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First trimester prediction of ischemic placental disease
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
First trimester prediction of ischemic placental disease Anthony M. Vintzileos, MDa,n, and Cande V. Ananth, PhD, MPHb,c a
Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, NY 11501 Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY c Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY b
article info
abstra ct
Keywords:
Ischemic placental disease is characterized by one or more of the clinical manifestations of
First trimester
preeclampsia, fetal growth restriction, and/or placental abruption, resulting in indicated
Prediction
preterm delivery. Since over half of the indicated preterm deliveries are due to ischemic
Ischemic placental disease
placental disease, accurate early prediction of the disease is of paramount importance in
Preeclampsia
developing prevention strategies. This review article focuses on studies that have used the
Fetal growth restriction
first trimester aneuploidy screening timing window to predict those patients who later
Placental abruption
develop ischemic placental disease. Emphasis was given to studies originating from the Fetal Medicine Foundation because of their uniformity in definitions and expertise of the personnel who performed the ultrasound screening exams. & 2014 Elsevier Inc. All rights reserved.
Introduction Preterm delivery continues to be a major contributor to long-term morbidity and mortality.1 The United States data indicate that approximately 60% of preterm deliveries result from spontaneous preterm delivery (spontaneous onset of labor or pre-labor rupture of membranes) and 40% from indicated preterm deliveries.2 The most frequent conditions leading to indicated preterm delivery are remarkably similar between singleton and twin pregnancies and include preeclampsia, fetal growth restriction, and placental abruption3,4 (Table 1). More than half of indicated preterm deliveries are linked to these three conditions.5
Definition and pathophysiology of ischemic placental disease We have previously hypothesized that preterm preeclampsia, fetal growth restriction, and placental abruption are different
clinical manifestations of a common pathophysiology characterized by abnormal trophoblast invasion, and we have used the term “ischemic placental disease.”5 Our hypothesis was based on several reasons. First, there is frequent coexistence of the above three conditions, especially in pregnancies that necessitate early preterm delivery (less than 34 weeks). In a study of 2434 women diagnosed with preeclampsia, the prevalence of fetal growth restriction was 18.2% in early preeclampsia as compared to 8.6% in the general hospital population and 5.6% (reduced) in late-onset preeclampsia.6 The prevalence of placental abruption (8.3%) and perinatal mortality rate (28.7%) were significantly higher in early-onset preeclampsia and fetal growth restriction. Second, there are remarkable similarities in the clinical characteristics, risk factors, placental histology, Doppler velocimetry, and angiogenic and anti-angiogenic placental factors. In fact, the similarities in these characteristics appear more homogeneous among preterm deliveries, indicating that endothelial cell dysfunction is involved in the
n Corresponding author: Anthony M. Vintzileos, MD, Department of Obstetrics and Gynecology, Winthrop-University Hospital, 256, First Street, Mineola NY 11501. E-mail address: [email protected] (A.M. Vintzileos).
http://dx.doi.org/10.1053/j.semperi.2014.03.006 0146-0005/& 2014 Elsevier Inc. All rights reserved.
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Table 1 – Conditions leading to indicated preterm delivery in singleton and twin gestations. Indications for delivery
Singleton pregnancies3 (%)
Twin pregnancies4 (%)
Preeclampsia Growth restriction/ fetal distress Placental abruption Fetal death Other
43 37
44 33
7 7 6
9 7 7
pathogenesis of all these conditions.7 Third, there is an increased crossover recurrence of ischemic placental disease, with those who develop preeclampsia being at a high risk for developing any of the other two conditions (fetal growth restriction or placental abruption) and vice versa.8 Fourth, mothers whose pregnancies are complicated by either preterm preeclampsia or fetal growth restriction are at a particularly high risk for developing cardiovascular disease later in life.7 Fifth, there are remarkable similarities in the placental bed biopsy findings in all these three conditions. In early preeclampsia, there is total absence of myometrial spiral artery remodeling; in preeclampsia with fetal growth restriction and also in abruptio placenta there is also total absence of myometrial spiral artery remodeling and “obstructive” lesions.9 In normal pregnancies, the trophoblastic invasion of the uterine spiral arteries begins at approximately 8–10 weeks and is almost completed by 16–18 weeks, although the second phase can last up to 24 weeks.10 In ischemic placental disease there is inadequate and incomplete trophoblast invasion of maternal spiral arteries, starting as early as 8–10 weeks’ gestation, leading to preterm preeclampsia, fetal growth restriction, and/or placental abruption. The degree and timing of the abnormal trophoblast invasion will most likely define the particular clinical manifestations, which could be either preterm preeclampsia alone or preterm preeclampsia associated with fetal growth restriction with or without placental abruption. This pathophysiology should be distinguished from term preeclampsia that is usually associated with normal fetal growth, normal blood flow, and frequently accompanied by large placental mass. In ischemic placental disease, the abnormal trophoblast invasion will lead to reduced uteroplacental blood flow (which can be detected by Doppler ultrasound) and uteroplacental ischemia, resulting in over- or under-production of various angiogenic and anti-angiogenic factors, which could be detected by maternal serum screening. Attempts at predicting and preventing ischemic placental disease in the general population have been unsuccessful mainly because the timing of these attempts was too late—in the second trimester—long after the completion of the process of abnormal trophoblast invasion.
