6/26/19

The Challenge of Screening in Pregnancy

PREECLAMPSIA & FGR

Herman Kristanto
Maternal Fetal Medicine Division
Faculty of Medicine – Diponegoro University
Diponegoro National Hospital

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Preeclampsia and fetal growth restriction (FGR) are

major contributors to perinatal mortality and morbidity.
Although there is an increasing understanding of the
pathophysiology of these conditions, their prevention
remains a considerable challenge in obstetrics.

It is now well-understood that, although the symptoms

of preeclampsia and FGR generally manifest in the
second to third trimesters of pregnancy, their underlying
pathology largely takes place in the first trimester

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According to the concept of placenta having a central

role in the development of preeclampsia and FGR,
placental hypoxic stress and ischemia precede a
generalized maternal endothelial dysfunction and
inflammatory response. Secondarily, clinical symptoms
of preeclampsia and impaired fetal growth develop

A 2-stage model has been proposed in which poor

placentation, the central initiating event, is thought to
occur early.
This first stage results from failure of the normal
physiologic process in early pregnancy where
endovascular trophoblast invades the maternal
vasculature replaces the smooth muscle normally
present in the spiral arterioles with a noncontractile
matrix material

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This lack of transformation predisposes to hypoperfusion,

hypoxia reperfusion injury, oxidative stress, and signs of
placental maldevelopment in the second trimester.
Recent evidence suggests that a significant part of placental
injury is mechanical damage resulting from intermittent
perfusion as a result of persistence of smooth muscle in the
spiral

The second stage of preeclampsia pathogenesis is the

maternal response to abnormal placentation, which is
initially adaptive, but subsequently results in
widespread systemic injury.
Key features of this second phase are systemic
endothelial dysfunction and an imbalance of circulating
vasoactive factors.

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Suppo, et al. NeoReviews 2011 ; 12 (4)

Rabaglino, et al. Hypertension 2015 ; 65

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Norwitcz, Schust & Fisher. NEJM, 2001 ; 345

Norwitcz, Schust & Fisher. NEJM, 2001 ; 345

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Norwitcz, Schust & Fisher. NEJM, 2001 ; 345

Moffet & Lake. Nature, 2006 ; 4

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Li, Lorca & Su. J Mol Endocrinol, 2018 ; 60

Degner, Magness & Shah. Reproductive Sciences, 2017 ; 24 .

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Espinoza, et al. J. Perinat. Med. 2006 ; 34

Kingdom, and Drewlo. Blood, 2011 ; 118

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Kingdom, and Drewlo. Blood, 2011 ; 118

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Degner, Magness & Shah. Reproductive Sciences, 2017 ; 24 .

James, Whitley & Cartwright. J Pathol, 2010 ; 221

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Magee, et al. Pregnancy Hypertension, 2014 ; 4

Burton, et. Al. Placenta, 2009 ; 30

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Candidate screening tests

for preeclampsia and fetal growth restriction
Placenta perfusion dysfunction related tests
• Uterine artery Doppler ultrasonography
• Two-dimensional placenta imaging
• Three-dimensional placenta imaging
• Placental volume
• Placenta quotient
• Placenta vascular indices

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Candidate screening tests

for preeclampsia and fetal growth restriction
Placenta perfusion dysfunction related tests
• Uterine artery Doppler ultrasonography
• Two-dimensional placenta imaging
• Three-dimensional placenta imaging
• Placental volume
• Placenta quotient
• Placenta vascular indices

Enhanced uterine artery resistance reflects a failure of

trophoblastic invasion of the spiral arteries and is associated
with the development of preeclampsia and FGR.
Increased resistance to vascular flow can be measured
noninvasively by Doppler flow studies of the myometrial
segments of the arteries supplying the spiral arterioles.
Increased uterine artery resistance as measured by pulsatility
index (PI) or resistive index above a chosen value and/or
percentile or the presence of unilateral orbilateral diastolic
notches has been investigated for the prediction of
preeclampsia and FGR.

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Transabdominal Transvaginal

Uterine artery

Uterine artery

Evaluation of UtA-PI at 11–13 weeks can be achieved at the level of the

internal cervical os in a greater proportion of women than at the level of
the apparent crossover with the external iliac vessels, and the
measurements obtained correlate better with second-trimester UtA-PI

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“How To” record uterine artery Doppler at 11–13 weeks

How To: Record uterine artery Doppler pulsatility index (PI)
at 11+0 to 13+6 weeks’ gestation
Indication: To screen in the first trimester for pre-eclampsia
and/or fetal growth restriction
Machine settings: Routine first-trimester scan preset with
color Doppler velocity 30–40 cm/s, pulsed wave Doppler
velocity 80–100 cm/s, low filter (50–100 Hz) and pulsed
Doppler sample volume 2 mm

