Background
Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation.
Objective
We sought to determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate.
Study Design
A cross-sectional study of 123 placentas (19-42 weeks’ gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1. Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with Fisher exact test and Wilcoxon rank sum test using a Bonferroni-adjusted level of significance (.025).
Results
We found that 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the intercellular adhesion molecule-1 activation marker ( P < .001). A significant correlation ( R 2 = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast intercellular adhesion molecule-1 ( P < .001) in activated placentas. Lesions of atherosis were found in 31.9% (30/94) of placentas with complete and/or partial failure of physiologic transformation of spiral arteries that were intercellular adhesion molecule-1-positive, in none of the 14 placentas with failure of physiologic transformation that were intercellular adhesion molecule-1-negative, and in none of the 15 placentas with complete spiral artery physiologic transformation without failure ( P = .001). All placentas (30/30, 100%) with atherosis were identified in placentas having concomitant spiral artery endothelial and interstitial extravillous trophoblast activation.
Conclusion
Failure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic, and other abnormal pregnancies.
Introduction
Remodeling of the spiral arteries during gestation leads to substantial dilation of these vessels, which at the point of discharge into the intervillous space attain a luminal diameter 10 times larger than myometrial spiral arteries. This remodeling is associated with a 10-fold increase in blood supply to the fetoplacental unit in the third trimester compared to the nonpregnant uterus. Spiral artery remodeling, which increases total uteroplacental blood flow from a baseline value of 20-50 mL/min to 450-800 mL/min in singleton pregnancies (as measured utilizing the diffusion equilibrium principle [most often nitrous oxide] or electromagnetic flow probes placed directly on the uterine artery), is considered key to accommodate the increased blood flow to the uteroplacental circulation in the third trimester. Initially, physiologic transformation of the spiral arteries includes endothelial vacuolation and smooth muscle swelling, and it has been attributed in part to immune processes within the decidua. Subsequently, trophoblasts invading the spiral arteries destroy the smooth muscle in the media, which is replaced by fibrinoid material.
Physiologic transformation of the spiral arteries is a normal process with the degree of transformation being greater in the center of the placental bed than in the periphery. Full conversion of both decidual and myometrial segments of the approximately 100-120 spiral arteries normally found in the placental bed into large, remodeled uteroplacental vessels is key for normal deep placentation. Such deep placentation can be defective when remodeling of the junctional zone of the spiral arteries (arterial segments in the inner third of the myometrium and overlying endometrium) is absent or incomplete. Insufficient physiologic transformation of the spiral arteries is associated with adverse pregnancy outcomes, including second-trimester spontaneous abortion, fetal death, abruptio placentae, preeclampsia, small for gestational age, preterm labor, preterm prelabor rupture of membranes, and maternal autoimmune diseases.
Failure of physiologic transformation of spiral arteries is seen in deep placentation disorders such as preeclampsia with or without intrauterine growth restriction, intrauterine growth restriction without preeclampsia, preterm labor and preterm prelabor rupture of membranes, abruptio placentae, and second-trimester abortion. This failure is characterized by the absence of spiral artery trophoblastic invasion and remodeling. Currently this condition can be identified only in placental bed biopsies because these specimens are required to demonstrate a defect of myometrial transformation. However, physiologic transformation begins in the decidual segment of the spiral arteries during the first wave of trophoblast invasion. Therefore, failure of transformation of the spiral arteries in the decidual segment represents a more severe disorder than lack of transformation of the myometrial segment only. Abnormal transformation of the decidual portion of the spiral arteries can be detected by examining the placental basal plate. This has practical implications because the basal plate of the placenta is available for examination in all cases while a placental bed biopsy requires a specialized procedure generally performed during a cesarean delivery. Immunohistochemistry allows in-depth examination of the vessel wall through antigen detection of its different cellular components, which reduces the subjectivity of using only conventional light microscopy for vessel recognition in the placental basal plate.
