaro
szew
icz
and
Boyd
5819
73Te
rtia
r Ho
spita
l; Ca
pe
Tow
n, S
outh
Afr
ica
NS10
0To
tal
0.9
——
——
——
——
—
Daw
odu
et
al59
1977
Mat
erni
ty u
nits
; Iba
dan,
Ni
geri
a29
–43
wk
100
Tota
l0.
900.
381.
41(−
2.39
, 3.
15)
74.0
94.0
81.5
98.6
95.7
93.5
Ragh
u
et a
l4119
81Pr
emat
ure
unit,
Uni
vers
ity
Hosp
ital;
Lusa
ka, Z
ambi
aNS
160
Tota
l0.
90—
——
——
——
——
Exte
rnal
0.82
Neur
olog
ic0.
80
LL, l
ower
lim
it; L
OA, l
imits
of a
gree
men
t; NP
V, n
egat
ive
pred
ictiv
e va
lue;
NS,
not
sta
ted;
PPV
, pos
itive
pre
dict
ive
valu
e; U
L, u
pper
lim
it; —
, ind
icat
es th
at th
e da
ta w
ere
not a
vaila
ble
for
that
pap
er.
a Fo
r a
34-w
k ne
wbo
rn w
ith a
wei
ght-f
or-a
ge z
sco
re o
f 0. T
here
was
evi
denc
e of
a s
igni
fican
t tre
nd a
cros
s GA
; mea
n bi
as d
ecre
ased
by
0.35
wk
per
wee
k in
crea
se in
new
born
GA.
b Pe
rcen
t with
in ±
3 w
k of
LM
P (r
efer
ence
) GA
.
TABL
e 3
Cont
inue
d
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
PEDIATRICS Volume 140, number 6, December 2017 11
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
TABL
e 4
Agre
emen
t and
Val
idity
of t
he B
alla
rd S
core
Stud
yYe
arSt
udy
Sett
ing
and
Loca
tion
GA o
f Co
hort
Sam
ple
Size
Asse
ssm
ent
Vers
ion
(Ori
gina
l or
New
Bal
lard
)
Agre
emen
tVa
lidity
Corr
elat
ion
Coef
ficie
nt
(R)
with
Re
fere
nce
GA
Mea
n Di
ffere
nce
(wk)
SD o
f Mea
n Di
ffere
nce
(wk)
Blan
d-Al
tman
95
% L
OA
±1.
96 S
D (L
L, U
L)
(wk)
Perc
ent
With
in 1
w
k
Perc
ent
With
in 2
w
k
Sens
itivi
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
Spec
ifici
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
<37
wk
PPV
<37
wk
NPV
Ultr
asou
nd
HICs
Sche
r an
d Ba
rmad
a6019
87NI
CU;
Pitt
sbur
gh,
PA
23–3
0 w
k by
LM
Pa24
Orig
inal
Ba
llard
—1.
352.
62(−
3.79
, 6.
49)
56.5
69.6
——
——
Alex
ande
r
et a
l6119
92Un
iver
sity
Ho
spita
l; Ch
arle
ston
, SC
28–4
4 w
k by
Ba
llard
4193
Balla
rd0.
79—
——
——
72.2
97.1
83.2
94.6
Sand
ers
et
al46
1991
NICU
; Ba
ltim
ore,
M
D
<150
0 g;
<3
7 w
k11
0Ba
llard
0.69
2.70
——
22.7
45.4
——
——
Smith
et a
l6219
99Un
iver
sity
Ho
spita
l; Ho
usto
n, T
X
<250
0 g;
85%
pr
eter
m82
Balla
rd0.
861.
401.
15—
—85
——
——
Dom
brow
ski
et a
l6319
92W
omen
's
Hosp
ital;
Detr
oit,
MI
24–4
3 w
k38
318
Balla
rd—
——
——
85.4
——
——
Gagl
iard
i et
al64
1992
NICU
s, te
rtia
ry
hosp
itals
; M
ilano
, Ita
ly
<37
wk;
<2
500
g22
7Ba
llard
—−
0.21
1.76
—20
.540
.4—
——
—
War
iyar
et a
l4719
97Ne
wca
stle
, UK
32–4
2 w
k34
7Ba
llard
—0.
571.
31(−
2.0,
3.1
4)—
——
——
—<3
0 w
k10
5Ba
llard
—3.
431.
97(−
0.43
, 7.
29)
<30
wk
105
New
Bal
lard
—1.
571.
75(−
1.86
, 5.0
)
Ba
llard
et a
l2019
91NI
CUs
and
nurs
erie
s;
Cinc
inna
ti,
OH
All G
As;
20−
44
wk
530
New
Bal
lard
0.97
0.15
1.46
——
——
——
—
Amat
o et
al65
1991
NICU
; Ber
n,
Switz
erla
ndAl
l pre
term
, LB
W38
Balla
rd
(phy
sica
l)—
——
——
——
——
—
L
MIC
Karl
et a
l6620
15He
alth
fa
cilit
ies;
M
adan
g,
Papu
a Ne
w
Guin
ea
25.5
–43.
7 w
k;
900–
4250
g
623
Balla
rd0.
350.
862.
41(−
3.86
, 5.
57)
——
39.0
92.0
21.0
97.0
668
(Ext
erna
l)0.