Uterine artery Doppler: identifying the cervix

Obtain a mid-sagittal section of the uterus

and cervix

Use HD zoom to enlarge the view of the

cervix

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Uterine artery Doppler: identifying the uterine artery

• Apply color flow mapping

• Slide the transducer to view the para-
cervical region
Mid-sagittal view
• Gently move the transducer from side
Bladder
to side to identify the uterine artery
• The uterine arteries are at the level of
the internal cervical os
Cervix

Paramedian view

Uterine artery Doppler: obtaining a spectral Doppler signal

Color Doppler of uterine arteries

• Set the sampling gate to 2 mm so as to cover

whole vessel
• Angle of insonation should be less than 30º
• The peak systolic velocity should be more
than 60 cm/s in the uterine artery
• Obtain three similar consecutive waveforms Uterine artery waveform

• The mean PI is obtained as the average of the

left PI and right PI

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DeVore GR. Fetal Diagnostic Centers. www.fetal.com

DeVore GR. Fetal Diagnostic Centers. www.fetal.com

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DeVore GR. Fetal Diagnostic Centers. www.fetal.com

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DeVore GR. Fetal Diagnostic Centers. www.fetal.com

DeVore GR. Fetal Diagnostic Centers. www.fetal.com

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DeVore GR. Fetal Diagnostic Centers. www.fetal.com

Everett & Lees, Placenta 2012 ; 33

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Gomez, et al. Ultrasound Obstet Gynecol 2008; 32

1st Trimester

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• The pulsatility index (PI) should be used for

examination of uterine artery resistance in the context
of PE screening (GRADE OF RECOMMENDATION: B).
• Doppler examination of the uterine arteries at 11+0 to
13+6 weeks can be performed either transabdominally
or transvaginally, according to local preferences
and resources (GOOD PRACTICE POINT).

Screening by first-trimester uterine artery PI

> 90th centile detects 48% of women who will
develop early PE and 26% of those who will
develop any PE, for a 10% screen-positive
rate (EVIDENCE LEVEL : 2++).

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• The 95th centile for mean uterine artery PI obtained using a

transabdominal approach between 11+0 and 13+6 weeks is
2.35 (EVIDENCE LEVEL : 2+).
• Uterine artery resistance is higher on transvaginal compared
with transabdominal measurement; the 95th centile for mean
uterine artery PI obtained using a transvaginal approach is
approximately 3.10 for crown–rump lengths (CRL) up to 65
mm, gradually declining with increased CRL thereafter
(EVIDENCE LEVEL : 2+).

• The uterine artery PI may also be affected by maternal

factors, including ethnic origin, BMI and previous PE
(EVIDENCE LEVEL : 2++).

• Given that maternal factors can affect uterine artery PI,

its inclusion in a multifactorial screening model should,
whenever feasible, be preferred over its use as a
standalone test with absolute cut-offs (GRADE OF
RECOMMENDATION: B).

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Khong, et al. Disease Makers 2015

• The uterine artery L-PI was significantly higher in early PE and

late PE than in the unaffected group (P < 0.0001), in early PE than
late PE or GH (P < 0.0001), and in GH than in the unaffected group
(P = 0.014).
• In screening by a combination of the maternal factor-derived
apriori risk, uterine artery L-PI and MAP, the estimated detection
rate at a 10% false-positive rate was 89.2% (95% CI, 74.6–96.9%)
for early PE, 57.0% (95% CI, 48.0–65.7%) for late PE and 50.0%
(95% CI, 41.4–58.6%) for GH.
Poon, et al. Ultrasound Obstet Gynecol 2009 ; 34

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• The mini-combined test (MAP

and PAPP-A)
Preterm Preeclampsia Term Preeclampsia
• Biophysical test (uterine artery
PI and MAP)
• Biochemical test (serum PLGF
and PAPP-A)
• The triple test (uterine artery PI,
MAP and serum PLGF)

Gorman, et al. Am J Obstet Gynecol 2016

Combined screening by maternal factors, uterine artery pulsatility index,

mean arterial pressure, and placental growth factor predicted 75% (95%
CI, 70-80%) of preterm-preeclampsia and 47% (95% CI, 44-51%) of term-
preeclampsia, at a false positive rate of 10%; inclusion of pregnancy-
associated plasma protein-A did not improve the performance of
screening. Such detection rates are superior to the respective values of
49% (95% CI, 43-55%) and 38% (34-41%) that were achieved by screening
with maternal factors alone.

