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Available online at www.sciencedirect.com

www.elsevier.com/locate/semperi

Second- and third-trimester biochemical and ultrasound markers predictive of ischemic placental disease Zeynep Alpay Savasan, MD, Luis F. Goncalves, MD, and Ray O. Bahado-Singh, MD, MBAn Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Rochester, MI

article info

abstra ct Ischemic placental disease is a recently coined term that describes the vascular insufficiency now believed to be an important etiologic factor in preeclampsia, intrauterine fetal growth restriction, and placental abruption. Given the increased risk for poor maternal and fetal outcomes, early prediction and prevention of this disorder is of significant clinical interest for many. In this article, we review the second- and third-trimester serum and ultrasound markers predictive of ischemic placental disease. Limited first-trimester data is also presented. While current studies report a statistical association between marker levels and various adverse perinatal outcomes, the observed diagnostic accuracy is below the threshold required for clinical utility. An exception to this generalization is uterine artery Doppler for the prediction of early-onset preeclampsia. Metabolomics is a relatively new analytic platform that holds promise as a first-trimester marker for the prediction of both early- and late-onset preeclampsia. & 2014 Published by Elsevier Inc.

Introduction In this article, we review potential second-trimester maternal serum analytes and imaging markers for predicting ischemic placental disease. Ischemic placental disease is a recently coined term that describes the common etiologic basis of a group of important obstetric syndromes. These are intrauterine growth restriction (IUGR), preeclampsia, and placental abruption.1 Due to their strong association with poor perinatal outcome, early prediction has been the focus of much research. Maternal serum analysis has yielded some putative biomarkers for the prediction of ischemic placental disease (Tables 1–3). However, the relevant literature is not uniform n

and, to date, none of these markers individually or in combination have been clinically accepted as screening tools for ischemic placental disease. Doppler velocimetry of the placental and fetal circulations is currently the main tool used in clinical practice to identify patients at risk for or those with established ischemic placental disease.

Maternal serum second-trimester biomarkers for ischemic placental disease Potential maternal second-trimester serum markers for ischemic placental disease can be divided into three major

Correspondence to: Beaumont Health System, Medical Office Building, Suite 233, 3535 West 13 Mile Road, Royal Oak, MI 48073. E-mail address: [email protected] (R.O. Bahado-Singh).

http://dx.doi.org/10.1053/j.semperi.2014.03.008 0146-0005/& 2014 Published by Elsevier Inc.

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Table 1 – Serum markers for prediction of preeclampsia. References

Risk status population

Marker

Sensitivity (%)

Specificity (%)

Risk

Ghosh et al.27

High and low risk

PIGF o 144 pg/ml

84

78

OR 18.83

Leaños-Miranda et al.24,a

High and low risk sflt-1 sflt-1/PlGF

– –

– –

27.7 15.4

95.4 99.0

22.4 16.3

93.5 99.2

27.7 12.3

90.4 97.6

60

–

–

–

AUC 0.715 AUC 0.80

–

–

AUC 0.85

51.6 58.1 40.3 69.4

76.4 73.3 78.5 60.6

AUC 0.65 0.68 0.602 0.681

11.74

97.01

–

–

–

–

– AOR 2.80 AOR 4.26

PIGF r 0.76 MoM

70

70

–

hCG Z2.3 MoM Inhibin A Z2.0 MoM

34.3 48.6

89.9 90.6

OR 4.7 9.1

AFP 42.5 MoM βhCG 4 2.5 MoM uE3 o 0.5 MoM

– – –

– – –

OR 1.6 1.4 1.3

Olsen et al.11

High and low risk

Ree et al.14

Lim et al.

High and low risk

28

High and low risk

Kusanovic et al.34,b

AFP (MoM) Z2 Z3 Inhibin (MoM) Z2 Z3 βhCG (MoM) Z2 Z3 Inhibin A (MoM) Z1.5 Inhibin A þ hCG þ AFP

sEng (44.5 pg/ml)

High and low risk PlGF (pg/ml) sEng (ng/ml) PlGF/sflt-1 PlGF/sEng

Dugoff et al.7,c

High and low risk

Su et al.

