Abstract
Objective
To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome.
Methods
This retrospective cohort study included placental samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion.
Results
(1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) maternal and fetal vascular lesions of malperfusion were detected in 35.7% and 19.7%, respectively. Two or more lesions with maternal or fetal vascular features consistent with malperfusion (high-burden lesions) were present in 7.4% and 0.7%, respectively.
Conclusion
Most placentas had lesions consistent with inflammatory or vascular lesions, but severe and/or high-burden lesions were infrequent. Mild placental lesions may be interpreted either as acute changes associated with parturition or as representative of a subclinical pathological process (intra-amniotic infection or sterile intra-amniotic inflammation) that did not affect the clinical course of pregnancy.
Introduction
In the evaluation of pregnancy complications, neglect of the placenta in developed countries has become a thing of the past. In 1997, the American College of Pathologists published guidelines for examining placentas in high-risk pregnancies [1]; subsequently, the Perinatal Section of the Society for Pediatric Pathology in the United States published a series of reports led by Redline et al. [2], [3], [4], [5], [6], [7], [8], [9] about the classification and reproducibility of the diagnosis of placental lesions. Such lesions were broadly categorized as those consistent with (1) amniotic fluid infection [2], [9], (2) maternal vascular underperfusion [2], [8] and (3) fetal vascular underperfusion [2], [7], to which was added a fourth category – chronic placental inflammation [5], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. During a workshop organized in Amsterdam in 2014, the recommendations for sampling and the definitions of placental lesions were updated [21].
However, to date, there is very little information on how frequently histologic inflammatory or vascular lesions are found in placentas of patients with normal pregnancy outcomes [22], [23], [24], and this information is required to interpret the significance of placental histopathologic findings patients who have obstetrical complications. Moreover, this information may also be useful in counseling patients about the outcome of the index pregnancy [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], the prognosis for subsequent pregnancies [41], [42], [43], [44], [45], [46], [47], and in a medicolegal context [48], [49], [50], [51], [52], [53], [54], [55], [56]. Often, the placenta has been considered a “witness” in litigation [57].
Therefore, the objective of this study was to determine the frequency of pathological lesions that can be detected histologically in the placentas from a large cohort of women who had a singleton pregnancy with no obstetrical complications and who delivered appropriate-for-gestational-age neonates at term without perinatal complications.
Methods
Study design
This report is based on a retrospective analysis of the placental histological lesions diagnosed by pediatric pathologists experienced in the assessment of placental lesions (CJK, JSK, YMK, SMJ and FQ). Subjects were recruited into a cohort study between January 11, 2006, and June 11, 2014, had no medical or obstetrical complications and delivered a singleton, term (37–42 weeks) neonate with a 5-min Apgar score ≥7 and a birthweight between the 10th and 90th percentiles of a United States’ reference population [58]. We excluded from the study (1) women with chronic diseases (e.g. chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease and coagulopathies) and (2) those with pregnancy complications, such as multifetal gestation, preeclampsia, eclampsia, clinical placental abruption, preterm labor, preterm premature rupture of fetal membranes, gestational hypertension, gestational diabetes, clinical chorioamnionitis, intrapartum fever, fetal malformations, chromosomal anomalies, and HELLP syndrome (abbreviated for its indicators: hemolysis, elevated liver enzymes and low platelet count).
Patients provided written informed consent before the collection of placentas. The collection and use of clinical data and specimens were approved by the Human Investigation Committee of Wayne State University (WSU) and the Institutional Review Board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Pathologic examination of the placentas was undertaken for research purposes.
Placental pathology examination
Placentas were collected in the Labor and Delivery Unit or Operating Room at Hutzel Women’s Hospital of the Detroit Medical Center (DMC) and transferred to the Perinatology Research Branch (PRB) laboratory. For all placentas, the maternal surface (basal plate), fetal surface (chorionic plate) and umbilical cord were photographed prior to dissection. The gross morphologic description and placental measurements were documented, and the placental weight was recorded before and after the trimming of the chorioamniotic membranes and umbilical cord. Sampling of the placentas was conducted according to protocols of the PRB and the Department of Pathology of the WSU School of Medicine and the DMC.
