biophysical markers for abnormal placentation first or second trimester

8/10/2019 Biophysical Markers for Abnormal Placentation First or Second Trimester

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REVIEW

Biophysical markers for abnormal placentation: rst and/orsecond trimesterAntonio Farina*

Department of Medicine and Surgery (DIMEC) Division of Prenatal Medicine, University of Bologna, Bologna, Italy

*Correspondence to: Antonio Farina, E-mail: [email protected]

ABSTRACTPlacental development is a major cause of a successful pregnancy, and in the presence of placental dysfunction, thereis a higher risk of pregnancy complications. Doppler technology can be used for screening and detecting the more

common pregnancy-associated diseases like preeclampsia, intrauterine growth retardation, and perinatal loss. In thisreview, the biophysical markers are discussed in the light of the latest information that appeared in the medicalliterature. 2014 John Wiley & Sons, Ltd.

Funding sources: None

Conicts of interest: None declared

INTRODUCTIONThe adequate development of the placenta is a crucial point for

the maintenance and success of pregnancy. Placental

development leads to remodeling of the maternal spiralarteries to allow enhanced blood supply to the uterus through

a low-pressure, low-velocity placental bed.

Because all of the respiratory gases, nutrients, and waste

products that are exchanged between the maternal and fetal

systems are transported through the placenta, placental

dysfunction represents, of course, a major cause of pregnancy

complications1. These include perinatal loss, placental

abruption, hypertensive complications of pregnancy including

preeclampsia (PE), and intrauterine growth restriction (IUGR).2

Etiology for placental dysfunction includes reduced

trophoblastic invasion, incomplete remodeling of maternal

spiral arteries, and premature entry of maternal blood into

the villous trophoblast, which can cause oxidative damage to

the villous tree.3 All of the mentioned complications are

associated with relatively high oxygen concentrations inside

the intervillous space in early pregnancy and with a reduction

in uteroplacental blood ow.3,4

Unexpectedly, despite the many important tasks that this organ

performs through the entire pregnancy, the placenta and its

development have traditionally received little attention, and only

recently, with the introduction of new technologies, several

biophysical parameters have been proposed in an attempt to

predict pregnancy complications related to abnormal placentation.

In this review, the role of ultrasound will be discussed.

Note that in this review, all the detection rates (DRs) areexpressed in relation to a false positive rate (FPR) of

approximately 10%, unless otherwise specied.

UTERINE ARTERY DOPPLER VELOCIMETRY (UTA DOPPLER)The use of UtA Doppler in the assessment of the uteroplacental

circulation was rst reported in 1983,5 and it is currently the

preferred method in the clinical management of high-riskpregnancies.6 During early pregnancy, there is a migration of

both endovascular extravillous and interstitial trophoblast into

the lumen of the spiral arteries and through the endometrial

stroma, respectively. The two invasions are associated with a

physiologic modication of the spiral arteries that, during this

process, loose the smooth muscle in their walls and their

elastic lamina to turn into low-resistance vessels. Inadequate

trophoblast invasion and the failure of the spiral arteries to

become low-resistance vessels are associated with higher risk

of subsequent placenta-related adverse pregnancy outcomes

(APOs). The inadequate differentiation and invasion are

associated with an increased impedance to ow in the uterine

arteries and likely reect high downstream resistance.

According to Everett,7 the UtA Doppler ow may provide a

proxy measure of the degree of vascular remodeling; however,

it is an indirect indicator of placental vascular development,

and its application as a screening tool for IUGR, PE, and

perinatal death is not unanimously accepted.8,9

Two types of UtA Doppler waveform analysis techniques

have been proposed for the prediction of placenta-related

APOs: the presence or absence of diastolic notching (unilateral

or bilateral) of the uterine arteries and ow waveform ratios,

expressed as resistance index (RI: the difference between the

peak systolic and end diastolic shift divided by the peak

systolic shift) or pulsatility index (PI = peak systolic ow minusend diastolic ow divided by mean ow). Typically, the average

of the left and right uterine arteries is used for the calculation

Prenatal Diagnosis2014,34, 628634 2014 John Wiley & Sons, Ltd.