Gorman, et al. Am J Obstet Gynecol 2016

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Screening with use of the FMF algorithm based on a combination

of maternal factors, mean arterial pressure (MAP), uterine artery
pulsatility index (UtA-PI) and serum placental growth factor (PlGF)
detected 100% (95% CI, 80–100%) of PE <32 weeks, 75% (95% CI,
62–85%) of PE <37 weeks and 43% (95% CI, 35–50%) of PE ≥37
weeks, at a 10.0% FPR.
Gorman, et al. Ultrasound Obstet Gynecol 2017 ; 49

2nd Trimester

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• As in the first trimester, uterine artery PI in the second

trimester is higher when measured transvaginally
(EVIDENCE LEVEL : 2++).

• The 95th centile for mean uterine artery PI is 1.44 for the
transabdominal approach and 1.58 for the transvaginal
approach at 23 weeks (EVIDENCE LEVEL : 2+).

• The 95th centile of the mean uterine artery PI decreases by

about 15% between 20 and 24weeks, and by <10% between 22
and 24 weeks (EVIDENCE LEVEL : 2++).

Mean uterine artery PI should be used for prediction of

PE. In case of a unilateral placenta, a unilaterally
increased PI does not appear to increase the risk for
PE if the mean PI is within normal limits
(GRADE OF RECOMMENDATION : B).

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3rd Trimester

• There are currently no randomized trials on the impact of

third-trimester screening for PE on maternal, fetal and
neonatal outcomes; consequently, its implementation
into routine practice cannot be recommended at present
(GOOD PRACTICE POINT).

• Mean uterine artery PI should be used for prediction of

PE, if this is offered in the third trimester
(GRADE OF RECOMMENDATION : B).

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Longitudinal changes in Doppler indices

Given that preventive strategies (e.g. low-dose aspirin) for
reducing the risk of PE are effective if started in the first
trimester, their use should be commenced as soon as
possible in women identified as being high-risk, without
waiting to assess the evolution of Doppler in the second
trimester (GOOD PRACTICE POINT).

Placental volume
Although placental volume and vascularization indices have
been assessed as predictors for PE, they cannot be
recommended for screening purposes given that their
reproducibility is limited, they require special equipment and
they are time-consuming (GOOD PRACTICE POINT).

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Combined screening strategies

• A combination of maternal factors, maternal arterial blood
pressure, uterine artery Doppler and PlGF level at 11–13
weeks appears to be the most efficient screening
model for identification of women at risk of PE (GRADE OF
RECOMMENDATION: B).

Combined screening strategies

• Given the superiority of combined screening, the use of
Doppler cut-offs as a standalone screening modality should
be avoided if combined screening is available (GRADE OF
RECOMMENDATION: B).

• The transabdominal approach is preferred for calculating

first-trimester individual patient risk, as most screening
algorithms were developed using this approach
(GOOD PRACTICE POINT).

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Management after screening

There is convincing evidence that low-dose aspirin

can decrease significantly the risk for development
of early PE, when administration commences at the
time of first-trimester screening
(GRADE OF RECOMMENDATION : A).

Multiple pregnancy
• Due to increased placental mass in twin pregnancy, resulting
in lower mean resistance in the uterine arteries, twin-specific
reference ranges should be used for Doppler examination, if
available (GRADE OF RECOMMENDATION : B).

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Multiple pregnancy
• The combined screening (maternal factors, uterine artery PI,
mean blood pressure, PlGF) algorithm for singletons can
also be used in twins and can identify more than 95% of
women with twin pregnancy who will develop PE. However,
the examiner should be aware that this is achieved at the
cost of a 75% screen-positive rate (GRADE OF
RECOMMENDATION : B).

Use of ultrasound in patients with established

pre-eclampsia

• Given that fetal deterioration is an indication for

delivery in established PE, fetal status should be
assessed regularly in these patients (GOOD
PRACTICE POINT).

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Use of ultrasound in patients with established

pre-eclampsia
• The sonographic follow-up in pregnancies affected by
PE includes assessment of fetal growth and biophysical
profile, and fetal Doppler studies (GOOD PRACTICE
POINT).
• As there have been no randomized controlled trials, the
components, frequency and impact of ultrasound
surveillance in pregnancies affected by PE have yet to
be determined (GOOD PRACTICE POINT).

Use of ultrasound in patients with established

pre-eclampsia
• Examination of fetal biometry, amniotic fluid volume,
uterine artery, UA and MCA PI and CPR, as well as
placental visualization to exclude abruption, should be
considered in women presenting with headache,
abdominal pain, bleeding and/or reduced fetal movements
(GOOD PRACTICE POINT).
• The same tests should be considered for women admitted
for PE or with suspected PE, as well as for those with
severe PE or HELLP syndrome (GOOD PRACTICE POINT).

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Thank You

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