Samples from the placenta were obtained using two approaches: (1) systematic random sampling at the PRB and (2) targeted sampling in the laboratory of the WSU/DMC Department of Pathology.
Systematic random sampling at the PRB
(1) Sampling of chorioamniotic membranes and the umbilical cord: samples were taken from the extraplacental membranes in the form of membrane rolls (n=3) and the umbilical cord (n=3). The chorioamniotic membrane roll was dissected into a 30-mm piece and placed into a labeled specimen cup containing ~20 mL of 10% formalin. The umbilical cord was bisected at 3 cm from the point of insertion into the chorionic plate, followed by the collection of three samples from the umbilical cord at these locations: (1) the distal end attached to the placenta, (2) the middle portion and (3) the proximal end closest to the fetus.
(2) Sampling of the placental disc: systematic random sampling of the placental disc was performed using a random sequence generator designed for this purpose, known as the PRB DICE software (in-house-developed software program, Detroit, MI, USA) (Supplementary Material and Figures). A minimum of six blocks of the placental disc was obtained using random sampling; then, three of the six blocks were embedded in paraffin and stained with hematoxylin and eosin (H&E), while the remaining three blocks were stored for further research. Additional samples were obtained at the discretion of the pathologist. The placenta was then transferred to the WSU/DMC Department of Pathology where targeted sampling was performed, according to standard clinical protocols [1].
Targeted sampling in the laboratory of the WSU/DMC Department of Pathology
This processing technique entailed taking sections of the selected non-randomized predefined areas from the placenta. A minimum of one section from the membrane roll and two sections of umbilical cord were placed together in one cassette. The sections taken from the villous parenchyma included the entire thickness of the placenta, extending from the chorionic plate (fetal surface) to the basal plate (maternal surface), and both the amnion and the decidua. A thick placenta necessitated bisecting the section to fit the cassette. The margins of the placenta were not sampled as they are often non-representative. Therefore, only appropriate sections from the central region were targeted. For those placentas that appeared grossly normal, a minimum of three full-thickness sections from the central portion of the placenta and three slivers from the basal plate were processed for histologic examination and stained with H&E, whereas for placentas with gross lesions, additional sections were taken at the discretion of the pathologist.
After sampling (both systematic random and targeted), tissues were fixed with 10% neutral buffered formalin (NBF) at a minimum of 1:20 ratio (tissue:NBF) for at least 12 h, but not more than 48 h, before further processing. After an NBF fixation, the samples were trimmed, processed and paraffin-embedded. A 5-μm-thick section was taken from each paraffin block and stained with H&E for microscopic evaluation.
All H&E-stained slides of the chorioamniotic membrane roll, umbilical cord and placental disc (minimum of seven: at least three by systematic random sampling and four by targeted sampling) were examined by pediatric pathologists who are specialists in the assessment of placental lesions (CJK, JSK, YMK, SMJ, FQ). Tables 1 and 2 show the terminology used in this study, which was based mainly on the criteria established by the Perinatal Section of the Society for Pediatric Pathology [2]. Subsequently, the terminology was revised by the Amsterdam Placental Workshop Group Consensus [2], [21] and we also used this classification for the purpose of this study. The grading and staging of chronic chorioamnionitis were scored following the publication of diagnostic criteria by our group [14].