Arteries with failure of physiologic transformation of the spiral arteries (but not those with physiologic transformation) are prone to develop atherosis. Intravascular inflammation and abnormal lipid metabolism can interfere with endothelial cell function, and predispose to atherosclerosis in nonpregnant subjects. Women with preeclampsia, the prototypic obstetrical complication characterized by failure of physiologic transformation of the spiral arteries, have evidence of intravascular inflammation, as well as changes in lipid metabolism, such as increased concentrations of triglycerides, and low-density lipoprotein, and decreases in low-density lipoprotein particle size and high-density lipoprotein. Macrophage infiltration of the intima and media is identified in both atherosis and the lesions found in transplant vasculopathy. Therefore, there are striking parallels between preeclampsia and atherosclerosis, as well as the lesions of atherosis and those observed in patients with ischemic heart disease.
Endothelial activation, identified by the expression of intercellular adhesion molecule (ICAM)-1, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Activated endothelial cells with overexpression of cell-surface ICAM-1 are more resistant to trophoblast displacement than nonactivated endothelial cells, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes associated with failure of physiologic transformation of the spiral arteries.
The purpose of this study was to determine whether there was an association among: (1) failure of physiologic transformation of the spiral arteries in the placental basal plate; (2) endothelial and trophoblast activation; and (3) the presence of atherosis.
Materials and Methods
Study design
A cross-sectional study was performed on 123 placentas (19-42 weeks’ gestation) collected at Hutzel Women’s Hospital, the Detroit Medical Center, under protocols approved by the Wayne State University and Eunice Kennedy Shriver National Institute of Child Health and Human Development institutional review boards, and the analyses were completed by 2015 at CBL Partners for Life, Indianapolis, IN, and the California Medical Innovations Institute, San Diego, CA. Placentas were obtained from: normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10). Normal pregnancies were defined as those without medical/obstetrical complications and with birthweights adequate for gestational age (>10th percentile) at term (≥37 weeks of gestation). Seventeen babies were delivered vaginally and 5 by cesarean (none of the mothers or babies were infected). Preeclampsia was defined as new-onset hypertension >20 weeks of gestation (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on at least 2 occasions, 4 hours to 1 week apart), edema, and proteinuria (≥300 mg in a 24-hour urine collection or 1 dipstick measurement of ≥2+). Infants with fetal growth restriction were considered small for gestational age if they were <10th percentile for weight for their gestational age. Pregnancies were preterm when the gestational age was <37 weeks. Birthweight percentiles were calculated using nationwide US natality data. Placentas from mothers with obesity (body mass index ≥30), known to be associated with a proinflammatory state, were not included in the study. All women provided written informed consent prior to the collection of placenta samples. The institutional review board of the sponsoring institution approved collection and use of samples for research purposes.
Definitions
The terms used in this study follow accepted nomenclature. Briefly, the placental bed is part of the decidua and adjoining myometrium that underlie the placenta and provide blood supply to the intervillous space. Extravillous trophoblasts are all trophoblasts (fetal-derived cells) located outside the placental villi. Interstitial extravillous trophoblasts are placental bed trophoblasts that have entered the decidual stroma but have not yet invaded the spiral artery walls. Extravillous trophoblasts invading spiral artery walls and replacing smooth muscle and endothelium are termed “intraarterial trophoblasts.” Physiologic transformation of the spiral arteries was defined as the complete trophoblastic invasion of the spiral arteries, partial failure of physiologic transformation of the spiral arteries as the incomplete trophoblastic invasion of the arterial muscular wall, and failure of physiologic transformation of the spiral arteries as the complete absence of trophoblastic replacement of the arterial wall.
