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***KEY POINTS***

Placental Function Testing

The 3 components of the placental function test are:


1. Maternal biochemistry
2. Placental morphology
3. Uterine artery Doppler

Maternal biochemistry is comprised of the screening blood tests for Down syndrome
and spina bifida, which are re-interpreted for placental function

Placental Function Testing


An Overview of the Techniques Used to Assess Placental Function

Maternal Biochemistry
Placental Ultrasound
Uterine Artery Doppler

Placental Function Testing


Components of the Placental Function Test:
Component

What is measured?

Maternal
Biochemistry

Specific proteins in maternal blood (re-interpretation of the prenatal screening blood tests for
Down syndrome and spina bifida). These values are reported as Multiples of Median (MoM).

Placental
Ultrasound

Uterine artery
Doppler

Placental morphology; size, shape and texture of the placenta

Blood flow from the mother to the placenta via her left and right uterine arteries

These tests are described in further detail below

Maternal Biochemistry
Prenatal screening for Down syndrome and spina bifida
There are several choices of prenatal screening tests available to determine the risk of having a
baby with Down syndrome and a blood test to screen for spina bifida and other birth defects.
Screening tests for Down syndrome combine the results of the analysis of proteins in the
mother's blood with an ultrasound of the baby's neck. These screening tests are describd below:
First trimester screen (FTS)

This is performed at 11-13 weeks gestation, and is comprised of a blood test to measure levels of
two proteins in the mother's blood: 1) pregnancy-associated plasma protein-A [PAPP-A], and 2)
free human chorionic gonadotropin [free hCG]. The mother's age and an ultrasound to measure
the amount of fluid at the back of the developing baby's neck (called nuchal translucency) are
also used.

Maternal serum screen (MSS)

This blood test is performed at 15-19 weeks gestation, and measures four proteins in the mother's
blood: 1) alpha-fetoprotein [AFP], 2) total human chorionic gonadotropin [total hCG], 3) estriol
[uE3], and 4) inhibin [dimeric inhibin assay or DIA].
Integrated prenatal screen (IPS)

This test combines the elements of the FTS and MSS tests to provide a more accurate (less risk
of a false positive test) determination of the risk of having a baby with Down syndrome. It
includes the same risk assessment for spina bifida and other birth defects, since it includes AFP.
Please see the Prenatal Diagnosis and Medical Genetics website for more information on using
these tests for prenatal screening.
The results from these tests can be re-interpreted for placental function
It is important to note that these biochemical markers are only currently used in prenatal
screening to indicate the risk of a chromosomal abnormality (Down syndrome) and birth defect
(spina bifida). If the screening tests results are high-risk for Down syndrome, the most common
action is to offer a diagnostic test called amniocentesis. This will determine if the developing
baby has Down syndrome or not. Since amniocentesis carries a small risk of pregnancy
complications, an alternative choice is to have a detailed fetal anatomical ultrasound examination
to look for specific markers that suggest Down syndrome. The same ultrasound examination is
performed in women with elevated AFP, to look for evidence of spina bifida.
In both instances, amongst women who test positive, the chances are much greater that the
developing baby is normal (29/30) than has either Down syndrome or spina bifida
(approximately 1/30).
Knowing that an amniocentesis test is normal and/or that the fetal anatomical ultrasound is
normal is an immense relief for parents, but does it mean that they have no risk? The answer is
NO-- a common explanation for false-positive testing is that the placenta is not working
normally, and is responsible for the abnormal protein levels in maternal blood, as shown below.
Multiply-abnormal test results are strongly associated with stillbirth or extremely preterm birth
(<32 weeks gestation) due to pregnancy complications from placental insufficiency.

Summary of Maternal Biochemistry Tests for Placental Function at 11-19 Weeks


Protein

Name

Function

PAPPA

Pregnancyassociated plasma
protein A

Activates growth
factors required for
fetal growth

Abnormal
values

What does an abnor

PAPP-A is released by the early developing


0.35 MoM*
in the maternal blood reflects the size of the
or less
wall

This protein is made in


2.0 MoM or
the developing baby's
greater
liver

AFP is a large protein that is made by the b


across any skin defect, like a spina bifid
structurally normal fetus, elevated matern
damaged p

AFP

Alpha fetoprotein

Total
hCG

Total human
chorionic
gonadotropin

This protein is made by


hCG is made by the outer 'skin' of the place
4.0 MoM or
the outer layer of the
layer also makes the anti-angiogenic prote
greater
placental villi
causing the hypertensive d

DIA

Inhibin (or Dimeric


Inhibin Assay)

This protein is made by


3.0 MoM or Inhibin is also made by the outer syncytiotr
the outer layer of the
greater
and DIA poses a very high ris
placental villi

* MoM = Multiples of Median. This expresses how far a test value deviates from a normal
population's median value at any gestational age. To understand the concept of MoM, imagine
sitting next to a 9ft tall man, who is 50% taller than a 6ft tall man: the taller man's height is 1.5
MoM. Another 6ft tall man's height is 1.0 MoM.
A placental health examination is indicated if one or more of the following are found with a
fetus that has a normal anatomy ultrasound and/or a normal karyotype:

PAPP-A < 0.35 MoM

AFP > 2.0 MoM (Mount Sinai Hospital neural tube defect cut-off)

Inhibin >3.0 MoM

Total hCG >4.0 MoM

This placental health examination is comprised of a placental morphology ultrasound and


uterine artery Doppler.

