Ul asound Obs e Gynecol 2017; : 373–38250
Published online in Wiley Online Lib a y (wileyonlinelib a y.com). 10.1002/uog.17373. This is an open access a icle unde he e msDOI:
o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s License, which pe mi s use and dis ibu ion in any medium, p o ided he
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sFl -1/PlGF o p edic ion o ea ly-onse p e-eclampsia:
STEPS (S udy o Ea ly P e-eclampsia in Spain)
A. PERALES1, J. L. DELGADO2, M. DE LA CALLE3, J. A. GARC´
IA-HERN ´
ANDEZ4,
A. I. ESCUDERO5, J. M. CAMPILLOS6, M. D. SARABIA2, B. LA´
IZ1, M. DUQUE3, M. NAVARRO4,
P. CALMARZA6, M. HUND7and F. V. ´
ALVAREZ5, on behal o he STEPS in es iga o s#
1Hospi al Uni e si a io y Poli ´ecnico La Fe, Valencia, Spain; 2Uni e sidad de Mu cia and IMIB-A ixaca, Mu cia, Spain; 3Hospi al
Uni e si a io La Paz, Mad id, Spain; 4Hospi al Uni e si a io Ma e no In an il de Cana ias, G an Cana ia, Spain; 5Hospi al Uni e si a io
Cen al de As u ias, O iedo, Spain; 6Hospi al Uni e si a io Miguel Se e , Za agoza, Spain; 7Roche Diagnos ics In e na ional L d,
Ro k euz, Swi ze land
KEYWORDS: bioma ke ; ea ly-onse p edic ion; hype ension; PlGF; p e-eclampsia; sFl -1; sFl -1/PlGF a io
ABSTRACT
Objec i e A high a io o soluble ms-like y osine
kinase-1 (sFl -1) o placen al g ow h ac o (PlGF) has
been linked o p e-eclampsia (PE). We e alua ed he
sFl -1/PlGF a io as a p edic i e ma ke o ea ly-onse
PE in women a isk o PE.
Me hods This p ospec i e, Spanish, mul icen e s udy
included p egnan women wi h a isk ac o o PE,
including in au e ine g ow h es ic ion, PE, eclampsia
o hemolysis, ele a ed li e enzymes and low pla ele
coun synd ome in p e ious p egnancy, p eges a ional
diabe es o abno mal u e ine a e y Dopple . The p ima y
objec i e was o show ha he sFl -1/PlGF a io a 20, 24
and 28 weeks’ ges a ion was p edic i e o ea ly-onse PE
( 0 weeks). Se um sFl -1 and PlGF we e measu ed<34 +
a 20, 24 and 28 weeks. Mul i a ia e logis ic eg ession
was used o de elop a p edic i e model.
Resul s A o al o 819 women we e en olled, o which
729 we e sui able o analysis. O hese, 78 (10.7%)
women de eloped PE (24 ea ly onse and 54 la e onse ).
Median sFl -1/PlGF a io a 20, 24 and 28 weeks was 6.3
(in e qua ile ange (IQR), 4.1–9.3), 4.0 (IQR, 2.6–6.3)
and 3.3 (IQR, 2.0–5.9), espec i ely, o women who
did no de elop PE (con ols); 14.5 (IQR, 5.5–43.7),
18.4 (IQR, 8.2–57.9) and 51.9 (IQR, 11.5–145.6) o
women wi h ea ly-onse PE; and 6.7 (IQR, 4.6–9.9),
4.7 (IQR, 2.8–7.2) and 6.0 (IQR, 3.8–10.5) o women
wi h la e-onse PE. Compa ed wi h ea ly-onse PE, he
sFl -1/PlGF a io was significan ly lowe in con ols
(P<0.001 a each imepoin ) and in women wi h ch onic
hype ension ( 0.001 a each imepoin ), ges a ionalP<
Co espondence o: D A. Pe ales, Hospi al Uni e si a io y Poli ´ecnico La Fe, A da F. Ab il Ma o ell 106 To e F, 3aPlan a, Valencia
46026, Spain (e-mail: [email p o ec ed])
The copy igh line o his a icle was changed on 14 Feb ua y 2018 a e o iginal online publica ion.
#STEPS in es iga o s a e lis ed a he end o he a icle.
Accep ed: 11 No embe 2016
hype ension ( 0.001 a each imepoin ) and la e-onse P<
PE (P<0.001 a each imepoin ). A p edic ion model
o ea ly-onse PE was de eloped, which included he
sFl -1/PlGF a io plus mean a e ial p essu e, being pa ous
and p e ious PE, wi h a eas unde he ecei e –ope a ing
cha ac e is ics cu es o 0.86 (95% CI, 0.77–0.95), 0.91
(95% CI, 0.85–0.97) and 0.93 (95% CI, 0.86–0.99) a
20, 24 and 28 weeks, espec i ely, and was supe io o
models using he sFl -1/PlGF a io alone o u e ine a e y
mean pulsa ili y index.
Conclusions The sFl -1/PlGF a io can imp o e p edic-
ion o ea ly-onse PE o women a isk o his condi ion.
©2016 The Au ho s. Ul asound in Obs e ics & Gyne-
cology published by John Wiley & Sons L d on behal o
he In e na ional Socie y o Ul asound in Obs e ics and
Gynecology.
INTRODUCTION
P e-eclampsia (PE) a ec s 2–5% o p egnancies1–5 and
can esul in in au e ine g ow h es ic ion (IUGR), enal
o hepa ic impai men , HELLP synd ome (hemolysis,
ele a ed li e enzyme le els and low pla ele coun ),
eclampsia, and ma e nal and e al mo ali y5–7. Ea ly
and la e mani es a ions o PE di e in ime o onse
o symp oms, ela i e equency, placen al mo phology,
gene ic isk and isk o ad e se ou comes8–13. Ea ly-onse
PE is associa ed wi h a highe incidence o ad e se
pe ina al ou comes, including oligohyd amnios, Apga
sco e 7, s illbi h and ea ly neona al dea h, compa ed<
wi h la e-onse PE14,15. As ea ly in e en ion is impo an
o imp o e ma e nal and e al ou comes16 and he classical
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d ORIGINAL PAPER
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].