Histopathology of placental inflammatory lesions.
| Histologic lesions |
| I. Acute inflammatory lesions |
| A. Maternal inflammatory response |
| Staging (location of neutrophil infiltration) |
| Stage 1: early acute subchorionitis or chorionitis |
| Stage 2: acute chorioamnionitis |
| Stage 3: necrotizing chorioamnionitis |
| Grading (intensity) |
| Grade 1 (not severe) |
| Grade 2 (severe): subchorionic microabscess |
| B. Fetal inflammatory response |
| Staging (location of neutrophil infiltration) |
| Stage 1: chorionic vasculitis or umbilical phlebitis |
| Stage 2: umbilical arteritis |
| Stage 3: necrotizing funisitis |
| Grading (intensity) |
| Grade 1 (not severe) |
| Grade 2 (severe): intense chorionic and/or umbilical vasculitis |
| II. Chronic inflammatory lesions |
| A. Maternal inflammatory response |
| Chronic deciduitis |
| Lymphocytic (without plasma cells) |
| Lymphoplasmacytic |
| Chronic villitis of unknown etiology |
| Low-grade lesions: <10 contiguous villi in any one focus |
| High-grade lesions: ≥10 contiguous villi in at least one focus |
| Chronic chorioamnionitis |
| Staging (location of lymphocyte infiltration) |
| Stage 1: lymphocytic infiltration limited to the chorionic trophoblast layer |
| Stage 2: lymphocytic infiltration into the chorioamniotic connective tissue |
| Grading (Intensity) |
| Grade 1: <2 foci of inflammation or patchy inflammation |
| Grade 2: diffuse inflammation |
| Chronic histiocytic intervillositis |
| Villitis of infectious origin |
| B. Fetal inflammatory response |
| Eosinophilic T-cell vasculitis |
Placental histopathology of maternal and fetal vascular malperfusion.
| Histologic lesions |
| I. Findings consistent with maternal vascular malperfusion |
| A. Villous changes |
| Villous infarct(s) |
| Increased syncytial knots |
| Villous agglutination |
| Increased intervillous fibrin deposition |
| Distal villous hypoplasia |
| B. Vascular lesions |
| Persistent muscularization of basal plate arteries |
| Mural hypertrophy of decidual arterioles |
| Acute atherosis of basal plate arteries and/or decidual arterioles |
| Spiral artery fibrinoid necrosis |
| Decidual vascular thrombosis |
| Persistence of endovascular trophoblast |
| Retroplacental hemorrhage |
| II. Findings consistent with fetal vascular malperfusion |
| A. Villous changes |
| Early |
| Villous stromal-vascular karyorrhexis |
| Late |
| Hyalinized avascular villi, small foci |
| Hyalinized avascular villi, variable-sized foci |
| Severe |
| Fetal thrombotic vasculopathy |
| B. Vascular lesions |
| Thrombi in large fetal vessels |
| Intimal fibrin deposition, large fetal vessels |
| Fibromuscular sclerosis, intermediate-sized fetal vessels |
Statistical analysis
All data analyses were performed in R [59]. For continuous data, comparisons between the groups were done using the Kruskal-Wallis test without making any distributional assumptions. For categorical data, proportions were compared between groups using exact tests for contingency tables. Generalized linear models were used to examine the associations between covariates, such as ethnicity (African American or others), nulliparity (nulliparous or multiparous), labor (yes or no), gestational age at delivery (continuous variable), duration of membrane rupture (continuous variable) and frequency of histopathologic lesions. Associations among the four major categories of histopathologic lesions (acute inflammatory, chronic inflammatory, maternal vascular malperfusion and fetal vascular malperfusion) were studied by fitting hierarchically nested log linear models for multiway contingency tables. Holm’s adjusted P value of less than 0.05 was considered significant. Prevalence of a placental histopathological lesion is defined as the proportion of mothers with this abnormality. For a categorical covariate, the prevalence ratio is defined as the fold-change in the prevalence between the different categories of the covariate. For a continuous covariate, the prevalence ratio is defined as the fold-change in the prevalence associated with a unit increase in the covariate.
Results
Demographic and clinical characteristics of the study population
The placentas from 944 women were examined. The demographic and clinical characteristics of the study population are shown in Table 3. The majority of subjects were multiparous (66.1%; 624/944), of self-identified African-American origin (81.0%; 764/943) and delivered vaginally (73.8%; 697/944) (Table 3).