Aquilina et al.

High and low risk 12

Yaron et al.17

OR 8.04 18.27 OR 4.17 25.7 OR 3.6 5.59

More than two abnormal markers

Elevated AFP and hCG Elevated AFP and inhibin A 26

OR 6.3 15.7

High and low risk

High and low risk

AOR: adjusted odds ratio; OR: odds ratio; AUC: area under the curve. Prediction of early-onset preterm preeclampsia. b Prediction of all cases with preeclampsia. c Abnormal values for this study: Z2 MoM for AFP, hCG, inhibin A, and r0.5 for uE3. a

groups: (a) those currently in use as aneuploidy markers, (b) angiogenesis-related markers, and (c) others.

Aneuploidy markers Early studies have reported an increased risk of adverse pregnancy outcomes in patients with abnormal second-trimester aneuploidy screening and normal fetuses.2 Subsequently, larger studies of patients undergoing second-trimester aneuploidy screening have shown an association between elevated second-trimester aneuploidy markers, such as maternal serum alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG),

inhibin, and low unconjugated estriol (uE3) with poor perinatal outcome. These outcomes were largely attributable to ischemic placental disease, which manifest clinically as preeclampsia, IUGR, abruption, or stillbirth. Since these markers were also secreted from or modified in the placenta, it has been proposed that they could be used as markers of placental health. However, no studies to date have shown conclusively that these are of clinical value for predicting or detecting ischemic placental diseases, either individually or in combination.3–6 Dugoff et al.7 analyzed 33,145 serum screen results of patients enrolled in the FASTER trial, a large multicenter prospective study. They evaluated the correlation between

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Table 2 – Serum markers for prediction of IUGR. References

Risk status population

Marker (MoM)

Sensitivity (%)

Specificity (%)

Risk

Proctor et al.9

High risk

AFP Z 2.0

–

–

RR 3.67

Odibo et al.16

High risk AFP 4 2 hCG 4 2.5 uE3 o 0.9

12 8 50

94 95 71

42 Abnormal markers

5.94

97.26

Elevated AFP and hCG

–

–

Elevated AFP and inhibin A

–

–

Elevated hCG and inhibin A

–

–

Elevated AFP, hCG, and inhibin A

–

–

– AOR 1.02 AOR 2.53 AOR 1.65 AOR 6.13

AFP 4 2.5 βHCG 4 2.5 uE3 o 0.5

– – –

– – –

OR 2.3 1.3 2.6

uE3 r 0.75

–

–

OR 6.73

AFP Z2–2.49 Z2.5

– –

– –

OR 1.6 3.2

Dugoff et al.7,a

Yaron et al.17

Kowalczyk et al.15

Waller et al.13

AOR 2.3 1.8 2.7

High and low risk

High and low risk

High and low risk

High and low risk

RR: relative risk; AOR: adjusted odds ratio; OR: odds ratio. a Abnormal values for this study: Z2 MoM for AFP, hCG, inhibin A, and r0.5 for uE3.

second-trimester levels of maternal serum AFP, hCG, uE3, and inhibin A (the quad screen) on obstetric complications. They reported associations between these markers and adverse perinatal outcomes (Tables 1 and 2). Importantly, the risk of having adverse outcomes was significantly increased if a patient had two or more abnormal markers. Similarly, Tikkanen et al.8 showed an association between elevated secondtrimester maternal serum AFP levels and placental abruption. Abnormalities of this marker persisted as an independent risk factor when adjusted for other confounders. Proctor et al.9 found that the risks of IUGR, preterm delivery before 32 weeks gestation, and of stillbirth were increased with elevated secondtrimester maternal serum AFP and small placental size. Similar findings were observed by Spaggiari et al.10 who reported an

association between elevated second-trimester maternal serum AFP and increased risk of preeclampsia, IUGR, and fetal death. Similarly, the risk of poor obstetrical outcomes correlated with the degree of elevation of the serum concentrations of maternal serum AFP, inhibin, and hCG in other studies.11,12 Waller et al.13 found a reduced risk of preeclampsia and placental complications in patients who had lower second-trimester MSAFP concentrations. In one study, inhibin B was the most useful marker among the second-trimester screening markers in the prediction of the development of early-onset preeclampsia.14 Several additional studies have reported that abnormal second-trimester maternal serum aneuploidy markers could be used for the prediction of development of ischemic placental disease including preeclampsia, IUGR, and