374 Pe ales e al.
clinical ma ke s o PE (hype ension and p o einu ia) a e
poo ly p edic i e o hose who will de elop he condi ion,
ma ke s o angiogenesis ha e been examined as aids o
PE p edic ion.
A key ea u e o PE is placen al insu ficiency.
Dys egula ion o p o- and an iangiogenic ac o s is
hough o be causally linked o he condi ion7,17,18;
be o e and du ing PE, ma e nal se um concen a ions o
an iangiogenic soluble ms-like y osine kinase-1 (sFl -1)
a e inc eased and le els o p oangiogenic placen al g ow h
ac o (PlGF) a e dec eased19,20. A high sFl -1/PlGF a io
has been linked wi h PE and demons a ed be o e clinical
onse o he condi ion, and di e ences in sFl -1 and PlGF
ha e been obse ed be ween ea ly- and la e-onse PE21–29.
The Elecsys®immunoassay sFl -1/PlGF a io is CE-IVD
(Con o mi ´e Eu op´eenne–In Vi o Diagnos ics) app o ed
as a diagnos ic aid o PE wi h ges a ional age-specific
cu -o alues, and as an aid in sho - e m p edic ion o
PE in women wi h suspec ed PE26,30,31. The P edic ion o
Sho -Te m Ou come in P egnan Women wi h Suspec ed
PE S udy (PROGNOSIS) de eloped a cu -o -based PE
p edic ion model. Op imum sFl -1/PlGF a io cu -o
le els o 38 and≤>38 we e iden ified o ule ou and ule
in, espec i ely, PE, in women wi h single on p egnancy
a 24 +0 o 36 +6 weeks’ ges a ion32 . Howe e , he
p edic i e alue o he sFl -1/PlGF a io has no been
examined specifically o ea ly-onse PE.
This s udy, he S udy o Ea ly P e-eclampsia in Spain
(STEPS), aimed o e alua e he sFl -1/PlGF a io a 20, 24
and 28 weeks as a p edic i e ma ke o ea ly-onse PE in
women a isk o PE.
METHODS
S udy design and pa icipan s
STEPS was a p ospec i e, double-blind, mul icen e (10
s udy si es in Spain) s udy, pe o med be ween Oc obe
2010 and Ma ch 2013, and en olled p egnan women
a isk o PE. To be conside ed a isk o PE, women
had o mee one o he ollowing inclusion c i e ia: PE,
eclampsia, HELLP synd ome o IUGR in a p e ious
p egnancy; p e-exis ing ch onic hype ension wi hou
p o einu ia; ges a ional hype ension (new-onse hype -
ension in p egnancy); p e-exis ing enal disease (kidney
ansplan a ion o c ea inine clea ance <60 mL/min);
p e-exis ing diabe es melli us Type I (insulin depen-
den ); mean u e ine a e y Dopple pulsa ili y index
(U A-PI) >1.45 (a 19–20 weeks); h ombophilia
(an iphospholipid synd ome, p o ein C deficiency,
p o ein S deficiency, an i h ombin deficiency, ac o V
Leiden mu a ion); mul iple p egnancy; age ≥40 yea s
and concei ed wi h assis ed ep oduc i e echnologies
(ART). Women wi h wo o mo e o he ollowing
isk ac o s we e also included: nullipa i y; body mass
index ≥35 kg/m2; dias olic blood p essu e >80 mmHg
a s udy inclusion; age 40 yea s; and amily his o y≥
(mo he o sis e ) o PE, eclampsia o HELLP syn-
d ome. Women we e excluded i hey we e bo h
hype ensi e and had p o einu ia o i majo e al
mal o ma ions/ch omosome diso de s we e obse ed.
Women p o ided in o med, signed consen . The
p o ocol was app o ed by applicable na ional/ egional
independen e hics commi ees and ins i u ional e iew
boa ds (Table S1). The s udy adhe ed o he Guidelines
o Good Clinical P ac ice.
The p ima y objec i e o he s udy was o demons a e
ha he sFl -1/PlGF a io was a p edic i e ma ke o
ea ly-onse PE. Seconda y objec i es included e alua ion
o sFl -1/PlGF a io as a p edic o o la e-onse PE and
he use o he sFl -1/PlGF a io o di e en ia ion o
hype ension om PE.
Diagnos ic c i e ia
Fo consis ency, in es iga o s used p edefined diagnos-
ic c i e ia (Table 1) based on he Repo o he
Na ional High Blood P essu e Educa ion P og am Wo k-
ing G oup on High Blood P essu e in P egnancy33. PE
was defined as newly occu ing hype ension (sys olic
blood p essu e 140 mmHg and/o dias olic blood p es-≥
su e ≥90 mmHg) wi h newly occu ing p o einu ia a e
20 weeks. To be conside ed ea ly onse , PE had o occu
be o e 34 +0 weeks.
Da a collec ion and isi s
A ges a ional weeks 19–20 (Visi 1), 23–24 (Visi 2)
and 27–28 (Visi 3), pa icipan s unde wen a blood
es o de e mine he sFl -1/PlGF a io, Dopple exam-
ina ion o he u e ine a e ies and assessmen o blood
p essu e (measu ed by alida ed au oma ed de ices), p o-
einu ia, PE s a us, hemoglobin, pla ele s and u ic acid
le els. Pos pa um, addi ional da a we e collec ed, includ-
ing blood p essu e, ype o deli e y, Apga sco e, weigh o
placen a, neona al ou comes (pe ina al/ e al dea h, deli -
e y 34 weeks, IUGR, placen al ab up ion, espi a o y<
dis ess synd ome, nec o izing en e ocoli is, in a en icu-
la hemo hage) and ma e nal ou comes (ma e nal dea h,
pulmona y edema, acu e enal ailu e, ce eb al hemo -
hage, ce eb al h ombosis, dissemina ed in a ascula
coagula ion). Unplanned isi s could be ca ied ou in he
e en o complica ions.
Se um samples (≥2 mL) we e collec ed acco ding o
a s anda d ope a ing p ocedu e and we e analyzed a
he indi idual s udy si es. Resul s we e checked o
consis ency be ween s udy si es by cen al analysis a
Hospi al Uni e si a io Cen al de As u ias.