Demographic and clinical characteristics of 944 women with a normal singleton pregnancy at term.
| Characteristics | Vaginal delivery | Cesarean delivery with labor | Elective cesarean delivery | P-valuea |
|---|---|---|---|---|
| Maternal age (years) | 23 (20–28) | 24 (20–29) | 28 (23–31) | <0.0001 |
| Nulliparous | 37.3% (260/697) | 54.4% (49/90) | 7% (11/157) | <0.0001 |
| African-American ethnicityb | 82.3% (573/696) | 80% (72/90) | 75.8% (119/157) | 0.16 |
| Tobacco use during pregnancyc | 10.7% (74/694) | 10% (9/90) | 17.9% (28/156) | 0.04 |
| Alcohol use during pregnancyd | 0.7% (5/693) | 0% (0/90) | 1.3% (2/156) | 0.66 |
| History of preterm births | 6.7% (47/697) | 7.8% (7/90) | 8.9% (14/157) | 0.57 |
| Obesitye,f | 24.8% (164/661) | 33.7% (28/83) | 45.8% (65/142) | <0.0001 |
| Gestational age at delivery (weeks) | 39.7 (38.7–40.4) | 40 (38.9–40.9) | 39.1 (39–39.4) | <0.0001 |
| Birth weight (g) | 3300 (3100–3565) | 3330 (3145–3630) | 3430 (3160–3620) | <0.01 |
| Male sex neonatec | 50.3% (349/694) | 59.6% (53/89) | 53.5% (84/157) | 0.23 |
Data are presented as median (interquartile range) or % (n/N).
aThe P-values were derived from the Kruskal-Wallis test for continuous variables and an exact test for 2 by 3 contingency tables in the case of categorical variables.
Due to missing demographic data, the total number of each type of case was bn=943, cn=940, dn=939 and en=886.
fObesity was defined by a pre-pregnancy BMI >30 kg/m2.
Of the 247 women who underwent a cesarean delivery, 63.6% (157/247) had the procedure performed before the onset of labor. Women who underwent cesarean delivery without labor had a statistically significant higher rate of advanced maternal age, multiparity, tobacco use during pregnancy, obesity [body mass index (BMI) >30 kg/m2], lower median gestational age at delivery and higher median birthweight than those in the other study groups (Table 3).
The indications for cesarean delivery were: a previous cesarean section, 64.8% (160/247); non-reassuring fetal heart tracing, 15.4% (38/247); malpresentation, 8.9% (22/247); failure to progress, 8.5% (21/247); failed induction, 0.8% (2/247); suspected macrosomia, 0.8% (2/247); a previous uterine surgical scar, 0.4% (1/247); and maternal request, 0.4% (1/247).
Placental histopathologic findings
The frequency of single and combined histopathologic placental lesions is displayed in Supplementary Table 1. Placental histologic inflammatory or vascular lesions were present in 77.8% (734/944) of the cases. Twenty-two percent (210/944) of the cases had neither inflammatory nor vascular lesions and 16.6% (157/944) of the cases had no placental histopathologic lesions. Figure 1 shows the frequency of the histologic placental lesions.
Distribution of placental lesions in term pregnancies with normal outcome.
The distribution of histopathologic placental lesions in women with normal pregnancies indicates that the majority of cases had multiple lesions (consistent with more than one type of histopathologic lesion). Among women with isolated placental lesions, the most frequent was acute placental inflammation, followed by maternal vascular malperfusion, chronic placental inflammation and fetal vascular malperfusion. Other lesions include: laminar necrosis, decidua capsularis; meconium-laden macrophages in fetal membranes; hemosiderin-laden macrophages in fetal membranes; nucleated red blood cells; massive perivillous fibrin deposition; basal plate myometrial fibers and hypervascularity of chorionic villi.
The frequency of lesions classified as other than inflammatory or vascular was as follows: meconium-laden macrophages in fetal membranes, 13% (122/941); laminar necrosis of the decidua capsularis, 5.5% (52/942); basal plate myometrial fibers, 3.0% (28/942); hemosiderin-laden macrophages in the fetal membranes, 0.3% (3/942); massive perivillous fibrin deposition, 0.2% (2/942); intervillous thrombus, 10.3% (97/942); hypervascularity of the chorionic villi, 3.5% (33/938); and villous edema, 0.1% (1/942). These findings did not alter the classification of inflammatory or vascular lesions.
