Optimal

mechanism of Preeclampsia

> unknown <

an effective an effective
screening PREVENTION

Other perspectives in personalized

screening and prevention of Preeclampsia

Aspirin Story
Just start early
Aspirin started by 16 weeks
• ASA and preeclampsia :

• < 16 weeks - RR 0.47 (0.34-0.65, prevalence 9.3%vs 21.3%)

• > 16 weeks - RR 0.81 (0.63-1.03, prevalence 7.3% vs 8.1%)

an early an early • ASA and fetal growth restriction :

screening PREVENTION • < 16 weeks - RR 0.44 (0.44-0.65, prevalence 7% vs 16.3%)

• > 16 weeks - RR 0.98 (0.87-1.10, prevalence 10.3% vs

10.5%)
 Diagram alur sampel penelitian

Faktor yang meningkatkan risiko PE

Status obstetri (multiparitas)
Riwayat DM
1321 data ibu hamil menjalani pemeriksaan untuk
IMT > 25 kg/m2
penapisan risiko preeklampsia di tiga rumah sakit
MAP > 95 mmHg, dan
PI arteri uterina yang tinggi
911 data ibu telah bersalin
Riwayat merokok tidak terbukti menurunkan risiko PE
147 data dengan subyek yang sama (dua
atau tiga data dari 1 subyek yang sama) Formulasi prediksi preeklampsia:

764 data dianalisis y = -4,646 + 2,837×(indeks massa tubuh) + 2,825×(status

obstetri) +1,937×(diabetes mellitus) + 2,368×(rerata tekanan
arterial) +0,966×(klasifikasi indeks pulsatilitas)

Nilai Ambang (cut-off) untuk Kategori Preeklampsia dan

Tidak Preeklampsia serta Kualitas Prediktifnya
 Smoking Figure 1 Receiver–operating characteristics
2 (6.7) curves of the 13Figure
(10.1)2 Receiver–operating characteristics
266 (9.5) curves of the
probability scores derived from five predictive
Chronic hypertension 14 (46.7) algorithms for 30probability
(23.3) scores derived from two206predictive
(7.3) algorithms for
Diabetes mellituspre-eclampsia requiring delivery prior
10to(33.3)
34 weeks for patients not 14pre-eclampsia
(10.9) requiring delivery after 34 weeks for patients not
96 (3.4)
Renal disease receiving aspirin. , Odibo et al.12
1;(3.3) , Poon et al.8 ; , 3receiving
(2.3) aspirin. , Parra-Cordero et al.7 ;
4 (0.1) , Scazzocchio
7 15 10
Thrombophilia Parra-Cordero et al. ; , Caradeux et al. ;
1 (3.3) , Scazzocchio al. .
2et(1.6) 60 (2.1)
Obstetric history et al.10 .
Nulliparous 16 (53.3) 75 (58.1) 1187 (42.2)
Previous PE 5 (16.7) 22prevalence
(17.1) of PE was twice 118 as high
(4.2) as reported for four
Ultrasound Obstet Gynecol 2014; 44: 279–285
Previous pretermdiscrepancies
Published labor 13 August
online between
2014 inreported
Wiley Online0 (0)
and observed
Library sensitivities. 2of(1.6)
(wileyonlinelibrary.com). the
DOI:prediction rules7,8,10,1350
10.1002/uog.13435 (1.8)
, whereas excluding women
BMI 31.33 (19.37–61.14) 29.11 (15.92–58.67) 26.63 (15.47–73.11)
Our study also demonstrated better prediction for the receiving aspirin resulted in comparable rates. Although
MAP (mmHg) 95.17 (81.33–130.00) 92.0 (66.33–135.67) 82.67 (48.33–138.00)
Lowest UtA-PI (n = five prediction rules that included
2962) maternal history or1.19 (0.25–2.86)
1.42 (0.11–2.43) one would expect a better 1.08 predictive
(0.11–3.68) accuracy with a
First-trimester prediction of pre-eclampsia: external validity
Mean UtA-PI (n =biomarkers.
2962) 1.71 (0.32–2.76) higher population prevalence
1.50 (0.38–3.04) of PE, this was not what we
1.38 (0.28–3.70)

Kualitas Model Skoring menurut Aspek Diskriminasi PAPP-A MoM (n = 2833) There are several potential 0.88 explanations
of algorithms in a prospectively enrolled cohort
PlGF MoM (n = 1565)
PP-13 MoM (n = 957)
ancies between reported and
(0.17–2.56)
0.66 observed
for discrep-0.75 (0.09–4.29)
observed. The tests performed
(0.16–1.40)performance of0.87 (0.10–2.78)
0.96 (0.55–2.82)
1.00
similarly in these patient
1.04 (0.08–5.13)
(0.30–4.09)
subsets, suggesting that variation in pretest probability
prediction rules. The population of origin may differ in0.86 (0.10–2.86)
of PE plays a minor role0.97 (0.06–12.24)
in the accuracy of multimarker
Gestational age at delivery (weeks) 31.86 (25.71–33.86) 37.57 (34.00–41.29) 39.14 (20.57–43.00)
their prevalence of risk factors,
Birth-weight percentile
risk factors may vary
7.78 (0.01–97.51)
algorithms. We observed
34.46 (0.04–97.94)
the greatest concordance for
43.70 (0.00–100)
in their contribution
N. OLIVEIRA*, to developing
L. S. MAGDER†, PE,BLITZER‡
M. G. and the preva-
and A.the
A. prediction
BASCHAT* rule that was developed in a USA popula-
Data are given as nlence
(%) orand clinical
median features
(range). of PE were
All parameters maymeasured
diverge infrom the patients,
the 2969 tion,unless
suggesting
indicateda otherwise.
potentialBMI,impact
bodyof the risk profile of
mass
*Department of Obstetrics, Gynecology
index; MAP, meanoriginal
arterial blood pressure;
population. When&
MoM, Reproductive
multiples Sciences,PAPP-A,
of the all
considering median; University
patients, of Maryland School
ourpregnancy-associated
the population of Medicine,
plasma
12 Baltimore,
protein-A;
. Scholten andPlGF, MD, USA;
placental
colleagues studied a large
†Department
growth factor; of Epidemiology13;
PP-13, placental-protein & Public
UtA-PI,Health,
uterineUniversity index. School of Medicine, Baltimore, MD, USA; ‡Department of
of Maryland
artery pulsatility
Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
Table 3 Comparison Table 4 Performance
of reported and observed performance
of prediction of prediction
rule probability models
scores for early
at cut-offs with(< 34 weeks’
highest gestation)
sensitivity and and late (≥for
specificity 34 early
weeks’(< 34 weeks’ gestation)
gestation) pre-eclampsia (PE)
and late (≥ 34 weeks’ gestation) pre-eclampsia
K E Y W O R D S: first trimester; multimarker prediction model; pre-eclampsia screening; validity
TP TN FP FN Sensitivity (%)
Sensitivity Specificity PPV NPV
Reference
Reported (n) AUC
(n)(95% CI)
(n) (n) at fixed
(95% 10% FPR(95% CI) (%) Probability
CI) (%) (95%score
CI) (%) (95%CI) (%)
Table 7. Hazard Ratios for the Prevalence of the Risk Profiles With Each Additional Gestational Week atReference PE rate* Reported Observed Reported Observed Cut-off Optimal cut-off
Delivery in Preceding Pregnancy Early pre-eclampsia
ABSTRACT
Early pre-eclampsia Parra-Cordero7 12 1091 450 5 research
71 (44–89)is required to determine 2.6
71 (68–73) the(1.4–4.6)
factors responsible
99.5 (99–100)
Parra-Cordero7 Scazzocchio
2619/17 10 20— 2331 0.70601(0.58–0.83)
10 for
6747the suboptimal
(47–82) 29 81 external validity.
0.0319465
(78–81) Copyright 99.6
0.0119318
3.2 (2.0–5.0) 2014(99–100)
Hazard Ratio (95% CI) P Adjusted Hazard Ratio (95% CI)* P Objective
Scazzocchio 10 To
Poon 8 evaluate0.96
5170/26 the(0.94–0.98)
18
performance0.77
2557
of(0.67–0.86)†
375
published
12 81
ISUOG. 43
60 (41–77)Published
87 by 0.0347586
John Wiley4.6
(86–88) 0.0090969
& (2.8–7.3)
Sons Ltd. 99.6 ç√
(99–100)
Poon 8 first-trimester
Poon
prediction
8366/37
13 algorithms
0.95 (0.92–0.99)
19
for pre-eclampsia
2366 0.78438(0.69–0.88)†
10 6689
(46–81) 53 84 (83–86)
0.0045660 0.0020121
4.2 (2.6–6.5) 99.6 (99–100)
Circulatory risk profile 0.96 (0.93–0.99) ,.001 0.96 (0.93–0.99) ,.001Poon
13
(PE) in a prospectively
8366/37
Odibo12 enrolled
0.96
8 cohort798of women.
(0.96–0.99) 0.80 (0.71–0.89)†
63 2
95
80 (44–97)
ç√ ç√
52 0.0032741
93 (91–94)
0.0008496
11.3 (5.3–21.5) 99.8 (99–100)
Odibo12 452/12 0.85 (0.69–1.00) 0.86 (0.73–0.99) 68 80 0.0172392 0.0948812
Metabolic syndrome 0.92 (0.88–0.95) ,.001 0.91 (0.87–0.96) ,.001Caradeux 15 Caradeux15 12 2731 201 18 INTRODUCTION
40 (23–59) 93 (92–94) 5.6 (3.1–9.9) 99.0 (99–100)
627/9
Method A MEDLINE 63 0.90
30 (−) identified0.69
search (0.59–0.80)
first-trimester 0.0882681 0.0539006
Any thrombophilia 0.99 Table 7.
(0.95–1.02) Hazard.81Ratios for the1.0
Prevalence
(0.96–1.03) of the Risk Profiles With Each Additional Gestational
.68Late pre-eclampsia Week
Late pre-eclampsia
screening-prediction algorithms at
for early-onset (requiring
Pre-eclampsia (PE) affects 2–3% of pregnancies but is
7
Parra-Cordero7 Parra-Cordero
2619/53 64— 549 0.61931 14
(0.55–0.68) 8229
(71–90) 18 37 (35–40)
0.4106497 6.4 (5.0–8.1)
0.0982396 97.5 (96–99)
Hyperhomocysteinemia 0.95 (0.91–0.98) Delivery
.004 in Preceding Pregnancy
0.95 (0.91–0.99) delivery
.01 Scazzocchio 10 34 weeks)
<Scazzocchio
5170/100
≥ 34 weeks) PE. Maternal variables, ultrasound param-
10 and late-onset
82 (requiring
1784
0.71 (0.66–0.76) 0.69933
7140 delivery
responsible
(61–79) for
34
(0.64–0.75)
10–15%
31 66 (64–67)
of maternal
0.1643843 8.1 0.0488402
or fetal mortali-
(6.5–10) 98.0 (97–99)
ties and an equal proportion of indicated preterm births
CI, confidence interval. Only the eters and
first authorOnly
is the first
given forauthor
biomarkers each is given
were for each reference.
determined
reference. *Number Predictive
prospectively
in study/number inscores
with were
worldwide
PE. 0.05 1for
†P <calculated to predict
. Early affected
prediction
comparison patients
of PE
of reported vs
andwouldall other
observedmakewomen. FN, false
it pos-
Hazard Ratio (95% CI)
* Hazard ratio after adjustments for age, parity, smoking, and additional diagnosis of hemolysis, elevated liver enzymes, and low platelet
area under the negative; FP,P
receiver–operating false positive; NPV,
characteristics Adjusted Hazard Ratio (95% CI)*
negative
curves
singleton pregnancies enrolled between 9 and 14 weeks. predictive
(AUC). value;
Predictive PPV,
scores positive
were predictive
calculated to value;
predict TN, true
affected 2 negative;
patients vs
sible to offer prophylaxis and enhanced surveillance TP,
all true
other Ppositive.
women; probability score cut-off was chosen based on the highest sensitivity and specificity. FPR, false-positive rate.
count syndrome and growth restriction in a neonate in the index pregnancy. Prediction algorithms were applied to this population of women at risk. Because PE has multiple underly-
ing risk factors3 , the most promising approach to early
Circulatory risk profile 0.96 (0.93–0.99) ,.001 to mance
calculate predicted probabilities for PE. The perfor-
Copyright
of  2014 ISUOG.
the detection
prediction
0.96 (0.93–0.99)
Published
algorithms by compared
John Wiley & Sons Ltd.prediction has been ,.001aUltrasound Obstet Gynecol 2014; 44: 279–285.
originally reported rates, with wasa negative with
study differs from that of Farina multifactorial
et al. becausescreening
we model
Metabolic syndrome 0.92 (0.88–0.95) ,.001 that in the original 0.91
publication
discrepancy in prediction sensitivity ranging from 2.5%and (0.87–0.96)
evaluated for factors
evaluated incorporating
a USA population ,.001
a combinationand of maternalPE
stratified history
into and bio-
explaining 4 – 15
the risk of future cardiovascular disease; however,
Any thrombophilia mocysteinemia is 0.99
associated with fetal closure defects
(0.95–1.02) and 6.8%.
.81 Farina differences
and colleagues in prediction.
conclude
1.0 that mixed
(0.96–1.03) early and physical and biochemical
late forms by gestational
.68 markers
age at .delivery.
However, even
prediction models containing with the application of a multifactorial approach, pre-
supplementation has not been proven effective in that can be reduced by (0.91–0.98)
vitamin B supplementation. 52 Results Six early and twomaternal history and
late PE prediction With the
algorithms exception of the prediction rule derived in
Hyperhomocysteinemia 0.95 .004
biomarkers yielded the most 0.95
reproducible
were applicable to 871–2962 women, depending on
(0.91–0.99)
results. Our a diction USA
comparative divergespopulation.01
considerably,
12
we ranging between
observed higher 46.7%
reducing that risk.48 Second, multivitamin supplemen- For these reasons, it seems warranted to screen for- the variables required. The prevalence of early PE was and 100% for PE requiring delivery before 34 weeks –
and between 29.4% and 71.1% for later-onset PE4 15 .
tation containing folic acid in womenCI,with confidence
hyperho-interval.
merly preeclamptic women for hyperhomocysteine- 1.0–1.2% and of late PE was 4.1–5.0% in these patient Potential explanations for this divergence include varia-
* Hazard ratio after adjustments for age, parity, smoking, and additionalCopyright
49,50 diagnosis
subsets. of hemolysis,
 2014 ISUOG.
One Published
early PE by Johnelevated
prediction & Sons liver
Wileyalgorithm enzymes,
Ltd.performed and low
Ultrasound platelet
Obstet Gynecol3,5 2014; 44: 279–285.
mocysteinemia reduces the risk of preeclampsia. mia. Formerly preeclamptic women are likely to better than in the original publication (80% detection tion in 16population risk profiles , utilization of low-dose
count syndrome and growth restriction in a neonate in the index pregnancy. aspirin , statistical approaches to model development4,17
Third, hyperhomocysteinemia increases the risk of benefit from screening and tailored treatment for their rate (DR) of early PE for 10% false-positive rate (FPR)); or limited external validity of these algorithms. It is
the remaining five prediction algorithms underperformed
venous and arterial thrombosis that can be reduced risk profiles.53 (29–53% DR). Prediction algorithms for late PE also
important to ascertain external validity of screening algo-
by vitamin supplementation.15,16,51 Fourth, hyperho- Our study may have some methodologic limita- underperformed (18–31% DR, 10% FPR). Applying the rithms before their widespread clinical application. It
was the aim of our study to evaluate the predictive
tions. First, our study population represents that of screening
the risk of future cardiovascular disease; however,
cut-offs based on the highest Youden index
mocysteinemia is associated with fetal closure defects
probability scores correctly detected 40–80% of women
performance of published first-trimester algorithms in
Co occurence of cardiovascular a tertiary clinic. This may limit generalization of the developing early PE and 71–82% who developed late PE. atrimester. cohort of women prospectively enrolled in the first
supplementation hasandnot been proven effective in that can be reduced by vitamin B supplementation. 52
Circulatory risk profile (66.1%)
prothrombothic risk factorsthat
reducing
Hyperhomocysteinemia (18.7%) in risk.
women results to the general population of formerly pre- Exclusion
with multivitamin supplemen-
48
Second, For these reasons, it seems warranted to screen for-
eclamptic women because of possible overrepresen- respectively.
DRs of 40–83% and 65–82% for early and late PE, Validation study in Jakarta
of patients on first-trimester aspirin resulted in