Ma e nal se um le els o sFl -1 and PlGF we e de e -
mined using he ully au oma ed Elecsys sFl -1 and
Elecsys PlGF assays on he cobas®e elec ochemilu-
minescence immunoassay pla o m (Roche Diagnos ics
GmbH, Mannheim, Ge many) and he sFl -1/PlGF a io
was calcula ed27,30,31. The sFl -1/PlGF a io esul s we e
concealed om bo h pa ien s and ca e s o ensu e ha
hey did no a ec he clinical moni o ing o pa ien s.
Ad e se e en s we e eco ded, al hough he s udy was
non-in e en ional.
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].
sFl -1/PlGF STEPS 375
Table 1 Diagnos ic c i e ia in S udy o Ea ly P e-eclampsia in Spain (STEPS)
Diagnosis C i e ia
Hype ension Sys olic blood p essu e ≥140 mmHg and/o dias olic blood p essu e ≥90 mmHg (on wo occasions a leas
6 h apa )
Ch onic
hype ension
Hype ension (sys olic blood p essu e ≥140 mmHg and/o dias olic blood p essu e ≥90 mmHg) diagnosed
be o e p egnancy o in fi s hal o p egnancy (<20weeks) and con inued o >12 weeks a e deli e y
P o einu ia Fo de e mina ion o u ina y p o ein using es s ips, a alue o 1 was no conside ed eliable o diagnosis+
o PE. Da a we e econfi med wi h p o ein es on 24-h u ine ( 0.3g p o ein/24 h); in an eme gency, i i ≥
was no possible o de e mine p o ein in 24-h u ine, p o ein de e mina ion was ca ied ou on isola ed
u ine sample (≥30 mg p o ein/dL o p o ein/c ea inine a io≥ 30 mg p o ein/mmol c ea inine)
Ges a ional
hype ension
New-onse hype ension (sys olic blood p essu e ≥ 140 mmHg and/o dias olic blood p essu e ≥ 90 mmHg)
a e 20 weeks o p egnancy, which esol ed by 12 weeks pos pa um
PE New-onse hype ension (sys olic blood p essu e ≥ 140 mmHg and/o dias olic blood p essu e ≥ 90 mmHg)
and new-onse p o einu ia a e 20 weeks o p egnancy
Se e e PE PE plus one o mo e o he ollowing: sys olic blood p essu e≥160 mmHg and/o dias olic blood
p essu e ≥110 mmHg (on wo occasions a leas 6 h apa ); p o einu ia (>5 g p o ein/24 h o es
s ip ≥ +3 in wo u ine samples collec ed a andom a leas 4 h apa ); impai men o enal unc ion
(se um c ea inine ≥1.2 mg/dL unless known o be ele a ed p e iously o oligu ia<500 mL/24 h);
pulmona y edema; impai men o hepa ic unc ion (ele a ed li e enzymes, epigas ic pain o igh uppe
quad an pain caused by dis ension o Glisson’s capsule); neu ological symp oms (ce eb al o isual
dis u bances, se e e headache); hema ological dis u bances ( h ombocy openia, hemolysis); IUGR
Eclampsia New-onse onic–clonic con ulsions in women wi h PE, no a ibu able o any o he cause
Ea ly- and la e-onse PE Ea ly onse : PE de eloping<34 34+ ≥0 weeks; la e onse : PE de eloping +0 weeks
HELLP synd ome Inc eased ASAT ( 70 IU/L); dec eased pla ele coun ( L); inc eased LDH (> < 100 000/μ>600 IU/L)
IUGR Es ima ed e al weigh o abdominal ci cum e ence<10 h pe cen ile (adjus ed o gende / ace in acco dance
wi h ables no mally used by s udy cen e ). P esence o pa hological p ocess ha inhibi s exp ession o
no mal in insic g ow h po en ial. Pa hological p ocess mus be demons a ed a leas once a e
22 weeks, acco ding o ei he oligohyd amnios (amnio ic fluid index <10 h pe cen ile) o pa hological
flow in umbilical a e y (pulsa ili y index>95 h pe cen ile)
SGA neona e Es ima ed e al weigh o abdominal ci cum e ence<10 h pe cen ile (adjus ed o gende / ace in acco dance
wi h ables no mally used by s udy cen e ); no pa hological p ocess
P e e m bi h Deli e y be o e end o 37 weeks (e.g. ges a ional age o 36 +6 weeks would be eco ded as 36 comple ed
weeks o p egnancy and baby would be defined as p e e m)
ASAT, aspa a e amino ans e ase; HELLP, hemolysis, ele a ed li e enzymes and low pla ele coun ; IUGR, in au e ine g ow h es ic ion;
LDH, lac a e dehyd ogenase; PE, p e-eclampsia; SGA, small- o -ges a ional-age.
S a is ical analysis
To ob ain 100 cases o PE, i was calcula ed ha 800 p eg-
nan women would need o be included in he s udy, based
on a p esumed p e alence o PE o 12% (including bo h
single on and mul iple p egnancies). The sFl -1/PlGF a io
was log- ans o med o co ec o igh skewness p io
o any calcula ion. Di e ences in means be ween inde-
penden g oups we e assessed using analysis o a iance
(ANOVA) o S uden ’s - es in he case o homogenei y o
a iances, and using gene alized leas squa es in he case
o he e oscedas ici y. App op ia eness o he me hods
was assessed by e alua ion o he plo s o esiduals.
To de elop a p edic i e model o PE, mul i a ia e
logis ic eg ession was used conside ing ma e nal cha -
ac e is ics, medical his o y and bioma ke s as po en ial
p edic o s. The a iables ha we e finally included in he
ea ly-PE p edic ion model we e selec ed acco ding o he
esul s o a logis ic eg ession model wi h L1 penaliza ion
(‘lasso’ echnique)34. The coe ficien s de i ed om he
mul i a ia e analysis we e used as weigh s in a nomog am
o p edic ea ly PE. Pe o mances o he models we e e al-
ua ed by ecei e –ope a ing cha ac e is ics (ROC) cu es
and a eas unde he cu e (AUC) wi h 95% CIs.
All s a is ical analyses we e pe o med using R ( e sion
3.1.2) and R-packages ms ( e sion 4.2-1) and ROCR
( e sion 1.0-5).