33—
——
——
58.0
81.0
14.0
97.0
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
LEE et al12
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
Stud
yYe
arSt
udy
Sett
ing
and
Loca
tion
GA o
f Co
hort
Sam
ple
Size
Asse
ssm
ent
Vers
ion
(Ori
gina
l or
New
Bal
lard
)
Agre
emen
tVa
lidity
Corr
elat
ion
Coef
ficie
nt
(R)
with
Re
fere
nce
GA
Mea
n Di
ffere
nce
(wk)
SD o
f Mea
n Di
ffere
nce
(wk)
Blan
d-Al
tman
95
% L
OA
±1.
96 S
D (L
L, U
L)
(wk)
Perc
ent
With
in 1
w
k
Perc
ent
With
in 2
w
k
Sens
itivi
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
Spec
ifici
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
<37
wk
PPV
<37
wk
NPV
668
(Neu
rolo
gic)
0.39
——
(−3.
57,
6.57
)—
—23
.093
.014
.096
.0
Rose
nber
g
et a
l5120
09Sp
ecia
l Car
e Nu
rser
y;
Dhak
a,
Bang
lade
sh
Pret
erm
, al
l <33
w
k
355
Balla
rd—
−0.
411.
08(−
0.7,
1.5
1)—
——
——
—
Lee
et a
l4020
16Co
mm
unity
; Sy
lhet
, Ba
ngla
desh
33–4
5 w
k71
0Ba
llard
0.12
−0.
402.
22(−
4.7,
4.0
)32
.064
15.0
87.0
9.0
92.0
Mor
aes
and
Reic
henh
eim
67
(tra
nsla
ted)
2000
Mat
erni
ty
unit;
Rio
de
Jan
eiro
, Br
azil
NS11
6Ne
w B
alla
rd—
——
——
—57
.0 (
41.0
to
73.
0)97
.0 (
90.0
to
99.
0)—
—
Sree
kum
ar
et a
l6820
13NI
CU a
nd
post
nata
l w
ards
; Be
ngal
uru,
In
dia
24–4
1.2
wk
284
New
Bal
lard
—−
0.04
——
——
——
——
Wyl
ie e
t al69
2013
Ndir
ande
Cl
inic
; Bl
anty
re,
Mal
awi
All G
As17
7Ne
w B
alla
rd—
0.80
2.19
(−3.
5, 5
.1)
——
——
——
Tayl
or e
t al70
2010
Com
mun
ity;
Kene
ba,
The
Gam
bia
All G
As80
Balla
rd
(ext
erna
l)—
−2.
231.
56(−
5.3,
0.8
2)—
——
——
—
Thi e
t al71
2015
Gene
ral
Hosp
ital;
Hoa
Binh
, Vi
etna
m
30–4
2 w
k by
ul
tras
ound
391
New
Bal
lard
0.90
——
——
——
——
—
LMP
HI
Cs
Ba
uman
n et
al72
(t
rans
late
d)19
93Un
iver
sity
Ho
spita
l; Be
rn,
Switz
erla
nd
27–3
5 w
k AG
A60
Balla
rd (
tota
l)0.
91—
——
——
——
——
28–3
6 w
k SG
A29
0.66
——
——
——
——
—
27–3
5 w
k AG
A60
Balla
rd
(ext
erna
l)0.
83—
——
——
——
——
TABL
e 4
Cont
inue
d
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
PEDIATRICS Volume 140, number 6, December 2017 13
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
Stud
yYe
arSt
udy
Sett
ing
and
Loca
tion
GA o
f Co
hort
Sam
ple
Size
Asse
ssm
ent
Vers
ion
(Ori
gina
l or
New
Bal
lard
)
Agre
emen
tVa
lidity
Corr
elat
ion
Coef
ficie
nt
(R)
with
Re
fere
nce
GA
Mea
n Di
ffere
nce
(wk)
SD o
f Mea
n Di
ffere
nce
(wk)
Blan
d-Al
tman
95
% L
OA
±1.
96 S
D (L
L, U
L)
(wk)
Perc
ent
With
in 1
w
k
Perc
ent
With
in 2
w
k
Sens
itivi
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
Spec
ifici
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
<37
wk
PPV
<37
wk
NPV
28–3
6 w
k SG
A29
0.66
——
——
——
——
—
27–3
5 w
k AG
A60
Balla
rd
(Neu
rolo
gic)
0.65
——
——
——
——
—
28–3
6 w
k SG
A29
0.66
——
——
——
——
—
Cons
tant
ine
et
al73
1987
AK, N
Y, M
A,
FL, P
A, T
X,
WA,
CN
All G
As12
46Ba
llard
0.81
0.60
2.18
——
—85
8189
75
(Phy
sica
l)0.
83−
0.1
2.14
——
—92
7487
87(N
euro
logi
c)0.
711.
42.
72—
——
7084
8960
Sche
r an
d Ba
rmad
a6019
87NI
CU; P
ittsb
urgh
, PA
23–3
0 w
k by
LM
P24
Balla
rd—
1.42
2.32
(−3.