METHODS
Metabolic syndrome (15.4%)
history oftation
Thrombophilic profile (10.8%) containing
preeclampsia tation ofacid
folic in women
women with hyperho-
with a history of more merly
severe preeclamptic women for hyperhomocysteine-
Conclusion First-trimester prediction algorithms for PE This was a secondary analysis of a prospective,
No abnormalities (22.4%)
mocysteinemia reduces
preeclampsia.the Itrisk is conceivable that this49,50
of preeclampsia. may have mia.shareFormerly
a high negative preeclamptic 1321
predictive data
value Ibu hamil
if applied to an menjalani
women arepemeriksaan
observationallikely
study with to
the primary aim of developing
untuk penapisan
external population but underperform resiko preeklampsia
in their ability a first-trimester di tiga model for PE . For the
predictive 18
resulted in overestimation of the prevalence of risk to correctly identify women who develop PE. Further
Third, hyperhomocysteinemia increases the risk of benefit from screening and tailored Rumah treatment
primary study,for
Sakit 3422 their
women who presented between 2007
profiles. This effect is probably small, because adjust-
venous and arterial
mentsthrombosis
for co-occurrence that ofcan be reduced
HELLP and the deliveryrisk profiles.53
15,16,51
by vitamin supplementation.
of IUGR, as indicators ofFourth, severity ofhyperho-
preeclampsia, did Our study
Correspondence may
to: Dr A. have
Penelitian
A. Baschat, Departmentsome methodologic
of Pendahuluan
Gynecology limita-
: 911 Johns Hopkins
and Obstetrics, University School of Medicine, 600 North
data USA
Wolfe Street, Phipps 287, Baltimore, MD 21287, ibu(e-mail:
telahaabaschat@hotmail.com)
bersalin
not affect the results, Second, the formerly preeclamp- tions.Accepted:
First,23 Mayour2014 study population represents that of
42.1 3.9 3.6 22.4 tic women in our study were evaluated 6–12 months a tertiary clinic. This may limit generalization 147 data dengan subyek
postpartum. We cannot rule out possible overestima- yang sama (duaof the
atau tiga
Circulatory risk profile (66.1%)
tionHyperhomocysteinemia
of the prevalence(18.7%) of cardiovascular risk factors results to
Copyright  the
2014 general
ISUOG. Published by population
John Wiley & Sons Ltd. ofdari formerly
1 subyek yangpre- sama) ORIGINAL PAPER

because improvement
Metabolic syndrome (15.4%) still may continue thereafter. eclamptic women because of possible
764 data (Penelitian overrepresen-
Although further
Thrombophilic (10.8%) has been reported up tation
recovery
profile to of women withpendahuluan) a history
baru !
+ 368of
dianalisis
datamore severe
54
2 years postpartum, abnormal hemodynamic varia- preeclampsia. It is conceivable thatData this totalmay
: 1500,have
No abnormalities (22.4%)
bles in formerly preeclamptic women largely (more drop out :
6.4 0.8 0.4 5.3
than 80%) resolve within 6 months after giving birth. resulted in overestimation of the prevalence
350, Data yangof dapat
1150
riskdinilai :

1.4 0.2 0.1 0.7 Third, our study includes only Caucasian women. profiles. This effect is probably small,
Aplikasi Prediktor
because adjust-
This may limit generalization, because other ethnic ments for co-occurrence of HELLP and the delivery
Preeklampsia
0.7 0.5 groups may display different profiles. of IUGR, as indicators of severity of preeclampsia, did
10.6 4.5
In conclusion, 77.6% of women with a history of
preeclampsia have one or more cardiovascular or not affect the results, Second, the formerly preeclamp-
Fig. 1. Scaled rectangle diagram indicating the prevalence
42.1
prothrombotic risk factors. 22.4
3.9 3.6 The circulatory risk tic
profile women in our study were evaluated 6–12 months
and co-occurrence of circulatory risk profile, metabolic was most prevalent. The prevalence of the circulatory postpartum. We cannot rule out possible overestima-
syndrome, thrombophilia, and hyperhomocysteinemia in risk profile and also components of the metabolic tion of the prevalence of cardiovascular risk factors
formerly preeclamptic women. Numbers represent per- syndrome other than obesity and hyperhomocystei-
nemia relate inversely with the gestational age because improvement still may continue thereafter.
centages relative to the total study population. Each rect-
angle area is scaled according to the prevalence of the
at
delivery in preceding pregnancy. Although these Although further recovery has been reported up to
 Kemampuan Diskriminasi dari Sistem Skoring Baru untuk
Memprediksi Preeklampsia

• Kemampuan diskriminasi 85%

(AUC 0,85) untuk membedakan
populasi preeklampsia dan tidak
• Model prediksi yang dibuat
merupakan instrumen yang
baik sebagai uji diagnostik
preeklampsia

Validation study in Jakarta Aspirin reduced prevalence of preeclampsia

to predicted level
Perempuan 25 tahun, hamil pertama, tanpa riwayat diabetes mellitus,
tekanan darah awal 110/70 mmHg, dan IMT 22 kg/m2, PI arteri uterina
normal akan memiliki risiko preeklampsia sebesar 0,9%.
y = -4,646
ey = 0,009
A priori risk = odds/(1 + odds) = 0.9%

Perempuan 27 tahun, hamil ketiga dengan riwayat preeklampsia di

kehamilan sebelumnya, tanpa riwayat diabetes mellitus, IMT 22,4 kg/
m2, tekanan darah awal 120/80 mmHg, dan PI arteri uterina yang tinggi
akan memiliki risiko preeklampsia sebesar 29%.
y = -0,855
ey = 0,425
A priori risk = 29%
 Medical Foundation, Cardiology, Yuba City, CA, 3University
mmHg and DBP of 75 mmHg, falling into the JNC-7 pre-HTN Heartrange. 41 weeks
Institute, Cardiology, in which
Lexington, the risk
KY, 4University of K
CONCLUSION: Women who fail ASA preeclampsia prevention have
Obstetrics contrast,
and Gynecology, the risk
Lexington, KY, 5of infant
Carolinas de
Healt
Fetal Medicine, Charlotte, NC
first-trimester BP meeting JNC-7 pre-HTN or HTN criteria more two groups. This
OBJECTIVE: Preeclampsia is a risk factor for ma
increased
often than do women for whom ASA prophylaxis works. Measured dysfunction. We posite
sought tofetal/infant mortality
examine clinical factors a
first-trimester BP elevation may be the most important echocardiographic target in period evidenceforof pregnancies
cardiac dysfunction.
affec
STUDY DESIGN: Preeclamptic women aged 18-43 wer
combined pregnancy
285 First trimestertreatment
aspirin (ASA)strategies to prevent preeclampsia.
fails to prevent CONCLUSION: The risk
this IRB approved study. Demographics, clinical data
of s
preeclampsia in hypertensive women chronic
1 1 1 were recorded during the hypertension
ante and postpartum is higco
Ozhan Turan , Dana Block-Abraham , Lauren Doyle ,
transthoracic echocardiography
term gestational was performed
ages, forhow
de
First
Jerometrimester
Kopelman1, characteristics of
Robert Atlas1, Chuka Jenkins women
2
, who myocardial function and myocardial strain with sp
Chris Harman1, Ahmet Baschat1
develop
1 preeclampsia despite aspirin prophylaxis complications of potential
Statistical analyses included t-test, Wilcoxon rank sum
University of Maryland, Baltimore, MD, 2Medstar Harbor Hospital,
Baltimore, MD correlations. livery.
OBJECTIVE: We studied first trimester (T1) ASA as preeclampsia (PE) RESULTS: We enrolled 23 women with mild
prophylaxis in women with hypertension (HTN) severe(n¼13) preeclampsia. Echocardiography was
STUDY DESIGN: At entry to a prospective T1 screening study for PE, partum on 21(strain imaging on 8) and postpartum
we identified women with pre-HTN (120-139/80-89) and HTN imaging on 11) women. Mean age was 28.7 "5.6 years
(>139/>89) blood pressure. ASA was begun by providers indepen- were Caucasian(n¼21) and primigravida(n¼14). Aver
dent of the study. ASA started >T1 was excluded. Obesity age at enrollment (32.0 "4.8 weeks) was not signific
(BMI>30), and Uterine Artery pulsatility index (UtA PI) at T1 and between mild and severe preeclamptics.
Question: T2 were recorded, with change in UtA PI expressed as per day ratio Speckle tracking on ante and postpartum echocar
not significantly different between those women wit
(%PI). PE<34 and PE>34 weeks were analyzed
At whom not working ? Editorial
RESULTS: Of 1007 total, 229 used ASA (23%), for prior HTN, severe preeclampsia. Worsening strain (circumferen
121
thrombophilia, prior PE, bilateral UtA Doppler notching (p<0.0001 partum echocardiography was associated with earlier
overall, vs no-ASA group). Women on ASA had better UtA at diagnosis and delivery (p¼0.05 and 0.03 respectiv
Parameter remodeling (%PI 0.69% Classified by category
vs 0.54% Classified
in no-ASA group,byp¼0.01). lower to
risk profileRisk Amenable birth weight (p¼0.03). Postpartum, worseni
treatment
Maternal age of PE<34 weeks was higher in those with diabetes, HTN, ne- associated with increasing mean arterial (MAP) and
pressure on delivery date (p¼0.01 and 0.01 respe
Maternal ethnicity phropathy, T1 UtA notching (p<0.0001 to 0.01), while PE
>34weeks was higher in patients with diabetes, HTN and prior PE partum fractional shortening (FS) was lower in wom
Tobacco use in pregnancy
Parity
(p<0.0001 to 0.01). InPersonal
those history Personal
with HTN, PE<34 was 2.7% inNo hydramnios (22.8 "1.8 vs 28.3 "4.5, p¼0.04) a
risk profile
weeks
no-ASA, 3.5% in ASA users, unaffected by ASA use (LR¼1.2 CI(0.7- umbilical artery dopplers (24.6 "3.1 vs 28.7 "4.8, p
Education level
2.2)). PE after 34 weeks was also higher in ASA users (13.5% vs partum, FS was lower in women with IUGR at admiss
Conception method
7.6%), unaffected by ASA use (LR¼1.6 CI(1.2-2.2). ASA use did not vs 33.3 "8.3, p¼0.03).
Family history of pre-eclampsia
lower PE in any group, (Table, many had multiple factors) CONCLUSION: Markers of preeclampsia severity includ
Prior pre-eclampsiaCONCLUSION: Although T1 ASA does enhance placental invasion, in age at diagnosis and delivery, MAP, oligohydramn
Data are presented as median values and ranges.
Prior preterm birth these hypertensive women ASA alone did not prevent PE. While
PAPP-A ¼ pregnancy-
umbilical artery dopplers, and fetal growth restrictio
associated
Renal disease plasma
interaction protein-A.
of multiple factors MoMcontributes
likely ¼ multiples
to ASAof the these
failure, median.dictors
Freeof cardiac
b risk given their association with echo
Past medical
data indicate other preventive
conditions interventions (such as strict BP con-
cardiac dysfunction.
Hypertension HCG ¼ free beta human chorionic gonadotropin.
trol) may be needed. Cardiovascular risk
Systolic blood pressure Yes: antihypertensives
profile
Diastolic blood pressure Physical examination
239 The risk of stillbirth and infant death by each additional
Mean arterial blood pressure
week
Prior gestational of expectant management
diabetes History stratified by maternal
Past medical
Editorial 121 chronic
Pre-existing hypertension
diabetes mellitus
conditions
S150 American Journal of Obstetrics & Gynecology
Metabolic risk profileto JANUARY
Supplement Yes: metformin,
2014
Jessica Page1, Jonathan Snowden2, Bethany Sabol2,
Maternal height pravastatin