Placental specimens and immunohistochemistry
Placental samples (10 × 10 × 5 mm) from placental septa near the center of the basal plate (3.5 [SD 0.6] per placenta) of 123 placentas obtained immediately after delivery were embedded in Tissue-Tek optimum cutting temperature compound (Miles, Elkhart, IN) and snap-frozen in liquid nitrogen. Seven serial sections (a total of 7 slides) from each basal plate sample were used for the evaluation of the single-, double-, and triple-antibody techniques performed. Sample slides having basal plate spiral arteries defined immunohistochemically were included in the study, and samples without any spiral artery were excluded. A triple-antibody technique with antibodies to α-smooth muscle actin to identify vascular smooth muscle cells, cytokeratin to identify extravillous trophoblasts and intraarterial trophoblasts, and von Willebrand factor to identify endothelial cells was used to detect complete or partial failure of physiologic transformation and physiologic transformation of the spiral arteries (median of 4 [minimum: 1; maximum: 9] vessels per placental basal plate). A triple-antibody immunohistochemistry with α-actin, cytokeratin, and ICAM-1 identified interstitial extravillous trophoblast and spiral artery endothelial cell activation.
Normal term placentas had cytokeratin-positive, α-actin-negative, and von Willebrand factor–positive uteroplacental arteries. Failure of physiologic transformation of the spiral arteries was characterized by cytokeratin-negative, α-actin-positive, and von Willebrand factor–positive spiral arteries. Spiral artery atherosis was cytokeratin-negative, α-actin-positive, and von Willebrand factor–positive and showed the presence of CD68 + macrophages in the intimal area of the spiral arteries. Serial sections (5 μm each) from each placental block were obtained for light microscopy (hematoxylin-eosin) and single, double, and triple immunohistochemistry. The use of immunohistochemistry allowed a clear identification of the spiral arteries in all slides from the different serial sections demonstrating 100% reproducibility. The deposition of neutral triglycerides and other lipids were examined using oil-red O to confirm atherosis. Individuals examining microscopic sections (C.A.L., H.L.D.) were blinded to clinical diagnosis.
Statistical analysis
Continuous measures were summarized using median, minimum, and maximum, and categorical measures were summarized as frequency (percent). Demographic variables were compared using Fisher exact (for discrete measures) and Kruskal-Wallis (for continuous measures) tests; these tests compared values for atherosis groups (atherosis vs no atherosis). Comparison of continuous measures for groups (atherosis vs no atherosis) were evaluated using the Wilcoxon rank sum test. We used analysis of variance to compare means from multiple groups. A Bonferroni-adjusted level of significance of <.025 was used to establish statistical significance for subsequent pairwise comparisons. Statistical analysis was performed by one of the authors (J.W.H.).
Materials and Methods
Study design
A cross-sectional study was performed on 123 placentas (19-42 weeks’ gestation) collected at Hutzel Women’s Hospital, the Detroit Medical Center, under protocols approved by the Wayne State University and Eunice Kennedy Shriver National Institute of Child Health and Human Development institutional review boards, and the analyses were completed by 2015 at CBL Partners for Life, Indianapolis, IN, and the California Medical Innovations Institute, San Diego, CA. Placentas were obtained from: normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10). Normal pregnancies were defined as those without medical/obstetrical complications and with birthweights adequate for gestational age (>10th percentile) at term (≥37 weeks of gestation). Seventeen babies were delivered vaginally and 5 by cesarean (none of the mothers or babies were infected). Preeclampsia was defined as new-onset hypertension >20 weeks of gestation (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on at least 2 occasions, 4 hours to 1 week apart), edema, and proteinuria (≥300 mg in a 24-hour urine collection or 1 dipstick measurement of ≥2+). Infants with fetal growth restriction were considered small for gestational age if they were <10th percentile for weight for their gestational age. Pregnancies were preterm when the gestational age was <37 weeks. Birthweight percentiles were calculated using nationwide US natality data. Placentas from mothers with obesity (body mass index ≥30), known to be associated with a proinflammatory state, were not included in the study. All women provided written informed consent prior to the collection of placenta samples. The institutional review board of the sponsoring institution approved collection and use of samples for research purposes.