Table 3 – Serum markers for prediction of placental abruption. References

Risk status population

Marker (MoM)

Sensitivity (%)

Specificity (%)

Risk

Tikkanen et al.8

High and low risk

AFP Z1.5 Z2.0

29 11

89 99

– –

AFP 4 2.5 βhCG 4 2.5 uE3 o 0.5

– – –

– – –

OR 2.3 1.2 1.6

Yaron et al.17

OR: odds ratio.

High and low risk

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abruption.15–17 The ability to predict preeclampsia improved slightly when the biomarkers were combined with clinical risk factors (AUC with clinical data alone: 0.63, serum markers alone: 0.76, both combined: 0.78).18 Fitzgerald et al.19 evaluated placentas of patients with elevated second-trimester maternal serum hCG and inhibin A and demonstrated a reduction in the volume of cytotrophoblast and increased pathological findings, e.g., distal villous hypoplasia and wavelike syncytial knot formation, which are consistent with ischemic damage in severe preeclampsia and IUGR. Second-trimester levels of PAPP-A and ADAM-12 were not as effective as first-trimester concentrations for predicting preeclampsia.20 Repeated measurements of PAPP-A and ADAM-12 levels in the second trimester (at 18–22 weeks) did not improve the ability to predict preeclampsia compared to a single first-trimester measurement.21 Finally, a systematic review concluded that currently, there is no identifiable combination of serum markers that performs well as a screening test for preeclampsia, small for gestational age, or stillbirth.22

Angiogenesis-related markers Recently, studies evaluated angiogenic/antiangiogenic factors for the prediction of ischemic placental disease. Despite some promising initial results, these markers are not currently regarded as clinical screening tools. Maternal circulating soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. In animal models, soluble endoglin (sEng), another antiangiogenic protein, acts together with sFlt-1 to induce a severe preeclampsia-like disease.23 The association with these markers was stronger for preterm vs. term preeclampsia.24 Soluble Flt-1 and PlGF are promising clinical markers that show high sensitivity in the first and second trimester for predicting preeclampsia (PIGF:AUC 0.76).25,26 Maternal serum PIGF concentration was reported to be better predictor of preeclampsia in the second trimester compared to first trimester.27 Second-trimester plasma levels of sEng were also shown to predict the development of severe preeclampsia and IUGR.28 Second-trimester serum levels of sEng were found to be elevated prior to the development of hypertension and placental abruption.29 However, a conflicting report found that sEng, PlGF, and sFlt-1 levels in early second trimester failed to predict placental abruption.30 Predictive models for estimating individualized risk estimates for early-onset preeclampsia and IUGR based on a combination of second-trimester levels of inhibin A, PlGF, and endoglin have been proposed.31,32 An increase in the serum levels of antiangiogenic markers and a decrease in the angiogenic markers from first trimester to second trimester were reported in patients destined to develop preeclampsia and IUGR.33 Better prediction of ischemic placental disease was observed when the ratios of these markers were used for screening (AUC for detecting preeclampsia: PIGF/sFlt-1 ¼ 0.95, PlGF/sEng ¼ 0.691).28,34 Combinations of angiogenic markers and uterine artery Doppler (the latter will be discussed in more detail in another section