DOI: 10.1002/pd.4377


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of risk. For PI measurement, the Maternal Fetal Medicine

Foundation provides such guidelines: The ability to achieve a

reliable measurement of UtA PI is dependent on appropriate

training of sonographers, as well as adherence to a standard

ultrasound technique in order to achieve uniformity of

results among different operators. Using transabdominal

ultrasonography, a sagittal section of the uterus should be

obtained, and the cervical canal and internal cervical os are

identied. Subsequently, the transducer is gently tilted from

side to side, and color ow mapping is used to identify each

UtA along the side of the cervix and uterus at the level of the

internal os. Pulsed wave Doppler is then used with the

sampling gate set at 2 mm to cover the whole vessel, and care

should be taken to ensure that the angle of insonation is less

than 30. When three similar consecutive waveforms are

obtained, the PI is measured and the mean PI of the left and

right arteries is calculated. It is important to ensure that the

peak systolic velocity is greater than 60 cm/s to ensure that

the arcuate artery is not being sampled instead of the UtA.8

Studies of UtA Doppler for prediction of APO are difcult to

compare because of the differences in populations, gestational

age at examination, Doppler sampling techniques, denitions

of abnormal ow velocity waveform, and criteria for the

diagnosis of APO.

SECOND TRIMESTER STUDIESThe initial studies were conducted at 22 to 24 weeks as an

attempt to identify pregnancies at risk, but in the more recent

past, the vast majority of the studies focused on the rst

trimester. A review by Chien in 20009 of 27 studies involving

12 994 subjects brought to the conclusion that UtA Dopplerow velocity in the second trimester, using RI, beyond a

predetermined cutoff, has limited diagnostic accuracy in

predicting PE, IUGR, and perinatal death. A higher positive

likelihood ratio (+LR) was found for all three of the outcomes

of interest (PE, IUGR, and perinatal death) in both low and

high-risk populations. Unfortunately, the sensitivity or DR

and the FPR were not calculated. In the low-risk population,

the +LR and LR for PE were 6.4 and 0.7, respectively. The

+LR and LR for IUGR were 3.6 and 0.8. The +LR and LR

for perinatal death were 1.8 and 0.9. In the high-risk

population, the +LR and LR for PE were 2.8 and 0.8

respectively. The+ LR and LR for IUGR were 2.7 and 0.7. The

+LR and

LR for perinatal death were 4.0 and 0.6, respectively.

In a more extensive and complete review by Cnossen,6 dated

2008, 74 studies including almost 80000 women were

considered. In this review, 15 UtA Doppler indices for

predicting PE and IUGR were evaluated. Given the different

criteria and thresholds for Doppler abnormality indices used

in the different papers, complex statistical methods have been

used to calculate a reliable DR and FPR with a 95%CI. Again,

derived LRs from the pooled DRs and FPRs were also

calculated. The authors concluded that a PI, alone or

combined with notching, is the most predictive Doppler index

and that abnormal UtA waveforms are a better predictor of PE

than of IUGR. Again, UtA Doppler ultrasonography was moreaccurate in the prediction of PE when performed in the second

trimester rather than in the rst trimester. An increased PI

(heterogeneous denition among the studies) with notching

was the best predictor of PE (+LR 21.0 among high-risk patients

and 7.5 among low-risk patients). It was also the best predictor

of overall (+LR 9.1) and severe (+LR 14.6) IUGR (heterogeneous

denition among the studies) among low-risk patients.

Furthermore, in the same review, the risk estimate was

stratied according to patient history: For women with a low

risk of developing PE, PE occurrence was best predicted by

the presence of second trimester elevation of PI (DR 42%,

positive +LR 4.5, negative LR 0.64). The risk of severe PE

was best predicted by either a second trimester elevated PI

(DR 78%, FPR 5%, +LR 15.6, LR 0.23) or bilateral notching

(DR 65%, FPR 5%, +LR 13.4, LR 0.37). For women with a high

risk of developing PE, the overall risk of PE was best predicted

by the presence of a second trimester elevation of PI

accompanied by UtA notching (DR 19%, FPR 1%, +LR 21,

LR 0.82), while the risk of severe PE was best predicted by

second trimester elevated RI (DR 80%, FPR 22%, +LR 3.7, LR

0.26). No data about DR at a 10% FPR are reported for thissubgroup of patients. Similar values, obtained, however, by

stratifying PE into early and late onset, rather there in severe

and all PE, were found in another paper by Onwudiwe et al.11

PI index yielded a DR of approximately 30 and 60% for the

prediction of late and early PE, respectively, in a consecutive

series of 3347 patients, including both high and low-risk

pregnancies at 22 to 24 weeks. Better results were found by

Yuet al.12 with a sample of more than 15 000 women. For early

and all PE, the DRs were 84.7 and 51.5%, respectively.