Parameter
Maternal age
Maternal ethnicity
Tobacco use in pregnancy
Parity
Education level
Conception method
Family history of pre-eclampsia
Prior pre-eclampsia
Prior preterm birth
Renal disease
Hypertension
Systolic blood pressure
Diastolic blood pressure
Mean arterial blood pressure
Prior gestational diabetes
Pre-existing diabetes mellitus
Maternal height
Maternal weight
Maternal body mass index
Thrombophilia
Uterine artery Doppler index
Uterine artery notching
free beta-human chorionic gonadotropin
Pregnancy-associated plasma protein-A
Placental growth factor
Placental protein-13
A disintegrin and metalloproteinase-12
Classified by category Classified by risk profile Amenable to treatment Yvonne Cheng3, Aaron
Maternal weight
Caughey2
Physical examination
Maternal body
1 mass index
University of Utah, Obstetrics and Gynecology, Salt Lake City, UT, 2Oregon
Past medical
Thrombophilia Prothrombotic risk profile Yes: heparin, aspirin
Health and Science University,
conditionsObstetrics and Gynecology, Portland, OR,
3 Doppler index
Uterine artery
Personal history Personal risk profile No University of CaliforniaPlacental
San Francisco,
blood flow Obstetrics, Gynecology and
Uterine artery notching
Reproductive Sciences, San Francisco, CA
free beta-human chorionic gonadotropin
OBJECTIVE: To determine the fetal/infant mortality risk associated with
Pregnancy-associated plasma protein-A
each additional week of expectant management during term in women
Placental growth factor
with chronic hypertension
Placental protein-13 Placentalcompared
biomarker to a low-risk
Placental risk profilepopulation.
No
A disintegrin and metalloproteinase-12
Past medical Soluble endoglin
conditions Soluble fms-like tyrosine kinase-1
Cardiovascular risk
Yes: antihypertensives P-selectin
Physical examination
profile
S128 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2014
Neutrophil gelatinase-associated lipocalin
Inhibin-A
History Vascular endothelial growth factor
Past medical
Tumor necrosis factor
conditions Metabolic risk profile Yes: metformin,
Pentraxin-3
pravastatin
Physical examination Angiopoietin
Past medical Figure 1 First-trimester variables associated with pre-eclampsia, listed by category, risk profile and treatability.
Prothrombotic risk profile Yes: heparin, aspirin
conditions
Hyperinsulinemia-related risks could potentially beneficial effect of metformin81 . Importantly, as there
Placental blood flow
be addressed by administration of metformin, an appear to be no adverse effects on the mother and
insulin-sensitizing agent. The potential benefit of met- offspring, these studies indicate that metformin can be
formin is suggested by a recent meta-analysis of women continued safely after conception78,82,83 .
with polycystic ovary syndrome who continued therapy
Because several lipid abnormalities, including hyper-
after conception80 . In these women, metformin reduced
triglyceridemia, increased low-density lipoprotein (LDL)
Placental biomarker Placental risk profile No pre-eclampsia by almost 50%, with a pooled odds ratio
of 0.53 (95% CI, 0.30–0.95). Interestingly, women with and lower HDL levels, have been shown to predate devel-
Cardiovascular hyperinsulinemia with at least two of the other three components.
hyperinsulinemia with at least two of the other three components.
Prothrombotic
Prothrombotic At the same time, animal and human studies suggest
At the same time, animal and human studies suggest that high blood pressure can damage the placental
that high blood pressure can damage the placental vasculature and that it is the severity of hypertension that
Figure 3 Adjusted
vasculature proportional
and that contribution of individual
it is the severity risk
of hypertension that
Figure 3 Adjusted proportional contribution of individual riskprofiles to pre-eclampsia risk, according to whether they112 is the predominant risk factor for SGA112 – 114 . Similarly,
Editorial risk, according to whether they are not is the predominant risk factor for SGA – 114 . Similarly, are not
123

\
profiles to pre-eclampsia treatable ( ) or treatable ( ). placental perfusion dependence on maternal cardiac
treatable ( ) or treatable ( ). placental perfusion dependence on maternal cardiac
output increases predominantly from the second trimester
output increases predominantly from the second trimester
Percent Table 1 Diagnostic criteria of the metabolic syndrome onwards and to
according some trials have demonstrated higher birth
onwards and some trials have demonstrated (WHO)69 have –higher
71 birth
0 10 20 30 develop50gestational
40 60 World Health Organization
hypertension or pre-eclampsia weight in treated groups despite a greater antihypertensive
develop gestational hypertension or pre-eclampsia have weight in treated groups despite a greater antihypertensive 115 – 117
mean blood effect . The preventative potential of early blood
mean blood pressures Placental above this threshold and deliv- effectpressures
115 – 117 above
. The
Components
this threshold
preventative potential and deliv-
Cut-off of early blood
ery of a pressure
small-for-gestational-age (SGA) infant is more pressure normalization is suggested by the significantly
ery of a small-for-gestational-age (SGA) infant is more normalization is suggested by the significantly
likely for decreased
diastolic blood pressure prevalence
Hyperinsulinemia
pre-eclampsia exceeding 80
Fasting
and glucose103
mmHg
hypertensive
decreased pre-eclampsia prevalence and hypertensive dis-
≥ .6.1 mmol/L
dis- 2
likely for diastolic blood pressure exceeding 80 mmHg103 .
Personal Birth weight and Obesity
perinatal
ease severityHypertension mortality appear Body
in women receiving antihypertensive to mass
be index ≥ 30 kg/m
related ease severity in women receiving antihypertensive therapy
therapy
Birth weight and perinatal mortality appear to be related
more closely
from to
the diastolic
second blood
trimester pressure, Systolic
111,112,117and – 119blood
.optimal pressure ≥
First-trimester,
140 mmHg
from or
the second trimester111,112,117 – 119 . First-trimester,
more closely to diastolic blood pressure, and optimal diastolic blood pressure ≥ 85 mmHg
growth and perinatalProteinuria
observational outcome
data indicateare observed
that high-risk for diastolic
women who observational
≥ 2.5are
data indicate that high-risk women who are
growth and perinatal Metabolic outcome are observed for diastolic Microalbuminuria g/mL or
blood pressures between 70 and
normotensive in the first trimester have 80 mmHg and systolic
a 50%
proteinuria reduction
≥ 0.30 normotensive
g/24 h in the first trimester have a 50% reduction
blood pressures between 70 and 80 mmHg and systolic
104,105 blood pressure > 110 mmHg (Figure 5) 104,105 . Once they
of pre-eclampsia, while those with pre-hypertension or of pre-eclampsia, while those with pre-hypertension or
blood pressure > 110 mmHg (Figure 5) . Once they The WHO defines metabolic syndrome as the presence of
Cardiovascular become established
hypertension in the first trimester,
have a greater women
than maintain hypertension have a greater than two-fold increased
become established in the first trimester, women maintain hyperinsulinemia with at least two-fold
two of the otherincreased
three components.
28 .
their blood pressure category throughout pregnancy and their bloodrisk pressure
28 . category throughout pregnancy and risk
it is the systolic and diastolic blood pressure changes
Prothrombotic it is the systolic and diastolic
Since maternal blood pressure
hypertension most prevalentSince maternal hypertension is the most prevalent
is the changes
from second to third
and consistently At the same time,
trimester,
demonstrated animalbyand
modified
first-trimester mater-human
risk factor,studies
and suggest demonstrated first-trimester risk factor,
consistently
from second to third trimester, modified by mater-
nalofcharacteristics,
there is a most that
that are high blood
associated
urgent pressure
need forwith can
the risk
research damage
of
to clarify the
there
the placental
is a most urgent need for research to clarify the
nal characteristics, that are associated with the risk
106,107 pre-eclampsia 106,107 vasculature and that it is
preventive .potential of first-trimester antihypertensives the severity of hypertension
preventive that
potential of first-trimester antihypertensives
pre-eclampsia .
Figure 3 Adjusted proportional contribution of individual risk 112 – 114
profiles to pre-eclampsia risk, according to whether and
First-trimester
they are not the is theand
thresholds
systolic predominant
and treatment
diastolic risk
blood factor
targets for
pressure for
suchSGA
val- and
therapy. . Similarly,
the thresholds and treatment targets for such therapy.
First-trimester systolic and diastolic blood pressure val-
treatable ( ) or treatable ( ). ues that are associated placental
with perfusion
normal outcome dependence
are notably on maternal cardiac
ues that are associated with normal outcome are notably
lower than any recommended output increasestreatment predominantly from the second trimester
threshold
lower than any recommended treatment threshold Thehigher
thrombotic
108,109
The thrombotic
utilized in pregnancy onwards
108,109risk profile
and some trials
. The concept of first-trimesterhave demonstrated birth risk profile
utilized in pregnancy . The concept of first-trimester
develop gestational hypertension or pre-eclampsia
normalization have of bloodweight pressure
in treated to groupsa valuedespitebelow a greater antihypertensive
normalization of blood pressure to a value below The maternal adaptation of the coagulation system makes The maternal adaptation of the coagulation system makes
mean blood pressures above this threshold and deliv- effect115 – 117 . The preventative potential of early blood
140/80 mmHg for prevention of pre-eclampsia is unex- 140/80 mmHg pregnancy for prevention of pre-eclampsia
a natural prothrombotic state.is Inunex- pregnancy a natural prothrombotic state. In this setting,
this setting,
pressure normalization is suggested by the significantly
plored andery of to
likely a small-for-gestational-age
be considered controversial. (SGA) infantand
Central
plored iscoagulation
more
likely to be considered
disorders such controversial.
as thrombophilia Centralor systemic
coagulation disorders such as thrombophilia or systemic
likely for diastolic blood pressure exceeding 103 decreased pre-eclampsia prevalence and hypertensive dis-
to this controversy is the concern that therapy to 80
offersthismmHg lupus .erythematosus
controversy is the concern are recognized
that therapy riskoffersfactors lupusfor erythematosus are recognized risk factors for
ease severity in women receiving antihypertensive therapy
no benefit Birth Other current perspectives
weight and
and increases theperinatal mortality
risk of growth appear
restriction, to be placental
no benefit related
109 – 111and optimal
and increasesdysfunction the riskand pre-eclampsia.
from thedisorders,
Other current perspectives
of growth restriction,
second trimester
In patients
111,112,117 – 119
with
placental dysfunction and pre-eclampsia. In patients with
. First-trimester,
presumablymore due toclosely to diastolic
uteroplacental blood pressure,
underperfusion .
presumably specific
due to coagulation
uteroplacental targeted therapy
underperfusion 109 – 111decreases
. specific coagulation disorders, targeted therapy decreases
growth and perinatal outcome are observed for diastolic observational data indicate that high-risk women who are
blood pressures between 70 and 80 mmHg and systolic normotensive in the first trimester have a 50% reduction
(a) Traditional first-trimester PE screening (b) First-trimester (a)screening with
Traditional risk profile identification
first-trimester PE screening while (b) First-trimester
blood pressure > 110 mmHg (Figure 5) 104,105 . Once they of pre-eclampsia, those with screening with risk profile
pre-hypertension or identification
become established
Low risk in the first trimester, women maintain Low risk hypertension
Low risk have a greater than
Non-treatable factors two-fold
Low increased
risk Non-treatable factors
their blood pressure category throughout
Multimarker Multimarkerpregnancy and risk28 . Placental Placental
Multimarker Multimarker
Personalis the most prevalent
it is the systolic and diastolic blood
algorithm algorithm pressure changes Since maternal hypertension Personal
algorithm algorithm
from second High toriskthird trimester, modified by High mater-risk and consistently
Risk
High risk profile demonstrated first-trimester High risk
risk factor, Risk profile
nal characteristics, that are associated with the risk of there is a most urgent Treatable need forfactors research to clarify the Treatable factors
106,107 preventive potential of Metabolic
first-trimester antihypertensives
pre-eclampsia . Metabolic
Cardiovascular
First-trimester systolic and diastolic blood pressure val- and the thresholds and treatment targets
Prothrombotic
for such therapy. Cardiovascular
Prothrombotic
ues that are associated with normal outcome are notably
lower than any recommended
Figure 4 Flowcharts comparing traditional
treatment threshold
(a) and risk-profile-based (b) first-trimester The thrombotic
screening risk profile
for pre-eclampsia (PE). Traditional
108,109 Figure 4 Flowcharts comparing traditional (a) and risk-profile-based (b) first-trimester screening for pre-eclampsia (PE). Traditional
first-trimesterutilized
screeninginprovides
pregnancya risk estimate . The
basedconcept of first-trimester
on a number of variables. First-trimester screening with risk profile identification also
first-trimester screening provides a risk estimate based on a number of variables. First-trimester screening with risk profile identification also
determines the normalization of bloodfactors
treatable and non-treatable pressure to the
that confer a value
increasedbelow The maternal
risk in screen-positive women.adaptation of the coagulation system makes
determines the treatable and non-treatable factors that confer the increased risk in screen-positive women.
140/80 mmHg for prevention of pre-eclampsia is unex- pregnancy a natural prothrombotic state. In this setting,
plored and likely to be considered controversial. Central coagulation disorders such as thrombophilia or systemic
Copyright  to 2015this controversy
ISUOG. Published by is John
the Wiley
concern & SonsthatLtd.therapy offers lupus erythematosus
Ultrasound Obstet Gynecol are recognized
2015; 45: 119–129. risk factors for
Copyright  2015 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2015; 45: 119–129.
no benefit and increases the risk of growth restriction, placental dysfunction and pre-eclampsia. In patients with
109 – 111
presumably due to uteroplacental underperfusion . specific coagulation disorders, targeted therapy decreases