13,
5.96
)45
.862
.5—
——
—
Mac
kanj
ee
et a
l7419
96NI
CU; L
ondo
n,
Onta
rio,
Ca
nada
23–3
3 w
k;
<150
0 g
47Ba
llard
0.87
1.50
1.50
——
——
——
—
Dom
brow
ski
et a
l6319
92W
omen
's
Hosp
ital;
Detr
oit,
MI
24–4
6 w
k38
818
Balla
rd—
——
——
69.9
——
——
Alex
ande
r
et a
l7519
90Un
iver
ity
Hosp
ital;
Char
lest
on,
SC
20–4
5 w
k10
794
Balla
rd0.
760.
48—
—52
.780
.3—
——
—
Balla
rd e
t al19
1979
NICU
and
nu
rser
y;
Cinc
inna
ti OH
26–4
4 w
k,
760–
5460
g
224
Balla
rd0.
85—
——
——
——
——
Alex
ande
r
et a
l7619
92Un
iver
sity
Ho
spita
l; Ch
arle
ston
, SC
28–4
4 w
k;
all A
fric
an
Amer
ican
po
pula
tion
3480
Balla
rd0.
820.
53—
——
68.2
——
——
28–4
4 w
k;
all w
hite
po
pula
tion
2091
Balla
rd0.
860.
17—
——
70.6
——
——
Balla
rd e
t al20
1991
NICU
s an
d nu
rser
ies;
Ci
ncin
nati,
OH
20–4
4 w
k57
8Ne
w B
alla
rd0.
96—
——
—88
.0—
——
—
TABL
e 4
Cont
inue
d
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
LEE et al14
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
ROUGH GALLEY PROOFOctober 2017
140
Stud
yYe
arSt
udy
Sett
ing
and
Loca
tion
GA o
f Co
hort
Sam
ple
Size
Asse
ssm
ent
Vers
ion
(Ori
gina
l or
New
Bal
lard
)
Agre
emen
tVa
lidity
Corr
elat
ion
Coef
ficie
nt
(R)
with
Re
fere
nce
GA
Mea
n Di
ffere
nce
(wk)
SD o
f Mea
n Di
ffere
nce
(wk)
Blan
d-Al
tman
95
% L
OA
±1.
96 S
D (L
L, U
L)
(wk)
Perc
ent
With
in 1
w
k
Perc
ent
With
in 2
w
k
Sens
itivi
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
Spec
ifici
ty
Pret
erm
<3
7 w
k (%
) (9
5% C
I)
<37
wk
PPV
<37
wk
NPV
Ahn77
2008
Neon
atal
uni
ts,
univ
ersi
ty
hosp
ital;
Inch
eon,
So
uth
Kore
a
All G
A,
773–
4870
g
213
New
Bal
lard
b0.
850.
46c
——
——
——
——
Sand
ers
et
al46
1991
NICU
; Bal
timor
e,
MD
<150
0 g;
<3
7 w
k11
0Ba
llard
0.66
2.60
2.2
—28
.251
.0—
——
—
LM
IC
Ce
vit e
t al57
1998
Tert
iary
car
e ce
nter
; Siv
as,
Turk
ey
Pret
erm
28
–38
wk;
<2
500
g
91Ba
llard
—0.
10—
—59
.398
.9—
——
—
Fere
su e
t al22
2002
Mat
erni
ty u
nit;
Hara
re,
Zim
babw
e
24–4
5 w
k36
4Ba
llard
0.80
——
——
——
——
—
(Phy
sica
l)d
0.75
——
——
——
——
—(N
euro
logi
c)d
0.74
——
——
——
——
—
Su
njoh
et a
l4220
04Te
rtia
ry H
ospi
tals
; Ya
ound
e,
Cam
eroo
n
25–4
4 w
k35
8Ne
w B
alla
rd0.
930.
341.
52—
—86
.0—
——
—
Bind
usha
et
al33
2014
Tert
iary
hos
pita
l; Ke
rela
, Ind
ia28
–37
wk
1000
New
Bal
lard
0.92
0.31
——
——
<36
wk:
85
.6<3
6 w
k:
94.6
<36
wk:
98
.0<3
6 w
k:
53.6
Sasi
dhar
an
et a
l7820
09NI
CU; N
orth
ern
Indi
a29
–35
wk
129
New
Bal
lard
——
——
—10
0.0
——
——
Mor
aes
and
Reic
henh
eim
67
(tra
nsla
ted)
2000
Mat
erni
ty
unit;
Rio
de
Jane
iro,
Bra
zil
NS14
0Ne
w B
alla
rd—
——
——
—68
.0 (
49.0
to
82.
0)92
.0 (
85.0
to
96.
0)—
—
Thi e
t al71
2015
Gene
ral H
ospi
tal;
Hoa
Binh
, Vi
etna
m
30–4
3 w
k by
LM
P28
2Ne
w B
alla
rd0.
81—
——
——
——
——
Tayl
or e
t al70
2010
Com
mun
ity;
Kene
ba, T
he
Gam
bia
All G
As76
Balla
rd
(ext
erna
l)—
−2.
23.
3(−
8.67
, 4.
27)
——
——
——
Verh
oeff
et
al79
1997
Tert
iary
Hos
pita
ls;
Chik
waw
a Di
stri
ct, M
alaw
i
All G
As;
liter
ate
mot
hers
76Ba
llard
(e
xter
nal)
—0.