Moreover, the cumulative probability of PE calculated using

KaplanMeier analysis was much higher for PI above the

highest quintile, which resulted in an approximately

vefoldhigher risk of PE at term (9 vs 2%) compared with cases with

a PI below the highest quintile. Also, a risk of early-onset PE

was observed for the group with PI above the highest quintile,

with detection starting at 180 days of pregnancy. The same

effect was also presented in another paper by the same Group

12 (in more than 30 000 pregnancies who had a Doppler

measurement at 2224weeks of gestation). An inverse

correlation was found between gestational age at delivery

and percentage of mean PI index above the 95th percentile

in the group of women who developed PE. In particular, the

mean PI was above the selected PI cutoff in 20/34 (58.8%)

women who developed PE requiring delivery before 34 weeks.

In cases in which IUGR was associated with PE, the rate of

abnormal PI and delivery before 34weeks increased to

82.2% (102/124). For a group with IUGR alone, instead, the

rate of abnormal PI Doppler and delivery before 34 weeks

was 43.8% (57/130). The authors concluded that PE requiring

early delivery is more likely to be associated with IUGR and

that Doppler ultrasound assessment of the uterine arteries is

more effective in identifying PE requiring preterm rather than

term delivery.13

In other studies, the Doppler PI index was converted into

multiple of the median (MoM), in an attempt to improve the

discriminant power between affected and unaffected cases.

For example, Gallo et al.14

in 2013 enrolled 50 490 singletonpregnancies, including 1442 (2.9%) that developed PE and

reported that UtA PI at 20 to 24weeks was above the 95th

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percentile (1.51 MoM) in 72.7, 36.1, and 14.9% of the cases of

PE requiring delivery at 1.50). The rate of

PE, IUGR, and perinatal death and their associated RRs were

found to be a direct function of the PI values and an inverse

function of the gestational age at the time of occurrence

(36 weeks). For the category36 weeks.Given the categorization of the explorative variable in three

levels, no data about DR at axed FPR were reported in the

paper. The authors concluded that, in women with a history

of PE, mean uterine PI at 11 to 13 weeks of gestation is a strong

predictor of early and preterm PE, IUGR, and perinatal death

but not term PE.

Lastly, Khalilet al.21 also demonstrated that the Doppler PI is

a function of both gestational age and early PE. By means of

repeated measurement analysis with a multilevel mixed-effects

linear model, it was demonstrated that during gestation, the PI

is a function of both gestational age and PE (early PE, late PE,

and gestational hypertension), but, more interestingly, there

is also a signicant interaction between gestational age and

early PE, yielding, as a consequence, a divergent prole, as

the gestation progresses, between the PI values of early PE

cases when compared with the values obtained for controls.

COMMENTGiven the different outcomes considered, the different

populations, and the different DRs and FPR cutoff, it is difcult

to compare the data of these reviews, but it seems clear thatUtA Doppler PI is a good indicator to predict PE, IUGR, and

perinatal mortality. Better predictive values can be found in

the second trimester compared with rst trimester

assessments. Nonetheless, elevated RI or PI greater than the

90th percentile in the rst trimester increases the risk of early

onset or severe PE or IUGR by about vefold in a low-risk

population.6,18 The predictive ability is more efcient when

applied to a high-risk population. If converted to MoM or

Log10 MoM values and adjusted for possible confounding

factors, the PI index gives a slightly improved performance

and can be more easily integrated with other markers, in order

to obtain a multivariable predictive model for the calculationof a patient-specic risk.

Not all studies have found an independent predictive ability

of UtA Doppler.22,23 Moreover, it has been objected that the

ndings would not affect prenatal care, as monitoring for PE

is already a major component of prenatal care.9,10 However,

rst trimester UtA Doppler ndings could have an impact in

strategies aimed at prediction and prevention of early-onset

PE or FGR, conditions that are responsible for the majority of

the perinatal morbidity and mortality in nonanomalous babies.

PLACENTAL VOLUMETRYPlacental size: thickness, diameter, volume, placental quotient

(PQ), standardized placental volume (sPlaV).