Aspirin : not enough
ker algorithm or risk profiles for prediction of preeclampsia
Suggested optimal approach for first trimester prediction of pre-eclampsia
hes may prove useful4,5,16,19,21,40) and the second step will
the appropriate threshold for cardiovascular, metabolic
thrombotic risk profiles to trigger intervention. This is
ngible for metabolic and prothrombotic risks and
rsial for defining blood pressure treatment targets for
identified with cardiovascular risk in the first trimester.
he prevalence and relevance of the cardiovascular risk
n pregnancy outcome and long-term health of women,
al first trimester PE screening algorithms may prove to
al to advance research in this area of women’s healthcare.
eless, our study has some limitations to consider: because
documented importance in determining the accuracy of
rker algorithms, we chose to include placental biomarkers
n our study. As these were only available for a subset of
rticipants this limited our sample size for the sequential
n approach. However, we chose to use the entire cohort
to obtain better accuracy for the individual risk factors
nivariate analysis. Also, this limited sample size prevented
splitting it to a training group and a validation group. This
d to be done in future greater samples. Moreover, the
Preeclampsia rate = 0%
n of women receiving aspirin and anticoagulation further
our population towards women with cardiovascular and
c risk profiles, which are prevalent in the environment
his study was conducted. Finally, we pre-determined that
sequential approach the multimarker algorithm was
before the risk profiles. This approach was chosen based
Editorial 125
11–14-week screening
Increased risk for pre-eclampsia
Determination of primary
profiles contributing to
increased risk
Personal Placental Cardiovascular Metabolic Prothrombotic
risk risk risk risk risk
Initiate risk profile specific therapy by 16 weeks’ gestation
Low-dose aspirin Low-dose aspirin Low-dose aspirin Low-dose aspirin Low-dose aspirin
Early blood Weight control Disease specific
pressure Pravastatin† anticoagulation
management* Metformin* Folate for high
homocysteine†
Figure 6 Personalized pre-eclampsia prevention: flowchart illustrating a personalized approach to pre-eclampsia that addresses all risk
factors contributing to a woman’s risk. *Randomized trials are needed. †Randomized trials are currently underway.
In summary, we present a new sequential approach for first
homocysteine may be incorporated as a first-trimester risk for subsequent pre-eclampsia. Trials to address
trimester prediction of PE using a multimarker risk factor
algorithm into multimarker algorithms to identify metabolic risks are already underway and will hope-
personalized treatment needs. fully clarify the most effective preventive agents.
followed by application of risk profiles. This approach correctly
First-trimester initiation of low-dose aspirin is already
predicts the highest proportion of women that develop PE and supported by many professional organizations. However,
has the advantage of identifying potential treatment First-trimester
targets to personalized prevention of pre-eclampsia a personalized-risk-directed preventative approach may
prevent PE. This sequential screening approach may prove not only have a greater statistical impact, but also open
Pre-eclampsia is a condition with multifactorial origins.
up possibilities for a significant move towards improving
beneficial to determine women who should First-trimester
receivescreening algorithms confirm historic long-term cardiovascular health in women.
management for metabolic risks and to clarify observations
appropriate and show that cardiovascular, metabolic and
prothrombotic risks are the primary treatable factors that
management of cardiovascular risks. converge and determine a woman’s risk of developing Conclusion
pre-eclampsia at a time in gestation when intervention
has the most favorable risk-to-benefit ratio. Current Pre-eclampsia is a disease with multifactorial origins.
prevention strategies largely target downstream effects First-trimester screening algorithms for pre-eclampsia
rather than the primary inciting conditions. As a result, incorporate multiple risk factors into the appropriate sta-
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? benefits are mostly apparent for patients falling into the tistical context to offer personalized risk prediction early
• First trimester prediction of preeclampsia is feasibletarget range of the therapeutic agent concerned, and
by multimarker in pregnancy. All these factors fall into one of five risk
algorithms incorporating maternal characteristics, risk ultrasound
profiles that are not targeted continue to place profiles: personal, placental, cardiovascular, metabolic
women
variables and serum biomarkers or by stratifying women at risk
based on for pre-eclampsia while women in whom and prothrombotic. While low-dose aspirin initiated by
these risk profiles are addressed have significantly lower 16 weeks’ gestation reduces significantly the incidence of
their risk profile: mainly thrombotic, cardiovascular or metabolic.
risks. As pre-eclampsia is multifactorial in origin, it is pre-eclampsia in women with personal and placental risk
• The optimal method of prediction is still unknown.
intuitive that prevention needs to address multiple factors. profiles, women with unaddressed cardiovascular and
• All women at high risk for developing preeclampsia are treated the
Modification of first-trimester screening algorithms to not metabolic risks continue to develop it. Early management
same by low dose aspirin.
only calculate the risk, but also identify individualized of blood pressure, insulin insensitivity, abnormal lipid
treatment targets, would offer an opportunity to provide profile, dietary calcium deficiency or hyperhomocysteine-
personalized prevention of pre-eclampsia (Figure 6). mia can all significantly reduce the rate of pre-eclampsia
WHAT DOES THIS STUDY ADD? In this context, the greatest impact is likely to in appropriately selected patients. This selection can be
arise from early optimization of blood pressure; trials achieved most effectivelyNature
by first-trimester
Medicine 15 (2012)screening algo-
• Combination of multimarker algorithm followed by direction
in this further are urgently needed. This risk fac- rithms, with subsequent identification of the risk profiles
tor is has
stratification of the screen positive women by risk profiles mosttwo frequent numerically and carries a high that require specific therapy. In this context, research into
advantages: (a) lowering false positive rate, therefore preventing
unnecessary treatment and (b) enabling the potential for targeted
Copyright  2015 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2015; 45: 119–129.
 turnover together establish an oscillating pattern of
Notch activation based on the availability of replenished
Notch receptors and ligands. Nuclear NICD is eventually
targeted for proteasomal degradation mediated by the
E3 ubiquitin ligase F box- and WD repeat domain-contain-
ing 7 (FBW7) [4,5]. A recent study showed that FBW7
transcription is repressed by the Notch target gene Hes5,
thus creating a positive feedback loop that prolongs Notch
signaling [6].
Notch signaling is a highly conserved intercellular com-
munication mechanism critical for many cellular processes
including survival, proliferation, and differentiation, as No. ofrate-limiting
TEM-1016;
well as maintaining stem cell quiescence and identity
Review
[7]. Thus, Notch signaling is widely employed to orches-
gluconeogenesis, and stimulates glucose utilization, in-
cluding glycolysis and lipogenesis. Recent studies have
revealed a key role of Notch signaling in regulating both
processes, with abnormal activation of Notch signaling in
hepatocytes leading to hyperglycemia and fatty liver dis-
ease (Figure 1) [10,11].
The effect of Notch signaling on hepatic glucose produc-
tion is mainly mediated through synergy of NICD with the
transcription factor forkhead box protein O1 (FoxO1)
(Figure 1). FoxO1 directly activates the transcription of
the catalytic subunit of glucose-6-phosphatase (G6pc), a
Pages 8 enzyme involved in hepatic glycogenolysis
and gluconeogenesis [11]. Compound haploinsufficiency
of FoxO1 and Notch1 (Foxo1+/!:Notch1+/!) markedly ame-

Human Embryo trate proper development and perturbation of the Notch

pathway is linked to various devastating genetic disorders
and cancers [8]. In addition, recent studies employing
liorates insulin resistance in diet-induced obese (DIO) mice
[11]. Liver-specific knockout of Rbpj using albumin-Cre
Notch signaling as a novel regulator
phenocopies FoxO1:Notch1 haploinsufficiency, indicating
transgenic mouse models of tissue-specific
TEM-1016;manipulation
No. of Pages 8 that Notch signaling is the key driver of hepatic insulin
of Notch signaling have begun to reveal the roles of the of metabolism
resistance. Consistently, adenovirus-mediated activation
Notch pathway in regulating metabolism in several key of Notch1 in liver induces G6pc expression and exacerbates
metabolic organs. Review Pengpenginsulin Bi1 andresistance
Shihuan Kuang 1,2
in a FoxO1-dependent mannerTrends [11]. in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
1
Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
2
Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA

trials of Notch inhibition-based intervention in tumor Molecular switch

Evolutionarily unprepared for modern high-calorie diets and metalloproteinase (ADAM) family peptidase, releases
angiogenesis [72]. and sedentary lifestyles, humans are now unprecedent- the NECD, whereas the second cleavage, mediated by
Notably, vascular dysfunction
edly susceptible to metabolic is not only
disorders such asinvolved
obesity, in the releases the
g-secretase, Classical The NICD then translo- Notch/Rbpj
NICD [1].ac!va!on Alterna!ve ac!va!on
type 2 diabetes (T2D), nonalcoholic fatty liver, and car- cates to the nucleus where it binds with recombination
development ofdiovascular obesitydisease. [72],These butSTAT3 is also
metabolic a consequence
mTORC1
conditions AMPKsignal binding
are of protein for immunoglobulin IFNγ kappa j region IL-4
metabolicInsulin disorders intertwined, together known as metabolic syndrome,
manifested asquality
atherosclerosis (Rbpj) and recruits a transcriptional
and oth- of downstream targets LPScomplex toIRF8, activate NF-κB
the IL-13
and compromise human life as well as lives.ATP transcription including Hairy/en- JMJD3
er types of cardiovascular Notch signaling, adisease. fundamental Jag1
Strikingly,
signal transductionblockade hancer ofofsplit (Hes) and Hes-related with YRPW motif
Insulin
pathwayreceptor
critical for cell–cell communication and devel- protein family genes. Simple in design, activation of Notch
Dll4–Notch signaling usingbeen
opment, has recently neutralizing
recognized as a keyanti-Dll4
player in
FFA
anti-orchestrated at multiple levels [1] and the
is tightly
metabolism. This review summarizes the emerging Notch roles M1 M2
Amino acidsbody elicited a of broad rangeinof
Notch signaling benefits,
NICD
regulating dramatically
the metabolism of vari- atten-
uating PI3K the development of atherosclerosis,
ous cell and tissue types, with emphasis on the underly- FFA Glossary
reducing macrophage macrophage
ing molecular Stabilize
mechanisms and the potential of targeting Atherosclerosis: a type of vascular disease characterized by plaque accumula-

inflammation, P
improving
this insulin
signal axis to treat metabolic resistance,
diseases. FFA and amelio- tion in arteries resulting from increased cytokines due to metabolic
tion, which leads to activation of the innate immune system and chronic
dysfunc-
Secre!on
Glucose
rating obesity AKT [68]. mTORC1of Notch signaling Srebp1c
inflammation.
An overview Beige adipocytes: a newly defined type of adipocyte within the WAT. They are

Cytoplasm The Notch signaling Ac!vatepathway is an evolutionarily con- TNFα

similar to brown adipocytes in that they express UCP1 and have the capacity
The vasculature also serves
served pathway importantas for the main
cell–cell niche factor
communication for
for thermogenesis. Their gene expression signature is distinct from those of
IL-10
G6pc both brown adipocytes and white adipocytes. IL-1β
both brown and and white adipocyteduring
cell-fate determination
required for adult tissue homeostasis.
precursors;
development and
Srebp1c
therefore,
It comprises Notch
is it
Brown adipocytes: a type of adipocyte that is abundant in rodents and
newborn humans but less abundant in adult humans and has MCP-1
a high capacity
Fasn and Notch
may regulate P P
adipose
receptors (seemass Glossary)and body insulin
ligands as well assensitivity
for adaptive thermogenesis. Brown adipocytes contain numerous mitochon-
dria expressing UCP1, which uncouples the proton gradient from ATP
intracellular proteins that function to transmit the Notch
[72]. Currently, Exclusion
it is unclear how
production to generate heat. Due to their ability to burn lipids (through b-

FoxO1 signal FoxO1

to the cell’s nucleus. Notchvasculature-derived
receptors (Notch1–4) are adi-
oxidation) to generate heat, brown adipocytes increase energy expenditure

Inflamma!on
and are negatively associated with obesity.
Lipid droplets pose stem cellssingle-pass contribute to athe heterogeneity
G6pc(TM) domain, of adipo-
transmembrane proteins comprising an extra-
cellular domain (NECD),FoxO1
Delta/Serrate/Lag-2 (DSL) family protein: single-pass transmembrane proteins
transmembrane whose extracellular domain acts as a ligand for Notch receptors on a

cytes in terms andofantheir distinct

intracellular Pck1
differentiation
domain (NICD). Notch ligands are potential
neighboring cell. In mammals, the family members include Delta-like (Dll1,
Obesity
TG
Dll3, Dll4) and Jagged (Jag1, Jag2).
FFA also transmembrane proteins and cells expressing Notch
Insulin resistance
Gluconeogenesis: a biochemical process that generates glucose from non-
towardFasn white versus beige/brown adipocytes.
Nucleus
Fasnligands must be in close proximity to Notch-expressing Future work
carbohydrate carbon substrates like pyruvate.