Prevention of ischemic placental disease Given the early invasion of the placental trophoblast, the ideal timing for prediction and start of preventive therapy
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should be in the first trimester of pregnancy. For nulliparous women or women at high risk for preeclampsia, based on history and/or ultrasound findings, recent meta-analyses showed that low-dose aspirin (50–150 mg/day) starting at r16 weeks is associated with approximately 60% reduction in perinatal deaths, 50% reduction in preeclampsia, 80–90% reduction in early severe preeclampsia (o34 weeks), 50–55% reduction in fetal growth restriction, and 65–80% reduction in preterm delivery.11,12 The mechanism of action of low-dose aspirin is not entirely understood, but it is possible that it may promote trophoblast invasion of uterine spiral arteries, thus reversing the incomplete invasion.11
First trimester prediction of ischemic placental disease Since the results of the above two meta-analyses, the tremendous amount of research and the extremely high number of publications regarding prediction of preeclampsia and/or fetal growth restriction in the first trimester of pregnancy is well justified. Ideally, accurate prediction of ischemic placental disease by screening the entire population (low- and highrisk pregnancies) could lead to dramatic decreases in severe early preeclampsia, fetal growth restriction, prematurity, and perinatal death rate by using low-dose aspiring for those identified as “high risk.” However, the road to “accurate” prediction has been long and difficult given the low sensitivities and low positive predictive values of the individual clinical factors (derived from maternal history/maternal characteristics); Doppler studies, the most commonly being used uterine artery pulsatility index (UtA PI); and the individual maternal serum (placental/biochemical) factors. Most of the research in the prediction of ischemic placental disease in the first trimester of pregnancy originates from the Fetal Medicine Foundation. Kypros Nicolaides’ group capitalized on the 11–13 weeks’ gestation window that they use for aneuploidy screening by developing the philosophy that the timing and prediction models should follow the same statistical approach as in the screening for trisomy 21. This statistical approach uses a combination of clinical factors (based on maternal history/characteristics), UtA PI, and maternal biophysical and biochemical markers to derive patient-specific risks for ischemic placental disease. Table 2 depicts the most pertinent 32 studies, involving the use of ultrasound (mainly UtA PI) with or without biophysical or biochemical serum markers, for first trimester prediction of ischemic placental disease. The table shows the evolution of the research findings by using different biophysical and biomedical markers alone and in combination, and it summarizes the findings of each pertinent study with special emphasis in the detection of severe early preeclampsia and SGA necessitating preterm delivery at less than 34 weeks. We included mainly studies produced from the Fetal Medicine Foundation because of the uniformity in training and certification of the personnel who perform the first trimester screening exam. These studies showed that the first trimester predictions of preeclampsia and SGA are much stronger for the pregnancies necessitating preterm delivery as compared to near-term or term gestations. The predictions for late
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Table 2 – Summary of studies using first trimester ultrasound and maternal serum markers for prediction of ischemic placental disease. References
Type of study (population)
Gestational age (weeks)
Predictors
Findings
Van den Elzen et al.13
Prospective cohort (n ¼ 352; women aged Z35 years)
12–13
UtA PI 4 1.67
Harrington et al.14
Prospective cohort (n ¼ 652)
12–16
UtA PI, RI, TAV, maximum systolic velocity, volume flow, UA PI, and UA RI
Martin et al.15
Prospective cohort (n ¼ 3324; 63 later developed PE and 290 developed SGA)
11–14
UtA PI 4 95%
Nicolaides et al.16
Nested case–control (10 later developed early PE and 423 controls)
11–13
Combination of UtA PI and maternal serum PP-13 levels
Plasencia et al.17
Prospective screening (107 later developed PE and 5041 were unaffected)
11–13
Combination of maternal history and UtA PI
Parra-Cordero et al.18
Nested case–control (18 later developed PE and 60 controls)
11–13
Combination of UtA PI and maternal serum of sVCAM-1 and sICAM-1 levels
Spencer et al.19
Nested case–control (64 later developed PE and 240 controls)
11–13
Combination of UtA PI, maternal serum inhibin-A, and activin-A levels
Spencer et al.20
Prospective screening for aneuploidy and SGA (3539 SGA and 46,262 controls)
11–13
Combination of maternal history/characteristics, maternal serum PAPP-A, and free beta-hCG levels
Akolekar et al.21
Case–control (127 later developed PE and 609 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum PlGF, and PAPP-A levels
Plasencia et al.22
Prospective screening (n ¼ 3107; 93 later developed PE)
11–13; 21–24
Combination of maternal history/characteristics and change in UtA PI between first and second trimester
Poon et al.23
Prospective cohort (n ¼ 8051; 156 later developed PE)
11–13
Combination of maternal history/characteristics, UtA PI and maternal serum PAPP-A levels
Poon et al.24
Prospective cohort (n ¼ 7797; 34 later developed PE); case–
11–13
Combination of maternal history/characteristics, MAP,
UtA PI was associated with development of hypertensive disorders (RR ¼ 4.2), SGA infants (RR ¼ 2.4), and prematurity (RR ¼ 3.1). Bilateral UtA notching was associated with development of PE (OR ¼ 42.02), SGA (OR ¼ 8.61), and prematurity (OR ¼ 2.38). UtA PI 4 2.35 detected 50% of early PE (PPV ¼ 4.5%, NPV ¼ 99.8%) and 24% of preterm SGA (with no PE) (PPV ¼ 3.9%, NPV ¼ 99.3%). For a 10% FPR, the detection rate of early PE was 80% by (low) serum PP-13, 40% by (high) UtA PI, and 90% by both markers combined. For a 10% FPR, the detection rate of early PE was 50% by maternal history alone, 82% by UtA PI alone, and 82% by both combined. The UtA PI was higher among those who developed PE; there were no differences in sVCAM-1 and sICAM-1 levels. For a 5% FPR, the detection rate of PE was 55% by UtA PI alone, 68% by UtA PI þ (high) inhibin-A, and 63% by UtA PI þ (high) activin-A. The combination of maternal factors and (low) PAPP-A detected 12%, 14%, and 14% of those who developed SGA (below the 10th, 5th, and 3rd centiles, respectively). For a 5% FPR, the highest detection rate of early PE (76%) was achieved by the combination of maternal history/characteristics þ UtA PI þ (low) PlGF with or without (low) PAPP-A. For a 5% FPR, the detection rate of early PE was 91% (change in UtA PI was steeper in pregnancies with normal outcome). For a 5% FPR, the highest detection rate of early PE (66%) was achieved by the combination of maternal history/characteristics and UtA PI; detection rates were not improved by inclusion of PAPP-A. For a 5% FPR, the combination of all five predictors had a
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Table 2 (continued) ) References
Type of study (population)
Leal et al.25
control (209 cases and 418 controls) Case–control (128 later developed PE and 569 controls)
Gestational age (weeks)
11–13
Predictors
Findings
UtA PI, maternal serum PAPPA, and PlGF levels Combination of maternal history/characteristics, UtA PI, and maternal serum TNFR1 levels
93% detection rate for early PE cases. For a 5% FPR, the highest detection rates (32% for PE and 24% for SGA) were achieved by the combination of maternal history/ characteristics and UtA PI; inclusion of (high) TNF-R1 did not improve prediction. For a 5% FPR, the highest detection rate of early PE (85%) was achieved by the combination of maternal factors, UtA PI, and (high) inhibin-A; inclusion of PAPPA did not improve prediction. Ang-2 levels were not different among those who develop PE or GH as compared to controls. Increased maternal serum pentraxin levels were observed only among those women who later developed early PE. Best prediction for early PE was achieved by a combination of maternal history/ characteristics, UtA PI, and (low) PAPP-A; inclusion of (high) TNF-R1 and (high) activin-A levels did not improve prediction. In cases with low PAPP-A, UtA PI can differentiate between trisomy 21 (normal UtA PI) and impending early PE (high UtA PI). Maternal serum sFlt-1 and freeVEGF levels were not useful in the prediction of PE.