RESULTS
S udy pa icipan s
O e all, 729 women we e eligible o analysis, including
447 wi h single on p egnancy and 282 wi h mul iple
p egnancy ( win p egnancy, 276; iple p egnancy,n=
n=6). A o al o 78 (10.7%) women de eloped PE
(single on p egnancy, 42; mul iple p egnancy,n=n=36),
o which 24 we e ea ly-onse PE (single on p egnancy,
n n=14; mul iple p egnancy, =10) and 54 we e la e-onse
PE (single on p egnancy, 28; mul iple p egnancy,n=
n=26) (Figu e 1). The numbe o pa icipan s pe s udy
si e is epo ed in Table S2. Women who de eloped
ea ly-onse PE had highe sys olic and dias olic blood
p essu es, mean a e ial blood p essu e (MAP) and lowe
ges a ional age a deli e y compa ed wi h he con ol
g oup (women who did no de elop PE/hype ension
du ing he en i e p egnancy) (Table 2).
sFl -1, PlGF and sFl -1/PlGF a io measu emen s
In he con ol g oup, median sFl -1/PlGF a io emained
low ( 7) be ween 20 and 28 weeks’ ges a ion (Table 3).<
In women who de eloped ea ly-onse PE, median
sFl -1/PlGF a io was al eady highe (14.5) a 20weeks’
ges a ion and inc eased u he o 18.4 a 24 weeks and
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].
376 Pe ales e al.
Pa icipan s excluded*
( 90)n=
(S, 75; M, 15)n=n=
Pa icipan s who did no de elop PE
( 651)n=
(S, 405; M, 246)n=n=
Pa icipan s who de eloped PE
( 78)n=
(S, 42; M, 36)n=n=
Pa icipan s wi h
la e-onse
PE
( 54)n=
(S, n= 28;
M, 26)n=
Pa icipan s wi h
ea ly-onse
PE
( 24)n=
(S, n= 14;
M, 10)n=
Pa icipan s
wi h IUGR
( 28)n=
(S, n= 15;
M, 13)n=
Pa icipan s
wi h
ges a ional
hype ension
( 35)n=
(S, n= 22;
M, 13)n=
Pa icipan s
wi h ch onic
hype ension
( 33)n=
(S, n= 32;
M, n= 1)
Pa icipan s
wi hou
hype ension
( 555)n=
(S, 336;n=
M, n= 219)
Pa icipan s en olled
( 819)n=
(S, 522; M, 297)n=n=
Pa icipan s eligible o analysis
( 729)n=
(S, 447; M, 282)n=n=
Figu e 1 Flowcha o pa icipan s in S udy o Ea ly P e-eclampsia in Spain (STEPS). *Reasons o exclusion: inclusion c i e ia no me
(n=4); signed consen gi en bu did no s a s udy (n=28); misca iage (n=7); e mina ion o p egnancy due o e al mal o ma ions
( 13); placen al ab up ion a 26 weeks (n=8); los o ollow-up (n=n=1); comple ed ollow-up un il 28 weeks bu da a could no be
e ie ed because o deli e y in ano he se ing (n=29). IUGR, in au e ine g ow h es ic ion; M, mul iple p egnancy; PE, p e-eclampsia;
S, single on p egnancy.
Table 2 Baseline cha ac e is ics o women who de eloped ea ly- o la e-onse p e-eclampsia (PE) and hose who did no de elop
PE (con ols)
Cha ac e is ic
Con ols
(n=651)
Ea ly-onse PE
(n=24)
La e-onse PE
(n=54)
Age (yea s) 34.6 ±5.3 35.6 ±3.9 34.7 ±0.7
Body mass index (kg/m2) 26.7 6.0 28.5 6.4 27.9 7.3± ± ±
Sys olic blood p essu e (mmHg) 119.1 ±13.7 127.9 ±13.5* 125.0 16.0*±
Dias olic blood p essu e (mmHg) 73.7 ±11.3 77.5 8.5* 77.7± ± 12.0*
Mean a e ial p essu e (mmHg) 88.9 ±11.1 94.3 ±8.1* 93.4 ±12.2*
Mul iple p egnancy 246 (37.8) 10 (41.7) 26 (48.1)
Ges a ional age a deli e y (weeks) 37.5 ±2.7 31.8 3.5* 36.6 1.4± ±
Bi h weigh o fi s in an (g) 2911 ±721 ( 646) 1745 830 ( 584 ( 54)n= ± n=22)* 2759 ±n=
Bi h weigh o second in an (g) 2303 ±552 ( 243) 1807 378 ( 364 ( 26)n= ± n=9)† 2285 ±n=
Bi h weigh o hi d in an (g) 1221 ±689 ( 4) 1445 304 ( 2) — ( 0)n= ± n=n=
Nullipa ous 272 (41.8) 15 (62.5) 31 (57.4)
P e ious PE 101 (15.5) 9 (37.5)* 14 (25.9)
Family his o y o PE 23 (3.5) 1 (4.2) 5 (9.3)
P e ious IUGR 55 (8.4) 3 (12.5) 5 (9.3)
Ch onic hype ension 81 (12.4) 6 (25.0) 12 (22.2)
Ges a ional hype ension 4 (0.6) 0 (0) 3 (5.6)
Neph opa hy 6 (0.9) 0 (0) 1 (1.9)
Diabe es melli us Type 1 42 (6.5) 1 (4.2) 1 (1.9)
Th ombophilia 50 (7.7) 1 (4.2) 3 (5.6)
Concei ed by assis ed ep oduc ion 93 (14.3) 5 (20.8) 11 (20.4)
Smoke a en ollmen 80 (12.3) 1 (4.2) 3 (5.6)
Abno mal U A Dopple 8 (1.2) 1 (4.2) 2 (3.7)
Da a a e gi en as mean 0.05, a e adjus men by±SD o n P(%). PE g oups compa ed wi h con ols using Dunne ’s es : * <0.001; †P<
Bon e oni co ec ion. IUGR, in au e ine g ow h es ic ion; U A, u e ine a e y.