Hepatocyte in characterizing cells for signaling to occur. Ligands bind to the Notch
how Notch signaling regulates the
Glycogenolysis: a biochemical process whereby glycogen is broken down to
fate
glucose 1-phosphate.
NECD to induce proteolytic cleavage and release of the Glycolysis: a biochemical process that converts glucose to pyruvate, releasing TRENDS in Endocrinology & Metabolism
choice of adipose NICD,stem cells
which enters the in response
cell nucleus to modifytogene
TRENDS inphysiological
ex- free energy in the form of ATP.
Endocrinology & Metabolism
Hairy/enhancer of split (Hes): a transcription repressor that belongs to the
pression. Notch ligands are members of the Delta/Serrate/
Figure 1. Notch regulates gluconeogenesis and(VEGF)lipogenesis of and metabolic (insulin, energy status) cues iswith YRPW
bHLH protein family with important roles in the Notch signaling pathway.
LAG-2
hepatocytes. (DSL)
Notch family
signaling of proteins
regulates that
hepatic includes Delta-like through
glucose production synergy
Hes-related Figure
with motif
forkhead 3.box
protein Notch
(Hey): signaling
a nuclear and tomacrophage polarization. M1 (classically activated)
protein that belongs
(Dll1, Dll3, Dll4) andsubunit
Jagged(G6pc)
(Jag1,and
Jag2) in mammals and
the Hes-related (HESR) family M2
of basic (alternatively
helix–loop–helix activated)
(bHLH)-type transcrip- macrophages are activated by distinct and
warranted.
protein O1 (FoxO1), which directly activates the transcription of glucose 6-phosphatase,
limiting enzymes in hepatic glycogenolysis and gluconeogenesis, respectively.
catalytic phosphoenolpyruvate
[1,2].Transcriptionally active FoxO1 is phosphorylated by AKT and
carboxykinase
excluded
Lipogenesis:
1 (Pck1),
from the
a metabolicmutually
the
nucleus.
pathway
rate-
tional repressors. Hey expression is induced by Notch signaling.
Inexclusive
that has activation
two separate processes: fatty acid programs. Notch signaling promotes M1
addition, Notch signaling promotes hepatic lipogenesis through an unknownNotch signal
factor that transduction
stabilizes mammalianis initiated onrapamycin
target of binding ofcomplex
a synthesis
1 (mTORC1),and triglyceride
which synthesis.
is normally polarization through synergy with nuclear factor kappa light chain
macrophage
Notch receptor pathway.
to a ligand located on a neighbor M1 and M2 macrophages:
cell.regulatory also known as classically and alternatively activated
activated by amino acids, as well as the insulin–phosphatidylinositol-3-kinase (PI3K)–AKT mTORC1 in turn activates sterol element-binding protein 1c
Notch regulates metabolic immunity Endocytosis
(Srebp1c), a key factor that turns on the transcription of fatty acid synthase of Notch-bound
(Fasn), which ligand generates
encodes a rate-limiting enzyme a mechanical
macrophages,
in lipogenesis. Inbacterial
obesity,
respectively. M1
high or
infections
enhancer
levels
macrophages are activated in response to
of activated B cells (NF-kB) and by upregulating expression of the M1
of glucoseand IFN-g and are highly inflamma-
lipopolysaccharide
pulling force that transducer
drives conformational
and activator changes of the 3 (STAT3) macrophage
tory. By contrast, M2 macrophages regulator
are activated in response interferon
to parasitic regulatory factor 8 (IRF8). Notch signaling
Notch signaling is emerging as an important regulator of
and free fatty acids (FFAs) activate the AMP-activated protein kinase (AMPK)–mTORC1–signal
upregulates Jagged 1 (Jag1) and activates Notch signaling in the neighboring receptor and
Notchhepatocyte. facilitates
Broken line indicates
of transcription
its sequential proteolytic
indirect effect. Abbreviation:
NotchTG,
pathway, which
triglyceride.
receptors (Notch1–4):
eventually
infections or IL-4 and -13 and are anti-inflammatory.
a family of M2
inhibits macrophage
single-pass polarization through repressing Jumonji domain-
transmembrane receptors
both innate and adaptive immune system development
cleavage [3]. The first cleavage, mediated by a disintegrin comprising an NECD, a TM domain, and an NICD. Activation of Notch
containing 3 (JMJD3), an M2 macrophage regulator. M1 and M2 macrophages
receptors leads to release of the NICD, which then acts as a transcription factor
2
and function [73], which
Corresponding authors: Bi, have crucial
P. (pbi@purdue.edu); Kuang,implications
S. (skuang@purdue.edu). inRecombination
met- signal binding have distinct secretory profiles that oppositely control inflammation and impact
to regulate gene expression.
protein for immunoglobulin kappa j region
Keywords: notch signaling; obesity; type 2 diabetes; insulin resistance. (Rbpj): also known as CBF1systemic
in humans;insulin sensitivity.
a highly conserved DNA-binding Abbreviations: IFN-g, interferon gamma; LPS,
abolic syndrome [74]. Among various cell types in innate
protein that mediates canonical Notch signaling.
lipopolysaccharide;
type of adipocyte in animals andMCP-1,
humans thatmonocyte chemotactic protein 1.
1043-2760/
White adipocytes: a major store
! 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2015.02.006
immunity, macrophages are the major players in terms energy in of
the form of triglycerides.

abundance and functional significance in metabolic disor- 1

Trends in Endocrinology and Metabolism xx (2015) 1–8

ders. Macrophages can be divided into M1 and through direct interactionRESEARCH with adipocytes.
ARTICLE Notch ligands
2987
M2 subtypes. M1 macrophages are proinflammatory and present on the surface of macrophages can potentially
secret chemokines [e.g., monocyte chemotactic protein 1 activate Notch signaling in neighboring adipocytes
Development 138, 2987-2998
(MCP-1)] (2011) doi:10.1242/dev.066589
and proinflammatory cytokines [e.g., tumor ne- (Figure 2), hepatocytes, and myofibers and consequently
© 2011. Published by The Company of Biologists Ltd
crosis factor alpha (TNFa)] that directly increase inflam- exacerbate the insulin resistance of these key metabolic
mation in peripheral tissues and impair local insulin tissues. Interferon gamma (IFN-g), which activates M1

Takes two to tango A role for Notch signaling in trophoblast endovascular

sensitivity (Figure 3) [75]. By contrast, M2 macrophages
ameliorate obesity-induced inflammation and secrete anti-
macrophages, induces Jag1 expression rapidly, thereby
amplifying Notch signaling in neighboring cells [80].

2988
mote insulin sensitivity
invasion and in the pathogenesis of pre-eclampsia
inflammatory cytokines [e.g., interleukin (IL)-10] that pro-
RESEARCH (Figure 3) ARTICLE [75]. Importantly, Notch
The macrophage–adipocyte interaction is of significance
in obesity and T2D, where systemic infiltration of macro-
1,2 3 1,2 other immune
Nathan M. Hunkapiller , Malgorzata Gasperowicz , Mirhan Kapidzicand
signaling regulates M1-versus-M2 macrophage specifica- phages , Vicki Plaks4, Emin cells Maltepe 1,5,6,7In this sce-
is prevalent. ,
tion, through
Jan Kitajewski 8,9,10various mechanisms
, Jay C. Cross3 and Susan (FigureJ.3) [76].1,2,4,5,11,12,
Fisher First, *nario, dynamic Notch ligand presentation on these
Rbpj promotes expression of the transcription factor inter- circulating cell types may produce functional diversity in
REFERENCES SUMMARY
feron regulatory factor 8 (IRF8) while suppressing expres- Notch activation, a direction deserving future investiga-
sion of the histone H3 Lys27 (H3K27) demethylase tion. The complexity is encoded by the diverse signaling
Placental trophoblasts (TBs) invade and remodel uterine vessels with an arterial bias. This process, which involves vascular mimicry,
Jumonji domain-containing 3 (JMJD3) [77], which are capacity of Notch ligands and receptors [81] and the pref-
re-routes maternal blood to the placenta, but fails in pre-eclampsia. We investigated Notch family members in both contexts, as
1. Finn, C. A. (1971) The biology of decidualthey play cells.
inducers of
importantAdv.
M1 and Reprod.
roles
M2 polarization, respectively [76]. Sec-
in arterial differentiation/function. Immunoanalyses of tissue sections showed step-wise modulation of
erential binding of ligands to different Notch receptors
Physiol. 5, 1–26 ond, Notch signaling boosts the inflammatory property of [82]. For instance, during angiogenesis, Dll4 has strong
Notch receptors/ligands during human TB invasion. Inhibition of Notch signaling reduced invasion of cultured human TBs and
M1 macrophages by interacting with NF-kB [78,79]. Com- while Jag1 has weak signaling potential and the relative
2. Jayatilak, P. G., Glaser, L. A., Warshaw,expression
M. L., Herz,
of the Z., Gruber,
arterial marker EFNB2. In mouse placentas, Notch activity was highest in endovascular TBs. Conditional deletion
pared with lean animals, DIO mice showed a shift from a abundance of these ligands creates distinct outcomes in
J. R., and Gibori, G. (1984) Relationship between
of Notch2, the onlyluteinizing
M2- and
receptor upregulated during mouse TB invasion, reduced arterial invasion, the size of maternal blood canals
to aplacental
M1-polarized state [75]. Consistently, Notch angiogenesis [83]. Similarly, the vasculature may repre-
hormone and decidual luteotropin in by the30-40%
maintenance
signaling
perfusion by 23%. By E11.5, there was litter-wide lethality in proportion to the number of mutant
of luteal
in adipose tissue isofactivated
offspring. In pre-eclampsia, expression the Notchby HFDJAG1
ligand feeding was absent sent in aperivascular
crucial metabolic and endovascular niche factor
TBs.byWepresenting
conclude Notch
steroidogenesis. Biol. Reprod. 31, 556 –564 [36], which in part can be explained by the infiltration of ligands to fine-tune Notch signaling in peripheral tissues
that Notch signaling is crucial for TB vascular invasion.
3. Lala, P. K., and Graham, C. H. (1990) Mechanisms Notch-primed of M1tropho- macrophages. It will be interesting to and metabolic disorders, either through regulating stem
blast invasiveness and their control: the role
KEY WORDS: ofEndovascular
determine proteases and whether
in the Invasion,
future Notch, Pre-eclampsia, and how inhibition Trophoblast of cells to maintain homeostasis of neurons, myocytes, and
protease inhibitors. Cancer Metastasis Rev. 9,Notch 369 –379
signaling promotes the transition from M1 to M2 adipocytes or through directly regulating enzyme expres-
4. Franco, H. L., Jeong, J. W., Tsai, S. Y., Lydon, macrophages in obese adipose tissues and its therapeutic
J. P., and DeMayo, sion in hepatocytes. These observations and speculations
potential
INTRODUCTION
F. J. (2008) In vivo analysis of progesterone receptor against
action obesity in and other metabolic disorders.members warrant that play futurea roleinvestigations
in arterial function into and
the identity
metabolic (Red-pheno-
Human Notch-mediated
placentation involves macrophage unique polarizationbetween
interactions contributes Horse types
et al., 2005).of mice Thewith macrophage-specific
significance of CTB endovasculardeletion of Notch
invasion
the uterus during embryo implantation. Semin. Cell Dev. Biol. 19,
to the development
embryonic/fetal cytotrophoblasts of metabolic
(CTBs) and disorders
maternalnot only
cells. CTBsthrough is illustrated ligand by genes.the fact Answers that thistoprocessthis question will inshed
largely fails pre- light
178 –186 thefromabovementioned inflammatory actions
that arise the placental surface colonize the uterine wallbut and also eclampsia on (PE). the distinct functions of different Notch ligands in
5. Pannuti, A., Foreman, K., Rizzo, P., Osipo,
resident
C., Golde,
maternal vessels
T., 1A), a process that requires
(Fig. PE is a serious complication that affects ~7% of first-time
Osborne, B., and Miele, L. (2010) Targeting 6
Notchofto
aggressive invasion targettissues (Fisher et al., 1989; Librach pregnancies (Levine et al., 1997; Redman and Sargent, 2005). The
maternal
Figure 9. Working model: Notch1 regulates cell fate in cancer stem cells. Clin. Cancer Res. 16,et3141–3152
al., 1991). During interstitial invasion, CTBs commingle with mother shows signs of widespread alterations in EC function such
endometrial stromal fibroblasts and is essential for successful 6. Artavanis-Tsakonas, S. (1988) The molecular biology and
decidual, myometrial of immune
the cells. During endovascular as hypertension, proteinuria and edema (Roberts and Lain, 2002).
Notch locus and the fine tuning of differentiation in Drosophila.
invasion, CTBs breach maternal spiral arterioles that supply blood Sometimes fetal growth is impaired. In PE, the extent of CTB
decidualization and the aversion of apoptosis, which are to the placenta. Subsequently, they replace the maternal interstitial invasion is variable, but frequently shallow;
Trends Genet. 4, 95–100
critical for maintaining endometrial integrity for the success- 7. Artavanis-Tsakonas, S., Rand, M. D.,endothelium
and Lake, andR.regions
J. (1999) of the smooth muscle wall, creating a endovascular invasion is consistently rudimentary (Brosens et al.,
ful establishment of pregnancy. Notch signaling: cell fate control and
novel chimeric vasculature composed of maternal and fetal cells, a 1972; Naicker et al., 2003; Zhou et al., 2007), resulting in increased
signal integration in
process that greatly increases arteriole diameter. By contrast, CTBs vascular resistance and decreased placental perfusion (Matijevic
development. Science 284, 770 –776 form only superficial connections with uterine veins. These and Johnston, 1999). The PE syndrome reveals the significance of
8. Artavanis-Tsakonas, S., Matsuno, K., and Fortini, M. E. (1995)
remarkable cell-cell interactions are accompanied by changes in CTB differentiation/invasion. Biopsies of the uterine wall of
alization and that Notch1 signaling in the uterus is Notch signaling. Science 268, 225–232 fundamental aspects of the phenotype of the cells with the net individuals with PE show that invasive CTBs fail to upregulate
9. Weinmaster, G. (1997) The ins and outs effect
of of mimicking
notch many aspects
signaling. Mol. of endothelial cells (ECs). They receptors that promote invasion and/or assumption of an EC-like
essential for this process. switch on the expression of vascular-type adhesion molecules phenotype (Zhou et al., 2003; Zhou et al., 2002). The upstream
Cell. Neurosci. 9, 91–102
The preimplantation uterus undergoes extensive (Damsky et al., 1992; Zhou et al., 1997), vasculogenic/angiogenic regulatory mechanisms that are responsible for these defects remain
10. Blaumueller, C. M., Qi, H., Zagouras, P., and Artavanis-Tsako-
factors (Zhou et al., 2003; Zhou et al., 2002) and Ephrin family enigmatic. Thus, ligands/receptors that are involved in vascular
proliferation and differentiation that results in a decid- nas, S. (1997) Intracellular cleavage of Notch leads to a het-
 spongiotrophoblasts (Tpbpa), TGCs
or GlyTCs (Pcdh12) therefore
(see Fig. S6 in success
the of the pregnancy. However, the role 2014, 2015). This study documents the first comparison of
data not shown). However, although
that DSC play in the control of trophoblast function is
ch2floxl+;Tpbpa-Cre placentas robustly
DSC isolated from first trimester pregnancies with impaired
rterioles at E12.5 still
(10/11 largely
placentasunknown. In this study, we have isolated spiral artery remodelling, and therefore, an increased risk
arged in Fig. 4E,G, respectively), this RESEARCH ARTICLE

majority of the Notch2 DSC floxlfloxfrom first trimester terminations of pregnancy,