Definitions
The terms used in this study follow accepted nomenclature. Briefly, the placental bed is part of the decidua and adjoining myometrium that underlie the placenta and provide blood supply to the intervillous space. Extravillous trophoblasts are all trophoblasts (fetal-derived cells) located outside the placental villi. Interstitial extravillous trophoblasts are placental bed trophoblasts that have entered the decidual stroma but have not yet invaded the spiral artery walls. Extravillous trophoblasts invading spiral artery walls and replacing smooth muscle and endothelium are termed “intraarterial trophoblasts.” Physiologic transformation of the spiral arteries was defined as the complete trophoblastic invasion of the spiral arteries, partial failure of physiologic transformation of the spiral arteries as the incomplete trophoblastic invasion of the arterial muscular wall, and failure of physiologic transformation of the spiral arteries as the complete absence of trophoblastic replacement of the arterial wall.
Placental specimens and immunohistochemistry
Placental samples (10 × 10 × 5 mm) from placental septa near the center of the basal plate (3.5 [SD 0.6] per placenta) of 123 placentas obtained immediately after delivery were embedded in Tissue-Tek optimum cutting temperature compound (Miles, Elkhart, IN) and snap-frozen in liquid nitrogen. Seven serial sections (a total of 7 slides) from each basal plate sample were used for the evaluation of the single-, double-, and triple-antibody techniques performed. Sample slides having basal plate spiral arteries defined immunohistochemically were included in the study, and samples without any spiral artery were excluded. A triple-antibody technique with antibodies to α-smooth muscle actin to identify vascular smooth muscle cells, cytokeratin to identify extravillous trophoblasts and intraarterial trophoblasts, and von Willebrand factor to identify endothelial cells was used to detect complete or partial failure of physiologic transformation and physiologic transformation of the spiral arteries (median of 4 [minimum: 1; maximum: 9] vessels per placental basal plate). A triple-antibody immunohistochemistry with α-actin, cytokeratin, and ICAM-1 identified interstitial extravillous trophoblast and spiral artery endothelial cell activation.
Normal term placentas had cytokeratin-positive, α-actin-negative, and von Willebrand factor–positive uteroplacental arteries. Failure of physiologic transformation of the spiral arteries was characterized by cytokeratin-negative, α-actin-positive, and von Willebrand factor–positive spiral arteries. Spiral artery atherosis was cytokeratin-negative, α-actin-positive, and von Willebrand factor–positive and showed the presence of CD68 + macrophages in the intimal area of the spiral arteries. Serial sections (5 μm each) from each placental block were obtained for light microscopy (hematoxylin-eosin) and single, double, and triple immunohistochemistry. The use of immunohistochemistry allowed a clear identification of the spiral arteries in all slides from the different serial sections demonstrating 100% reproducibility. The deposition of neutral triglycerides and other lipids were examined using oil-red O to confirm atherosis. Individuals examining microscopic sections (C.A.L., H.L.D.) were blinded to clinical diagnosis.
Statistical analysis
Continuous measures were summarized using median, minimum, and maximum, and categorical measures were summarized as frequency (percent). Demographic variables were compared using Fisher exact (for discrete measures) and Kruskal-Wallis (for continuous measures) tests; these tests compared values for atherosis groups (atherosis vs no atherosis). Comparison of continuous measures for groups (atherosis vs no atherosis) were evaluated using the Wilcoxon rank sum test. We used analysis of variance to compare means from multiple groups. A Bonferroni-adjusted level of significance of <.025 was used to establish statistical significance for subsequent pairwise comparisons. Statistical analysis was performed by one of the authors (J.W.H.).
Results
The various statuses of the spiral artery physiologic transformation in the placental basal plate were defined immunohistochemically as follows: physiologic transformation of the spiral arteries had complete muscular wall replacement by cytokeratin-positive trophoblasts that surrounded the endothelial lining of the vessels ( Figure 1 , A); spiral arteries with failure of physiologic transformation and atherosis maintained an actin-positive muscular wall, and cytokeratin-positive trophoblastic cells (interstitial extravillous trophoblasts) surrounded but did not invade the arterial walls ( Figure 1 , B). Spiral arteries with partial failure of physiologic transformation had a combination of smooth muscle cells and intraarterial trophoblasts in the arterial walls ( Figure 1 , C). The immunohistochemical characteristics of the different statuses of spiral artery physiologic transformation and atherosis are summarized in Table 1 .
