Biophysical markers for abnormal placentation: 1st and/or 2nd trimester Running Head : placental markers and fetal complications Manuscript count: 5034

Antonio Farina, MD, PhD Department of Medicine and Surgery (DIMEC) Division of prenatal medicine University of Bologna Bologna Italy Email: [email protected] Tel ++39 051 636 3110

No funding sources supported the work The author does not have any conflict of interest

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/pd.4377

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what's already known about this topic? Biophysical markers are commonly used as a screening tool for fetal and maternal complications. In the past years many papers have reported, by means of different strategies, the univariable and multivariable discriminant ability of biophysical markers for preeclampsia, intrauterine growth restriction, and fetal loss . The results are sometime discordant and the various authors use different criteria for defining of the outcomes of interest what does this study add? This review is an update on the biophysical markers including the more recent papers, and reports the performance of any single marker including uterine artery Doppler, placental size and placental Doppler

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Abstract Placental development is a major cause of a successful pregnancy and, in the presence of placental dysfunction,

there is a higher risk of pregnancy complications . Doppler

technology can be used for screening and detecting the more common pregnancyassociated diseases like preeclampsia, intrauterine growth retardation and perinatal loss. In this review the biophysical markers are discussed in the light of the latest information appeared in the medical literature

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Introduction The adequate development of the placenta is a crucial point for the maintenance and success of pregnancy.

Placental development leads to remodeling of the maternal spiral

arteries to allow enhanced blood supply to the uterus through a low-pressure, low-velocity placental bed. Since 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. Etiologies for placental dysfunction include 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 tree3 . 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 flow 3-4 . Unexpectedly, despite the many important tasks that this organ performs through the entire pregnancy, 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 are expressed in relation to a False Positive Rate of approximately 10%, unless otherwise specified.

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Uterine artery Doppler Velocimetry (UtA Doppler) The use of Uterine artery Doppler velocimetry (UtA Doppler) in the assessment of the uteroplacental circulation was first reported in 19835 and it is currently the preferred method in the clinical management of high-risk pregnancies6 . 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 modification 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 outcome (APO). The inadequate differentiation and invasion are associated with an increased impedance to flow in the uterine arteries and likely reflect high downstream resistance. According to Everett7, the UtA Doppler flow 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 accepted8-9. Two types of uterine artery Doppler waveform analysis techniques have been proposed for prediction of placenta-related APOs: the presence or absence of diastolic notching (unilateral, bilateral) of the uterine arteries, and flow waveform ratios, expressed as resistance index (RI: difference between the peak systolic and end-diastolic shift divided by the peak systolic shift) or pulsatility index (PI= Peak systolic flow minus end diastolic flow divided by mean flow). Typically, the average of the left and right uterine arteries is used for the calculation of risk. For PI measurement the Maternal Fetal Medicine foundation provides such guidelines: “The ability to achieve a reliable measurement of UtA PI is

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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 identified. Subsequently, the transducer is gently tilted from side to side and color flow mapping is used to identify each uterine artery 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 30º. 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 the peak systolic velocity is greater than 60 cm/s to ensure the arcuate artery is not being sampled instead of the uterine artery 8. Studies of UtA Doppler for prediction of APO are difficult to compare because of the differences in populations, gestational age at examination, Doppler sampling techniques, definitions of abnormal flow velocity waveform, and criteria for the diagnosis of APO. Second trimester studies The initial studies were conducted at 22-24 weeks as an attempt to identify pregnancies at risk, but in the more recent past the vast majority of the studies focused on the first trimester. A review by Chien in 20009 of 27 studies involving 12,994 subjects, brought to the conclusion that UtA Doppler flow velocity in the second trimester, using RI, beyond a predetermined cut-off, has limited diagnostic accuracy in predicting PE, IUGR and perinatal death.

A higher positive likelihood Ratio (+LR) was found for all 3 of the outcomes of

interest (PE, IUGR, perinatal death) in both low and high risk populations. Unfortunately the sensitivity or Detection Rate (DR) and the false positive rate (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 –

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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 80,000 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 abnormalities 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 pulsatility index (PI) , alone or combined with notching, is the most predictive Doppler index, and that abnormal uterine artery waveforms are a better predictor of PE than of IUGR. Again, UtA Doppler ultrasonography was more accurate in the prediction of PE when performed in the second trimester rather than in the first trimester. An increased PI (heterogeneous definition 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 definition among the studies) among low-risk patients. Furthermore, in the same review, the risk estimate was stratified 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 uterine artery notching (DR 19%, FPR 1%, +LR 21, -LR 0.82), while the risk of severe PE was best

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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 this subgroup 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 3,347 patients, including both high and low risk pregnancies at 22–24 weeks. Better results were found by Yu et al12 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 Kaplan-Meier analysis, was much higher for PI above the highest quintile, which resulted in an approximately 5-fold higher 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 22-24 weeks 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 cut-off 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 34 weeks 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 delivery13 .