;Tpbpa-Cre of pre-eclampsia, with DSC from
Downregulation of Notch normal
SignalingRI pregnancies.
Pathway
and using
mined) (Fig. 4B,D; enlarged uterine
in Fig. 4F,H, artery Doppler RI, where RI is a proxy in Late Preterm
Cyclic decidualisation, where decidualisation and and Term Placentas from
Development 138 (14)
ssible differences in marker expression Pregnancies Complicated by Preeclampsia
pa-Cre placentas, measurement
we confirmed we confirmed these of spiral artery remodelling, have separated menstruation occur monthly in the absence of pregnancy, Persefoni Fragkiadaki1, Nikolaos Soulitzis1, Stavros Sifakis2, Demetrios Koutroulakis2,
Victor Gourvas1, Nikolaos Vrachnis3, Demetrios A. Spandidos1*
mparison with
with the Tromo-1 antibody
ersus 8.44±2.6; the DSC (see into
Fig. S7normal RI and high RI groups (Prefumo et al. has been termed ‘menstrual preconditioning’ to allow
Notch Pathway Downregulation in Preeclampsia
1 Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Crete, Greece,
2 Department of Obstetrics & Gynecology, University Hospital of Heraklion, Crete, Greece, 3 2nd
al), which reacts with a cytokeratin that Department of Obstetrics & Gynaecology, Aretaieion Hospital, National and Kapodistrian University of

st
TCspopulations
failed 2004). A high
(Amarante-Paffaro et al., RI uterine artery Doppler measurement for embryo selection and deep placentation (Teklenburg Athens, Athens, Greece

* spandidos@spandidos.gr
hich was
placental
correlates to a 5-fold higher risk of developing pre- et  al. 2010). Aberrant decidualisation has been linked
dasion
thefailed
functional
in consequences of these Abstract
we looked for abnormalities
RNA in situ
ers. No overt
eclampsia,inifthethe pregnancy were to continue (Leslie et al. with clinical disorders, including endometriosis and Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3–5% of
all pregnancies. The Notch signaling pathway plays an important role during placental de-
t-lined
en Notch2 canals
floxl+
, that transport maternal
e placentas with 2015). Our study has shown significant differences in the recurrent pregnancy loss, and therefore, affects disorders velopment, activating several target genes. Defects in the Notch pathway have adverse ef-

ohianobtain
trophoblast an integrated view of the
fect on placentation. The aim of this study was to investigate the expression of receptors
NOTCH1,-2,-3,-4, ligands DLL1,-3,-4, JAG1,-2 and target genes HEY1,-2 in placental tis-
wesecretion of decidualisation markers IGFBP1 and PRL in where placentation is impaired, such as pre-eclampsia
OPEN ACCESS
Tpbpa), TGCs
ntal perfusion,
ee Fig. S6 in the prepared vascular Citation: Fragkiadaki P, Soulitzis N, Sifakis S,
sue samples from 20 late preterm or term pregnancies complicated by PE versus 20 normal
pregnancies. mRNA levels of the studied molecules were measured by quantitative Real-
Koutroulakis D, Gourvas V, Vrachnis N, et al. (2015)
wever, although
nal
centascirculation at E10.5 and E14.5 (Fig.
re-decidualised DSC, confirming that first trimester DSC (Klemmt et al. 2006, Salker et al. 2012). This study suggests
Downregulation of Notch Signaling Pathway in Late Time PCR (qRT-PCR), while the protein expression of the intracellular domain of NOTCH2
robustly Preterm and Term Placentas from Pregnancies
in Notch2floxlflox;Tpbpa-Cre and
(NICD2) and NOTCH3 (NICD3) was measured by Western Blot (WB). qRT-PCR analysis
atterns
0/11 placentas
pectively), this
Complicated by Preeclampsia. PLoS ONE 10(5):
e0126163. doi:10.1371/journal.pone.0126163 revealed that NOTCH1, NOTCH4 and DLL1 were not expressed in the placenta. On the

centas were similar;

xlflox
;Tpbpa-Cre
ged in Fig. 4F,H,
canmaternal be re-decidulised blood in culture. We have demonstrated that DSC from pregnancies with an increased risk of
Academic Editor: Myon-Hee Lee, East Carolina
University, UNITED STATES
contrary, NOTCH2, NOTCH3, DLL3, DLL4, JAG1, JAG2, HEY1 and HEY2 mRNA levels
were downregulated in PE samples vs. controls (p<0.01). WB confirmed that NICD2 (p =
ugh a tortuous network of ~8-12
rker expression 0.014) and NICD3 (p<0.001) protein levels were also lower in PE specimens. Statistical
onfirmed these
les(seethat
dy
that the chemoattraction of trophoblast by rDSC is
Fig. S7converged into ~1-4 canals at
developing pre-eclampsia are able to decidualise in vitro.
Received: November 6, 2014

Accepted: March 30, 2015

analysis revealed several significant associations: of NOTCH3 mRNA expression with
smoking during pregnancy (p = 0.029), of NICD3 protein levels (p = 0.028) and DLL3 mRNA
Fig. 5. The trophoblast-lined vascular canals that supply blood to
ry before spreading impaired
into a sinusoidal in early thegestation
placenta werepregnancies smaller in Notch2with floxlflox a high RI.
;Tpbpa-Cre mice. (A- However, there are additional markers of decidualisation,
cytokeratin that Published: May 11, 2015 levels (p = 0.041) with birth weight centile, and of HEY2 transcript levels with parity (p =
e-Paffaro et al., Copyright: © 2015 Fragkiadaki et al. This is an open 0.034) and mode of delivery (p = 0.028). Our results suggest that Notch pathway downregu-
abyrinth. Given the complexity of the H) Vascular corrosion casts of the maternal blood spaces of the placenta access article distributed under the terms of the lation is associated with PE. Further studies are required in order to determine the role of

Consequently,
on the terminal impaired chemoattraction of trophoblast including LEFTY2, a NODAL signalling pathway inhibitor,
Creative Commons Attribution License, which permits
uences of these these molecules in PE pathogenesis and to evaluate their potential use for the early detec-
focused
malities in theour analysis were prepared at E10.5 and E14.5. In placentas of Notch2floxl+;Tpbpa-
60 3
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are tion and treatment of PE.
sport maternal floxl+
10.5,
d view of thethe canals incells Notch2in the ;Tpbpa- first Cre trimester
and Notch2 of pregnancy,
floxlflox
;Tpbpa-Cre offspring, due to decidual
a complex
credited.
array of maternalwhich is highly expressed by decidualising cells, the key
Data Availability Statement: All relevant data are

agnified
and E14.5 (Fig.in Fig. 5C) were larger than
pared vascular
spiral arterioles converged into several large canals before branching within the paper.

a-Cre
Tpbpa-Creplacentas
maternal blood
and secretions,
(Fig. 5B;
Journal magnified
of Molecular couldin into contribute
the labyrinthianto
L B James-Allan et al. the At
sinusoids. reduced
Stromal regulation of spiral
E10.5, the canals 60 :3 in artery
239–246 transcription factor
report. CCAAT/enhancer-binding protein
Funding: The authors have no support or funding to
Introduction
Endocrinology floxl+ trophoblast function
ifferences betweenremodelling Notch2 floxl+
;Tpbpa- Notch2 ;Tpbpa-Cre placentas (A; enlarged in C) (n 6) were larger Competing Interests: The authors have declared Preeclampsia (PE) affects 3–5% of all pregnancies worldwide and is a major cause of maternal
ork of ~8-12
observed in high floxlflox RI pregnancies. (C/EPB) and secreted products, such as Wnt5a, Dickkopf
that no competing interests exist. mortality and morbidity [1]. PE is a consequence of diverse pathological processes involving

;Tpbpa-Cre than those in Notch2 ;Tpbpa-Cre placentas (B; enlarged in D)

~1-4 canals at
Fig. 5G) and Notch2floxlflox
to a sinusoidal RESEARCH
Fig. 5. The trophoblast-lined vascular canals that supply blood to
the placenta were smaller in Notch2floxlflox;Tpbpa-Cre mice. (A- floxl+
Fig. 5H) at E14.5.Re-decidualisation
mplexity of the
dn the
interminal These results (n 7).
H) Vascular corrosion casts of the maternal blood spaces of the placenta We noted similar
is necessary floxlflox differences between Notch2
in vitro as isolated ;Tpbpa-Cre (E; 1 (DKK1) and prokinectin (PROK1), which could be
Decidual cell regulation of8)trophoblast is altered
PLOS ONE | DOI:10.1371/journal.pone.0126163 May 11, 2015 1 / 16
enlarged in G) (n
were prepared at E10.5 and E14.5. In placentas of Notch2floxl+;Tpbpa-
and Notch2 ;Tpbpa-Cre animals (F; enlarged
ng the estimated vessel diameters into Defective decidualization
(Tabibzadehduring et  al.and afterChristian severe
floxl+
ch2 ;Tpbpa- Cre and Notch2floxlflox;Tpbpa-Cre offspring, a complex array of maternal
ere larger than
B;5I). The
stromal
in pregnancies cells loseintheir
significant (I)at
H) (n 4)differentiated
spiral arterioles converged into several large canals before branching
in results showed riskatofE14.5. Scale bars: phenotype
pre-eclampsia 1 mm in A,B,E,F; 500 with m time
in C,D,G,H. investigated further 1998,
preeclampsia reveals a possible maternal
magnified into the labyrinthian sinusoids. At E10.5, the canals in
ch2 floxl+
;Tpbpa- The vessel diameter was used to calculate the cross-sectional areas of
Notch2floxl+;Tpbpa-Cre placentas (A; enlarged in C) (n 6) were larger
;Tpbpa-Cre placentasin
pbpa-Cre
xlflox
culture
at E10.5 (40%)and and increased
than those in Notch2floxlflox;Tpbpa-Cre placentas (B; enlarged in D) passage number (Brosens floxlflox et  al. et al. 2002, Matsuoka et al. 2010, Macdonald et al. 2011).
the canals. At E10.5 and E14.5, vessels in Notch2 ;Tpbpa-Cre
nt.diameters
These results
differences
(n 7). We noted similar differences between Notch2floxl+;Tpbpa-Cre (E;
were observed between
enlarged in G) (n 8) and Notch2floxlflox;Tpbpa-Cre
placentas
animals (F; enlarged
were and 40% and 34% smaller, respectively, when compared
contribution to the etiology
4) and
wed significant
into
Notch2 1999,
floxlflox
;Tpbpa-Cre
(I) The vessel diameter
Saleh
L B James-Allan
was used
1Molecular andtoClinical
calculate
et al.with
, G S Whitley , K Leslie
(n
1

11)
the Research
Sciences
1
2011).
in H) (n 4) at E14.5. Scale bars: 1 mm in A,B,E,F; 500 m in C,D,G,H.
cross-sectional
, A E Wallace

Notch2
areas
Institute,
1,2

of
The
floxl+
St. George’s,
decidual
J E Cartwright
1

;Tpbpa-Cre animals.
University of London, London, UK
process
1

Group means
is are
initiated
represented as
An alternative interpretation
Tamara Garrido-Gomez of, Alicia
, Francisco Dominguez
c,d
this
a,b,c,d data
Quiñonero isDiaz-Gimeno
, Patricia
c,d
that ,aberrant
b
Mirhan Kapidzic ,
e
b
f
b
c,d
c,d
e,g
10.5 (40%) and the canals. At E10.52Fetal
and Medicine
E14.5, vessels Notch2floxlflox
in George’s
Unit, St. ;Tpbpa-Cre
Hospital, London, UK
Matthew Gormley , Katherine Ona , Pablo Padilla-Iserte , Michael McMaster , Olga Genbacev , Alfredo Perales ,
mber
erved of canals per placenta (3.2±1.2 solid bars.
between
bpa-Cre (n 11)
placentas were 40% and 34% smaller, respectively, when compared
Correspondence should be addressed to J Cartwright: jcartwri@sgul.ac.uk
with Notch2floxl+;Tpbpa-Cre animals. Group means are represented as
decidualisation does not play a key factor in the pathology
Susan J. Fisher
a
, and Carlos c,d,h,i,1,2
Simón a,b,g,j,1,2

Fundación Igenomix, 46980 Valencia, Spain; bInstituto Universitario IVI, Instituto de Investigación Sanitaria Hospital Clinico de Valencia INCLIVA, 46010
centa (3.2±1.2 solid bars.
of disorders such as pre-eclampsia. We have previously
Valencia, Spain; cCenter for Reproductive Sciences, University of California, San Francisco, CA 94143; dDepartment of Obstetrics, Gynecology, and
Fig 1. Bar chart depicting Notch pathway members normalized (A) mRNA and (B) protein expression in normal and preeclamptic (PE) late preterm
Reproductive Sciences, University of California, San Francisco, CA 94143; eDepartment of Obstetrics and Gynecology, Hospital Universitario La Fe, 46026
floxlflox
in
-Cre Notch2
placentas ;Tpbpa-Cre placentas and term placentas,
Valencia,
associations between
School
respectively.
Spain; f
DepartmentFloating
PE and
of Medicine,
numbers
of Cell and
controlsUniversity,
Valencia (*: p<0.05;
Tissuerepresent
**: p<0.01;
46010
fold change
Biology, University
***:
Valencia,
of between
p<0.001).
Spain; h
The EliError
theSan
California, twoFrancisco,
bars depict
& Edythe
sample groups.
Broad standard
CA 94143;
error
Center for
Asterisks
g

of the mean
Regeneration
represent
Department statistically
of Obstetrics
(SEM). (C)
Medicine
andsignificant
andRepresentative
Gynecology,
Stem Cell Research,
floxlflox
counterparts (Fig. 6C,D) revealed increased floxlflox
fusion
ecting a 70 kDa might
omised. To test Notch2
be compromised.
fluorescence intensity. Although weTo
;Tpbpa-Cre
Abstract testobserve Notch2
did not differences ;Tpbpa-Cre counterparts (Fig. 6C,D) revealed increasedshown that trophoblast from high RI pregnancies are
WesternUniversity
blots of NICD2 and NICD3
of California, proteins, along
San Francisco, with iβ-Actin
CA 94143; (ACTB)
Department housekeeping
of Anatomy,
and Gynecology, School of Medicine, Stanford University, Palo Alto, CA 94305
geneof
University (N:California,
Controls;San Francisco, CA 94143; and jDepartment of Obstetrics
P: Preeclampsia).
doi:10.1371/journal.pone.0126163.g001
ssible
d measuring differences
its between theby two injecting
groups a 70
in theimplantation
Successful relative sizekDa
ofand fluorescence
the placentation
placental labyrinth
are dependent on intensity.
the interactionAlthough
between we did not observe differences
Key Words Edited by R. Michael Roberts, University of Missouri-Columbia, Columbia, MO, and approved August 11, 2017 (received for review April 20, 2017)