Akolekar et al.26
Prospective screening (121 later developed PE, 87 with GH, and 208 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum inhibin-A, and PAPP-A levels
Akolekar et al.27
Prospective screening (126 later developed PE, 88 with GH, and 207 controls)
11–13
Akolekar et al.28
Case–control (120 later developed PE, 87 with GH, and 207 controls)
11–13
Combination of maternal history/characteristics, UtA PI, and maternal serum Ang2 levels Combination of maternal history/characteristics, UtA PI, and maternal serum pentraxin levels
Akolekar et al.29
Case–control (126 later developed PE, 88 with GH, and 214 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, TNF-R1, and activin-A levels
Staboulidou et al.30
Nested case–control (165 who later developed PE and 301 cases of fetal aneuploidy)
11–13
UtA PI and maternal serum PAPP-A levels
Akolekar et al.31
Case–control (90 later developed PE and 180 controls)
11–13
Ashoor et al.32
Prospective screening (127 later developed PE and 3592 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum sFlt-1, free-VEGF, and PlGF levels UtA PI, MAP, maternal serum TSH, free T4, and free T3 levels
Sifakis et al.33
Case–control (50 later developed PE and 106 controls)
11–13
Karagiannis et al.34
Prospecting screening for SGA in the absence of hypertension (1536 cases and 31,314 controls)
11–13
Case–control (60 later developed PE and 120 controls)
11–13
Sifakis
35
Combination of maternal history/characteristics, UtA PI, and maternal serum IGF-I levels Combination of maternal history/characteristics, MAP, NT, UtA PI, maternal serum PAPP-A, free beta-hCG, PlGF, PP-13, and ADAM12 levels
Combination of maternal history/characteristics, UtA
UtA PI and MAP were increased among those who developed early PE. In late PE (434 weeks), TSH was increased and free T4 was decreased. UtA PI was increased and IGF-I level was decreased among those who developed early PE. In the SGA group, the UtA PI and MAP were increased and serum PAPP-A, free beta-hCG, PlGF, PP-13, ADAM12, and NT were decreased. For a 5% FPR, the combination of all above markers detected 61% of preterm SGAs (for a 10% FPR the detection rate was 73%). UtA PI was increased and serum IGFBP-1 levels were decreased among those who developed
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Table 2 (continued) ) References
Type of study (population)
Gestational age (weeks)
Predictors
Findings
PI, and maternal serum IGFBP-1 levels Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, and adiponectin levels
PE (more drastic decrease in early PE). Serum adiponectin levels were increased among those who developed early, but not late, PE. For a 5% FPR, the combination of maternal factors and UtA PI detected 57% of early PE cases. UtA PI was increased and serum PAPP-A levels were decreased among those who developed PE (more drastic decrease in early PE); hPGH levels were not different between PE and controls. Placental volume and serum PAPP-A levels were decreased among SGA pregnancies. Combination of maternal characteristics, serum PAPPA, and placental volume detected 35% of the SGA cases (FPR ¼ 10%). SGA pregnancies had lower PAPP-A and 25(OH)D levels.
Nanda et al.36
Case–control (90 later developed PE and 300 controls)
11–13
Sifakis et al.37
Case–control (60 later developed PE and 120 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, and hPGH levels
Plasencia et al.38
Prospective screening (144 developed SGA and 2811 controls)
11–13
Combination of maternal history/characteristics, maternal serum PAPP-A, and placental volume by 3D ultrasound
Ertl et al.39
Case–control (150 developed SGA and 1000 controls)
11–13
Sifakis et al.40
Case–control (60 later developed PE and 120 controls)
11–13
Combination of maternal history/characteristics, maternal serum PAPP-A, and 25(OH)D levels Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, and IGFBP-3 levels
Wright et al.41
Prospective screening (1426 later developed PE and 57,458 controls)
11–13
Combination of maternal history/characteristics, UtA PI, and MAP
Akolekar et al.42
Prospective screening (1426 later developed PE and 57,458 controls)
11–13
Combination of maternal history/characteristics, UtA PI, MAP, maternal serum PAPP-A, and PlGF levels
Ferreira et al.43
Case–control (80 later developed PE and 240 controls) Prospective combined screening for both PE and SGA (1426 later developed PE, 3168 with SGA and no preeclampsia, and 57,458 controls)
11–13
UtA PI and maternal visfatin levels
11–13
Combination of two algorithms using maternal history/ characteristics, UtA PI, MAP, maternal serum PAPP-A, and PlGF levels
Poon et al.44
In late PE, but not in early PE, serum IGFBP-3 was increased; in early PE, but not in late PE, UtA PI was increased and serum PAPP-A was decreased. The combined model detected 80–90% of early PE cases (for FPRs 5% and 10%, respectively) and 35–57% of all PE cases (for FPRs 5% and 10%, respectively). The combined model detected 93–96% of early PE cases (for FPRs 5% and 10%, respectively) and 38–54% of all PE cases (for FPRs 5% and 10%, respectively). The UtA PI and serum visfatin levels were higher among those who developed PE. For a 10% FPR, the detection rates of early PE, late PE, preterm SGA, and term-SGA were 95%, 46%, 56%, and 44%, respectively.
UtA PI, uterine artery pulsatility index; RR, relative risk; RI, resistance index; TAV, time-averaged mean velocity; UA, umbilical artery; PE, preeclampsia; OR, odds ratio; SGA, small for gestational age; PPV, positive predictive value; NPV, negative predictive value; PP-13, plasma protein 13; FPR, false-positive rate; sVCAM-1, soluble vascular cell adhesion molecule 1; sICAM-1, intercellular adhesion molecule 1; PAPP-A, pregnancy-associated plasma protein-A; hCG, human chorionic gonadotropin; PlGF, placental growth factor; MAP, mean arterial pressure; TNF-R1, soluble receptor-1 of tumor necrosis factor-α; GH, gestational hypertension; Ang-2, angiopoietin-2; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor; TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothyronine; IGF-1, insulin-like growth factor-1; NT, nuchal translucency; ADAM12, A Disintegrin and Metalloprotease 12; IGFBP-1, insulin-like growth factor-binding protein1; hPGH, human placental growth hormone; 3D, three dimensional; 25(OH)D, serum vitamin D; IGFBP-3, insulin-like growth factor-binding protein-3; early PE, PE necessitating delivery o 34 weeks.
