Pre-eclampsia screening

in 1st trimester of pregnancy

Early screening for pre-eclampsia with PlGF and PAPP-A
for timely intervention and optimal patient care
 Early screening – early intervention
Pre-eclampsia screening in 1st trimester
for optimal patient care

Serum PlGF determination in combination with other factors

allows early risk assessment for pre-eclampsia

Pre-eclampsia is a leading cause of maternal morbidity The high sensitivity assays Thermo Scientific™
and mortality.1 A combined first trimester screening B·R·A·H·M·S™ PlGF plus KRYPTOR™ and
approach including measurement of Placental Growth B·R·A·H·M·S PAPP-A KRYPTOR can reliably detect
Factor (PlGF) and Pregnancy-Associated Plasma Protein A PlGF and PAPP-A in maternal serum already at weeks
(PAPP-A) can reliably identify women at high risk for early- 11–13+6 of gestation to support a high quality first
onset pre-eclampsia. Early identification of women at high trimester pre-eclampsia screening.
risk allows for intensified maternal and fetal monitoring
and timely intervention to significantly reduce the pre­
valence for pre-eclampsia.

First trimester
screening for
pre-eclampsia
with PlGF and
PAPP-A

Administer low-dose aspirin

to high risk patients
(start <16 weeks)

Week of gestation 8 9 10 11 12 13 14 15 16 17 18

First trimester screening for pre-eclampsia

A combination of
• maternal characteristics
• uterine artery pulsatility index (UAPI)
• mean arterial pressure (MAP) and
• maternal serum PAPP-A and PlGF
at 11–13+6 weeks’ gestation can identify a high proportion of
pregnancies at high-risk for pre-eclampsia.2

2
 Low-dose aspirin can reduce the risk
of pre-eclampsia

A meta-analysis has shown that the application of low- Recent prospective studies proved the efficacy of low-
dose aspirin (<150 mg/day) started before week 16 of dose aspirin in reducing pre-eclampsia. Women identified
gestation caused a significant reduction in pre-eclampsia at high risk for pre-eclampsia after first trimester screening
and intrauterine fetal growth restriction (IUGR) compared to either received low-dose aspirin or nothing. In the aspirin
controls, while aspirin started after 16 weeks of gestation group the prevalence of pre-eclampsia was reduced by 90%.5
did not.3,4

First onset of clinical

symptoms of pre-eclampsia
(hypertension, proteinuria)

Confirm or exclude diagnosis of pre-eclampsia with sFlt-1/PlGF ratio

Prognosis of adverse outcome using sFlt-1/PlGF ratio

19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Early-onset (severe) pre-eclampsia Intermediate- Late-onset (moder­

onset (medium) ate) pre-eclampsia
pre-eclampsia

Severe and rapidly progressing form of pre-eclampsia with Milder forms of pre-eclampsia with
multiple complications and the need to deliver the baby less complications occurring after 34
preterm 6 weeks of gestation 6

Figure 1 First clinical symptoms of pre-eclampsia are observed >20 weeks of gestation.
The gestational age at onset correlates with the severity of maternal and fetal consequences.7

3
 Pre-eclampsia: a leading cause
of maternal morbidity and mortality
Severe complications for the mother Severe complications for the fetus

With an incidence between 2-8%, pre-eclampsia is a Due to an insufficient supply of oxygen and nutrients,
frequent pregnancy disorder 8 affecting more than 4.1 pre-eclampsia causes severe complications for the fetus,
million women per year worldwide.1 such as prematurity, IGUR, bronchopulmonary dysplasia
and sometimes even death.9
The severe pre-eclampsia variant HELLP syndrome About 15-20% of preterm deliveries are due to
(Hemolysis, Elevated Liver enzymes, Low Platelets) pre-eclampsia.9
occurs in about 20% of the affected women and is
defined by additional complications of the liver and
the coagulation system resulting in symptoms such as
Eclampsia
abdominal pain, hemorrhage, placental abruption,
hepatic infarction and rupture, intra-abdominal bleeding 12%
Infections
and edema. Eclampsia is the final and most feared
15%
stage of the disease, associated with severe tonic-clonic Obstructed
labor
seizures and coma as well as brain injury, cerebral 8%
edema and stroke.9
HELLP syndrome and eclampsia account for
more than 50 000 maternal deaths each year.8 Severe bleeding Unsafe abortion
(haemorrhage) 13%
25%