in the relative size of the placental labyrinthmore sensitive to undergoing apoptosis (Whitley et  al. wall in
2.5 (Plaks et al., or its vascular spaces, quantification of the total labyrinthian-FITC
decidual stromal cells (DSC) and extravillous trophoblast (EVT) cells. The extent of decidua
ran
ch2 via
floxl+
;Tpbpa- the signal
tailshowed
veinthatand Notch2measuring
trophoblast
floxlflox
;Tpbpa-Cre
invasion placentas
relies between
itson communication
accumulated the two
between groups
the placenta and maternal stromal
in studying the CTB
In preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus subpopulation that invades the uterine
the context of this syndrome. Targeted analyses of particular mo-
and spiral arteries is often shallow. Thus, the placenta’s role has
d with their 23% less fluorescein-conjugated dextran (Fig. 6E). Together, the
hin the labyrinth at E12.5 (Plaks et al., or its vascular spaces, quantification of the total labyrinthian-FITC2007) and therefore the contribution
decidua. The cyclical process of decidualisation induces a transformation of endometrial
fibroblasts to secretory DSC; these secreted products have many functions including the
trophoblast
pre-eclampsia
lecular families, such as the vascular-type adhesion molecules that
of both
been a focus. In this study, we tested the hypothesis that decidual
are up-regulated
defects are an important determinant of the placental phenotype. as the the placental
extravillous CTBs enter the uterine wall,
floxl+ floxlflox PLOS ONE | DOI:10.1371/journal.pone.0126163 May 11, 2015 8 / 16
tissue sections from Notch2 ;Tpbpa-
control of trophoblast signaltrophoblast
invasion. Inadequate showed invasion remodelling of the;Tpbpa-Cre placentas accumulated
thatandNotch2 chemotaxis
revealed focal defects in differentiation (8). These results were
We isolated human endometrial stromal cells from nonpregnant
confirmed and augmented by global transcriptional profiling of
with their 23% less fluorescein-conjugated dextran (Fig. 6E). Together, theand decidual cells needs to be considered inthe partnership.
donors with a previous pregnancy that was complicated by severe
,B) when compared uterine vessels (the spiral arteries) are associated with pregnancy disorders such as pre-
eclampsia. Uterine artery Doppler resistance index (RI) in the first trimester of pregnancy
CTBs isolated from
PE (sPE). Compared with control cells, they failed to decidualize in placentas of affected pregnancies as they
differentiated along the invasive pathway over a period of 48 h in
vitro as demonstrated by morphological criteria and the analysis of
culture (9). The surprising finding that the abnormal pattern of
Decidualisation induces stromal cells toto control
become
can be used as a proxy measure of remodelling. DSC were isolated from pregnancies with stage-specific antigens (i.e., IGFBP1, PRL). These results were bol-
gene expression
stered by global transcriptional profiling data that showed they autocorrected levels by the end of the
normal (normal RI) or impaired (high RI) spiral artery remodelling. Following isolation,
culture period pointed to a potentially important role for paracrine
were transcriptionally inert. Additionally, we used laser microdissec-
DSC were re-decidualised using cAMP and MPA and secretion of the decidualisation effectors. In this regard, the decidua, which supports placental
tion to isolate the decidua from tissue sections of the maternal–fetal
markers IGFBP-1 and prolactin assessed. We examined the impact of DSC-secreted
factors on trophoblast cell function, using the EVT cell line SGHPL-4. We demonstrated
secretory; in the first trimester, DSC growth andproduce
interface in sPE. Global transcriptional profiling revealed defects in a milieu
function, is a prime candidate.
In humans, formation of the decidua does not depend on the
gene expression. Also, decidual cells from patients with sPE, which
presence of a conceptus (10). This progressive process, which
dedifferentiated in vitro, failed to redecidualize in culture. Condi-
that DSC exposed to decidual factors were able to re-decidualise in vitro and that the

Figure 4
chemoattraction of trophoblasts by DSC is impaired in pregnancies with high RI. This of factors that influence trophoblast function (Sharma
involves hormonally regulated differentiation of human endo-
tioned medium from these cells failed to support CTB invasion. To mimic
metrial stromal cells (hESCs), begins during the midsecretory
aspects of the uterine environment in normal pregnancy, we added
study provides new insights into the role that DSC play in regulating EVT functions phase of the menstrual cycle (11). The transformation is initiated
PRL and IGFBP1, which enhanced invasion. These data suggested that
Effect
during of rDSC
the first CM
trimester from This
of pregnancy. normal andto high
is the first study demonstrate RI that
pregnancies
DSC on chemotaxis of et  al. 2016). As EVT invade from teries, theultimately
in areas
failed decidualization is an important contributor to down-regulated
CTB invasion in sPE. Future studies will be aimed at determining
tips
that
ofthroughout
spreading anchoring
are immediately adjacent to the uterine spiral ar-
the entire endometrium
from pregnancies with impaired vascular remodelling in the first trimester secrete (12). In vivo and in vitro, this process is driven by increasing levels
whether this discovery has translational potential with regard to
SGHPL-4 cells. SGHPL-4 cells were cultured in chemotaxis chambers to
factors that inhibit the directional movement of trophoblast cells. This finding may be
placental villi, they come into contact of
assessing a woman’s risk of developing this pregnancy complication.
with
progesterone and
this
local cAMP
enriched
production (13–15), which
important in understanding aberrant trophoblast invasion in pregnancies where vascular
analyse
remodelling chemotactic
is impaired. capacity of normal and high RI rDSC CM. Non- Journal of Molecular
| | |
preeclampsia human endometrial stromal cells Significance decidua

decidual environment. In order to assess the influence

Endocrinology
(2018) 60, 239–246 |
cytotrophoblast transcriptomics
directional movement of cells gives expected chemotaxis of 50%. (A) We provide evidence of a decidualization defect in the endo-

that DSCPcies,
reeclampsia (PE), which affects ∼8% of first-time pregnan- metrium of women with severe preeclampsia (PE) that was
Normal RI rDSC CM from pregnancies <10 weeks gestation is significantly have on mother–infant
impacts 8 million EVT pairs cells
worldwideduring
each the first trimester detected at the time of delivery and persisted years after the
affected pregnancy. We went on to link this defect to impaired
 Clinical Opinion www. AJOG.org

OBSTETRICS

There is could be an answer for women with A role for menstruation in preconditioning
Aspirin reduced prevalence of preeclampsia the uterus for successful pregnancy
Repeated early onset of preeclampsia K.P. Conrad et al. / Placenta 60 (2017) 119e129 125
to predicted level Jan J. Brosens, MD, PhD; Malcolm G. Parker, PhD; Angus McIndoe, MD, PhD;
(even with prevention) Robert Pijnenborg, PhD; Ivo A. Brosens, MD, PhD

E utherian (placental) mammals have

evolved different strategies to en-
sure reproductive success. The type of
Menstruation is widely viewed as serving no purpose other than to reinitiate the
endometrial cycle in the absence of pregnancy. Yet, it is striking that cyclic endometrial
placenta and the depth of trophoblast in- decidualization followed by menstrual shedding is confined to the few species, including
vasion among various primate species human beings, where placenta formation entails deep trophoblast invasion of maternal
appear to correlate with the extent of tissues and its vasculature. Both menstruation and pregnancy are inflammatory condi-
endometrial remodeling prior to con- tions that cause a degree of physiological ischemia-reperfusion tissue injury, albeit much
ception and the occurrence of menstru- more so in pregnancy. Thus, the emergence of cyclic menstruation may not have been
ation.1 For instance, strepsirrhine pri- an evolutionary coincidence but serves to protect uterine tissues from the profound
mates (lemurs and lorisiforms) have hyperinflammation and oxidative stress associated with deep placentation, a process
noninvasive epitheliochorial placentae known as preconditioning. The concept of menstrual preconditioning provides a novel
and completely lack menstruation paradigm for understanding how reproductive disorders impact on pregnancy outcome.
whereas simian primates (Old World For example, endometriosis could be viewed as a disorder of exaggerated menstrual
monkeys, apes, and human beings) uni- preconditioning that confers protection against placentation-related disorders, such as
formly posses invasive hemochorial pla- preeclampsia.
centae and typically exhibit some form of Key words: endometriosis, menstruation, preconditioning, preeclampsia, pregnancy
menstruation, although there is consid-
Cite this article as: Brosens JJ, Parker MG, McIndoe A, et al. A role for menstruation in preconditioning
erable variation in the degree of blood the uterus for successful pregnancy. Am J Obstet Gynecol 2009;200:615.e1-615.e6.
loss.1 Compared with our primate rela-
tives, menstruation in human beings is
not only extraordinarily heavy but pla- the myometrium, termed the “uterine role of cyclic endometrial remodeling
centation is also exceptionally deep, with junctional zone,” and its spiral arteries.2,3 and menstruation in determining subse-
trophoblast invading not only the decidual Endometriosis is foremost a men- quent pregnancy outcome.
endometrium but also the inner third of strual disorder, characterized by the
Fig. 3. Aberrant decidualization in the late secretory phase and during early pregnancy may play a role
presence in the development ofectopic
of hormone-dependent preeclampsia The for linksome betweenwomen. menstruation
See text for details.
endometrial implants, impaired differ- and placentation
From the Institute of Reproductive and entiation of the eutopic endometrium, Menstruation is defined by shedding of
1.7. Future investigations Developmental Biology, Imperial College andpotential
thickening pitfalls, a positive
of the uterine junctionalstudy outcome the superficial could be followed
endometrial layerup in inre-
London, Hammersmith Campus, London, future As
zone. 4,5
investigations
endometriosisof and banked, pre- formalin-fixed
sponse to decreasing paraffin embedded
progesterone levels
Although fraught with formidable logistical
United Kingdom (Drs J.challenges
J. Brosens, Parker, and (FFPE) are
eclampsia endometrial
disorders at opposite biopsiesends that accompanied
were obtained by overt to assisted
priorbleeding. Nota-
inherent shortcomings, additionaland McIndoe), and
prospective the Department
studies are needed of ofreproductive
the reproductivecycles process,(“mock”there maycycles) be bly,starting uterine with bleeding associated with
identification of
Woman and Child (Dr Pijnenborg), few reasons to suspect that both disease ovulation or intercourse occurs in a va-
to reinforce the concept of endometrial antecedents of pre- obstetrical outcomes and followed by gene expression analysis

Just start early

Catholic University of Leuven and Leuven processes are interrelated. Yet, a recent riety of species but does not constitute
eclampsia. To this end, further “omics” Instituteanalyses
for Fertilityofand
surplus
Embryology CVS(Dr are (technology for extracting sufficient quality RNA from FFPE tissues
case-control study reported that women menstrual bleeding. Apart from simian
Abnormal Uterine Doppler Is Related to Vasculopathy in needed in larger cohorts of womenI.who develop
A. Brosens), Leuven,preeclampsia.
Belgium. The forendometriosis-related
gene expression infertility analysisre- is emerging). However, this under-
with primates, true menstruation is found
Pregestational Diabetes Mellitus several institutions around the world Receivedstill performing
Aug. 14, 2008; revised CVS Sept.in22,suf- takingin would be huge,treatment and the approach involving endometrial
ceiving vitro fertilization only in certain bat species, such as wild
numbers could collaborate 2008;
andaccepted Nov.
coordinate 18, 2008.
collection of biopsies after the index pregnancy of preeclampsia may indeed
Marek Pietryga, MD, PhD; Jacek Bra˛zert, MD, PhD; Ewa Wender-Oėgowska, MD, PhD; ficient the be
Romuald Biczysko, MD, PhD; Mariusz Dubiel, MD, PhD; Saemundur Gudmundsson, MD, PhD
2498 Circulation October 18, 2005 surplus CVS to be processed for RNA Reprints: Jan J. Brosens, MD, PhD, Institute of
(and other analyses) imme-
have
ingmore
a markedly reduced risk
feasibleoraspregnancy-induced
preeclampsia
of develop-
the first step. Thephant
fulvous
second
fruit
shrew.
bats,
potential
7,8
and perhaps
pitfall feature
One unifying is diffi-of
ele-
Background—The aim of the study was to evaluate the relation between maternal placental Doppler velocimetry, levels Reproductive and Developmental Biology, 6
of the maternal glucose, and clinical signs of vasculopathy in pregnancy complicated by pregestational diabetes mellitus.
Methods and Results—A retrospective study of 155 pregestational diabetic women between the 22nd and 40th weeks of
diately after uterine extraction. Clearly, the London,
Imperial College logisticalDu Cane challenges
Rd, London cult to address
hypertension. except by
Admittedly, the obtaining
protec- the a positive
endometrium outcome to the study.
of menstruating spe-
pregnancy, categorized in White classification as B, 49; C, 40; D, 22; R, 20; F, 5; and RIF, 19. Cases in classes R, F, include the recent emergence of non-invasive prenatal diagnosis,
W12 0NN, United Kingdom. tive effect of endometriosis
Regarding the last of against the potential pre- cies, including
pitfalls, it isbats, notappears to be the
inconceivable
Pietryga et al Uterine Doppler and andR/F were defined
Vasculopathy inasType
having vasculopathy.2497
1 Diabetes Doppler velocimetry of umbilical and uterine arteries was evaluated for
vascular impedance, both in terms of pulsatility index (PI) for both arteries and a notch in early diastole in the uterine
arteries. The last examination before delivery was used for analysis. Increased umbilical artery PI was seen in 19 and
an effective j.brosens@imperial.ac.uk.
which is dramatically reducing CVS procedures, the requirement
without vascularDrscomplications J.J. Brosens and Parker are were supported similar
by
eclampsia
(6.5"1.1%
associated
or other an effective
obstetric
anddeep
disorders
that the same impairment of pre-decidualization persists in sub- profound progesterone-driven remodel-
a uterine artery abnormality in 45 cases. There was a correlation between levels of HbA and increased vascular for rapid processing of the surplus CVS tissue to preserve high sequentwith impaired
menstrual cycles placenta-
after theing of thepreeclamptic
index stromal compartment, pregnancy, a pro-
screening PREVENTION
lc
impedance in the uterine and umbilical arteries. Signs of increased uterine artery vascular impedances were significantly the Institute of Obstetrics and Gynecology tion–such as fetal growth restriction, cess termed “decidualization” (Figure, A
related to pregestational vasculopathy. In cases of small-for– gestational-age newborn infants, PI was significantly quality RNA,6.4"1.2%).
and the need for obtaining Trust. obstetrical outcomes. but that compensatory maternal responses or compensation by
increased in uterine and umbilical arteries. Furthermore, PI in macrosomic fetuses was significantly lower than in normal Editorial placental abruption, and preterm labor– and B). This differentiation process is 123
Nevertheless, to our knowledge, there is no other way to obtain
0002-9378/$36.00 extravillous trophoblasts mitigates preeclampsia recurrence.
There was a correlation between levels of HbA and
infants. Abnormal uterine artery Doppler was also strongly related to adverse outcome.
Conclusions—Abnormal uterine artery Doppler is related to pregestational vasculopathy and adverse outcome of requires further validation
1c in prospec- primarily defined by the transformation
pregnancy. The results suggest that the uterine arteries are affected in women with clinical signs of pregestational © 2009 Published
decidua from early pregnancy and the obstetrical outcome, which by Mosby, Inc. Alternatively,
Percent inadequate Table 1 pre-decidualization
Diagnostic criteria of the metabolic syndrome may be
according to a secretory
predispos-
20tive 30studies.40 Nevertheless, these observa- of stromal fibroblast into epi-
69 – 71

uterineforand umbilical PI values.