87—
——
——
——
—
LL, l
ower
lim
it; L
OA, l
imits
of a
gree
men
t; NP
V, n
egat
ive
pred
ictiv
e va
lue;
NS,
not
sta
ted;
PPV
, pos
itive
pre
dict
ive
valu
e; U
L, u
pper
lim
it; —
, ind
icat
es th
at th
e da
ta w
ere
not a
vaila
ble
for
that
pap
er.
a Al
l inf
ants
in th
is s
tudy
die
d; a
ll de
aths
occ
urre
d af
ter
the
asse
ssm
ents
.b
This
stu
dy u
sed
an “
Exte
nded
New
Bal
lard
” sc
orin
g sy
stem
to e
stim
ate
GA (
sim
ply
the
stan
dard
New
Bal
lard
sco
re e
xten
ded
to b
e us
ed to
est
imat
e a
grea
ter
GA r
ange
, whi
ch w
as c
alcu
late
d m
athe
mat
ical
ly).
c For
infa
nts
<39
wk
GA. M
ean
diffe
renc
e =
−0.
58 w
k fo
r in
fant
s >3
9 w
k GA
.d
This
stu
dy u
sed
a “r
evis
ed”
vers
ion
of th
e ph
ysic
al a
nd n
euro
logi
c po
rtio
ns o
f the
Bal
lard
ass
essm
ent.
TABL
e 4
Cont
inue
d
by guest on March 30, 2019www.aappublications.org/newsDownloaded from
tendency of the Dubowitz score to overestimate GA (0.48 weeks), although the precision of the GA estimates was similar to HIC studies (Supplemental Table 11).
In 2 studies, researchers showed evidence that Dubowitz scoring tended to overestimate GA in early preterm infants (Supplemental Table 12).42, 54
Ballard and New Ballard Score
We identified 30 studies in which researchers assessed the validity of the Original Ballard score (n = 20), the New Ballard score (n = 9), or both (n = 1) (Table 4) (17 ultrasound/BOE, 20 LMP reference), with 14 from LMIC. The Original and New Ballard scores assess the same clinical signs, with the New Ballard score20 having additional scoring categories for early preterm infants. Studies in which researchers used the Ballard score (Original or New) were combined for this analysis. Ballard assessments were performed by medically trained health workers (physicians, nurses, or research assistants) in the majority of studies and by community health workers in 2 studies.
Ultrasound or BOE Reference Standard
The correlation coefficients comparing Ballard score GA versus ultrasound or BOE ranged from 0.12 to 0.97 (median = 0.85, n = 7 studies). The mean GA difference ranged from −0.41 weeks (underestimation) to +1.4 weeks (overestimation) in 9 studies. The pooled mean difference was 0.40 weeks (95% CI: 0.00 to 0.81) (Table 5, Supplemental Fig 8), indicating a trend towards overestimation of GA. The pooled SD across the studies was 1.9 weeks, indicating that 95% of the differences in GA by Ballard assessment versus ultrasound dates fell within ±3.8 weeks (n = 9 studies, Table 5) of the mean. For the studies in which researchers reported on agreement in weeks, Ballard score dates fell
PEDIATRICS Volume 140, number 6, December 2017 15
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2017https://doi.org/10.1542/peds.2017-1423
4Pediatrics
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140
TABL
e 5
Pool
ed D
ata
for
Agre
emen
t and
Val
idity
of N
eona
tal C
linic
al A
sses
smen
ts
Asse
ssm
ent
Type
No. o
f St
udie
s Id
entifi
ed
Refe
renc
e St
anda
rdAg
reem
ent
Valid
ity
Mea
n Di
ffere
nce
Perc
ent W
ithin
1 w
kPe
rcen
t With
in
2 w
kSe
nsiti
vity
Spec
ifici
ty
N Po
oled
Diff
eren
ce (
95%
CIs
)Po
oled
SD
N Po
oled
% (
95%
CI
s)N
Pool
ed %
(9
5% C
Is)
N Po
oled
Sen
sitiv
ity
(%)
(95%
CIs
)Po
oled
Spe
cific
ity
(%)
(95%
CIs
)
Dubo
witz
9Ul
tras
ound
or
BOE
70.
02 (
−0.
51–
0.55
)1.
273
53.4
(46
.6–
71.3
)3
74.8
(44
.7–
91.6
)1
6199
20LM
P6
0.65
(0.
01–1
.30)
1.45
458
.5 (
40.9
–74
.2)
687
.0 (
71.2
–94
.8)
181
.598
.6
Balla
rd14
Ultr
asou
nd o
r BO
E9
0.40
(0.
00–0
.81)
1.90
334
.0 (
21.8
–44
.6)
572
.2 (
53.8
–85
.3)
464
.1 (
60.8
to 6
7.4)
95.1
(94
.5 to
95.
7)
18LM
P5
1.25
(0.
64–1
.87)
2.10
344
.6 (
24.9
–66
.2)
975
.8 (
70.6
–80
.5)
284
.1 (
81.6
to 8
6.3)
83.5
(79
.5 to
87.
0)
Park
in3
Ultr
asou
nd o
r BO
E3
−0.
17 (
−0.
26–
−0.
08)
1.97
0—
0—
——
—Er
egie
2LM
P1
——
0—
293
.4 (
91.3
–95
.1)
——
—
Capu
rro
4Ul
tras
ound
or
BOE
20.
11 (
−0.
02–
0.23
)1.