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].
sFl -1/PlGF STEPS 377
Table 3 Measu emen s o soluble ms-like y osine kinase-1 (sFl -1), placen al g ow h ac o (PlGF) and sFl -1/PlGF a io in ma e nal se um
a 20, 24 and 28weeks in women who de eloped ea ly- o la e-onse p e-eclampsia (PE) and in hose who did no de elop PE (con ols)
Bioma ke Con ols Ea ly-onse PE La e-onse PE
20 weeks
n612 21 52
PlGF (pg/mL) 264.5 (172.0–403.6) 193.1 (68.0–262.4) 267.8 (151.5–414.0)
sFl -1 (pg/mL) 1623.0 (1081.0–2531.0) 1972.0 (1331.0–3473.0) 1967.0 (1120.5–2903.8)
sFl -1/PlGF a io 6.3 (4.1–9.3) 14.5 (5.5–43.7) 6.7 (4.6–9.9)
24 weeks
n580 20 52
PlGF (pg/mL) 424.5 (277.0–615.6) 168.9 (62.1–329.7) 415.0 (259.7–595.7)
sFl -1 (pg/mL) 1725.0 (1123.5–2674.3) 3127.5 (1961.8–4202.5) 1882.5 (1134.5–3115.8)
sFl -1/PlGF a io 4.0 (2.6–6.3) 18.4 (8.2–57.9) 4.7 (2.8–7.2)
28 weeks
n557 16 49
PlGF (pg/mL) 540.0 (339.0–821.5) 176.5 (67.2–278.6) 335.0 (263.0–485.9)
sFl -1 (pg/mL) 1826.0 (1231.0–2766.0) 6370.0 (2385.3–8788.3) 2499.0 (1522.0–3681.0)
sFl -1/PlGF a io 3.3 (2.0–5.9) 51.9 (11.5–145.6) 6.0 (3.8–10.5)
Da a a e gi en as median (in e qua ile ange) unless s a ed o he wise.
51.9 a 28weeks. The e was li le change in he median
sFl -1/PlGF a io be ween 20 and 28weeks in women
who de eloped la e-onse PE, emaining low h oughou
a <7.
Mean sFl -1 le els and PlGF le els we e significan ly
di e en be ween single on and mul iple p egnancies
a 20, 24 and 28 weeks (P=0.001). Howe e , he
mean sFl -1/PlGF a io was only significan ly di e en
a 28weeks’ ges a ion ( 0.001) (Table S3) and, a P=
all imepoin s, he di e ence be ween median alues in
single on and mul iple p egnancies was small.
sFl -1/PlGF a io: p edic ion o PE
Compa ed wi h con ol pa icipan s, he sFl -1/PlGF a io
was consis en ly significan ly highe in women wi h
ea ly-onse PE ( 0.001 a all imepoin s) (Figu e 2).P<
Women wi h ea ly-onse PE also had significan ly highe
sFl -1/PlGF a ios a 20, 24 and 28weeks ela i e o
women wi h ch onic o ges a ional hype ension and
women wi h la e-onse PE (Figu e 3). Di e ences be ween
ea ly-onse PE and con ol/hype ension/la e-onse PE
became mo e p onounced as he p egnancy p og essed.
Women wi h la e-onse PE we e no easily di e en i-
a ed om con ol pa icipan s by he sFl -1/PlGF a io
a 20 and 24weeks (di e ence was non-significan a
20 (P P=0.15) and 24 ( =0.21) weeks, Figu e 2). A
28 weeks, he e was a s a is ically significan di e ence in
he sFl -1/PlGF a io be ween women wi h la e-onse PE
and con ol pa icipan s (P<0.001), al hough he nume i-
cal di e ence in he median a io was small (2.7) (Table 3).
De elopmen o a p edic ion model o ea ly-onse PE
P edic ion models o ea ly-onse PE we e de eloped,
which included a ia ions o he ollowing ac o s:
sFl -1/PlGF a io, PlGF, U A-PI, MAP, being pa ous,
p e ious PE and use o ART. The AUC was op imal o a
model including he sFl -1/PlGF a io, MAP, being pa ous
20
3
5
7
10
20
sFl -1/PlGF a io (log scale)
50
75
24
Ges a ional age (weeks)
28
†
Figu e 2 Soluble ms-like y osine kinase-1 (sFl -1)/placen al
g ow h ac o (PlGF) a io a 20, 24 and 28weeks in con ol g oup
o women who did no de elop p e-eclampsia (PE; ) and in
hose who de eloped ea ly-onse ) o la e-onse ) PE.
Compa ison wi h con ols: *P<0.001; † 0.15; ‡ 0.21.P=P=
and p e ious PE (he ea e e e ed o as he ‘ea ly-onse
PE p edic ion model’) (Figu e S1) compa ed wi h models
ha used he sFl -1/PlGF a io alone o U A-PI alone
(Table 4). The accu acy o he p edic ion model was no
subs an ially imp o ed by including ART o U A-PI and
ART in he model. A 20 and 24 weeks, including hese
wo pa ame e s in he model inc eased he AUC om
0.86 (95% CI, 0.77–0.95) o 0.87 (95% CI, 0.79–0.96),
and om 0.91 (95% CI, 0.85–0.97) o 0.92 (95% CI,
0.85–0.97), espec i ely. Howe e , a 28weeks, includ-
ing U A-PI and ART in he model educed he AUC om
0.93 (95% CI, 0.86–0.99) o 0.91 (95% CI, 0.82–0.99)
(Figu e 4). A nomog am o p edic ion isk is p esen ed in
Figu es S2 and S3. The de ec ion a e o ea ly-onse PE
using di e en p edic ion models is epo ed in Table 5.
We also compa ed he pe o mance o a s anda d
p edic ion model (ma e nal his o y, MAP and U A-PI)
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].

378 Pe ales e al.
Con ols
0.5
1
5
10
100
†
*
*
*
*
*
*
† † †
50
sFl -1/PlGF a io (log scale)
500
1000
(a)
GH La e PECH Ea ly PE
Con ols GH La e PECH Ea ly PE
Con ols GH La e PECH Ea ly PE
0.5
1
5
10
100
†
*
*
*
† † †
50
sFl -1/PlGF a io (log scale)
500
1000
(b)
0.5
1
5
10
100
†
*
*
*
† † †
50
sFl -1/PlGF a io (log scale)
500
1000
(c)
Figu e 3 Box-and-whiske plo s o soluble ms-like y osine
kinase-1 (sFl -1)/placen al g ow h ac o (PlGF) a io in con ol
women who did no de elop p e-eclampsia (PE) and in hose who
de eloped ch onic hype ension (CH), ges a ional hype ension
(GH), la e-onse PE o ea ly-onse PE a : (a) 20 weeks, (b) 24 weeks
and (c) 28 weeks. †P<0.001 in compa ison wi h ea ly-onse PE.