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of this article) have also been reported. The combination in the second trimester has been reported to have a higher prediction rate for the development of early-onset preeclampsia (Doppler velocimetry alone vs. combination with sEng: sensitivity of 62.5% vs. 80% and specificity of 66.7% vs. 43%, respectively).35 A combination of second-trimester serum inhibin A, activin A, PlGF, and second-trimester uterine artery Doppler PI have been shown to have a high prediction rate of preeclampsia development with a sensitivity of 93% and a specificity of 80%.36

Other biomarkers A number of other placental-related hormones/proteins have been evaluated as markers for ischemic placental disorders. Activin A and inhibin A are secreted from the trophoblast and several reports showed an association of these proteins with the preeclampsia.37–39 However, a recent study examining these markers in the second trimester did not find that they predict the subsequent development of preeclampsia.40 Plasma protein 13 (PP-13), which is thought to play an important role in placental spiral artery remodeling, reportedly holds promise for the prediction of placental-related diseases when measured in both the first and second trimesters.41–43 In addition, decreased maternal serum, secondtrimester concentrations of pregnancy-associated plasma protein A (PAPP-A), pregnancy-specific beta1-glycoprotein (SP1), or human placental lactogen (HPL) has been associated with IUGR and preeclampsia.44 Circulating second-trimester serum markers of placental implantation defects such as leptin, transforming growth factor-beta 1, and plasminogen activator inhibitor type 2 was found to be elevated in patients who developed preeclampsia.45 Insulin-like growth factor (IGF) system in early pregnancy was evaluated as a marker of abnormal placentation. High decidual insulin-like growth-factor-binding protein production may block IGF-1 activity and reduce trophoblast invasion. Interestingly, an increase in maternal serum IGF-1 concentrations from the first to second trimester was reported to be associated with an elevated risk of preeclampsia development (OR ¼ 4.9, 95% CI: 1.1, 21.8).46 Oxidative stress markers have also been studied for the early prediction of ischemic placental diseases since oxidative stress is a known component of the pathophysiology of these diseases. However, Anastasakis et al.47 did not observe any difference in the maternal serum oxidative stress marker levels (malondialdehyde and uric acid) in ischemic placental disease (preeclampsia and IUGR) when patients with abnormal uterine artery were compared to patients with normal uterine artery Doppler velocimetry between 20 and 23 gestational weeks. Maternal serum-cell-free fetal DNA (CffDNA) has also been evaluated and was observed to be elevated in patients who developed ischemic placental diseases. It has been theorized that placental origin CffDNA may be more into the maternal circulation in patients who have disturbed placentation. Cellfree fetal DNA levels were elevated in the early second trimester in women who subsequently developed clinical symptoms of preeclampsia.48,49 However, in another study second-trimester maternal serum CffDNA was not found to be a marker for an adverse pregnancy outcome in low-risk pregnancies.50