Other direct
causes
8%
Indirect causes
20%

Figure 2 Causes of maternal death worldwide

(Total is more than 100% due to rounding) 1

4
Long-term complications for the women Risk factors

Pre-eclampsia is responsible for long-term complications There are many risk factors for pre-eclampsia including
later in life. Large retrospective epidemiological studies • Maternal and paternal family history
have shown that women with a previous pre-eclampsia • Previous pregnancy with pre-eclampsia
have a 3-4 times higher risk for cardiovascular disorders • Multiple pregnancy (triplets > twins)
later in life than non ­pre-eclamptic women. The risk is • Maternal Age (>40 years)
even higher (4-8 fold) if the onset of pre-eclampsia was • Body Mass Index (BMI >30)
before 34 weeks of gestation or pre-eclampsia was • Pre-existing hypertension, Diabetes mellitus
combined with a preterm birth.9 or renal disease
• Systemic inflammation
The risk of death from cardiovascular and • Ethnical origin
cerebrovascular disease is 50% greater in women
with a history of pre-­eclampsia.9

The underlying mechanism that accounts for the elevated

risk is not yet well understood, but it was shown that
endothelial dysfunction persists for many years in women
with a former ­pre-eclampsia episode.9

Early PE
BMI Intermediate PE
Late PE
Caucasian

African

South Asian

Assisted conception

Family history of PE

Chronic hypertension

Nulliparous

Figure 3 Odds ratio and 95%

Parous previous PE confidence interval (CI) of
risk factors for development of
Parous no previous PE pre-eclampsia (PE)10

0.1 0.2 0.4 1 2 4 10

Odds ratio (OR)

5
 Imbalance of pro- and
antiangiogenic proteins
A key factor for developing
pre-eclampsia

Normal pregnancy Deoxygenated blood Myometrium

Ma­­t­­­ern
al vein
Placenta and developing fetus Cytotrophoblast
stem cells
are provided with sufficient Fetal blood
vessels
maternal oxygen and nutrients11
• Fetal cytotrophoblast cells invade
maternal uterine wall (into smooth Maternal
muscle and endothelial layer) Mater­nal blood Blood endothelial cells
flow
• M aternal spiral arteries are
remodeled into large vessels with Spiral artery

high capacity and low resistance Endovascular

cytotrophoblast
Decidua Tunica media
smooth muscle
Cytotrophoblast

Pre-eclamptic pregnancy Deoxygenated blood Myometrium

Ma­­t­­­ern
al vein
Inadequate circulation between Cytotrophoblast
stem cells
placenta and uterus11 Fetal blood Cytotrophoblast
vessels
• I nvasion of cytotrophoblasts is
incomplete, they can only be found
in superficial layers of decidua Maternal
Mater­nal blood endothelial cells
• M aternal spiral arteries fail to be Blood
flow
invaded/remodeled, resulting in
vessels with a decreased capacity Spiral artery

and increased resistance.

Decidua
• As a consequence of the decreased Tunica media
smooth muscle
blood flow the fetus is not supplied
sufficiently with oxygen and nutrients.

6
 Maternal PlGF serum concentration is significantly
decreased in pre-eclampsia in the first trimester

The cause of pre-eclampsia is still not well understood, but the placenta has been identified as the
central organ in pathogenesis.9

Studies suggest that an imbalance of angiogenic proteins secreted by the placenta account for
many complications with respect to pre-eclampsia. PlGF is a proangiogenic factor, belonging to the
Vascular Endothelial Growth Factors (VEGF) family, which are promoting proliferation and survival of
endothelial cells and inducing vascular permeability.12 sFlt-1 (soluble FMS-like tyrosine kinase) is an
antiangiogenic factor, binding PlGF and VEGF with high affinity, therefore antagonizing their effects.13
In contrast to a healthy pregnancy, PlGF levels are significantly lower in pre-eclamptic patients
(Figure 4). This difference is measurable in the first trimester.14 sFlt-1 levels in pre-eclamptic women
are significantly higher compared to normal, but this difference is only notable after week 20.