Boxes wi h in e nal lines ep esen median and in e qua ile ange,
whiske s a e 1.5 in e qua ile ange and s a s a e ou lie s.×
wi h he same model bu including he sFl -1/PlGF
immunoassay a io o es ima e ea ly-onse PE isk a
20, 24 and 28weeks’ ges a ion. The addi ion o he
sFl -1/PlGF immunoassay a io subs an ially inc eased he
de ec ion a e a all ges a ional ages s udied (assuming a
alse-posi i e a e o bo h 5% and 10%) (Table 6).
sFl -1 and PlGF as single bioma ke s: de elopmen
o PE
Women wi h ea ly-onse PE had lowe PlGF (P<0.001
a 20, 24 and 28 weeks) and highe sFl -1 (P=0.018,
P P<0.001 and <0.001 a 20, 24 and 28 weeks,
espec i ely) compa ed wi h hose who did no de elop
ea ly-onse PE (women who de eloped la e-onse PE
and hose who did no de elop any PE combined)
(Figu e S4).
A compa ison o p edic ion models ha included he
sFl -1/PlGF a io wi h models ha used sFl -1 o PlGF
alone was pe o med by e alua ing hei espec i e AUCs
and Akaike in o ma ion c i e ion (AIC), which measu es
goodness o fi 35. The AUC o p edic ion models ha
included he sFl -1/PlGF a io (0.86–0.87, 0.91–0.92 and
0.91–0.93 a 20, 24 and 28 weeks’ ges a ion, espec i ely)
was g ea e han ha o models ha used single
bioma ke s (0.81–0.83, 0.88–0.90 and 0.88–0.91 o
sFl -1 and 0.79–0.83, 0.85–0.89 and 0.86–0.89 o PlGF
a 20, 24 and 28 weeks’ ges a ion, espec i ely) (Table S4).
Da a consis ency
No inconsis encies we e ound be ween si e and cen al
es ing (da a no shown).
DISCUSSION
Subs an ial e idence suppo s he use o he sFl -1/PlGF
a io in PE diagnosis and p edic ion20,21,23,27,36–40.
Howe e , di e ences be ween ea ly- and la e-onse
PE sugges di e en e iologies; hus, di e en ‘ ules’
o he sFl -1/PlGF a io could be applied. In a
s udy o 257 women wi h suspec ed PE, he op imal
sFl -1/PlGF a io cu -o o diagnose PE <34 weeks’ and
≥34 weeks’ ges a ion was 23 (92.0% sensi i i y, 81.1%
specifici y) and 45 (83.7% sensi i i y, 72.6% specifici y),
espec i ely41. In PROGNOSIS, a sFl -1/PlGF a io cu -o
≤38 uled ou PE wi hin 1 week in women wi h suspec ed
PE and single on p egnancy a 24 +0 o 36 +6 weeks’
ges a ion32 . PROGNOSIS had a highe p e alence o PE
compa ed wi h ou s udy (19% 11%, espec i ely), s
possibly due o he ac ha PROGNOSIS en olled women
wi h suspicion o PE, while we en olled women wi h a
mode a e o high isk o de eloping PE. The p e alence
o PE in ou s udy alls be ween he es ima ed anges o
women wi h mode a e o high isk o PE (5.29–6.19%
and 16.09–19.49%, espec i ely)42.
In STEPS, he sFl -1/PlGF a io was significan ly
di e en be ween women who did no de elop PE and
hose who did. The combina ion o he sFl -1/PlGF a io
wi h o he clinical measu es p oduced a p edic i e model
wi h conside ably inc eased specifici y and sensi i i y
compa ed wi h using U A-PI o sFl -1/PlGF a io alone.
We also e alua ed how he models used o es ima e
ea ly-onse PE isk would pe o m when using he
single bioma ke s, ins ead o he sFl -1/PlGF a io. Based
on bo h AUC and AIC, models wi h he sFl -1/PlGF
a io demons a ed consis en ly he highes p edic i e
pe o mance. Using ou ea ly-onse PE p edic ion model
(sFl -1/PlGF a io, MAP, being pa ous, p e ious PE),
ea ly-onse PE could be p edic ed om 20weeks onwa d,
wi h an AUC o 0.86 and 60% sensi i i y o a
alse-posi i e a e o 10%. A p e ious model de eloped
wi hou se um bioma ke s, which used a his o y o
diabe es, hype ension and MAP, epo ed an AUC o
0.83 wi h 55% sensi i i y o a alse-posi i e a e o 10%
( hese we e no high- isk women)43.
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].
sFl -1/PlGF STEPS 379
Table 4 P edic ion o ea ly-onse p e-eclampsia (PE) a 20, 24 and
28 weeks using di e en indi idual pa ame e s and ea ly-onse PE
p edic ion model
P edic ion pa ame e AUC (95% CI)
20 weeks
Ea ly-onse PE p edic ion model 0.86 (0.77–0.95)
MAP 0.67 (0.55–0.79)
U A-PI 0.50 (0.35–0.66)
PlGF 0.70 (0.58–0.82)
sFl -1 0.61 (0.49–0.74)
sFl -1/PlGF a io 0.77 (0.65–0.89)
24 weeks
Ea ly-onse PE p edic ion model 0.91 (0.85–0.97)
MAP 0.72 (0.62–0.83)
U A-PI 0.55 (0.39–0.72)
PlGF 0.81 (0.72–0.90)
sFl -1 0.71 (0.58–0.84)
sFl -1/PlGF a io 0.86 (0.76–0.96)
28 weeks
Ea ly-onse PE p edic ion model 0.93 (0.86–0.99)
MAP 0.77 (0.66–0.89)
U A-PI 0.63 (0.45–0.80)
PlGF 0.86 (0.78–0.94)
sFl -1 0.81 (0.67–0.95)
sFl -1/PlGF a io 0.89 (0.79–0.98)
Ea ly-onse PE p edic ion model includes soluble ms-like y osine
kinase 1(sFl -1)/placen al g ow h ac o (PlGF) a io, mean a e ial
p essu e (MAP), being pa ous and p e ious PE. AUC, a ea unde
he ecei e –ope a ing cha ac e is ics cu e; U A-PI, u e ine a e y
pulsa ili y index.