doi: 10.1016/j.ajog.2008.11.037
An increase ofingmean raisePI value
vasculopathy. This may influence placental perfusion and fetal well-being. (Circulation. 2005;112:2496-2500.) 0 10 50 60 World Health Organization (WHO)
Key Words: diabetes mellitus ! perfusion ! pregnancy ! vessels ! vasculopathy are both essential testing the endometrial antecedents of tions dofactor, and
questions a “second
regardinghit” isthelioid-like
the Cut-off needed todecidual initiate cellsthe
and disease
is further
Placental Components
preeclampsia. in the uterine and umbilical arteries was significantly process. Although related these potential
Hyperinsulinemia
pitfalls are all valid criticisms,
Fasting glucose ≥ 6.1 mmol/L
D frequently
iabetes mellitus, especially of the pregestational type, is and monitoring of serum glucose levels. One of the instru-
Because our transcriptomic and bioinformatics analyses Personalof sur- they should not derail pursuit of
Bodyobtaining endometrial biopsies,
Downloaded from http://ahajournals.org by on October 12, 2019

related to adverse outcome of pregnancy, ments of modern perinatal surveillance is Doppler velocim- Obesity
JUNE 2009 American mass index ≥of
Journal kg/m 2
30Obstetrics & Gynecology 615.e1
including perinatal death. The main objective in reducing the
likelihood of complications is adequate serum-glucose con-
etry, which may estimate vascular impedance in placental
circulation. The utero-placental circulation is important for
to an increase of glycosylated
plus CVS suggested deficiency of both pre-decidualization and hemoglobin (P!0.0001, R
because the rewards, in the event for Hypertension Systolic blood pressure ≥ 140 mmHg or
diastolicofbloodpositive results, would be
pressure ≥ 85 mmHg
trol both before conception and during pregnancy. Hypergly- fetal development and growth. Information about correlations Proteinuria Microalbuminuria ≥ 2.5 g/mL or
umbilical artery was 0.27; for uterine artery, enormous. 0.54; Figure 2). specific molecular
Metabolic
cemia may cause changes in maternal-placental blood flow
during the pregnancy that may lead to fetal distress, pre-
between glycemic control and changes in utero-placental decidualization in women who developed preeclampsia [28,58] Moreover, proteinuria ≥ 0.30 g/24deficiencies
h or defects
circulation are conflicting, and the value of Doppler exami-
eclampsia, and intrauterine growth restriction (IUGR). 1–3
nation for surveillance of diabetic pregnancies is still not (Fig. 2), we have been obtaining endometrial biopsies during the could conceivably The beWHO identified,
defines metabolicand syndrome preventative
as the presence of or therapeutic
Ketoacidosis can also be lethal for the fetus. Changes in
maternal placental blood vessels during the course of preg-
nancy under the influence of hyperglycemia may be consid-
widely accepted. 7–13

The aim of the present study was to evaluate the relation

A significant relation
late secretory phase of women who experienced severe pre- still existed
Cardiovascular
after values of uterine hyperinsulinemia with at least two of the other three components.
countermeasures designed and tested to improve (pre)
eclampsia inartery PI #1.2 wereThe excluded. Furthermore, a higher uterine
between maternal placental Doppler velocimetry and levels
ered as characteristic for microangiopathic diabetica. Thick-
the previous pregnancy. overall goal is to deter-
Prothrombotic
decidualization.
2

ening of basement membranes, proliferation of endothelial

of maternal glucose and signs of vasculopathy in pregnancy At the same time, animal and human studies suggest
complicated by pregestational diabetes mellitus (PGDM).
cells, and disarrangement in perivascular space with increase that high blood pressure can damage the placental
mine whether there is dysregulation of pre-decidualization in a Finally, as depicted in and Table
that it is1,thethere
severity ofmay be circulating bio-
of collagen, proteoglycans, and glycosaminoglycans are char-
acteristic vessel changes as a consequence of hyperglycemia.
Changes in placental terminal villi in patients with nephrop- A multicenter, retrospective
Methods
4

study was carried out in 155 insulin-

artery score was significantly
non-conceptive cycle as assessed by “omics” and functional
related
Figure to
profiles to pre-eclampsia
pregestational
3 Adjusted proportional
ana-
contribution of individual risk signs
markers
risk, according ofare
to whether they
vasculature
(pre)decidualization
not is the predominant risk thatfactor could
hypertension
112 – 114
for SGAidentify
that
women who are
. Similarly,

of vasculopathy (Table 2). A more severe increase in uterine

dependent women with PGDM delivered between 1994 and 2002 at
Figure 1. Ultrasound Doppler spectrum of uterine artery blood velocity. Upper athy and Normal
panel: retinopathy
blood (class R/F)
velocity. have
Lower alsoDecreased
panel: been reported. 2,4
treatable ( ) or treatable ( ). placental perfusion dependence on maternal cardiac
Downloaded from http://ahajournals.org by on October 12, 2019

blood velocity with a characteristic notch in early diastole as a sign of increased

The placental
likelihood vascular impedance.
of adverse perinatal outcome is reduced in
the University of Medical Sciences, Poznan, Poland, and the Uni-
versity Hospital MAS, Malmö, Sweden. The study group comprised lyses of cultured endometrial stromal cells derived from the biopsy. at increased risk of developing
output increases predominantlypreeclampsia.
from the second These trimester biomarkers
well-controlled diabetic pregnancies.
No need for multiple markers
5–7
80 cases delivered in Poznan and 75 cases in Malmö between the
If so, then theseartery would corroborate
vascular impedance our transcriptomic
(UAS and
points) could be informed by theanddifferential
onwards gene andhigher
some trials have demonstrated protein
birth expression
hypertensionwas seen in 11
findings
develop#2
according to White classification. There were 49 women in class B
14 Bio-RadPerinatal
affinity chromatography
care of pregnant method,
women butwith
using differences
diabetes mellitus 22nd and 40th weeks of pregnancy. All pregnancies were singleton.
(duration of diabetes, 0 to 10 years); 40 in class C (duration of analyzers
lies inBio-Rad
correct Hitachi Analyzer 912, normally defined as
metabolic management, stringent
"6.4% (Polish group), and the Abbott Imx (Abbott Laboratories),
surveillance, All the women were evaluated at the beginning of pregnancy gestational or pre-eclampsia have weight in treated groups despite a greater antihypertensive
bioinformatics analyses of surplus CVS, which indicated impair- in the endometrial biopsies . The preventative potential of earlyOr,
as discussed above. they could be
diabetes, 10 to 20 years); 22 in class D (duration of diabetes, more
115 – 117
than 20 years); 20 in class R (retinopathy); 5 in class F (nephropa- normally defined as "6.0% (Swedish group). The HbA determi- mean blood pressures above this threshold and deliv- effect blood
cases withactually signs beginsof vasculopathy ery of a (9 cases ininformed
R/F class), in
1c
thy); and 19 in class R/F (retinopathy and nephropathy). Women in
classes R, F, and R/F were defined as having vasculopathy. Both
clinics adopted a strict program for surveillance of these pregnancies.
nations were part of the routine workup for diabetic patients.

Screening by Ut Arteri notching and multiple markers

Repeated
the course
measurements
Received
Fromofthe
July 16,were
pregnancy, and
Division of Figure
2004;performed for eachJuly
revision received
the mean
Obstetrics andwas
woman
used for
Maternal 2.
throughout
2, 2005;
analysis.
Diseases Scatterplot
E.W.-O., R.B.) and the Departmentof
accepted July 15, 2005.
(M.P., J.B., red
of Perinatology blood
and Gynecology cell
(M.D.), Karol HbA 1c in relation to mean
ment of decidualization (for independent factors)
before pregnancy
likely for
small-for-gestational-age
[28]
diastolic blood pressure
(SGA) infant
exceeding 80
byis transcriptomic
mmHg
more
103
.
pressure normalization is suggested by the significantly
decreased
analyses
pre-eclampsia
available
prevalence and
in thedis-
hypertensive
public domain
comparison
downsidestotoonly 2 cases include: without (i)andvascular of complications
The main uterine arteries were located by color Doppler ultra- Adverse perinatalUniversity
outcome of was defined as operative
Poznan,delivery
Poland; for
uterine artery pulsatility index (PI), a marker of vascular (Fig. 2). Potential this approach pre- normal
appear to be decidualization fromreceiving earlyantihypertensive
ectopic therapy and intrauterine
Marcinkowski Medical Sciences, and the University of Lund, Department of Obstetrics and Gynecology (S.G.), University
fetal Hospital
distress, MAS,
including cesarean
Sweden.section and vacuum or forceps Birth weight perinatal mortality related ease severity in women
Start low dose
sound and Doppler velocimetry, using the Aloka 2000, 5500, and Malmö,
extraction because of abnormal cardiotocograph
Gudmundsson, and/or scalp pH,
from the second trimester111,112,117 – 119 . First-trimester,
It has been too late to preventing
Acuson-Sequoia machines with an abdominal transducer. The uter- Correspondence to Saemundur MD, PhD, Lund University, Department of Obstetrics and Gynecology, University Hospital MAS, S-205
more closely to diastolic blood pressure, and optimal
ine artery flow signals were obtained from the vessels cranial to the preterm deliverySweden.
02 Malmö, ("37 weeks
E-mail ofsaemundur.gudmundsson@obst.mas.lu.se
gestation), 5# Apgar score "7, and
impedance. eclampsia per se in the index pregnancy may adversely affectoutcomepregnancies [67]. Of course, dataall of thatthese prospective
women who are approaches
endometrial (Table 2).inVasculopathy was cycles,
not related the to umbilical artery
anatomic crossover with the external iliac arteries. Umbilical artery umbilical vein pH
© 2005 American
"7.20. Macrosomia
Heart was
Association, Inc.defined as birth weight growth and perinatal are observed for diastolic observational indicate high-risk
Doppler spectrum was, at the same examination, obtained from a !4000 g. A small-for– gestational-age newborn infant was defined
free-floating loop of the umbilical cord. The Doppler spectrum was
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.104.492843
maturation subsequent menstrual blood pressures(ii) between could
70 and 80 mmHg be andapplied
systolic tonormotensive
investigating in the firstthe role
trimester haveofa 50%
aberrant reduction (pre)decidu-
2496 blood pressure > 110 mmHg (Figure 5)104,105 . Once they of pre-eclampsia, while those with pre-hypertension or
blood offlow class.
evaluated for vascular impedance by pulsatility index (PI) according TABLE 1. Definitions of the Uterine Artery Score System and
to Gosling et al. The angle of insonation was always less than 30
15

degrees. Apart from PI, uterine artery blood flow spectrum was
Umbilical Artery Flow Classes quality and extent pre-decidualization in the conceptive
become established cycle alization
in the first trimester, women inmaintain
other adverse hypertension obstetrical
have a greateroutcomes than two-foldthat may arise from
increased
evaluated for a notch in early diastole according to Campbell et al 28
risk .
preceding the index preeclamptic pregnancy may not bebloodthepressure
same deficient placentation, too, such as preterm labor and normotensive
16
Uterine artery score
their category throughout pregnancy and
(Figure 1) and the uterine artery score (UAS) according to
Gudmundsson et al (Table 1). UAS is based on the PI value and
17

presence or absence of notching in both uterine arteries. Both arteries

as birth
0$Normal blood flow velocity waveforms in both uterine arteries
weight
1$One abnormal parameter present (ie, high PI (!1.2) or diastolic notch) below the 5th percentile. Values of measurements An increase of
in subsequent non-conceptive cycles, and (iii) from
uterine artery it is the score
systolic
preeclampsia
and was
diastolic
second to third trimester,
also
blood related
pressure
intrauterine
changes
modified by mater-
to Since maternal hypertension is the most prevalent
growthandrestriction.
consistently demonstrated first-trimester risk factor,
were reported as means and standard deviations. No conflictsrecurrence of
were evaluated for high PI (!1.20), or the presence of a notch was 2$Two abnormal parameters present

isadverse outcome ofrespect

pregnancy, including
of these preterm birth and
there is a most urgent need for research to clarify the
to thenal characteristics, that are associated with the risk of
reported as 1 for each abnormality. The values of the UAS ranged
from 0 to 4, depending on the number of abnormal parameters, a
3$Three abnormal parameters present
4$Four abnormal parameters present (ie, high PI and diastolic notching)
only ~ 20% [117]. With first
pre-eclampsia106,107 . preventive potential of first-trimester antihypertensives
interest were involved in the study.
UAS of 4 having a bilateral notch and a bilateral PI !1.20 (Table 1).

small-for– gestational-age newborn infants (Tableoutcome are2).

notablyAd-
and the thresholds and treatment targets for such therapy.
Umbilical artery blood velocities were also graded according to
blood flow class according to Gudmundsson et al17 (Table 1). The
Umbilical artery blood flow class First-trimester systolic and diastolic blood pressure val-
0$Normal umbilical artery blood flow velocity waveforms
last examination before delivery was used for analysis. Gestational ues that are associated with normal
 Thank you
ありがとうございました
If it doesn't kill the cat, curiosity is a luxury

⾃信は努⼒から