1100 Controls
Mean PlGF concentration [pg/mL]

1000 PlGF Women who had pre-eclampsia

900 >5 weeks later
800 Women who later had pre-eclampsia
700
Women with clinical pre-eclampsia
600 p =0.02
500 p =0.03
p =0.003
400
p =0.002
300
200
p =0.01
100 p =0.01
p <0.001 p <0.001
p =0.01
0
8-12 13-16 17-20 21-24 25-28 29-32 33-36 37-41

Gestational age (week)

Figure 4 Mean PlGF concentrations of healthy women and

those women who later developed pre-eclampsia14

7
 1 trimester screening for
st

pre-eclampsia
Identification of women at risk for pre-eclampsia
before clinical symptoms appear

Combined first trimester screening for pre-eclampsia

Pre-eclampsia screening can be easily integrated into clinical
routine pregnancy assessments in weeks 11+0 – 13+6.

1 M
 aternal characteristics including medical
and obstetric history

PAPP-A
2 
Serum Biomarkers PAPP-A and PlGF
PlGF

3 
Mean arterial blood pressure (MAP)

4 
Uterine artery pulsatility index (UAPI)

5 
Risk assessment with appropriate PNS
software to calculate individual risk to
develop pre-eclampsia

Risk assessment for fetal trisomies

and maternal pre-eclampsia can be
performed at the same time
8
Combined screening achieves highest detection rates

Using the traditional screening method, based on maternal history only, detection rate for women
who are at risk for developing pre-eclampsia is about 30%. Detection rates become more accurate
when maternal charac­teristics are combined with PlGF measurement as well as other factors such
as serum PAPP-A (both measured in weeks 11–13+6), mean arterial pressure (MAP), and uterine
artery Doppler (uA-PI), resulting in a detection rate of >90% for cases of early pre-eclampsia for
a fixed false positive rate of 5% before any clinical symptoms appear.7 Therefore, an effective
prediction of pre-eclampsia can be achieved already in first trimester.6, 15

Screening test FPR (%) Detection rate (%)

PE < 34 wks PE < 37 wks PE < 42 wks
Maternal characteristics 5 36 33 29
PAPP-A 5 44 37 32
PlGF 5 59 41 29
PAPP-A and PlGF 5 60 43 30
MAP 5 58 44 37
UAPI 5 59 40 31
MAP and UAPI 5 80 55 35
MAP, UAPI and PAPP-A 5 82 53 36
MAP, UAPI and PlGF 5 87 61 38
MAP, UAPI, PAPP-A and PlGF 5 93 61 38

Table 1 Screening performance for early-, intermediate- and late-onset pre-eclampsia by combining different factors 15

Highly sensitive PlGF and PAPP-A assays

are needed to reliably detect these biomarkers
in weeks 11–13+6.

9
 Thermo Scientific B·R·A·H·M·S
pre-eclampsia biomarkers
High sensitivity and exceptional precision

Thermo Scientific
B·R·A·H·M·S PlGF plus KRYPTOR

Automated immunofluorescent assay for the quantitative

determination of the concentration of PlGF (Placental
Growth Factor) in human serum. The assay is specific for
the measurement of human free PlGF-1.

•C
 E mark for trisomy and pre-eclampsia first
trimester screening

• 75 determinations per kit

• 29 min incubation time

• FAS: 6.7 pg/mL

• Single-point calibration

• Wide measuring range: 3.6-7000 pg/mL

• Lowest cross reactivity to PlGF-2 and PlGF-3

With the lowest FAS and lowest cross-reactivity to other

PlGF isoforms B·R·A·H·M·S PlGF plus KRYPTOR provides
the highest sensitivity needed for reliably measuring low
PlGF levels in the first trimester of pregnancy. 16

10
Thermo Scientific
B·R·A·H·M·S PAPP-A KRYPTOR

Automated immunofluorescent assay for the determination

of pregnancy associated plasma protein-A (PAPP-A) in
human serum and heparin plasma.