| Immunohistochemical characteristics | Complete physiologic transformation | Partial physiologic transformation | Failure of physiologic transformation | Atherosis |
|---|---|---|---|---|
| Cytokeratin | Positive | Positive/negative | Negative | Negative |
| Smooth muscle α-actin | Negative | Positive/negative | Positive | Positive |
| Von Willebrand factor | Positive | Positive | Positive | Positive |
| ICAM-1, endothelial | Negative | Positive/negative | Positive | Positive |
| ICAM-1, interstitial extravillous trophoblast | Negative | Positive/negative | Positive | Positive |
Of the 123 placentas studied, 108 had spiral arteries with failure of physiologic transformation ( Table 2 ): 79 had failure of physiologic transformation in all spiral arteries examined and 29 had both failure of physiologic transformation and physiologic transformation ( Table 2 ). Fifteen placentas had complete spiral artery physiologic transformation without any failure of physiologic transformation ( Table 2 ). Spiral arteries with partial failure of physiologic transformation (n = 36) had α-actin-positive cells in part of the arterial wall and cytokeratin-positive trophoblastic cells in the rest of the wall ( Table 1 and Figure 1 , C). Partial failure of physiologic transformation of the spiral arteries in the basal plate was associated with failure of physiologic transformation (n = 22), physiologic transformation (n = 8), or both (n = 6).
| Characteristics | Physiologic transformation without failure of physiologic transformation n = 15 | Failure of physiologic transformation, n = 108 a | P value b | ||
|---|---|---|---|---|---|
| Failure of physiologic transformation with or without physiologic transformation n = 108 | Failure of physiologic transformation with physiologic transformation n = 29 | Failure of physiologic transformation without physiologic transformation n = 79 | |||
| Gestational age at delivery, wk c | 39.5 (26.1, 41.6) | 31.2 (18.5, 41.2) | 31.3 (18.5, 40.4) | 31.2 (19.2, 41.2) | <.001 |
| Birthweight, percentile c | 62.5th (7.5th, 99th) | 25.5th (1st, 99th) | 47th (1st, 99th) | 17.5th (1st, 99th) | <.001 |
| Abnormal pregnancies, n = 101 d | 1 (1%) | 100 (99%) | 22 (21.8%) | 78 (77.2%) | <.001 |
| Preeclampsia, n = 27 | 0 (0%) | 27 (100%) | 5 (18.5%) | 22 (81.5%) | |
| Small for gestational age, n = 10 | 0 (0%) | 10 (100%) | 1 (10%) | 9 (90%) | |
| Fetal death, n = 15 | 0 (0%) | 15 (100%) | 3 (20%) | 12 (80%) | |
| Preterm labor, n = 23 | 0 (0%) | 23 (100%) | 7 (30.4%) | 16 (69.6%) | |
| Preterm prelabor rupture of membranes, n = 26 | 1 (3.8%) | 25 (96.2%) | 5 (19.2%) | 20 (76.9%) | |
| Normal pregnancies, n = 22 | 14 (63.6%) | 8 (36.4%) | 7 (31.8%) | 1 (4.5%) | <.001 |
| Placentas ICAM-1-positive, n = 94 e | 0 (0%) | 94 (100%) | 21 (22.3%) | 73 (77.7%) | <.001 |
| Abnormal pregnancies, n = 92 | 0 (0%) | 92 (100%) | 20 (21.7%) | 72 (78.3%) | |
| Preeclampsia, n = 23 | 0 (0%) | 23 (100%) | 5 (21.7%) | 18 (78.3%) | |
| Small for gestational age, n = 9 | 0 (0%) | 9 (100%) | 1 (11.1%) | 8 (88.9%) | |
| Fetal death, n = 14 | 0 (0%) | 14 (100%) | 3 (21.4%) | 11 (78.6%) | |
| Preterm labor, n = 23 | 0 (0%) | 23 (100%) | 7 (30.4%) | 16 (69.6%) | |
| Preterm prelabor rupture of membranes, n = 23 | 0 (0%) | 23 (100%) | 4 (17.4%) | 19 (82.6%) | |
| Normal pregnancies, n = 2 | 0 (0%) | 2 (100%) | 1 (50%) | 1 (50%) | |
| Placentas with atherosis, n = 30 | 0 (0%) | 30 (100%) | 6 (20%) | 24 (80%) | <.001 |
| Abnormal pregnancies, n = 29 | 0 (0%) | 29 (100%) | 6 (20.7%) | 23 (79.3%) | |
| Preeclampsia, n = 7 | 0 (0%) | 7 (100%) | 2 (28.6%) | 5 (71.4%) | |
| Small for gestational age, n = 3 | 0 (0%) | 3 (100%) | 0 (0%) | 3 (100%) | |
| Fetal death, n = 4 | 0 (0%) | 4 (100%) | 0 (0%) | 4 (100%) | |