Acute placental inflammation
The frequency of all acute placental inflammatory lesions was 42.3% (399/944) (Table 4), but severe lesions (defined as stage 3 and/or grade 2 maternal and/or fetal inflammatory responses) were present in only 1.0% (9/944) of the cases. The distribution of acute placental inflammatory lesions according to the mode of delivery is shown in Figure 2.
Frequency of acute inflammatory placental lesions in women with a normal singleton pregnancy at term.
| Histologic lesionsa | % (n/N) |
|---|---|
| Acute inflammatory lesions | 42.3 (399/944) |
| Maternal inflammatory response | 36.1 (341/944) |
| Stage 1: early acute subchorionitis or chorionitis | 23.3 (220/944) |
| Grade 1 | 23.3 (220/944) |
| Grade 2 | 0 (0/944) |
| Stage 2: acute chorioamnionitis | 12.1 (114/944) |
| Grade 1 | 12.1 (114/944) |
| Grade 2 | 0 (0/944) |
| Stage 3: necrotizing chorioamnionitis | 0.7 (7/944) |
| Grade 1 | 0.6 (6/944) |
| Grade 2 | 0.1 (1/944) |
| Fetal inflammatory response | 23.2 (219/944) |
| Stage 1: chorionic vasculitis or umbilical phlebitis | 18.8 (177/944) |
| Grade 1 | 18.6 (176/944) |
| Grade 2 | 0.1 (1/944) |
| Stage 2: umbilical arteritis | 4.3 (41/944) |
| Grade 1 | 4.3 (41/944) |
| Grade 2 | 0 (0/944) |
| Stage 3: necrotizing funisitis | 0.1 (1/944) |
| Grade 1 | 0.1 (1/944) |
| Grade 2 | 0 (0/944) |
aA placenta may have more than one type an acute inflammatory lesion.
The distribution of acute placental inflammatory lesions according to the mode of delivery.
(A) The distribution of lesions consistent with a maternal inflammatory response, according to mode of delivery. (B) The distribution of lesions consistent with a fetal inflammatory response, according to mode of delivery. Red box: vaginal delivery with labor; Yellow box: cesarean delivery with labor; Blue box: elective cesarean delivery.
There were 137 patients with induced labor and 650 patients with spontaneous labor. The frequency of acute maternal inflammatory placental lesions was significantly lower in patients with induced labor than in those with spontaneous labor [induction of labor: 33% (45/137) vs. spontaneous labor 43% (279/650); P=0.003]. However, there was no significant difference in the frequency of acute fetal inflammatory placental lesions between the two groups [induction of labor: 21.2% (29/137) vs. spontaneous labor: 26.6% (175/650); P=0.19].
The rate of acute placental inflammation was significantly higher in women who underwent labor than in those who delivered without labor: 46.9% (369/787) vs. 19.1% (30/157), P<0.0001. Among women with labor, African-American ethnicity, nulliparity and duration of membrane rupture were independently associated with an increased frequency of acute placental histologic lesions [African American vs. other: prevalence ratio=1.3, P=0.02; nulliparity vs. multiparity: prevalence ratio=1.3, P<0.01 and a 2-h duration of membrane rupture: prevalence ratio=1.02, P=0.01].
Maternal inflammatory response
The frequency of acute maternal inflammatory lesions (n=341) according to grading and staging was as follows: (1) stage 1 (early acute subchorionitis/chorionitis) in 64.5% (220/341) of the cases; (2) stage 2 (acute chorioamnionitis) in 33.4% (114/341) of the cases; and (3) stage 3 (necrotizing chorioamnionitis) and/or grade 2 maternal acute placental inflammatory lesions in 2.1% (7/341) of the cases; of note, these lesions were only observed in patients who delivered vaginally (Table 4). A maternal inflammatory response was associated with the presence of labor (P<0.0001), African-American ethnicity (P=0.02), gestational age (P<0.0001) and nulliparity (P<0.001) (Supplementary Table 2).