Placental Morphology Ultrasound


Ultrasound is a non-invasive diagnostic tool initially developed in obstetrics to visualize and
measure the developing fetus and its surrounding structures (amniotic fluid, umbilical cord,
placenta, uterus, cervix, and ovaries). Ultrasound sends sound waves into the body through a

transducer. These sound waves bounce off internal structures and are sent back to be interpreted
and represented as an image on the monitor. The imagine is real-time and can show the
developing baby as a live moving person. At present, the ideal window for the placental
morphology ultrasound is 19-22 weeks' (combined with, or near to, the established fetal
anatomical ultrasound).
Placental ultrasound determines the placental morphology the placentas size, shape and
texture.

Size and Shape


The placenta should appear long (>12cm in length) and thin (<3cm in width) in size

Normal shape

Abnormal shape

Long and thin

Thick and small

Texture
The placenta should be a smooth, consistent (homogenous) texture

Normal texture

Abnormal texture

Smooth consistent texture

Abnormal, heterogenous texture

What Other Abnormalities Can Be Determined Through Ultrasound


Scanning?
Placental Location

In a typical pregnancy, the placenta attaches to the upper wall of the uterus (called the fundus).
However, when the placenta is in the lower uterine segment of the uterus, it may cover part of all
of the internal os (opening) of the cervix. A low-lying placenta near or covering the internal os is
termed placenta previa. This is an important complication of pregnancy to recognize, and as
such, the determination of placental location is currently part of the fetal anatomical ultrasound
examination.
Abnormal Umbilical Cord Insertion

At the end of the first trimester of pregnancy (12 weeks or 3 months), the placenta has become
distinct from the membranes. Typically, the umbilical cord is seen to insert in the central part of
the placental disc. If part of the placenta becomes damaged or does not develop properly, then
that area of the placenta thins out into membranes leaving the umbilical cord near the edge of the
placental disc. Using ultrasound, we can visualize the development of the placenta and the
location of the umbilical cord.
o Marginal cord insertion: the cord inserts into the edge of the placenta
o Velamentous cord insertion: the cord inserts into the membranes, not into the
placenta. If this occurs, the woman is at risk of developing vasa previa.
Abnormal Number of Blood Vessels in the Umbilical Cord

The umbilical should have three blood vessels; two umbilical arteries and one umbilical vein.
The umbilical arteries transport deoxygenated blood and waste from the fetus to the placenta.
The umbilical vein carries oxygenated blood and nutrients from the placenta to the fetus to
support growth and development. Occasionally, the umbilical cord contains only one umbilical
artery (called a two-vessel cord). When this occurs, the remaining umbilical artery is wider, and
thus has a compensatory larger volume of blood flow. Sometimes, this compensation does not
occur, and the developing baby's growth may be restricted. Conversely, a single umbilical artery
may have nothing to do with abnormal placental development and may be associated with birth
defects (for example, a missing kidney) or other more serious problems. Therefore, pregnancies
with a 2-vessel-cord require careful ultrasound examination.

Uterine Artery Doppler


Uterine artery Doppler uses high frequency sound waves and their echoes to visualize blood
flow. This ultrasound uses a probe to transmit high-frequency sound pulses into your body. Once
a pulse is sent, the probe waits for the pulse to hit a boundary and be echoed back. The frequency
that the pulses return to the probe is interpreted and presented as an image or as a graph. The
analogy is to remember the change in sound from a train that approaches, and continues past you
in a train station without slowing down. The similar information obtained from the Doppler
ultrasound can be displayed in two complementary modes:

An image (colour Doppler) [the upper portion of each image below] superimposed on
an ordinary ultrasound, this Doppler shows blood moving away from the probe as BLUE
and blood moving towards the probe as RED

Graphically (spectral Doppler) [the lower portion of each image below] represents the
changing blood flow through the cardiac cycle and allows for semi-quantitative
measurements. From this graph, the echoes are interpreted as one high peak followed by
a lower peak; together this represents a heartbeat. The higher peak corresponds to peak
systolic velocity (blood flow when the heart has contracted). The lower peak corresponds
to end diastolic velocity (blood flow when the heart is relaxed).