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preeclampsia and SGA (at Z34 weeks, Table 2) are weak but still significant because this group still includes preterm gestations (34–37 weeks). Thus, one could argue that the predictions for term preeclampsia and SGA (at Z37 weeks) may have not been statistically or clinically significant. This observation provides further support that ischemic placental disease has its origin in the first trimester and it is characterized by the need for preterm delivery. Another observation that further supports the above concept is that low-dose aspirin administered in high-risk patients prior to 16 weeks appears to exert its beneficial overall effect on preeclampsia (50% reduction) by the dramatic reduction (80–90%) in the risk of early severe preeclampsia (o34 weeks).11 Data regarding the prediction of the third component of ischemic placental disease (i.e., placental abruption) by first trimester screening are scarce. However, we located one study that showed that placental abruption could be predicted by first trimester screening.45 This was a prospective study of 878 consecutive women at 11–14 weeks using the same predictors as the Nicolaides’ group (maternal demographic characteristics, UtA PI, and maternal serum PAPP-A). The authors found that increased UtA PI, low PAPP-A, and maternal history of preeclampsia/hypertension were predictive of preeclampsia and SGA. In addition, they found that increased UtA PI detected 43% of the cases that later developed placental abruption. Increased UtA PI was the only independent factor in the prediction of placental abruption with an odds ratio of 8.5 (95% confidence interval 2.8–25.9). From the prevention point of view, the most recent metaanalysis showed that low-dose aspirin in high-risk patients, if initiated, prior to 16 weeks is associated with a 45% reduction in placental abruption; however, this reduction was not statistically significant most likely because of small numbers.11 Unfortunately, the first trimester screening studies for predicting preterm preeclampsia and/or SGA (Table 2) have not included placental abruption as an “outcomes of interest” despite the strong likelihood of a common pathophysiology among preterm preeclampsia, SGA, and placental abruption and its strong link to prematurity.5 It is possible that the current first trimester prediction algorithms may detect some of the cases with placental abruption since placental abruption frequently coexists with early preeclampsia and SGA. However, some cases with placental abruption will be missed by the current algorithms. For instance, patients with hypertension with no proteinuria and with birth weight between 5% and 10%, i.e., who develop placental abruption at 28 weeks, resulting in a preterm delivery, will be missed. In our view, future prediction algorithms should be modified to predict placental abruption, so that the detection rate of the entire spectrum of ischemic placental disease is improved.
Technique of UtA PI measurement A prerequisite for accurate prediction of ischemic placental disease, based on first trimester algorithms, is the appropriate technique and measurement of UtA PI. In the studies, where the final algorithms were constructed appropriately, the UtA PI was measured by Doppler ultrasound using the
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following technique.15 A sagittal image of the uterus and the cervical canal was first obtained abdominally and the internal cervical os was identified. Then, the transducer was tilted from side to side and color flow mapping was applied to visualize the uterine arteries aliasing alongside of the cervix and the uterus. The flow velocity waveforms were obtained from the ascending branch of the uterine artery as close to the internal os as possible. After obtaining three similar consecutive waveforms, the PI was measured and the mean PI of the left and the right arteries was determined as the final UtA PI.15 Subsequent research found that UtA PI measurements at the level of the internal cervical os are possible to be obtained in a greater proportion of women, as compared to the level of uterine artery crossover with the external iliac vessels, and correlate better with second trimester UtA PI measurements.46 This finding may be important in future combined (first and second trimester) prediction models of ischemic placental disease.
Conclusion Currently, the models for predicting ischemic placental disease (preeclampsia and SGA) use a combination of maternal history/characteristics, UtA PI, mean arterial pressure, maternal serum pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF).42,44 The reasonably low false-positive rates (5–10%) are associated with remarkably high detection rates of severe preeclampsia and SGA prior to 34 weeks of 95% and 55%, respectively. This degree of prediction is ideal for conducting a large scale, multicenter, randomized controlled trial of early prediction and prevention of ischemic placental disease by administration of lowdose aspirin to those identified as high risk by first trimester screening between 11 and 13 weeks gestation. However, future studies in our view should also focus in the detection of placental abruption, in addition to early preeclampsia and SGA, in order to increase the detection rate of ischemic placental disease, so that the impact of prevention strategies can be larger. Finally, the new definition of preeclampsia should be applied in future studies that do not require the presence of proteinuria.47
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protein-A and pre-eclampsia. Ultrasound Obstet Gyencol. 2009;33:23–33. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53:812–818. Leal AM, Poon LCY, Frisova V, Venduta A, Nicolaides KH. Firsttrimester maternal serum tumor necrosis factor receptor-1 and pre-eclampsia. Ultrasound Obstet Gynecol. 2009;33:135–141. Akolekar R, Minekawa R, Veduta A, Ximena C, Romero R, Nicolaides KH. Maternal plasma inhibin A at 11–13 weeks of gestation in hypertensive disorders of pregnancy. Prenat Diagn. 2009;29:753–760. Akolekar R, Casagrandi D, Skyfta E, Ahmed AA, Nicolaides KH. Maternal serum angiopoietin-2 at 11 to 13 weeks of gestation in hypertensive disorders of pregnancy. Prenat Diagn. 2009;29: 847–851. Akolekar R, Casagrandi D, Livanos P, Tetteh A, Nicolaides KH. Maternal plasma pentraxin 3 at 11 to 13 weeks of gestation in hypertensive disorders of pregnancy. Prenat Diagn. 2009;29: 934–938. Akolekar R, Etchegaray A, Zhou Y, Maiz N, Nicolaides KH. Maternal serum activin A at 11–13 weeks of gestation in hypertensive disorders of pregnancy. Fetal Diagn Ther. 2009;25:320–327. Staboulidou I, Galindo A, Maiz N, Karagiannis G, Nicolaides KH. First-trimester uterine artery Doppler and serum pregnancyassociated plasma protein-A in preeclampsia and chromosomal defects. Fetal Diagn Ther. 2009;25:336–339. Akolekar R, deCruz J, Foidart JM, Munaut C, Nicolaides KH. Maternal plasma soluble fms-like tyrosine kinase-1 and free vascular endothelial growth factor at 11 to 13 weeks of gestation in preeclampsia. Prenat Diagn. 2010;30:191–197. Ashoor G, Maiz N, Rotas M, Kametas A, Nicolaides KH. Maternal thyroid function at 11 to 13 weeks of gestation and subsequent development of preeclampsia. Prenat Diagn. 2010;30:1032–1038. Sifakis S, Akolekar R, Kappou D, Mantas N, Nicolaides KH. Maternal serum insulin-like growth factor-I at 11–13 weeks in preeclampsia. Prenat Diagn. 2010;30:1026–1031. Karagiannis G, Akolekar R, Sarquis R, Wright D, Nicolaides KH. Prediction of small-for-gestation neonates from biophysical and biochemical markers at 11–13 weeks. Fetal Diagn Ther. 2010;11:1–7. Sifakis S, Akolekar R, Kappou D, Mantas N, Nicolaides KH. Maternal serum insulin-like growth factor-binding protein-1 (IGFBP-1) at 11–13 weeks in pre-eclampsia. Prenat Diagn. 2011;31:196–201. Nanda S, Yu CKH, Giurcaneanu L, Akolekar R, Nicolaides KH. Maternal serum adiponectin at 11-13 weeks of gestation in preeclampsia. Fetal Diagn Ther. 2011;29:208–215. Sifakis S, Akolekar R, Mantas N, Kappou D, Nicolaides KH. Maternal serum human placental growth hormone (hPGH) at 11 to 13 weeks of gestation in preeclampsia. Hypertens Pregnancy. 2011;30:74–82. Plasencia W, Akolekar R, Dagklis T, Venduta A, Nicolaides KH. Placental volume at 11-13 weeks’ gestation in the prediction of birth weight percentile. Fetal Diagn Ther. 2011;30:23–28. Ertl R, Yu CKH, Samaha R, Akolekar R, Nicolaides KH. Maternal serum vitamin D at 11–13 weeks in pregnancies delivering small for gestational age neonates. Fetal Diagn Ther. 2012;31:103–108. Sifakis S, Akolekar R, Kappou D, Mantas N, Nicolaides KH. Maternal serum insulin-like growth factor-binding protein-3 (IGFBP-3) at 11–13 weeks in preeclampsia. J Hum Hypertens. 2012;26:253–258. Wright D, Akolekar R, Syngelaki A, Poon LCY, Nicolaides KH. A competing risks model in early screening for preeclampsia. Fetal Diagn Ther. 2012;32:171–178.