Fetal inflammatory response
The frequency of acute fetal inflammatory lesions (n=219) according to grading and staging was as follows: (1) stage 1 (chorionic vasculitis/umbilical phlebitis) in 80.8% (177/219) of the cases; (2) stage 2 (umbilical arteritis) in 18.7% (41/219) of the cases; and (3) stage 3 (necrotizing funisitis) and/or grade 2 acute fetal inflammatory lesions 0.5% (1/219) of the cases (Table 4). A fetal inflammatory response was associated with labor (P<0.001), and gestational age (P=0.0001) adjusting for ethnicity and nulliparity (Supplementary Table 2).
Chronic placental inflammation
The overall frequency of chronic placental inflammation was 29.9% (282/944); however, severe lesions (defined as high-grade lesions of chronic villitis of unknown etiology or grade 2 chronic chorioamnionitis) were present in only 2.4% (23/944) of the cases. Table 5 shows the frequency of the specific lesions. Chronic deciduitis, the most common lesion, was present in 19.3% (182/944) of the cases, followed by chronic villitis of unknown etiology present in 18.5% (175/944) and chronic chorioamnionitis present in 12.7% (120/944) of the cases. Nulliparity was negatively associated with chronic inflammatory lesions (P <0.001), adjusting for the presence of labor, ethnicity and gestational age (Supplementary Table 2).
Frequency of chronic inflammatory placental lesions in women with a normal singleton pregnancy at term.
| Histologic lesionsa | % (n/N) |
|---|---|
| Chronic inflammatory lesions | 29.9 (282/944) |
| Maternal inflammatory response | 29.8 (281/944) |
| Chronic deciduitis | 19.3 (182/944) |
| Lymphocytic (without plasma cells) | 10.3 (97/944) |
| Lymphoplasmacytic | 9.0 (85/944) |
| Chronic villitis of unknown etiology | 18.5 (175/944 ) |
| Low-grade lesions | 13.1 (121/925) |
| High-grade lesions | 1.2 (11/925) |
| Chronic chorioamnionitis | 12.7 (120/944) |
| Stage 1 | 3.8 (36/940) |
| Grade 1 | 3.6 (34/940) |
| Grade 2 | 0.2 (2/940) |
| Stage 2 | 7.7 (72/940) |
| Grade 1 | 6.6 (62/940) |
| Grade 2 | 1.1 (10/940) |
| Chronic histiocytic intervillositis | 0.4 (4/942) |
| Villitis of infectious origin | 0 (0/942) |
| Fetal inflammatory response | |
| Eosinophilic T-cell vasculitis | 0.4 (4/942) |
aA placenta may have more than one type of a chronic placental inflammatory lesion.
Maternal vascular malperfusion
The overall rate of lesions consistent with maternal vascular malperfusion was 35.7% (337/944). The frequency of specific lesion groups was as follows: (1) villous changes in 18.6% (176/944); (2) vascular lesions in 20.6% (194/944); and (3) high-burden lesions (defined as two or more lesions of maternal vascular malperfusion) were present in only 7.4% (70/944) of the cases (Table 6). Obesity was associated with lesions of maternal vascular malperfusion (P=0.02), adjusting for the presence of labor, ethnicity, nulliparity and gestational age (Supplementary Table 2).