• CE mark for trisomy and pre-eclampsia first trimester

screening

• 75 determinations per kit

• 19 min incubation time

• FAS: 10 mIU/L

• Single-point calibration

• Wide measuring range: 0.004 - 90 IU/L

• Excellent precision

B·R·A·H·M·S PAPP-A KRYPTOR provides an outstanding

precision with a mean CV of only 3.1%, proven by UK NEQAS
data 2003-2016. 17

Exceptionally precise, fast and easy

Thermo Scientific B·R·A·H·M·S KRYPTOR compact PLUS

­ 8 Years Reliable Results

1
18 Years Confident Decisions
• All KRYPTOR platforms FMF approved

• In routine use by FMF since 1999

• Excellent precision and proven median stability

• OSCAR compatible

11
 Your BENEFITS performing a Your ACCESS to
1st trimester pre-eclampsia screening our interactive e-detail

Early identification of high risk pregnancies Get more information on pre-eclampsia

for pre-eclampsia weeks before first clinical management throughout pregnancy:
symptoms appear
 arly risk assessment allows for closer
E
http://prenatal.world-of-
surveillance and in time administration of low
biomarkers.com
dose aspirin (<16 weeks) to significantly reduce
the incidence of pre-eclampsia
Pin code: plgf01
10 min

Thermo Scientific B·R·A·H·M·S Biomarkers References

Prenatal Screening Portfolio on KRYPTOR Systems 1. The World Health Report 2005; p62
2. O ’Gorman et al. Am J Obstet Gynecol. 2016 Jan; 214(1): 103.
B·R·A·H·M·S AFP KRYPTOR Art. no.: 816.075 e1-103.e12
3. Bujold E et al. J Obstet Gynaecol 2010; 116: 402-14
B·R·A·H·M·S Free βhCG KRYPTOR Art. no.: 809.075 4. Bujold E et al. J Obstet Gynaecol can 2009; 31: 818-26
5. Park et al. Ultrasound Obstet Gynecol. 2015 Oct; 46(4): 419-23
B·R·A·H·M·S hCG+β KRYPTOR Art. no.: 841.050 6. Poon LCY et al. Hypertension 2009; 53: 812-818
7. Akolekar R et al. Prenat Diagn 2011; 31: 66-74
B·R·A·H·M·S Inhibin A KRYPTOR (under development) 8. G hulmiyyah L and Sibai B. Seminars in Perinatology 2012; 36:
56-59
B·R·A·H·M·S PAPP-A KRYPTOR Art. no.: 866.075 9. Powe CE et al. Circulation 2011; 123: 2856-69
10. Nicolaides KH. Fetal Diagn Ther 2011; 29(3): 183-96
B·R·A·H·M·S PIGF plus KRYPTOR* Art. no.: 859.075 11. Lam C et al. Hypertension 2005; 46: 1077-85
12. De Vivo et al. Acta Obstet et Gynecol 2008; 87: 837-42
B·R·A·H·M·S sFlt-1 KRYPTOR* Art. no.: 845.075 13. Hagmann et al. Clin Chem 2012; 58 (5), 837-45
B·R·A·H·M·S uE3 KRYPTOR** Art. no.: 803.075 14. Levine RJ et al. N Engl J Med 2004; 350: 672-83
15. Poon et al. Prenat Diagn. 2014 Jul; 34(7): 618-27
B·R·A·H·M·S Fast Screen pre I plus Software Art. no.: 105750 16. Nucci et al. Fetal Diagn Ther. 2014; 36(2): 106-16
17. Monthly UK NEQAS reports, February 2003 – December 2016
* Available on KRYPTOR compact PLUS
** Available on KRYPTOR and KRYPTOR compact PLUS

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