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42. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risk model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther. 2013;33:8–15. 43. Ferreira AF, Rezende JC, deCassia C, Oliveira R, Akolekar R, Nicolaides KH. Maternal serum visfatin at 11–13 weeks’ gestation in preeclampsia. J Hum Hypertens. 2013;27:261–264. 44. Poon LCY, Syngelaki A, Akolekar R, Lai J, Nicolaides KH. Combined screening for preeclampsia and small for gestational age at 11–13 weeks. Fetal Diagn Ther. 2013;33:16–27. 45. Pilalis A, Souka AP, Antsaklis P, Daskalakis G, Papantoniou N, Mesogitis S, et al. Screening for pre-eclampsia and fetal growth
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restriction by uterine artery Doppler and PAPP-A at 11-14 weeks’ gestation. Ultrasound Obstet Gynecol. 2007;29:135–140. 46. Lefebvre J, Demers S, Bujold E, et al. Comparison of two different sites of measurement for transabdominal uterine artery Doppler velocimetry at 11–13 weeks. Ultrasound Obstet Gynecol. 2012;40:288–292. 47. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy (Collaborators 22). Obstet Gynecol. 2013;122: 1122–1131.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
First trimester prediction of ischemic placental disease Anthony M. Vintzileos, MDa,n, and Cande V. Ananth, PhD, MPHb,c a
Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, NY 11501 Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY c Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY b
article info
abstra ct
Keywords:
Ischemic placental disease is characterized by one or more of the clinical manifestations of
First trimester
preeclampsia, fetal growth restriction, and/or placental abruption, resulting in indicated
Prediction
preterm delivery. Since over half of the indicated preterm deliveries are due to ischemic
Ischemic placental disease
placental disease, accurate early prediction of the disease is of paramount importance in
Preeclampsia
developing prevention strategies. This review article focuses on studies that have used the
Fetal growth restriction
first trimester aneuploidy screening timing window to predict those patients who later
Placental abruption
develop ischemic placental disease. Emphasis was given to studies originating from the Fetal Medicine Foundation because of their uniformity in definitions and expertise of the personnel who performed the ultrasound screening exams. & 2014 Elsevier Inc. All rights reserved.
Introduction Preterm delivery continues to be a major contributor to long-term morbidity and mortality.1 The United States data indicate that approximately 60% of preterm deliveries result from spontaneous preterm delivery (spontaneous onset of labor or pre-labor rupture of membranes) and 40% from indicated preterm deliveries.2 The most frequent conditions leading to indicated preterm delivery are remarkably similar between singleton and twin pregnancies and include preeclampsia, fetal growth restriction, and placental abruption3,4 (Table 1). More than half of indicated preterm deliveries are linked to these three conditions.5
Definition and pathophysiology of ischemic placental disease We have previously hypothesized that preterm preeclampsia, fetal growth restriction, and placental abruption are different
clinical manifestations of a common pathophysiology characterized by abnormal trophoblast invasion, and we have used the term “ischemic placental disease.”5 Our hypothesis was based on several reasons. First, there is frequent coexistence of the above three conditions, especially in pregnancies that necessitate early preterm delivery (less than 34 weeks). In a study of 2434 women diagnosed with preeclampsia, the prevalence of fetal growth restriction was 18.2% in early preeclampsia as compared to 8.6% in the general hospital population and 5.6% (reduced) in late-onset preeclampsia.6 The prevalence of placental abruption (8.3%) and perinatal mortality rate (28.7%) were significantly higher in early-onset preeclampsia and fetal growth restriction. Second, there are remarkable similarities in the clinical characteristics, risk factors, placental histology, Doppler velocimetry, and angiogenic and anti-angiogenic placental factors. In fact, the similarities in these characteristics appear more homogeneous among preterm deliveries, indicating that endothelial cell dysfunction is involved in the
n Corresponding author: Anthony M. Vintzileos, MD, Department of Obstetrics and Gynecology, Winthrop-University Hospital, 256, First Street, Mineola NY 11501. E-mail address: [email protected] (A.M. Vintzileos).
http://dx.doi.org/10.1053/j.semperi.2014.03.006 0146-0005/& 2014 Elsevier Inc. All rights reserved.