Pulsatility index

The standard method of measurement of Doppler waveforms is the pulsatility index (PI). The
pulsatility index reflects the impedance (the pulsatile resistance in an elastic vessel) in the uterine
arteries. During pregnancy, the uterine arteries enlarge and dilate; this is termed decreased
resistance, as it permits a larger volume of blood to be diverted to flow into the intervillous space
of the placenta.

A LOW pulsatility index is equivalent to LOW resistance. This means that a large volume
of blood can easily travel to the placenta through the uterine arteries.

A HIGH pulsatility index is equivalent to HIGH resistance. This means that it is more
difficult for blood to travel to the placenta through the uterine arteries, and thus the
placenta (and fetus) are receiving less blood than they should be.

Changes in PI values during normal pregnancy

Note the two values obtained


at 18, 22, and 24 weeks of
gestation, demonstrating the
expected changes over the
course of the pregnancy.
At the 19-22 week window, the mean PI of the right and left uterine arteries should be below
1.45. A mean PI greater than 1.45 indicates impaired uterine artery blood flow.

The shape of the Doppler waveform is also important. If there is a dip following the higher peak,
we call this an early diastolic notch (see images below). These notches are normally present in
early pregnancy and should have disappeared by 19-22 weeks gestation as blood flow increases.
If these notches persist at the 19-22 week placenta ultrasound, this suggests an impaired maternal
blood supply to the developing placenta. Our research demonstrates that women with bilateral
abnormal uterine artery Doppler are 7 times more likely to have a small placenta (70% vs. 10%);
the combination of a small placenta and abnormal uterine artery Doppler confers a high risk of
preterm delivery <32 weeks due to combinations of pre-eclampsia and IUGR. (See abstract,
article by Dr Toal, published in the American Journal of Obstetrics and Gynecology, March
2008)

Uterine artery Doppler


Maternal blood flow to the placenta via the uterine arteries

Normal uterine artery Doppler in a pregnant woman

During the pregnancy, maternal blood vessels feeding the


lower resistance thus increasing her blood flow to the inte
placenta. As pregnancy progresses, the early diastolic not
disappears and the PI decreases as more blood flows thro
blood vessels during diastole.

Abnormal uterine artery Doppler in a pregnant woman: persistent diastolic notch

The early diastole notch remains potentially due to the ve


as they should. This means that there is lower blood flow
for the developing baby.

We call this utero-placental vascular insufficiency or UPV


blood supply. (See abstract, article by Dr Kingdom and D
Placenta, June 2009)

This also poses a significant risk factor for long-term mat


Women who develop pre-eclampsia, IUGR, and delivery
of their own health, even with their blood pressure return
original article by Dr Yinon, published in Circulation, No
evidence).

The medical research literature on screening for placental insufficiency is dominated a focus on
identifying women at risk of early pre-eclampsia by combining the results of early uterine artery
Doppler (at 11-13 weeks with the nuchal translucency examination) with additional blood tests.
Our view is that there is really no urgency to identify this subset of women so early, since at
present, no effective intervention exists. Women judged to be at risk of pre-eclampsia should be
started on low-dose aspirin (81mg/day) as prophylaxis before 16 weeks of gestation (see
reference). Our philosophy is that a delay in screening allows greater use of pre-existing test
information (the maternal biochemistry) and when combined with both placenta morphology and
uterine artery Doppler, we can assign a risk for the range of perinatal problems attributable to
placental insufficiency rather than focusing on just one aspect. (See abstract, article by Dr Toal,
published in the American Journal of Obstetrics and Gynecology, April 2007).

Summary of Placenta Function Testing

Evidence for Placental Function Testing


The extensive research linking the prenatal blood test results (described above in maternal
biochemistry) to adverse pregnancy outcomes has been summarized by a research method called
systematic review and meta-analysis. In this review, only two blood tests (elevated AFP for
IUGR and stillbirth; elevated inhibin for severe pre-eclampsia) achieved sufficient test
characteristics to be justified as blood tests for placental function. We agree with these findings
and hence re-interpret these tests in their original MoM values, as opposed to merely looking at
the bottom line risks of neural tube defect or Down syndrome.
However, to date, the data for PAPP-A is more limited, as the test was only introduced on a wide
scale to screen for Down syndrome since approximately 2004 in North America. PAPP-A has
been a recent significant research focus in our clinic. We recently reported our research in 90
women with very low PAPP-A when the developing baby did not have Down syndrome.

Approximately 1 in 4 women were found on ultrasound to have a small, thick and abnormallyshaped placenta. This finding was associated with the subsequent risks listed under placental
complications. Interestingly, our data suggested that the placental shape is much more important
than the uterine artery Doppler test to identify women with low PAPP-A at the most risk.
- See more at: http://www.mountsinai.on.ca/care/placenta-clinic/placentaltesting#sthash.UfGm3ZND.dpuf