O he s udies ha e included sFl -1 and PlGF in
hei models. An obse a ional s udy o women a
high isk o PE de eloped a p edic ion model o
ea ly-onse PE using sFl -1 a 28 +0 o 31 +6 weeks’
ges a ion, which had an AUC o 0.85 (67% sensi i i y,
96% specifici y)44. A model including ges a ional age,
U A-PI and sFl -1/PlGF a io showed an associa ion wi h
pe ina al complica ions wi h an AUC o 0.89 (64%
sensi i i y, 95% specifici y)45. Ano he model combined
PlGF wi h ma e nal cha ac e is ics, obs e ic his o y and
U A-PI o p edic ea ly-onse PE in he fi s imes e wi h
an AUC o 0.9446 . Al hough an abno mal U A-PI was
associa ed wi h he de elopmen o PE in ou s udy, i was
no included in ou model since i did no subs an ially
imp o e PE p edic ion. F om a p ac ical pe spec i e, he
U A can be di ficul o loca e in he fi s imes e and
he In e na ional Socie y o Ul asound in Obs e ics and
Gynecology does no include U A Dopple as pa o
he ou ine fi s - imes e e al ul asound examina ion47.
O he s udies ha e also no included U A-PI in hei
models48,49 .
A ecen s udy demons a ed ha a p ospec i e
sc eening model a 19–24 weeks’ ges a ion, in ol ing
ma e nal ac o s, U A-PI, MAP and PlGF, was supe io
o sc eening by ma e nal ac o s alone. The pe o mance
o he model was in e sely ela ed o he ges a ional
age a which deli e y became necessa y; de ec ion a es
( alse-posi i e a e o 10%) o PE 32 weeks, be ween<
32 0 and 36 37 weeks we e 99%, 85%+ + ≥6 weeks, and
and 46%, espec i ely. Howe e , his s udy e alua ed
1.0
0.8
0.6
0.4
0.2
0
T ue-posi i e a e
0 0.2 0.4
False-posi i e a e
0.6 0.8 1.0
1.0
0.8
0.6
0.4
0.2
0
T ue-posi i e a e
0 0.2 0.4
False-posi i e a e
0.6 0.8 1.0
(b)
(a)
1.0
0.8
0.6
0.4
0.2
0
T ue-posi i e a e
0 0.2 0.4
False-posi i e a e
0.6 0.8 1.0
(c)
Figu e 4 Recei e –ope a ing cha ac e is cs cu es o p edic ion o
ea ly-onse p e-eclampsia (PE) using di e en models a
20 weeks (a), 24 weeks (b) and 28 weeks (c). Tables S4 and 5
p esen nume ical alues o a eas unde cu es. Ea ly-onse PE
p edic ion model ) includes soluble ms-like y osine kinase-1
(sFl -1)/placen al g ow h ac o (PlGF) a io, mean a e ial p essu e
(MAP), being pa ous and p e ious PE. ART, assis ed ep oduc i e
echnologies; U A-PI, u e ine a e y pulsa ili y index.
, sFl -1/PlGF a io, MAP, being pa ous, p e ious PE, ART.
, sFl -1/PlGF a io, MAP, being pa ous, p e ious PE, U A-PI,
ART.
, MAP, being pa ous, p e ious PE, ART, PlGF.
, MAP, being pa ous, p e ious PE, U A-PI, ART, PlGF.
PlGF and sFl -1 sepa a ely; i did no assess he sFl -1/PlGF
a io50 . O no e, he s udy defined ea ly-onse PE as
equi ing deli e y be o e 32 weeks’ ges a ion, a he han
be o e 34weeks. A ela ed s udy showed ha a wo-s age
sc eening model, in which U A-PI and PlGF measu emen s
we e ese ed o a - isk indi iduals, achie ed simila
de ec ion a es o p e e m PE ( 37 weeks’ ges a ion),<
compa ed wi h sc eening he whole popula ion by
ma e nal ac o s, MAP, U A-PI and PlGF51.
Va ious guidelines ecommend PE sc eening based on
ma e nal his o y52–54. Howe e , he addi ion o MAP,
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].
380 Pe ales e al.
Table 5 P edic ion a es o ea ly-onse p e-eclampsia (PE) using di e en models a 20, 24 and 28weeks
De ec ion a e (%)
P edic ion model FPR =5% FPR =10%
20 weeks
Ea ly-onse PE p edic ion model 45 60
sFl -1/PlGF a io, MAP, being pa ous, p e ious PE, U A-PI and ART 50 60
sFl -1/PlGF a io, MAP, being pa ous, p e ious PE and ART 55 60
MAP, being pa ous, p e ious PE, U A-PI, ART and PlGF 35 55
MAP, being pa ous, p e ious PE, ART and PlGF 45 45
24 weeks
Ea ly-onse PE p edic ion model 60 70
sFl -1/PlGF a io, MAP, being pa ous, p e ious PE, U A-PI and ART 72 78
sFl -1/PlGF a io, MAP, being pa ous, p e ious PE and ART 60 70
MAP, being pa ous, p e ious PE, U A-PI, ART and PlGF 56 67
MAP, being pa ous, p e ious PE, ART and PlGF 56 67
28 weeks
Ea ly-onse PE p edic ion model 81 81
sFl -1/PlGF a io, MAP, being pa ous, p e ious PE, U A-PI and ART 73 80
sFl -1/PlGF a io, MAP, being pa ous, p e ious PE and ART 81 81
MAP, being pa ous, p e ious PE, U A-PI, ART and PlGF 53 53
MAP, being pa ous, p e ious PE, ART and PlGF 53 53
Ea ly-onse PE p edic ion model includes soluble ms-like y osine kinase 1(sFl -1)/placen al g ow h ac o (PlGF) a io, mean a e ial
p essu e (MAP), being pa ous and p e ious PE. A eas unde ecei e –ope a ing ch ac e is ics cu es o each model a e p o ided in
Table S4. ART, assis ed ep oduc i e echnologies; FPR, alse-posi i e a e; U A-PI, u e ine a e y pulsa ili y index.