Frequency of placental lesions of maternal and fetal vascular malperfusion in women with a normal singleton pregnancy at term.
| Histologic lesionsa | % (n/N) |
|---|---|
| Maternal vascular malperfusion | 35.7 (337/944) |
| Villous changes | 18.6 (176/944) |
| Villous infarct(s) | 5.6 (53/943) |
| Increased syncytial knots | 8.5 (80/944) |
| Villous agglutination | 2.0 (19/944) |
| Increased intervillous fibrin deposition | 6.4 (60/944) |
| Distal villous hypoplasia | 0.1 (1/944) |
| Vascular lesions | 20.6 (194/944) |
| Persistent muscularization of basal plate arteries | 16.3 (154/944) |
| Mural hypertrophy of decidual arterioles | 1.8 (17/944) |
| Acute atherosis of basal plate arteries and/or decidual arterioles | 0.8 (8/944) |
| Spiral artery fibrinoid necrosis | 0.3 (3/942) |
| Decidual vascular thrombosis | 1.7 (16/942) |
| Persistence of endovascular trophoblast | 0.3 (3/942) |
| Retroplacental hemorrhage | 0.8 (8/942) |
| ≥2 lesions of maternal vascular malperfusion | 7.4 (70/944) |
| ≥3 lesions of maternal vascular malperfusion | 1.2 (11/944) |
| Fetal vascular malperfusion | 19.7 (186/944) |
| Villous changes | 11.3 (107/944) |
| Villous stromal-vascular karyorrhexis | 2.5 (24/944) |
| Hyalinized avascular villi, small foci | 6.6 (62/944) |
| Hyalinized avascular villi, variable-sized foci | 2.0 (19/944) |
| Fetal thrombotic vasculopathy | 0.2 (2/944) |
| Vascular lesions | 9 (85/944) |
| Thrombi in large fetal vessels | 2.6 (25/944) |
| Intimal fibrin deposition, large fetal vessels | 6.5 (61/944) |
| Fibromuscular sclerosis, intermediate-sized fetal vessels | 0 (0/944) |
| ≥2 lesions of fetal vascular malperfusion | 0.7 (7/944) |
aA placenta may have more than one type of a lesion consistent with maternal vascular malperfusion or fetal vascular malperfusion.
Fetal vascular malperfusion
The prevalence of lesions consistent with fetal vascular malperfusion was 19.7% (186/944). The frequency of specific lesion groups was as follows: (1) villous changes in 11.3% (107/944); (2) vascular lesions in 9.0% (85/944); and (3) high-burden lesions (defined as two or more lesions of fetal vascular malperfusion) were present in only 0.7% (7/944) of the cases (Table 6).
Neither maternal nor fetal lesions of vascular malperfusion were significantly associated with the presence of labor, gestational age at delivery, African-American ethnicity and nulliparity (Supplementary Table 2).
Associations among placental histologic lesions
While almost 40% of the placentas in normal pregnancies showed multiple histological lesions, we investigated whether they co-occur in the same placenta purely by chance. A four-level contingency table was constructed by cross-classifying (1) acute and chronic inflammatory lesions and (2) fetal and maternal lesions of vascular malperfusion, which was examined with log-linear models to determine whether the associations between different types of lesions could have occurred by chance. Only the association between chronic inflammatory lesions and fetal malperfusion lesions of the villous type was significant (P<0.01), and only chronic villitis of unknown etiology was associated with fetal malperfusion lesions of the villous type (P<0.01).
Discussion
Principal findings of the study
(1) Seventy-eight percent of the placentas had lesions consistent with acute or chronic inflammation or maternal or fetal vascular malperfusion; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas – however, only 1.0% had severe acute inflammatory lesions; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) multiple histologic lesions consistent with acute or chronic inflammation or maternal or fetal vascular malperfusion were present in 38.7% of the cases.
The need for this study
Original research, review articles [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], monographs [80], [81], [82] and textbooks of placental pathology [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96] have described the morphologic features of this organ. Placenta, a journal dedicated specifically to the biology of the organ, reports regularly on histologic findings of human placentas [97].
Recent studies suggest that placental examination provides information that may be helpful in understanding the mechanisms of disease responsible for adverse pregnancy outcomes [98], [99], [100], [101], [102], [103], [104] as well as in assessing the risk for adult disease [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124]. The importance of placentology is increasingly recognized as evidenced, in part, by the launching of the Human Placenta Project by the Eunice Kennedy Shriver NICHD, National Institutes of Health, U. S. Department of Health and Human Services [125].