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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 singleton pregnancies, including 1,442

(2.9%) that developed PE, and reported that uterine artery PI at 20-24 weeks was above the 95th percentile (1.51 MoM) in 72.7%, 36.1% and 14.9% of cases of PE requiring delivery at = 90th centile. The DR for any PE was 26.4% and for early onset preeclampsia it was 47.8% for false positive rates of 7% and 8%, respectively. Presence of

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notching (unilateral or bilateral) was also considered but pooled estimates could not be obtained. The use of uterine artery Doppler for the prediction of IUGR at any gestational age was associated with a DR of 15.4% and for early onset IUGR the DR was 39.2%, with false positive rates of 7%. PI MoM conversion yields a better performance for screening purposes, since it allows to correct for confunders like gestational age at screening, maternal weight, racial origin and history of pre-existing diabetes mellitus

19

. Poon et al

19

reported the DR of the lowest PI

MoM between the two uterine arteries in association with maternal history for early and late PE. The DRs were 81.1% and 43.5% respectively. Demers et al. 20 selected 1810 women with a history of previous PE, to evaluate the relative risk (RR) of PE recurrence, IUGR and perinatal death by using the mean PI UtA Doppler. The PI MoM equations were created based on 48,500 women. When the PI values were stratified in three different levels (1.40 MoM) the rate of the complication under exam was much higher in the category with the highest PI MoM value (>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 wks). For the category < 34 wks the RR of PE and perinatal death were 64.6 and 20.5 respectively . No significant RRs were reported for the category >36 wks. Given the categorization of the explorative variable in 3 levels, no data about DR at a fixed 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 gestation is a strong predictor of early and preterm PE, IUGR, and perinatal death, but not term PE. Lastly, Khalil et 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-

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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 significant interaction between gestational age and early PE, yielding, as a consequence, a divergent profile, as the gestation progresses, between the PI values of early PE cases when compared with the values obtained for controls. Comment Given the different outcome considered, the different populations, and the different DRs and FPR cut-off, it is difficult to compare the data of these reviews, but it seems clear that UtA 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 first trimester assessments. Nonetheless, elevated RI or PI >90th centile in the first trimester increase the risk of early onset or severe PE or IUGR by about 5-fold in a low risk population

6,18

. The

predictive ability is more efficient 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 calculation of a patientspecific risk. Not all studies have found independent predictive ability of UtA Doppler

22,23

. Moreover it

has been objected that the findings would not affected prenatal care , as monitoring for PE is already a major component of prenatal care

9,10

. However, 1st trimester UtA Doppler

findings could have an impact in strategies aimed at prediction and prevention of earlyonset PE or FGR, conditions which are responsible for the majority of the perinatal morbidity and mortality in non-anomalous babies. Placental volumetry

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Placental size: thickness, diameter, volume, Placental Quotient, 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 2D and 3D ultrasound techniques has been described in several studies as a possible marker of maternal-fetal complications

24-27

. The results, however, in terms of DR and/or

predictive values for specific adverse outcomes are conflicting. Placental thickness Placental thickness is a non-specific marker and it is usually grossly evaluated. If the thickness upon visual inspection appears to be normal (approximately 2-4 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 hydrops

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infection

28

and placental

mesenchymal dysplasia 29 . In a paper by Elchalal 30 , which included more than 500 women, a placental thickness >90 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 Cooley et al 31

increased placental thickness was associated with a higher rate of fetal acidosis .

Placental diameter McGinty 32 attempted to establish reference ranges for placental diameter and thickness at 18–24 weeks in a low-risk obstetric population for SGA. In that series of 30 IUGR cases and 474 controls,a placental length < 10th centile at gestational ages between 18 and 24 weeks was a significant but weak predictor of IUGR (odds ratio OR = 2.8). No DRs or predictive values were reported. Interestingly Costantini et 33 al did not find any reliable association

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between maximum placental length

or second trimester.

Placental development is a major cause of a successful pregnancy, and in the presence of placental dysfunction, there is a higher risk of pregnancy co...
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