Table 6 Pe o mance o s anda d p edic ion model and same model plus soluble ms-like y osine kinase-1 (sFl -1)/placen al g ow h ac o
(PlGF) a io o es ima e isk o ea ly-onse p e-eclampsia a 20, 24 and 28weeks
De ec ion a e (%)
P edic ion model AUC (95% CI) FPR=5% FPR =10%
20 weeks
S anda d p edic ion model (ma e nal his o y, MAP, U A-PI) 0.81 (0.71–0.89) 17 48
S anda d p edic ion model plus sFl -1/PlGF a io 0.91 (0.85–0.97) 60 70
24 weeks
S anda d p edic ion model (ma e nal his o y, MAP, U A-PI) 0.87 (0.79–0.94) 40 60
S anda d p edic ion model plus sFl -1/PlGF a io 0.95 (0.90–0.99) 72 83
28 weeks
S anda d p edic ion model (ma e nal his o y, MAP, U A-PI) 0.89 (0.83–0.95) 42 58
S anda d p edic ion model plus sFl -1/PlGF a io 0.95 (0.90–1.00) 80 80
AUC, a ea unde ecei e –ope a ing cha ac e is ics cu e; FPR, alse-posi i e a e; MAP, mean a e ial p essu e; U A-PI, u e ine a e y
pulsa ili y index.
U A-PI and angiogenic se um ma ke s o he assessmen
o ma e nal his o y has been shown o inc ease he PE
de ec ion a e be ween 12 and 36 weeks’ ges a ion55–58. In
STEPS, he addi ion o he sFl -1/PlGF a io inc eased he
de ec ion a e a all ges a ional ages s udied, suppo ing
he inclusion o he sFl -1/PlGF a io in he isk es ima ion
o ea ly-onse PE.
The p ospec i e, longi udinal design and la ge coho
in ou s udy p o ided a obus da ase and he angiogenic
ma ke esul s we e hidden om he in es iga o s o a oid
bias in he diagnosis o ou comes. Howe e , despi e he
la ge sample size, he e we e ela i ely small numbe s o
women in he ea ly-onse PE g oup and he esul s o
his s udy, which included women a isk o de eloping
PE, canno be applied o a low- isk popula ion, i.e. in
sc eening o PE. The da a we e alida ed using he
Elecsys immunoassay sFl -1/PlGF a io and he p edic i e
alue may di e when o he assays a e used. The
de eloped p edic ion model o ea ly-onse PE has o
be alida ed in an independen p ospec i e s udy coho
in a compa able a ge popula ion, and in e en ional
s udies a e equi ed o confi m he clinical u ili y o he
esul s.
STEPS p o ides u he e idence ha he addi ion o
he sFl -1/PlGF a io o clinical p o ocols o women
a isk o PE imp o es p edic ion o ea ly-onse PE
in he second imes e . This complemen s he findings
o PROGNOSIS, which showed ha , in women wi h
signs and/o symp oms o PE and a sFl -1/PlGF a io
abo e 38, he posi i e p edic i e alue o PE wi hin
he ollowing 4 weeks was 36.7%32
. In STEPS, women
who de eloped ea ly-onse PE had a median sFl -1/PlGF
a io a 28weeks’ ges a ion o 51.9, indica ing ha
hese women had an inc eased isk o de eloping PE
in he ollowing 4 weeks be o e 34 0 weeks’ ges a ion.+
Be e p edic ion o PE could acili a e a ge ing o
moni o ing and he apeu ic p ocedu es owa ds a - isk
women and allow be e u iliza ion o heal hca e
esou ces.
©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].
sFl -1/PlGF STEPS 381
ACKNOWLEDGMENTS
We hank all women who pa icipa ed in he STEPS
s udy and he ec ui men o fice s, nu ses, midwi es and
midwi e y s a who suppo ed he s udy. We hank
he STEPS in es iga o s and MaJos´e Rami ez and
Nu ia Piella (Roche Diagnos ics, Spain). Suppo o
hi d-pa y w i ing assis ance o his manusc ip was
p o ided by Emma McConnell, PhD (Ga dine -Caldwell
Communica ions), and was unded by Roche Diagnos ics.
DISCLOSURES
The STEPS s udy was sponso ed by Roche Diagnos ics
Spain who we e in ol ed in s udy design, in e p e a ion
o he da a and w i ing o he manusc ip . ELECSYS
and cobas a e adema ks o Roche. A.P. is a consul an
o Roche, GE Heal hca e, Fe ing, I al a maco, EFFIK,
Me ck and Gynea. J.L.D. is a consul an o Roche and
I al a maco. M.H. is employed by Roche Diagnos ics and
has sha es in F. Ho mann-La Roche.
STEPS INVESTIGATORS
Azaha Rome o and F ancisco Cab e a, Hospi al Ma e no
In an il de Cana ias, G an Cana ia, Spain; Ma ´
ıa V ´azquez,
F ancisco Mo eno and ´
Osca Vaque izo, Hospi al Uni e si a io
Cen al de As u ias, O iedo, Spain; My iam Miguel, Ca alina
de Paco, Mi iam Pe egal and Alicia A eaga, Hospi al Vi gen de
la A ixaca, Mu cia, Spain; M. Jes´us F anco and Blanca En id,
Hospi al Miguel Se e , Za agoza, Spain; Elena Ma in, Jos´e
Luis Ba ha and An onio Bu ˜
no, Hospi al de la Paz, Mad id,
Spain; Gema P´e ez, Sil ia Roig, Rosa G´omez and Da id He ´as,
Hospi al Uni e si a io y Poli ´ecnico La Fe, Valencia, Spain;
´
Angel Agua on de la C uz and Nie es L´
opez, Hospi al G ego io
Ma a ˜n ´on, Mad id, Spain; Vic o ia Mele o and Me cedes Cale o,
Hospi al Pue a del Ma , Cadiz, Spain; Ma a de Ram´on and
An onio Paya, .Hospi al del Ma , Ba celona, Spain
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©2016 The Au ho s. Ul asound in Obs e ics & Gynecology published by John Wiley & Sons L d Ul asound Obs e Gynecol 2017; : 373–382.50
on behal o he In e na ional Socie y o Ul asound in Obs e ics and Gynecology.
P in ed by [Obs e ics and Gynecology - 095.022.056.057 - /doi/epd /10.1002/uog.17373] a [15/03/2021].