962
40.1
(34
.7–
45.8
)3
79.2
(65
.3–
88.6
)3
42.7
(35
.6 to
50.
0)96
.7 (
95.7
to 9
7.5)
—, n
ot a
pplic
able
.
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within 1 week of ultrasound dates in 34% (n = 3; 95% CI: 22% to 44%) of infants and within 2 weeks in 72% (n = 5, 95% CI: 54% to 85%) of newborns. The Ballard score had a pooled sensitivity (n = 4) of 64% (95% CI: 61% to 67%) and specificity of 95% (95% CI: 95% to 96%) for identifying preterm newborns. Among LMIC studies, the trend of GA overestimation was similar to HIC studies. However, the imprecision of GA estimation was greater in LMIC compared with HIC studies (pooled SD of 2.12 vs 1.49 weeks) (Supplemental Table 11).
In several studies, researchers reported evidence of greater bias in Ballard scoring among smaller babies (Supplemental Table 12). In 3 studies, researchers reported that the Original Ballard systematically overestimated GA by up to 2 to 3 weeks, in particular among preterm infants, 46, 47, 61 and generally, the trend was toward increasing bias in lower GAs. However, in a study in Papua New Guinea, Karl et al66 found the opposite trend. Wariyar et al47 reported that the New Ballard overestimated GA to a lesser degree than the Original Ballard in infants <30 weeks (1.6 vs 3.4 weeks, respectively). Among SGA infants, researchers in 2 studies showed that GA was underestimated by the original Ballard.40, 61
LMP Reference Standard
The correlation coefficients of Ballard and LMP GA ranged from 0.66 to 0.96 (median = 0.85; n = 13). The mean difference in GA was reported in 6 studies, ranging from 0.34 to 2.6 weeks (overestimation). The pooled mean difference was 0.70 weeks (95% CI: 0.36 to 1.04), indicating systematic overestimation (Table 5, Supplemental Fig 8). Ninety five percent of mean differences fell within ±4.2 weeks (n = 5 studies) of the mean. Ballard GA fell within 1 week of LMP GA in 45% (n = 3, 95% CI: 25% to 66%) of newborns and
within 2 weeks of LMP in 76% (n = 9, 95% CI: 71% to 81%) of newborns. The Ballard score had a pooled sensitivity (n = 2) of 84.1% (95% CI: 81.6% to 86.3%) and specificity of 83.5% (95% CI: 79.5% to 87.0%) for identifying preterm newborns (Fig 2). There were an inadequate number of studies to stratify analysis by LMIC versus HICs.
In 2 studies, researchers demonstrated overestimation of GA among preterm infants by the Original Ballard exam, 73, 79 but researchers in 1 study used the External Ballard only (Supplemental Table 12).79 In addition, researchers in 2 studies found that the Original Ballard performed differently among SGA infants: Baumann et al72 reported that the correlation of Ballard with GA was lower among SGA infants compared with those appropriate for gestational age. Constantine et al73 showed that for SGA babies, the bias for GA dating was 1 to 1.5 weeks lower than for non-SGA infants.
Other Clinical Assessments
Eighteen studies were identified in which researchers reported on the validity of other clinical methods of GA assessment (ie, Eregie et al, 40, 42, 80 Capurro et al, 15, 40, 81 – 84 Parkin et al, 16, 40, 47, 52, 54, 68 Bhagwat et al, 18, 33, 40 Tunçer et al, 26, 57 Finnström, 24 Narayanan et al, 30 and Robinson32, 47). These findings are reported in Supplemental Information 3 and Supplemental Table 13. In general, the majority of these exams were simplified assessments with fewer signs and were found to be less accurate than the Dubowitz or Ballard scores for GA dating (Supplemental Information 3; Supplemental Table 13; Table 5).
Interrater Agreement
In 10 studies, researchers reported upon the interrater agreement of GA estimates (Supplemental Table 14).
The κ for the classification of preterm births ranged from 0.73 to 0.93 (good to excellent; n = 3).20, 67, 85 The GA estimates were also highly correlated (r = 0.71–0.95)20, 86 and without significant differences between raters.49, 62, 64, 78
Anterior Vascularity of Lens
The literature searches for examination of the anterior vascular capsule of the lens (AVCL) yielded a total of 344 unique manuscripts (Fig 3), of which 10 met inclusion criteria (Table 6). Three were from LMIC (2 from South Asia, 1 from Africa). The studies were generally of smaller sample size (N = 30–356), and the latest was published in 1993. In general, study quality was poor, with a high risk of bias related to patient selection and reference standard. The overall QUADAS–2 assessment is in Supplemental Fig 9.
Assessments were typically performed at <72 hours of life by physicians in tertiary health facilities, with most studies performed in NICU settings and including only preterm and/or LBW infants. An ultrasound/BOE-based date was available in only 2 studies. Pupil dilation was performed before the assessment in 3 studies.
Correlation of AVCL Grading With GA
Hittner et al87, 89 reported that as the infant matures in gestation, the AVCL disappears in stages. In Grade 4 (27–28 weeks), the entire anterior surface of the lens is vascularized, reducing to no vasculature in Grade 0 (>34 weeks). Of note, the reference standard in the original Hittner study87 was the Dubowitz score.