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Table 1 – Conditions leading to indicated preterm delivery in singleton and twin gestations. Indications for delivery
Singleton pregnancies3 (%)
Twin pregnancies4 (%)
Preeclampsia Growth restriction/ fetal distress Placental abruption Fetal death Other
43 37
44 33
7 7 6
9 7 7
pathogenesis of all these conditions.7 Third, there is an increased crossover recurrence of ischemic placental disease, with those who develop preeclampsia being at a high risk for developing any of the other two conditions (fetal growth restriction or placental abruption) and vice versa.8 Fourth, mothers whose pregnancies are complicated by either preterm preeclampsia or fetal growth restriction are at a particularly high risk for developing cardiovascular disease later in life.7 Fifth, there are remarkable similarities in the placental bed biopsy findings in all these three conditions. In early preeclampsia, there is total absence of myometrial spiral artery remodeling; in preeclampsia with fetal growth restriction and also in abruptio placenta there is also total absence of myometrial spiral artery remodeling and “obstructive” lesions.9 In normal pregnancies, the trophoblastic invasion of the uterine spiral arteries begins at approximately 8–10 weeks and is almost completed by 16–18 weeks, although the second phase can last up to 24 weeks.10 In ischemic placental disease there is inadequate and incomplete trophoblast invasion of maternal spiral arteries, starting as early as 8–10 weeks’ gestation, leading to preterm preeclampsia, fetal growth restriction, and/or placental abruption. The degree and timing of the abnormal trophoblast invasion will most likely define the particular clinical manifestations, which could be either preterm preeclampsia alone or preterm preeclampsia associated with fetal growth restriction with or without placental abruption. This pathophysiology should be distinguished from term preeclampsia that is usually associated with normal fetal growth, normal blood flow, and frequently accompanied by large placental mass. In ischemic placental disease, the abnormal trophoblast invasion will lead to reduced uteroplacental blood flow (which can be detected by Doppler ultrasound) and uteroplacental ischemia, resulting in over- or under-production of various angiogenic and anti-angiogenic factors, which could be detected by maternal serum screening. Attempts at predicting and preventing ischemic placental disease in the general population have been unsuccessful mainly because the timing of these attempts was too late—in the second trimester—long after the completion of the process of abnormal trophoblast invasion.
Prevention of ischemic placental disease Given the early invasion of the placental trophoblast, the ideal timing for prediction and start of preventive therapy
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should be in the first trimester of pregnancy. For nulliparous women or women at high risk for preeclampsia, based on history and/or ultrasound findings, recent meta-analyses showed that low-dose aspirin (50–150 mg/day) starting at r16 weeks is associated with approximately 60% reduction in perinatal deaths, 50% reduction in preeclampsia, 80–90% reduction in early severe preeclampsia (o34 weeks), 50–55% reduction in fetal growth restriction, and 65–80% reduction in preterm delivery.11,12 The mechanism of action of low-dose aspirin is not entirely understood, but it is possible that it may promote trophoblast invasion of uterine spiral arteries, thus reversing the incomplete invasion.11
First trimester prediction of ischemic placental disease Since the results of the above two meta-analyses, the tremendous amount of research and the extremely high number of publications regarding prediction of preeclampsia and/or fetal growth restriction in the first trimester of pregnancy is well justified. Ideally, accurate prediction of ischemic placental disease by screening the entire population (low- and highrisk pregnancies) could lead to dramatic decreases in severe early preeclampsia, fetal growth restriction, prematurity, and perinatal death rate by using low-dose aspiring for those identified as “high risk.” However, the road to “accurate” prediction has been long and difficult given the low sensitivities and low positive predictive values of the individual clinical factors (derived from maternal history/maternal characteristics); Doppler studies, the most commonly being used uterine artery pulsatility index (UtA PI); and the individual maternal serum (placental/biochemical) factors. Most of the research in the prediction of ischemic placental disease in the first trimester of pregnancy originates from the Fetal Medicine Foundation. Kypros Nicolaides’ group capitalized on the 11–13 weeks’ gestation window that they use for aneuploidy screening by developing the philosophy that the timing and prediction models should follow the same statistical approach as in the screening for trisomy 21. This statistical approach uses a combination of clinical factors (based on maternal history/characteristics), UtA PI, and maternal biophysical and biochemical markers to derive patient-specific risks for ischemic placental disease. Table 2 depicts the most pertinent 32 studies, involving the use of ultrasound (mainly UtA PI) with or without biophysical or biochemical serum markers, for first trimester prediction of ischemic placental disease. The table shows the evolution of the research findings by using different biophysical and biomedical markers alone and in combination, and it summarizes the findings of each pertinent study with special emphasis in the detection of severe early preeclampsia and SGA necessitating preterm delivery at less than 34 weeks. We included mainly studies produced from the Fetal Medicine Foundation because of the uniformity in training and certification of the personnel who perform the first trimester screening exam. These studies showed that the first trimester predictions of preeclampsia and SGA are much stronger for the pregnancies necessitating preterm delivery as compared to near-term or term gestations. The predictions for late
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Table 2 – Summary of studies using first trimester ultrasound and maternal serum markers for prediction of ischemic placental disease. References
Type of study (population)
Gestational age (weeks)
Predictors
Findings
Van den Elzen et al.13
Prospective cohort (n ¼ 352; women aged Z35 years)
12–13
UtA PI 4 1.67
Harrington et al.14
Prospective cohort (n ¼ 652)
12–16
UtA PI, RI, TAV, maximum systolic velocity, volume flow, UA PI, and UA RI
Martin et al.15
Prospective cohort (n ¼ 3324; 63 later developed PE and 290 developed SGA)
11–14
UtA PI 4 95%
Nicolaides et al.16
Nested case–control (10 later developed early PE and 423 controls)
11–13
Combination of UtA PI and maternal serum PP-13 levels
Plasencia et al.17
Prospective screening (107 later developed PE and 5041 were unaffected)
11–13
Combination of maternal history and UtA PI
Parra-Cordero et al.18
Nested case–control (18 later developed PE and 60 controls)
11–13
Combination of UtA PI and maternal serum of sVCAM-1 and sICAM-1 levels