Placental size and morphology as a screening tool for

placental failure has long been a topic of research, but it is only

in the past few years that the criteria for size measurement

have been standardized, and the evaluation has become less

empirical. Placental size evaluated both by two-dimensional

(2D) and three-dimensional (3D) ultrasound techniques has

been described in several studies as a possible marker of

maternalfetal complications.2427 The results, however, in

terms of DR and/or predictive values for specic adverse

outcomes are conicting.

Placental thicknessPlacental thickness is a nonspecic marker, and it is usually

grossly evaluated. If the thickness upon visual inspection

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appears to be normal (approximately 24 cm in a central

point), there is no need for further delineation. Only in dubious

cases can the maximal vertical thickness be measured.

Diseases weakly associated with a thick placenta include

maternal diabetes, maternal anemia, IUGR, fetal hydrops28

infection,28 and placental mesenchymal dysplasia.29 In a paper

by Elchalal,30 which included more than 500 women, a

placental thickness greater than the 90th percentile was

associated with fetal macrosomia (20.4 vs 5.3%), IUGR (15.9

vs 7.3%), and perinatal mortality (6.82 vs 0.66%). In a paper

by Cooleyet al.,31 increased placental thickness was associated

with a higher rate of fetal acidosis.

Placental diameterMcGinty32 attempted to establish reference ranges for

placental diameter and thickness at 18 to 24 weeks in a low-risk

obstetric population for small for gestational age. In that series

of 30 IUGR cases and 474 controls, a placental length less than

the tenth percentile at gestational ages between 18 and24 weeks was a signicant but weak predictor of IUGR [odds

ratio (OR) = 2.8]. No DRs or predictive values were reported.

Interestingly, Costantini et al .33 did not nd any reliable

association between maximum placental length


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COMMENTThe available evidence suggests that for the placental size,

regardless of how it is expressed and evaluated, it does not

predict consistently and accurately the occurrence of IUGR

or PE.

3D power Doppler ultrasound for placental bed vascularization:vascularization index (VI), ow index (FI), and vascularizationow index (VFI)Two-dimensional Doppler ow velocity waveforms are of

limited value in the study of placental compromise in IUGR.

3D power Doppler ultrasonography, on the other hand,

provides new insight into placental pathophysiology, enabling

the investigation of placental vascularization and blood ow.

This technique can depict intraplacental blood vessel

characteristics such a caliber changes, branching, and

tortuosity. 3D Doppler can also be useful to detect successful

trophoblastic invasion by evaluation of dilated spiral arteries

at the terminal ends, and the vessel modications can be seenthat are represented by the discharging of blood into the

intervillous space.49 Total reduced placental vascularity and

impaired budding of the villous circulation are predictive of

cases of IUGR not identied by uterine and/or umbilical

artery Doppler.50 The VI is the ratio between the number of

colored voxels to the total number of voxels; therefore, VI

indicates the concentration of blood vessels in a placental

segment. The FI is the ratio between the sum of the voxel

velocities (scaled on a scale of 0100) to the total number of

color voxels and thus provides information on placental

blood ow. Finally, VFI or VI FI/100 is the ratio of the sum

of voxel velocities (scaled on a scale of 0

100) to the totalnumber of voxels in the sample. The markers of fractional

blood ow indices have been evaluated during the rst

trimester in some studies.

Yu et al.49 were the rst to correlate the fractional blood

volume through the placenta with gestational age. Index values

were lower than expected in PE and IUGR cases35,51 compared

with controls, but the results in terms of the prediction of

adverse effects were quite poor or generated from small

populations. Noguchi et al . in 2009,51 in a series with

approximately 200 women, outlined the reference values for

VI, FI, and VFI for each gestational age, from 12 to 40 weeks.

They also proceeded to compare the reference values with

those obtained in 13 IUGR fetuses. VI and VFI emerged as the

best markers, with values below 1.5 standard deviation of the

expected value in IUGR cases. Similar results were also found

in a recent prospective nonintervention study of 277 women

between 10 and 13weeks: Among the 24 cases who later

presented PE, a DR of approximately 30% was found for all

three indexes (VI, FI, and VFI).52 Pomorski et al.53 in 2011

reported a DR for IUGR of 60% for VFI that revealed itself as

the best parameter, followed by VI (50%) and FI (40%; all the

DRs have been visually derived from the ROC curve presented

in the article).