| Preterm labor, n = 6 | 0 (0%) | 6 (100%) | 2 (33.3%) | 4 (66.7%) | |
| Preterm prelabor rupture of membranes, n = 9 | 0 (0%) | 9 (100%) | 2 (22.2%) | 7 (77.8%) | |
| Normal pregnancies, n = 1 | 0 (0%) | 1 (100%) | 0 (0%) | 1 (100%) | |
a Failure of physiologic transformation includes complete and partial failure
b P values compare listed characteristic for group of physiologic transformation (n = 15) and group of failure of physiologic transformation (n = 108)
c Values are expressed as median (minimum, maximum) according to nationwide US natality data
d Values in both columns are expressed as number (percentage) of each clinical/immunopathological group
e ICAM-1-positive placentas includes endothelial and/or extravillous trophoblast reactivity.
Of the 108 placentas with failure of physiologic transformation of the spiral arteries in the basal plate, 100 (100/101, 99%) were from women with complicated pregnancies, and 8 (8/22, 36.4%) from normal pregnancies ( Table 2 ). Of the 15 placentas with complete physiologic transformation of the spiral arteries and no failure, however, only 1 (1/101, 1%) was from a woman with an abnormal pregnancy, and 14 (14/22, 63.6%) were from women with normal pregnancies ( Table 2 ). Placentas with only physiologic transformation of the spiral arteries ( Table 2 ) were found mostly in normal pregnancies, and placentas having only failure of physiologic transformation of the spiral arteries ( Table 2 ) were seen predominantly in abnormal pregnancies with preeclampsia, small for gestational age, intrauterine fetal death, preterm labor, and preterm prelabor rupture of membranes ( Table 2 ).
Of placentas from abnormal pregnancies, 99% had spiral arteries with failure of physiologic transformation in the basal plate and only 1% of them had all spiral arteries with physiologic transformation ( P < .001) ( Table 2 ). Contrarily, most placentas (63.6%) from normal pregnancies had all spiral arteries with physiologic transformation, and a smaller percentage of them (36.4%) had spiral arteries with failure of physiologic transformation ( P < .001). All groups of abnormal pregnancies had a similarly high proportion of placentas with failure of physiologic transformation in all spiral arteries, which was highest in pregnancies with small for gestational age (9/10, 90%), preeclampsia (22/27, 81.5%), and intrauterine fetal death (12/15, 80%), and lowest in preterm labor (16/23, 69.6%) ( Table 2 ). The combination of both failure of physiologic transformation and physiologic transformation of the spiral arteries was more frequently identified in preterm labor. Physiologic transformation of the spiral arteries without any failure of physiologic transformation was found predominantly in normal pregnancies ( Table 2 ). We performed quantitative studies and evaluated the percentage of arteries with different degrees of physiologic transformation in the basal plate of the placentas of the different groups and subgroups studied ( Table 3 ). The percentage of arteries with physiologic transformation and failure of physiologic transformation was significantly different between groups, but no differences were found in the percentage of arteries with partial failure of physiologic transformation ( Table 3 ). The highest percentage of arteries with failure of physiologic transformation was found in placentas from fetal death and preeclampsia; the highest percentage of partial failure of physiologic transformation was found in small-for-gestational-age babies; the highest percentage of arteries with physiologic transformation was found in normal pregnancies and preterm labor; and the lowest percentage of arteries with physiologic transformation was found in small-for-gestational-age placentas ( Table 3 ).