Spencer et al.19
Nested case–control (64 later developed PE and 240 controls)
11–13
Combination of UtA PI, maternal serum inhibin-A, and activin-A levels
Spencer et al.20
Prospective screening for aneuploidy and SGA (3539 SGA and 46,262 controls)
11–13
Combination of maternal history/characteristics, maternal serum PAPP-A, and free beta-hCG levels
Akolekar et al.21
Case–control (127 later developed PE and 609 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum PlGF, and PAPP-A levels
Plasencia et al.22
Prospective screening (n ¼ 3107; 93 later developed PE)
11–13; 21–24
Combination of maternal history/characteristics and change in UtA PI between first and second trimester
Poon et al.23
Prospective cohort (n ¼ 8051; 156 later developed PE)
11–13
Combination of maternal history/characteristics, UtA PI and maternal serum PAPP-A levels
Poon et al.24
Prospective cohort (n ¼ 7797; 34 later developed PE); case–
11–13
Combination of maternal history/characteristics, MAP,
UtA PI was associated with development of hypertensive disorders (RR ¼ 4.2), SGA infants (RR ¼ 2.4), and prematurity (RR ¼ 3.1). Bilateral UtA notching was associated with development of PE (OR ¼ 42.02), SGA (OR ¼ 8.61), and prematurity (OR ¼ 2.38). UtA PI 4 2.35 detected 50% of early PE (PPV ¼ 4.5%, NPV ¼ 99.8%) and 24% of preterm SGA (with no PE) (PPV ¼ 3.9%, NPV ¼ 99.3%). For a 10% FPR, the detection rate of early PE was 80% by (low) serum PP-13, 40% by (high) UtA PI, and 90% by both markers combined. For a 10% FPR, the detection rate of early PE was 50% by maternal history alone, 82% by UtA PI alone, and 82% by both combined. The UtA PI was higher among those who developed PE; there were no differences in sVCAM-1 and sICAM-1 levels. For a 5% FPR, the detection rate of PE was 55% by UtA PI alone, 68% by UtA PI þ (high) inhibin-A, and 63% by UtA PI þ (high) activin-A. The combination of maternal factors and (low) PAPP-A detected 12%, 14%, and 14% of those who developed SGA (below the 10th, 5th, and 3rd centiles, respectively). For a 5% FPR, the highest detection rate of early PE (76%) was achieved by the combination of maternal history/characteristics þ UtA PI þ (low) PlGF with or without (low) PAPP-A. For a 5% FPR, the detection rate of early PE was 91% (change in UtA PI was steeper in pregnancies with normal outcome). For a 5% FPR, the highest detection rate of early PE (66%) was achieved by the combination of maternal history/characteristics and UtA PI; detection rates were not improved by inclusion of PAPP-A. For a 5% FPR, the combination of all five predictors had a
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Table 2 (continued) ) References
Type of study (population)
Leal et al.25
control (209 cases and 418 controls) Case–control (128 later developed PE and 569 controls)
Gestational age (weeks)
11–13
Predictors
Findings
UtA PI, maternal serum PAPPA, and PlGF levels Combination of maternal history/characteristics, UtA PI, and maternal serum TNFR1 levels
93% detection rate for early PE cases. For a 5% FPR, the highest detection rates (32% for PE and 24% for SGA) were achieved by the combination of maternal history/ characteristics and UtA PI; inclusion of (high) TNF-R1 did not improve prediction. For a 5% FPR, the highest detection rate of early PE (85%) was achieved by the combination of maternal factors, UtA PI, and (high) inhibin-A; inclusion of PAPPA did not improve prediction. Ang-2 levels were not different among those who develop PE or GH as compared to controls. Increased maternal serum pentraxin levels were observed only among those women who later developed early PE. Best prediction for early PE was achieved by a combination of maternal history/ characteristics, UtA PI, and (low) PAPP-A; inclusion of (high) TNF-R1 and (high) activin-A levels did not improve prediction. In cases with low PAPP-A, UtA PI can differentiate between trisomy 21 (normal UtA PI) and impending early PE (high UtA PI). Maternal serum sFlt-1 and freeVEGF levels were not useful in the prediction of PE.
Akolekar et al.26
Prospective screening (121 later developed PE, 87 with GH, and 208 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum inhibin-A, and PAPP-A levels
Akolekar et al.27
Prospective screening (126 later developed PE, 88 with GH, and 207 controls)
11–13
Akolekar et al.28
Case–control (120 later developed PE, 87 with GH, and 207 controls)
11–13
Combination of maternal history/characteristics, UtA PI, and maternal serum Ang2 levels Combination of maternal history/characteristics, UtA PI, and maternal serum pentraxin levels
Akolekar et al.29
Case–control (126 later developed PE, 88 with GH, and 214 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, TNF-R1, and activin-A levels
Staboulidou et al.30
Nested case–control (165 who later developed PE and 301 cases of fetal aneuploidy)
11–13
UtA PI and maternal serum PAPP-A levels
Akolekar et al.31
Case–control (90 later developed PE and 180 controls)
11–13
Ashoor et al.32
Prospective screening (127 later developed PE and 3592 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum sFlt-1, free-VEGF, and PlGF levels UtA PI, MAP, maternal serum TSH, free T4, and free T3 levels
Sifakis et al.33
Case–control (50 later developed PE and 106 controls)
11–13
Karagiannis et al.34
Prospecting screening for SGA in the absence of hypertension (1536 cases and 31,314 controls)
11–13
Case–control (60 later developed PE and 120 controls)
11–13
Sifakis
35
Combination of maternal history/characteristics, UtA PI, and maternal serum IGF-I levels Combination of maternal history/characteristics, MAP, NT, UtA PI, maternal serum PAPP-A, free beta-hCG, PlGF, PP-13, and ADAM12 levels
Combination of maternal history/characteristics, UtA
UtA PI and MAP were increased among those who developed early PE. In late PE (434 weeks), TSH was increased and free T4 was decreased. UtA PI was increased and IGF-I level was decreased among those who developed early PE. In the SGA group, the UtA PI and MAP were increased and serum PAPP-A, free beta-hCG, PlGF, PP-13, ADAM12, and NT were decreased. For a 5% FPR, the combination of all above markers detected 61% of preterm SGAs (for a 10% FPR the detection rate was 73%). UtA PI was increased and serum IGFBP-1 levels were decreased among those who developed
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Table 2 (continued) ) References
Type of study (population)
Gestational age (weeks)
Predictors
Findings
PI, and maternal serum IGFBP-1 levels Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, and adiponectin levels
PE (more drastic decrease in early PE). Serum adiponectin levels were increased among those who developed early, but not late, PE. For a 5% FPR, the combination of maternal factors and UtA PI detected 57% of early PE cases. UtA PI was increased and serum PAPP-A levels were decreased among those who developed PE (more drastic decrease in early PE); hPGH levels were not different between PE and controls. Placental volume and serum PAPP-A levels were decreased among SGA pregnancies. Combination of maternal characteristics, serum PAPPA, and placental volume detected 35% of the SGA cases (FPR ¼ 10%). SGA pregnancies had lower PAPP-A and 25(OH)D levels.