In 2 studies, researchers presented data on the average GA determined by Hittner’s AVCL grading system (Table 6).46, 91 The correlation of AVCL grade with GA ranged from −0.84 to −0.96 (median: −0.88, n = 7) for preterm and/or LBW populations For the 2 studies in
LEE et al16
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
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which researchers analyzed all GA populations, correlation was lower (−0.64 to −0.45).24, 30 Among SGA preterm newborns, the median correlation coefficient was −0.77 (range: −0.68 to −0.91, n = 3).72, 87, 89
other signs
The results of searches for intermammillary distance, skin impedance, and palmar creases are in Supplemental Information 4.
dIsCussIoN
Accurate GA determination is a public health priority to target and reduce preterm birth–related morbidity and mortality in LMIC. The Every Newborn Action Plan has prioritized GA measurement as a high-priority area to improve the epidemiology of preterm birth and SGA.34 In our systematic literature review, we identified 18 different newborn assessments that have been used for GA dating. The most commonly reported and validated scores in the literature were the Dubowitz and Ballard scores. The Dubowitz score dated 95% of newborns within ±2.6 weeks of ultrasound dating. The Ballard score tended to overestimate GA by 0.4 weeks compared with
ultrasound and dated 95% of infants within ±3.8 weeks of this mean. Newborn clinical assessments tend to overestimate GA among preterm infants and therefore may misclassify preterm infants as term. They also tended to underestimate GA in growth-restricted babies. Simplified assessments were less accurate. Although researchers in several studies showed promise of the anterior vascularity of the lens to classify GA <34 weeks, few compared AVCL with an ultrasound-based reference standard.
Study quality was a major limitation of the studies identified in the review, with half of studies having high risk of bias. Many of the original validation studies were from the 1970s, when LMP was the gold standard for pregnancy dating and ultrasound was not widely available. Many hospital-based studies were performed in NICUs among LBW babies and thus were prone to selection and measurement biases (eg, lack of blinding). Fewer than half of the studies were in LMIC, and studies in HICs may not be generalizable to LMIC settings because of health worker availability and training, and differences in the prevalence of SGA and preterm birth.
The majority of individual physical and neurologic signs that have been used in different scoring systems had fair to moderate correlation with GA. Skin opacity was the most weakly correlated and is perhaps the most affected by the timing of the assessment after birth. Although neurologic signs may be more affected by neonatal morbidity (birth asphyxia, neonatal infection, maternal medications, etc), the correlation coefficients of most signs were in a similar range to the physical criteria. In 2 studies21, 40 in which researchers excluded early to moderate preterm infants, the correlation of clinical signs with GA was lower, suggesting that the criteria may be more discriminating at lower GAs.
A critical consideration in LMIC is the validity of neonatal assessments in populations with high rates of SGA. Distinguishing whether a small baby is preterm, SGA, or both is a challenge in these settings. Most neonatal assessments were designed to measure infant maturity as opposed to gestational length. SGA infants may act less mature during a neonatal clinical assessment. Three studies have revealed that among SGA infants, neonatal clinical exams
PEDIATRICS Volume 140, number 6, December 2017 17
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
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FIGuRe 2Forest plots of the Ballard score sensitivity and specificity for identifying preterm births compared with ultrasound (A, B) and LMP (C, D).
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tend to systematically underestimate GA.40, 61, 73 Improving the validity of the neonatal assessment in growth-restricted populations is a critical research need in LMIC.30, 87, 92
The disappearance of the AVCL, or pupillary membrane, was found to correlate well with GA, although overall study quality was poor, with few studies with ultrasound-based references. AVCL may show promise in LMIC with high rates of fetal growth restriction because the grading correlated relatively well with GA, even among
growth-restricted or SGA infants.87 An important consideration is that the AVCL completely disappears after ∼34 weeks’ GA; thus, it may not help with GA dating >34 weeks. Furthermore, the AVCL exam requires specialized skills with an opthalmoscope, which may limit the feasibility and scalability in LMIC.
Several factors should be considered in interpreting and generalizing the validity of neonatal GA assessments in different settings. Imprecision of the Ballard score was greater in LMIC studies compared with HIC studies
(HICs: ±3.0 weeks; LMIC: ±4.2 weeks). The validity of a clinical assessment may vary with the level of medical training of the assessor.40, 70 Most of the LMIC studies used physicians, nurses, or midwives, and there were few studies with frontline health workers. The validity of the newborn assessment has primarily been studied in the facility and/or hospital-based setting, and the few studies in home-based settings had poorer performance.40, 70 Certain factors may improve the validity in the hospital setting, including the timing of assessment sooner after birth, being in a more controlled environment, and lighting. The development of some characteristics may vary by ethnicity. For example, plantar creases progress differently in African American populations93 and skin color may vary. Morbidities, such as gestational diabetes, are more common in specific populations94 and may affect the maturity assessment. Finally, the performance may also be affected by the GA ranges in which it is tested. The performance and validity of the assessments may vary in a general population with a larger representation of late preterm and near-term infants compared with a NICU.