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Maternal serum third-trimester biomarkers in prediction of ischemic placental disease Mainly angiogenic and antiangiogenic markers have been studied in the third trimester in predicting the ischemic placental disease. In a study done on patients who presented to obstetrics triage for evaluation for possible preeclampsia before 37 weeks gestation, the angiogenic and antiangiogenic factors and their ratios were compared to identify patients who went on to develop preeclampsia requiring preterm delivery. There was significant association between low plasma concentrations of PlGF/sVEGFR-1 (r0.05 MoM) and PlGF/sEng (r0.07 MoM) and the development of severe preeclampsia even after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension (AOR ¼ 27; 95% CI: 6.4, 109, and 30; 95% CI: 6.9, 126, respectively). Among patients who presented before 34 weeks gestation, a plasma concentration of PlGF/sVEGFR-1 o 0.03 MoM identified patients who delivered within 2 weeks because of preeclampsia with a sensitivity of 93% and a specificity of 78%. The authors reported that this cutoff was associated with a shorter interval-to-delivery due to preeclampsia (HR ¼ 6; 95% CI: 2.5, 14.6).51 In another study, maternal serum angiogenic and antiangiogenic markers at 30–34 gestational weeks have better prediction of late-onset preeclampsia and stillbirth compared to first- and second-trimester markers. A plasma concentration of PlGF/sEng o 0.3 MoM was associated with severe late preeclampsia (AOR ¼ 16); the addition of PlGF/ sEng to clinical risk factors increased the area under the receiver-operating characteristic curve from 0.76 to 0.88 (P ¼ 0.03). The ratio of PlGF/sEng or PlGF/sVEGFR-1 in the third trimester outperformed those obtained in the first or second trimester and uterine artery Doppler velocimetry at 20–25 weeks of gestation for the prediction of severe late preeclampsia (comparison of areas under the receiver-operating characteristic curve; each P r 0.02). Both PlGF/sEng and PlGF/sVEGFR-1 ratios achieved a sensitivity of 74% with a fixed false-positive rate of 15% for the identification of severe late preeclampsia. A plasma concentration of PlGF/ sVEGFR-1 o 0.12 MoM at 30–34 weeks of gestation had a sensitivity of 80%, a specificity of 94%, and a likelihood ratio of a positive test of 14 for the prediction of subsequent stillbirth.52 A secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies have shown the risk of preeclampsia development significantly increased with each twofold elevation of sFlt-1, sEng, and the ratio of angiogenic factors (OR ¼ 2.2; 95% CI: 1.5, 3.3) and significantly decreased for each twofold elevation in circulating PIGF (OR ¼ 0.5; 95% CI: 0.3, 0.8) in patients with multiple gestations. The authors have reported that when data was examined in relation to the gestational week when preeclampsia was diagnosed, only sFlt-1 was significantly higher 2–5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia.53 Another study analyzed whether third-trimester maternal serum AFP levels could predict the adverse pregnancy

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outcomes. The authors found no association between elevated third-trimester MSAFP levels and adverse pregnancy outcomes; however, as described with several other studies, the second-trimester elevation of MSAFP was associated with preterm delivery, preterm rupture of membranes, and low birthweight.54

Metabolomics Metabolomics is the newest member of the “omics” family. It precisely catalogs the metabolic activity of cells and tissue. Further, the impact of intrinsic and extrinsic influences, e.g., age, race, obesity, stress, and medication on cellular function, can be determined with this technique. Recently metabolomics has been deployed for biomarker development for complex non-obstetric disorders, such as cancer and Alzheimer’s disease. Recent studies using new metabolomics technology have reported promising results in the early prediction of preeclampsia.55,56 The sensitivity of a combination of first-trimester metabolomics markers (citrate, glycerol, hydroxyisovalerate, and methionine) for the prediction of early-onset preeclampsia (i.e., preeclampsia requiring delivery before 34 weeks) was 75.9% for a false-positive rate of 4.9%.55 Similarly, the first-trimester metabolomics biomarkers pyruvate; hydroxybutyrate 3, 1-methylhistidine; glycerol; trimethylamine; and valine, when combined with maternal characteristics such as weight, race, and medical disorders had a sensitivity of 76.6% with 100% specificity in detecting the development of late-onset preeclampsia.56 This significantly exceeds our current capacity to predict lateonset preeclampsia.

Imaging markers for ischemic placental disease Although ischemic placental disease may be first suspected clinically (e.g., through poor growth of fundal height, elevated blood pressure, or vaginal bleeding associated with placental abruption), obstetrical ultrasonography plays an important additional role. More specific imaging markers of ischemic placental disease include Doppler abnormalities involving the uteroplacental and fetoplacental circulations and, more recently, abnormal MRI findings related to poor placental perfusion or placental ischemia.