Nanda et al.36
Case–control (90 later developed PE and 300 controls)
11–13
Sifakis et al.37
Case–control (60 later developed PE and 120 controls)
11–13
Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, and hPGH levels
Plasencia et al.38
Prospective screening (144 developed SGA and 2811 controls)
11–13
Combination of maternal history/characteristics, maternal serum PAPP-A, and placental volume by 3D ultrasound
Ertl et al.39
Case–control (150 developed SGA and 1000 controls)
11–13
Sifakis et al.40
Case–control (60 later developed PE and 120 controls)
11–13
Combination of maternal history/characteristics, maternal serum PAPP-A, and 25(OH)D levels Combination of maternal history/characteristics, UtA PI, maternal serum PAPP-A, and IGFBP-3 levels
Wright et al.41
Prospective screening (1426 later developed PE and 57,458 controls)
11–13
Combination of maternal history/characteristics, UtA PI, and MAP
Akolekar et al.42
Prospective screening (1426 later developed PE and 57,458 controls)
11–13
Combination of maternal history/characteristics, UtA PI, MAP, maternal serum PAPP-A, and PlGF levels
Ferreira et al.43
Case–control (80 later developed PE and 240 controls) Prospective combined screening for both PE and SGA (1426 later developed PE, 3168 with SGA and no preeclampsia, and 57,458 controls)
11–13
UtA PI and maternal visfatin levels
11–13
Combination of two algorithms using maternal history/ characteristics, UtA PI, MAP, maternal serum PAPP-A, and PlGF levels
Poon et al.44
In late PE, but not in early PE, serum IGFBP-3 was increased; in early PE, but not in late PE, UtA PI was increased and serum PAPP-A was decreased. The combined model detected 80–90% of early PE cases (for FPRs 5% and 10%, respectively) and 35–57% of all PE cases (for FPRs 5% and 10%, respectively). The combined model detected 93–96% of early PE cases (for FPRs 5% and 10%, respectively) and 38–54% of all PE cases (for FPRs 5% and 10%, respectively). The UtA PI and serum visfatin levels were higher among those who developed PE. For a 10% FPR, the detection rates of early PE, late PE, preterm SGA, and term-SGA were 95%, 46%, 56%, and 44%, respectively.
UtA PI, uterine artery pulsatility index; RR, relative risk; RI, resistance index; TAV, time-averaged mean velocity; UA, umbilical artery; PE, preeclampsia; OR, odds ratio; SGA, small for gestational age; PPV, positive predictive value; NPV, negative predictive value; PP-13, plasma protein 13; FPR, false-positive rate; sVCAM-1, soluble vascular cell adhesion molecule 1; sICAM-1, intercellular adhesion molecule 1; PAPP-A, pregnancy-associated plasma protein-A; hCG, human chorionic gonadotropin; PlGF, placental growth factor; MAP, mean arterial pressure; TNF-R1, soluble receptor-1 of tumor necrosis factor-α; GH, gestational hypertension; Ang-2, angiopoietin-2; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor; TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothyronine; IGF-1, insulin-like growth factor-1; NT, nuchal translucency; ADAM12, A Disintegrin and Metalloprotease 12; IGFBP-1, insulin-like growth factor-binding protein1; hPGH, human placental growth hormone; 3D, three dimensional; 25(OH)D, serum vitamin D; IGFBP-3, insulin-like growth factor-binding protein-3; early PE, PE necessitating delivery o 34 weeks.
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preeclampsia and SGA (at Z34 weeks, Table 2) are weak but still significant because this group still includes preterm gestations (34–37 weeks). Thus, one could argue that the predictions for term preeclampsia and SGA (at Z37 weeks) may have not been statistically or clinically significant. This observation provides further support that ischemic placental disease has its origin in the first trimester and it is characterized by the need for preterm delivery. Another observation that further supports the above concept is that low-dose aspirin administered in high-risk patients prior to 16 weeks appears to exert its beneficial overall effect on preeclampsia (50% reduction) by the dramatic reduction (80–90%) in the risk of early severe preeclampsia (o34 weeks).11 Data regarding the prediction of the third component of ischemic placental disease (i.e., placental abruption) by first trimester screening are scarce. However, we located one study that showed that placental abruption could be predicted by first trimester screening.45 This was a prospective study of 878 consecutive women at 11–14 weeks using the same predictors as the Nicolaides’ group (maternal demographic characteristics, UtA PI, and maternal serum PAPP-A). The authors found that increased UtA PI, low PAPP-A, and maternal history of preeclampsia/hypertension were predictive of preeclampsia and SGA. In addition, they found that increased UtA PI detected 43% of the cases that later developed placental abruption. Increased UtA PI was the only independent factor in the prediction of placental abruption with an odds ratio of 8.5 (95% confidence interval 2.8–25.9). From the prevention point of view, the most recent metaanalysis showed that low-dose aspirin in high-risk patients, if initiated, prior to 16 weeks is associated with a 45% reduction in placental abruption; however, this reduction was not statistically significant most likely because of small numbers.11 Unfortunately, the first trimester screening studies for predicting preterm preeclampsia and/or SGA (Table 2) have not included placental abruption as an “outcomes of interest” despite the strong likelihood of a common pathophysiology among preterm preeclampsia, SGA, and placental abruption and its strong link to prematurity.5 It is possible that the current first trimester prediction algorithms may detect some of the cases with placental abruption since placental abruption frequently coexists with early preeclampsia and SGA. However, some cases with placental abruption will be missed by the current algorithms. For instance, patients with hypertension with no proteinuria and with birth weight between 5% and 10%, i.e., who develop placental abruption at 28 weeks, resulting in a preterm delivery, will be missed. In our view, future prediction algorithms should be modified to predict placental abruption, so that the detection rate of the entire spectrum of ischemic placental disease is improved.
Technique of UtA PI measurement A prerequisite for accurate prediction of ischemic placental disease, based on first trimester algorithms, is the appropriate technique and measurement of UtA PI. In the studies, where the final algorithms were constructed appropriately, the UtA PI was measured by Doppler ultrasound using the
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following technique.15 A sagittal image of the uterus and the cervical canal was first obtained abdominally and the internal cervical os was identified. Then, the transducer was tilted from side to side and color flow mapping was applied to visualize the uterine arteries aliasing alongside of the cervix and the uterus. The flow velocity waveforms were obtained from the ascending branch of the uterine artery as close to the internal os as possible. After obtaining three similar consecutive waveforms, the PI was measured and the mean PI of the left and the right arteries was determined as the final UtA PI.15 Subsequent research found that UtA PI measurements at the level of the internal cervical os are possible to be obtained in a greater proportion of women, as compared to the level of uterine artery crossover with the external iliac vessels, and correlate better with second trimester UtA PI measurements.46 This finding may be important in future combined (first and second trimester) prediction models of ischemic placental disease.
Conclusion Currently, the models for predicting ischemic placental disease (preeclampsia and SGA) use a combination of maternal history/characteristics, UtA PI, mean arterial pressure, maternal serum pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF).42,44 The reasonably low false-positive rates (5–10%) are associated with remarkably high detection rates of severe preeclampsia and SGA prior to 34 weeks of 95% and 55%, respectively. This degree of prediction is ideal for conducting a large scale, multicenter, randomized controlled trial of early prediction and prevention of ischemic placental disease by administration of lowdose aspirin to those identified as high risk by first trimester screening between 11 and 13 weeks gestation. However, future studies in our view should also focus in the detection of placental abruption, in addition to early preeclampsia and SGA, in order to increase the detection rate of ischemic placental disease, so that the impact of prevention strategies can be larger. Finally, the new definition of preeclampsia should be applied in future studies that do not require the presence of proteinuria.47
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