Feasibility and scalability are critical factors to consider in LMIC. As shown in this review, there is a positive correlation between the number of parameters and accuracy of a GA assessment. Yet there is likely to be a negative correlation between the number of parameters (especially neurologic) and the feasibility of use. While the Dubowitz score had the best accuracy, the assessment is complex, may take 15 to 20 minutes to complete, and includes more difficult-to-train neurologic criteria. In South Asia and sub-Saharan Africa, approximately half of births occur outside of hospital facilities, and community-based health workers or traditional birth attendants may be the first point of contact for
LEE et al18
Lee et alDiagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review
2017https://doi.org/10.1542/peds.2017-1423
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140
FIGuRe 3AVCL: flow diagram. Diagram of the screening process to identify studies for inclusion in AVCL review; adapted from the PRISMA (Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009 Jul 21;6(7):e1000097).
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PEDIATRICS Volume 140, number 6, December 2017 19
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TABL
e 6
Corr
elat
ion
of A
VCL
With
GA
Auth
orYe
arSt
udy
Sett
ing
and
Loca
tion
Popu
latio
nSa
mpl
e Si
ze (
N)Re
fere
nce
Stan
dard
Tim
e of
As
sess
men
t Aft
er
Birt
h
Corr
elat
ion
Coef
ficie
nt (
R) it
h Re
fere
nce
GA
GA
A) R
ange
or
B) M
ean
(SD)
(n)
Grad
e 0a
Grad
e 1
Grad
e 2
Grad
e 3
Grad
e 4
Finn
strö
m24
1972
Univ
ersi
ty H
ospi
tal;
Umea
, Sw
eden
All G
As17
4LM
PFr
om b
irth
up
to
60 h
0.45
b—
——
——
Hitt
ner
et a
l8719
77Te
rtia
ry H
ospi
tal;
Hous
ton,
TX
Pret
erm
(27
–34
wk)
100
LMP
and
Dubo
witz
With
in 3
0 h
−0.
88—
——
——
Subp
opul
atio
n:
pret
erm
SGA
12LM
P an
d Du
bow
itzW
ithin
30
h−
0.91
——
——
—
Guill
ory
et a
l8819
80Te
rtia
ry H
ospi
tal;
Hous
ton,
TX
Pret
erm
43LM
P an
d Du
bow
itz“S
oon
afte
r bi
rth”
−0.
88—
——
——
24 h
aft
er b
irth
−0.
86—
——
——
Hitt
ner
et a
l8919
81Te
rtia
ry H
ospi
tal;
Hous
ton,
TX
“Pre
term
SGA
”33
Dubo
witz
With
in 2
4 h
−0.
77—
A) >
33 w
k (n
=
24c )
A) 3
1–34
w
k (n
=
7)
A) 3
3 w
k (n
=
1)A)
28
wk;
(n
= 1)
Kris
hnam
ohan
et
al90
1982
NICU
s; F
arm
ingt
on
and
Hart
ford
, CT
Pret
erm
(28
–32
wk)
30Ba
llard
, with
in
2 w
k of
LM
PW
ithin
24
h−
0.94
——
——
—
Nara
yana
n et
al30
1982
Child
ren’
s Ho
spita
l; Ne
w D
elhi
, Ind
iaAl
l new
born
s; a
ll GA
s35
6LM
P, o
r OB
es
timat
e if
avai
labl
e
With
in 4
8 h
−0.
64—
——
——
Subp
opul
atio
n:
<35
wk
GA18
4Sa
me
as a
bove
With
in 4
8 h
−0.
96—
——
——
Sasi
vim
olku
l et
al91
1986
Univ
ersi
ty H
ospi
tal;
Bang
kok,
Th
aila
nd
LBW
80Ba
llard
and
LM
P24
–48
h−
0.83
9B)
36.
3 (1
.86)
(n
= 43
)
B) 3
4.0
(2.1
) (n
=
13)
B) 3
2.4
(1.4
) (n
=
12)
B) 2
9.9
(0.4
); (n
=
7)
B) 2
7.8
(0.8
) (n
= 5
)
Subp
opul
atio
n:
LBW
≥34
wk
40Ba
llard
and
LM
P24
–48
h−
0.88
——
——
—
Skap
inke
r an
d Ro
thbe
rg92
1987
Univ
ersi
ty H
ospi
tal;
Joha
nnes
burg
, So
uth
Afri
ca
Pret
erm
(<3
5 w
k)58
Balla
rdW
ithin
36
h−
0.84
——
——
—
Sand
ers
et a
l4619
91NI
CU; B
altim
ore,
MD
Pret
erm
and
bir
th
wei
ght <
1500
g89
BOE (u
ltras
ound
w
as
avai
labl
e fo
r 92
% o
f w
omen
)
With
in 7
2 h
—B)
32.
4B)
30.
4B)
29.
8B)
28.
7B)
26.
7
Baum
ann
et a
l72
(tra
nsla
ted)
1993
Univ
ersi
ty
Hosp
ital;
Bern
, Sw
itzer
land
<34
wk
AGA
60Ul
tras
ound
NS−
0.92
± 0
.04
(CI:
0.81
– 0.