Uterine artery Doppler velocimetry Adequate placental implantation and physiologic transformation of the spiral arteries is key to establishment of a healthy placenta. During early pregnancy, the trophoblast invades the decidua and myometrium, transforming the maternal spiral arteries from vessels of high to low resistance and high capacitance vessels. This trophoblast cells invade the endothelium and media of the spiral arteries and replace muscular and elastic tissue of the arterial wall with fibrinoid material. Thus, physiologic transformation of the spiral arteries results in vessels that resemble more veins than arteries, with significantly increased lumen and loss of contractile response to vasoconstrictors. This phenomenon is in

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keeping with the need to accommodate a 40% increase in maternal blood volume during pregnancy and increased perfusion demands of the uteroplacental circulation.57,58 Patients that have normal physiologic transformation of the spiral arteries are at low risk for preeclampsia, small for gestational age (SGA), and placental abruption, whereas those with abnormal physiologic transformation are at an increased risk for these conditions, particularly for preeclampsia requiring early delivery (before 32–34 weeks).58 Doppler velocimetry of the uterine arteries represents a non-invasive, technically easy, and widely available method to evaluate the uteroplacental circulation.59 In the past, uterine artery Doppler was mainly performed in the second trimester of pregnancy and considered abnormal when the mean PI of the uterine arteries was greater than a certain threshold value, e.g., 1.63, or when bilateral diastolic notches persisted into the second trimester.60 In the largest multicenter study conducted to date, which performed uterine artery Doppler screening at 23 weeks, the sensitivities for the detection of preeclampsia with SGA, and preeclampsia with SGA requiring delivery before 32 weeks were 69% and 93%, respectively, for a false-positive rate of 5%. Data from a systematic review of second-trimester uterine artery Doppler studies report a positive likelihood ratio of 5.9 and a negative likelihood ratio of 0.55 for the prediction of preeclampsia, and a positive likelihood ratio of 3.71 and a negative likelihood ratio of 0.80 for the prediction of SGA.61 Even when used in the third trimester, bilateral pathologic uterine artery Doppler waveforms, defined as those with pulsatility indices 490th percentile or bilateral diastolic notches identifies a population at high risk for cesarean delivery and SGA neonates among patients with IUGR and/or preeclampsia.62,63 More recently, interest has shifted towards first-trimester screening with uterine artery Doppler velocimetry. An early study involving 3195 pregnancies determined that the 95th percentile for the combined average the left and right uterine artery pulsatility indices obtained between 11 and 14 weeks was 2.35. Uterine artery Doppler identified 27% of preeclampsia cases with SGA and 60% of preeclampsia with SGA requiring delivery before 32 weeks at a false-positive rate of 5%.64 Importantly, since diastolic notching is present in more than 40% of pregnancies examined during the first trimester, this finding by itself is not sufficient to reliably identify pregnancies at risk for ischemic placental disease.65 A recent meta-analysis that included 18 studies with 55,974 women screened between 11 and 14 weeks showed that the sensitivity for the detection of early-onset preeclampsia and earlyonset IUGR were 47.8% (95% CI: 39.0%, 56.8%) and 39.2% (95% CI: 26.3–53.8%), respectively. The corresponding specificities were 92.1% (95% CI: 88.6%, 94.6%) and 93.1% (95% CI: 90.6%, 95.0%), respectively. Uterine artery Doppler findings were classified as abnormal when flow velocity waveforms (resistance index or pulsatility index) were greater than or equal to the 90th percentile for gestational age. The positive and negative likelihood ratios for early-onset preeclampsia were 6.1 (95% CI: 4.1, 8.89) and 0.57 (95% CI: 0.48, 0.67), whereas the positive and negative likelihood ratios for early-onset growth restriction were 5.7 (95% CI: 4.3, 7.6) and 0.65 (95% CI: 0.52, 0.81), respectively. For the prediction of placental abruption, the sensitivity and specificity were 44.4% (95% CI: 13.7%,