| Characteristics | Abnormal pregnancies, n = 101 | Normal pregnancies, n = 22 | P value a | |||||
|---|---|---|---|---|---|---|---|---|
| Total, n = 101 | Preeclampsia, n = 27 | Small for gestational age, n = 10 | Fetal death, n = 15 | Preterm labor, n = 23 | Preterm prelabor rupture of membranes, n = 26 | |||
| Percent arteries with physiologic transformation | 8.1 ± 18.9 | 7.7 ± 19.4 | 1.4 ± 4.5 | 5.1 ± 11.9 | 11.8 ± 20.4 | 9.6 ± 23.3 | 81.7 ± 29.7 | <.0001 |
| Percent arteries with partial failure of physiologic transformation | 8.3 ± 15.1 | 5.3 ± 10.5 | 15.5 ± 22.8 | 5.6 ± 10.2 | 10.4 ± 17.2 | 8.5 ± 16 | 12.4 ± 21.8 | .30 |
| Percent arteries with failure of physiologic transformation | 83.5 ± 25.7 | 87.0 ± 23 | 83.1 ± 25.9 | 89.3 ± 16.5 | 77.8 ± 33.9 | 81.9 ± 25 | 6.0 ± 17.4 | <.0001 |
| Percent arteries with endothelial ICAM-1 | 81.8 ± 35.1 | 77.5 ± 38.1 | 88.6 ± 31.4 | 84.4 ± 34.8 | 81.2 ± 34.1 | 82.7 ± 36.4 | 4.5 ± 21.3 | <.0001 |
| Percent arteries with atherosis | 10.4 ± 21.7 | 10.7 ± 19.9 | 18.3 ± 33.7 | 16.0 ± 30.5 | 4.3 ± 7.7 | 9.2 ± 20.4 | 2.3 ± 10.7 | <.0001 |
a P values are for comparison of total abnormal results (n = 101) vs normal results (n = 22).
Of the 94 placentas with ICAM-1 expression in arterial endothelium and/or extravillous trophoblasts, all (94/94, 100%) were associated with failure of physiologic transformation ( Figure 1 , E, and Table 2 ), and none with physiologic transformation without failure ( Figure 1 , D, and Table 2 ) ( P < .001). A significant correlation ( R 2 = 0.84) was found between interstitial extravillous trophoblasts and spiral artery endothelial ICAM-1 expression ( P < .001). Spiral arteries with partial failure of physiologic transformation also showed endothelial ICAM-1 expression ( Figure 1 , F). A high proportion of spiral arteries with endothelial and/or extravillous trophoblasts that were ICAM-1-positive ( Table 2 ) was observed in complicated pregnancies. The combination of both failure of physiologic transformation of the spiral arteries and physiologic transformation was associated with a lower proportion of endothelial and/or extravillous trophoblasts that were ICAM-1-positive ( Table 2 ). The percentage of arteries with endothelial ICAM-1 was significantly different between groups, being higher in small for gestational age and lower in normal pregnancies ( Table 3 ). Interestingly, spiral arteries with physiologic transformation had fewer CD68 + macrophages surrounding extravillous trophoblasts ( Figure 2 , A) and spiral artery endothelium ( Figure 2 , C) than arteries with failure of physiologic transformation, which had increased number of CD68 + macrophages around smooth muscle cells of uninvaded arteries ( Figure 2 , B and D), suggesting that increased inflammation is associated with arterial endothelial and/or extravillous trophoblast activation.
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