97)
——
——
—
<34
wk
SGA
29Ul
tras
ound
NS−
0.68
± 0
.09
(CI:
0.49
–0.8
2)—
——
——
OB, o
bste
tric
; NS,
not
sta
ted;
—, i
ndic
ates
that
the
data
wer
e no
t ava
ilabl
e fo
r th
at p
aper
.a
The
AVCL
gra
ding
sys
tem
is a
s de
scri
bed
in H
ittne
r et
al.87
b Fin
nstr
öm24
use
d th
e Ha
rnac
k an
d Os
ter
(195
8) g
radi
ng s
yste
m, a
cla
ssifi
catio
n sy
stem
with
gra
des
1–3,
in w
hich
1 e
qual
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newborns. These health workers may not have the medical training or the time required to perform the assessment. The duration of the assessment as well as the feasibility of training, standardization, and quality control are critical considerations for scalability in LMIC.
Finally, when evaluating methods of GA assessment, the clinical, research, and programmatic objectives should be weighed. For the clinician, the primary objective is to identify preterm infants requiring special care, and individual-level misclassification may result in missed intervention opportunities. A measurement tool with high sensitivity is desired to identify all preterm infants, perhaps at the expense of specificity. A very simple tool based on a single parameter (such as foot size or another anthropometric parameter) may be suitable to meet these needs. On the other hand, for research, a more precise and continuous measurement of GA is desirable and early pregnancy ultrasound should be used. At the population level, inaccuracy and imprecision in GA dating may result in biased estimates of preterm birth rates and epidemiologic associations with preterm birth.95 Determining the optimal precision (ie, a 95% CI of ±1 or 2 vs 3 weeks) and diagnostic accuracy is also critical to choosing an appropriate method of GA measurement for LMIC. Future research priorities for improving GA determination in LMIC are shown in Fig 4.
CoNCLusIoNs
As part of the Metrics Group of the Every Newborn Action Plan, we have conducted the first systematic review and meta-analysis assessing the diagnostic accuracy of neonatal GA assessments and scores. The most commonly used
assessment, the Ballard score, tended to overestimate GA and had wide margins of error. The Dubowitz score had improved accuracy, although feasibility is a critical consideration in LMIC, and the complexity, training, and time to conduct the assessment are challenges to scale up. Additional high-quality studies are needed in LMIC to determine the accuracy of neonatal assessment compared with an early ultrasound reference, particularly in settings with SGA, as well as to explore the feasibility of implementation of complex GA assessments. This work also underlines the importance of future focus on increasing the maternal demand for knowledge of the GA of their pregnancy, improving coverage of early pregnancy ultrasound scans, and innovations to improve GA assessment in late pregnancy, such as novel ultrasound approaches. In settings where early ultrasound is not possible, increased efforts and innovation are urgently needed to develop simpler yet specific approaches for clinical GA assessment of the newborn, either through new combinations of existing parameters, new signs, or technology.
ACkNowLedGMeNTs
We acknowledge the students who were also part of the GA working group in the Brigham and Women’s Hospital global newborn health laboratory (Chelsea Clark). We also thank the Brigham and Women’s Hospital Department of Newborn Medicine and Dr Terrie Inder for their support of this work. Finally, we thank the following individuals for their assistance in translating foreign articles: Madeline Gilbert, Alison Leschen, Maria Dąbrowska, Susan Throckmorton, Felix Bergmann, and Lina Driouk.
ABBReVIATIoNs
AVCL: anterior vascular capsule of the lens
BOE: best obstetric estimateCI: confidence intervalGA: gestational ageHIC: high-income countryLBW: low birth weightLMIC: low- and middle-income
countriesLMP: last menstrual periodQUADAS–2: Quality Assessment
of Diagnostic Accuracy Studies–2
SGA: small for gestational age
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FIGuRe 4Research priorities to improve GA dating in LMIC.
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Partners International, Yangon, Myanmar; and hFaculty of Epidemiology and Population Health and iThe Centre for Maternal, Adolescent, Reproductive, and Child Health (MARCH), London School of Hygiene and Tropical Medicine, London, United Kingdom
Dr Lee conceptualized and designed the study, coordinated and supervised data collection, completed secondary data extraction, and drafted, reviewed, revised, and finalized the manuscript; Dr Panchal designed the database searches, carried out initial screening and data extraction for postnatal clinical exams, conducted meta-analyses, and reviewed and revised the manuscript; Ms Folger screened and extracted data for anterior vascularity of the lens, helped write sections of the manuscript, and formatted, reviewed, and revised the manuscript; Dr Whelan undertook initial screening and data extraction for postnatal clinical exams and reviewed the manuscript; Ms Whelan coordinated and supervised data collection and data extraction, reviewed the extracted data, and reviewed and revised the manuscript; Dr Rosner advised the statistical analysis of the data extracted, provided feedback on analyses, and reviewed and revised the manuscript; Drs Blencowe and Lawn helped synthesize the data and data analysis and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.
This systematic review was registered with the International Prospective Register of Systematic Reviews. PROSPERO registration number: CRD42015020499.
doI: https:// doi. org/ 10. 1542/ peds. 2017- 1423
Accepted for publication Jul 25, 2017
Address correspondence to Anne CC Lee, MD, MPH, Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, BB502A, 75 Francis St, Boston, MA 02115. E-mail: alee6@bwh.harvard.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2017 by the American Academy of Pediatrics
FINANCIAL dIsCLosuRe: The authors have indicated they have no financial relationships relevant to this article to disclose.
FuNdING: This work was supported by the Bill & Melinda Gates Foundation through grant OPP1130198.
PoTeNTIAL CoNFLICT oF INTeResT: The authors have indicated they have no potential conflicts of interest to disclose.
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