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78.8%) and 95.2% (95% CI: 93.8%, 96.4%), and the positive and negative likelihood ratios were 9.3 (95% CI: 4.3, 20.3) and 0.58 (95% CI: 0.33, 1.1), respectively. Only two of the 18 studies included in the meta-analysis reported the accuracy of uterine artery notching to predict early-onset preeclampsia and IUGR (unilateral or bilateral). Sensitivities of 75.8% (95% CI: 57.7%, 88.9%) and 37.5% (95% CI: 8.5%, 75.5%), respectively, were reported. As expected, since uterine artery notching is encountered in approximately 40% of patients normally examined during the first trimester, the specificities were low (57%; 95% CI: 55.2%, 58.7% for early-onset preeclampsia and 65.9%; 95% CI: 62.7%, 69.0% for IUGR).66 The prevailing trend for prediction of patients at high risk for early preeclampsia relies on an first-trimester risk assessment approach that takes into consideration maternal clinical risk factors (previous history of hypertension in pregnancy, chronic kidney disease, autoimmune disease, type 1 and 2 diabetes, and chronic hypertension or moderate risk factors, such as first pregnancy, 40 years of age or more, pregnancy interval of more than 10 years, body mass index of 35 or more, family history of preeclampsia, and multiple pregnancy),66 mean arterial blood pressure measurements, uterine artery Doppler velocimetry, and biochemical markers (i.e., PAPP-A and PlGF),67,68 as well as metabolomics.56 This integrated assessment can be performed at the time of the 11–14-week scan with reported detection rates for early preeclampsia, late preeclampsia, preterm SGA, and term SGA neonates of 95.3%, 45.6%, 55.5%, and 44.3%, respectively, for a false-positive rate of 10.9%. Early identification of patients at risk for ischemic placental disease is of particular interest in light of a relatively recent meta-analysis of aspirin prophylaxis and placental-related disorders. The authors reported that early low-dose aspirin (50–150 mg) was effective in reducing the risks of preeclampsia (RR ¼ 0.47, 95% CI: 0.34, 0.65), severe preeclampsia (RR ¼ 0.09, 95% CI: 0.02, 0.37), gestational hypertension (RR ¼ 0.62, 95% CI: 0.45, 0.84), preterm delivery (RR ¼ 0.22, 95% CI: 0.10, 0.49), and IUGR (RR ¼ 0.44, 95% CI: 0.30, 0.65) but not placental abruption (RR ¼ 0.62, 95% CI: 0.08, 5.03) when given to highrisk patients before 16 weeks of gestation.69

Third-trimester umbilical artery Doppler velocimetry Doppler velocimetry of the umbilical arteries is one of the pillars of antenatal surveillance in fetuses at risk for or diagnosed with ischemic placental disease.70,71 Patients managed with umbilical artery Doppler have significant reduction in the rate of labor induction (RR ¼ 0.89, 95% CI: 0.80, 0.99), cesarean delivery (RR ¼ 0.90, 95% CI: 0.84, 0.97), and perinatal death (RR ¼ 0.71, 95% CI: 0.52, 0.98; 1.2% vs. 1.7%) without increasing the rate of unnecessary interventions.72 Umbilical artery Doppler is known to correlate with downstream resistance in the placental microcirculation. Early placental pathology studies have determined that there is a strong correlation between the average arteriolar counts in tertiary placental villi and resistance indices measured from umbilical artery Doppler waveforms.73 Thus, placentas from pregnancies at high risk for ischemic placental disease but normal umbilical arterial Doppler waveforms have similar average arteriolar counts in the tertiary villi when compared to low-risk pregnancies, whereas those with abnormal umbilical artery