A recent study by Hafner et al.54 successfully used the

placental bed VI to predict several complications of pregnancy,such as PE, in more than 4000 cases. In the rst trimester, VI

values below the tenth percentile for normal pregnancies

detected 60% of the cases of severe PE and 66.2% of severe

PE accompanied by IUGR. Furthermore, in a multivariable

comparison (that included BMI and parity) with UtA Doppler

performed in the second trimester, VI yielded a much higher

DR (80 vs 60%). The authors concluded that VI could be used

for a quick and reliable rst trimester assessment of severe

pregnancy risks.

COMMENTEven if discordant data exist in medical literature, it seems that

lower values of VI and VFI as early as the rst trimester are the

best placental indexes for early identication of cases at risk for

IUGR and PE, with DR as high as 60%.

ABNORMAL CORD INSERTION: MARGINAL ANDVELAMENTOUS CORD INSERTIONSIn most pregnancies, the umbilical cord inserts at or near the

center of the placenta. Marginal cord insertion is dened as

cord insertion near the margin of the placenta, within 2 cm ofthe placental edge, but with the insertion site supported by

very little placental tissue. Marginal cord insertion can develop

into velamentous cord insertion (VCI) as the pregnancy

progresses. This change may result from atrophy of the

placental tissue at the cord insertion site because of a relatively

poor local blood supply. In VCI, the umbilical vessels insert

into the membranes before they reach the placental margin.

Both velamentous and marginal insertions are thought to

reect poor placental implantation, with impaired

development and function of the placenta55,56 and are

reported to occur in 0.5 to 2.4% and 8.5% of all pregnancies,

respectively, with higher prevalence (approximately 16%) inmultiple pregnancies.57 VCI has been associated with an

increased risk of adverse perinatal outcomes including

placental abruption, placenta previa, IUGR, PE, perinatal

death, and abnormal intrapartum fetal heart rate pattern58,59

as reviewed by Hasegavaet al.60 In a population-based registry

study by Ebbing57 on more than 600 000 patients, the risk of PE,

placental abruption, and preterm delivery (PTD) has been

evaluated. For marginal cord insertion, a slightly higher risk

of placental abruption and PE (ORs of 1.48 and 1.45) has been

reported, followed by the risk for PTD (OR of 1.28), and for VCI,

ORs of 2.6, 1.51, and 2.03 are reported for placental abruption,

PE, and PTD, respectively.57 Limitations of ultrasonographic

studies of abnormal cord insertion are that the condition is

more frequently found in the second than in the rst trimester

and in twins rather than singletons.

Controversial is the association between VCI, twin-to-twin

transfusion syndrome, and fetal weight in monochorionic twin

pregnancies.

Hanleyetal.61 insteadreport thatabnormal cordinsertion into

the placenta is a risk factor for birth weight discordance in twin

gestation, based on a population of 447 twin pairs. Again, in

in vitrofertilization twin pregnancies, a higher rate of IUGR has

been found in cases with abnormal cord insertion.62

COMMENTGiven the discordant results, the different populations, and the

detection ofndings mainly in the second trimester, it seems

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that abnormal cord insertion is just a cofactor inuencing the

fetal growth and eventual pregnancy complications, but no

data about the DR are available, and the possible inclusion in

predictive investigation strategies does not seem suitable.

CONCLUSIONPlacental biophysical markers evaluated in the rst and second

trimester have been mainly used to predict PE, IUGR, and

stillbirth. UtA Doppler is the most studied marker and is also

probably the most predictive. Furthermore, it can be easily

integrated with other nonultrasound-based markers. The vascular

indices calculated with the aid of new technologies are an

emerging screening tool for IUGR and PE prediction, but further

studies are necessary to evaluate their role in clinical practice.

WHATS ALREADY KNOWN ABOUT THIS TOPIC?

Biophysical markers are commonly used as a screening tool for fetaland maternal complications.

In the past years many papers have reported, by means of differentstrategies, the univariable and multivariable discriminant ability ofbiophysical markers for preeclampsia, intrauterine growth

restriction, and fetal loss. The results are sometime discordant and the various authors use

different criteria for dening of the outcomes of interest.

WHAT DOES THIS STUDY ADD?

Thisreview is an updateon the biophysical markers including themorerecent papers, and reports the performance of any single markerincluding UtA Doppler, placental size and placental Doppler.

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