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Doppler velocimetry have significantly lower arteriolar counts. Subsequently, mathematical modeling of the fetoplacental circulation has shown that approximately 50–60% of terminal arterial vessels may be compromised before any alterations are noticed by umbilical artery Doppler velocity waveforms.74 Indeed, accumulating evidence indicates that umbilical artery Doppler velocimetry may not be sensitive enough to detect mild forms of ischemic placental disease.75–78 Umbilical artery Doppler velocimetry is considered abnormal when the pulsatility index of the umbilical artery is 495th percentile for the given gestational age. Although the S/D ratio and resistance indices can also be used, the pulsatility index has a better correlation with increased downstream resistance when compared to the other two indices; therefore, it is the index we prefer to use in our daily clinical practice.79 When umbilical artery Doppler PI is 4 95th percentile but there is still diastolic flow present, we rely on trends since it is not unusual to have abnormal Doppler waveforms in one study and a few days later, a normal test. In such cases, the trend should dictate clinical management, not a single Doppler measurement. Persistently abnormal umbilical artery Doppler velocimetry mandates increased fetal surveillance by other methods, such as a combination of other Doppler parameters (i.e., middle cerebral artery and ductus venosus Doppler velocimetry) and biophysical profile to determine the best time of delivery, balancing the risks between an abnormal fetal health status and extreme preterm delivery.70,71 Current guidelines published by the Society for Maternal Fetal Medicine in the United States recommend the following: (1) antepartum surveillance of a viable fetus with suspected IUGR include umbilical artery Doppler; (2) in pregnancies complicated by IUGR, antenatal corticosteroids should be administered in case of absent or reversed end-diastolic flow in the umbilical arteries o34 weeks; (3) pregnancies complicated by IUGR and absent end-diastolic velocities in the umbilical artery may be managed expectantly until delivery at 34 weeks as long as fetal surveillance remains reassuring; and (4) pregnancies complicated by IUGR and reverse end-diastolic velocities in the umbilical artery may be managed expectantly until delivery at 32 weeks as long as fetal surveillance remains reassuring.70 Although a simple test, Doppler velocimetry of the umbilical arteries requires attention to technique for proper interpretation. For example, most nomograms published to date have relied on waveforms obtained from a free loop of umbilical cord and, therefore, if such nomograms are used, the waveforms should be obtained from a free loop.80 Doppler velocimetry waveforms obtained from the placental insertion of the umbilical cord tend to have lower resistance indices, whereas those obtained from the umbilical cord insertion into the abdomen tend to have higher resistance indices.81,82 Proper technique requires that umbilical artery Doppler velocimetry measurements not be utilized during periods of excessive fetal movement, breathing, or hiccups. On occasions, it might therefore not be possible to obtain technically adequate waveforms. Finally, it should be borne in mind that there are generally two umbilical arteries, whereas waveforms are usually obtained from a single artery. In most cases, there should be no significant difference between the waveforms obtained from the two umbilical arteries due to the presence of the Hyrtl anastomosis, i.e., an anastomosis

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between the umbilical arteries that occurs approximately 3 cm from the insertion of the umbilical cord into the placenta and which is thought to equalize the pressures between the two umbilical arteries.83 In the few cases where persistent discordance is apparent, this raises concern for asymmetric placental damage such as in placental ischemia or infarction in the placental area supplied by one of the arteries.84,85 The preceding Doppler review relates to umbilical artery velocimetry performed later in pregnancy. There is currently no good evidence for umbilical artery Doppler screening in the first or early mid-trimesters of pregnancy.

Magnetic resonance imaging Recent research has focused on anatomical or functional imaging of the placenta by MRI to detect ischemic placental disease.86–91 Although still in early stages of investigation, initial research suggest the following: (i) MRI can detect placental vascular pathology (i.e., infarction with or without hemorrhage, intervillous thrombi and hemorrhage, and retroplacental hematoma)87; (ii) placental perfusion can be measured using arterial spin labeling (ASL) and intravoxel incoherent motion echoplanar imaging; (iii) placental perfusion is lower for SGA when compared to AGA neonates; and (iv) that there is a strong association between uterine artery Doppler PI and placental perfusion assessed by functional MRI techniques.90

Conclusion Overall, although second-trimester maternal serum and/or ultrasound markers are not effective when used alone in predicting the ischemic placental diseases, it is possible that more useful predictive models can be developed when these markers are combined with other predictors, such as maternal demographic characteristics and Doppler markers. Recently published data suggest that metabolomics may be a promising tool for identifying placental dysfunction well before the onset of clinical disease. This has significant potential benefits, such as the opportunity for prophylactic therapy using aspirin to obviate the development of severe ischemic placental disorders, and provides an opportunity early and appropriate triaging patients with rationalization of health care expenditures.

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