However, to date, there is very little information available about the frequency and type of histologic lesions in the placentas from uncomplicated pregnancies with normal outcome [22], [23], [24]. Therefore, we sought to address this question to assist in the interpretation of the results of placental pathology reports.
Maternal and fetal acute inflammatory lesions are more frequent in placentas delivered after labor
The prevalence of acute placental inflammatory lesions in uncomplicated term pregnancies ranges from 3.8% to 54.0% [18], [23], [24], [126], [127], [128], [129], [130], [131] in previous studies. This broad range may be due to (1) the lack of uniformity of placental pathologic diagnostic and reporting criteria, e.g. different definitions of inflammation [23], [132] and inclusion of decidual inflammation [22]; (2) variations in the methods of placental sampling [23], [127], [129], [132]; (3) socioeconomic status and ethnicity [133]; (4) the presence of spontaneous labor [130], [134], [135], [136]; and (5) the duration of labor [130], [136], [137].
In our study, the frequency of acute placental inflammatory lesions were higher in patients who had labored than in those who delivered without labor. Among women in labor, African-American ethnicity, nulliparity and duration of membrane rupture were independently associated with the increased frequency of these lesions. Our findings are consistent with previous reports that the frequency of acute histologic chorioamnionitis in women with spontaneous labor was significantly higher than in those without labor [24], [130], [134], [136], [138]. Specifically, Lee et al. [136], in a seminal study, reported that the risk of intra-amniotic infection or intra-amniotic inflammation (defined by analysis of amniotic fluid) increased with cervical dilatation in a group of patients who underwent cesarean delivery during labor at term [136]. In addition, the current study found that the frequency of the early stages (stages 1 and 2) of the maternal inflammatory response was associated with the presence of labor (Figure 2).
Acute placental inflammatory lesions at term most often represent the inflammatory process related to parturition rather than acute infection
The presence of early-stage acute inflammatory lesions in the placenta may represent the inflammatory process associated with labor per se, and not necessarily infection [135], [139], [140], [141]. Whether some forms of acute chorioamnionitis reflect mild forms of microbial invasion of the amniotic cavity during spontaneous labor or sterile intra-amniotic inflammation generated by the presence of danger signals is not known. While microbial invasion of the amniotic cavity has been reported in 13%–19% of women in spontaneous labor at term with intact membranes [140], [142], [143], intra-amniotic inflammation [defined as elevated interleukin (IL)-6, IL-8 or other inflammatory mediators] is also more common in patients with spontaneous labor at term than in those without labor [129], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156]. Spontaneous labor at term is considered prototypical of a sterile inflammatory phenomenon accompanied by an activation of the inflammasome [157], [158], [159], [160], [161], [162]. Therefore, the presence of acute inflammatory lesions in the placenta should not be construed as indicators of the presence of an intra-amniotic infection.
Acute histologic chorioamnionitis represents a maternal host response, as neutrophils infiltrating the chorion and amnion are of maternal origin [163] that, in some cases, can reach the amniotic cavity [139], [164].
By contrast, funisitis and chorionic vasculitis represent a fetal inflammatory response, and these lesions are considered the histological counterpart of the fetal inflammatory response syndrome [139], [165], [166], [167], [168], [169].
The term “placental lesion consistent with intra-amniotic infection” should be abandoned
Although the Society of Pediatric Pathologists and the Amsterdam group categorized as acute chorioamnionitis and funisitis under the label “amniotic fluid infection,” it is now clear that such lesions can also be present in the context of sterile intra-amniotic inflammation [139], [170], [171], [172], [173], [174], [175], [176]. Therefore, we recommend that, when referring to acute placental inflammatory lesions, the term “amniotic fluid infection” be abandoned [139]. Our interpretation is consistent with the results of Roberts et al. [177] who reported, based on placental cultures and molecular microbiologic studies for the identification of microbial footprints, that among nulliparous women who delivered at term following an uneventful pregnancy, the overall rate of histologic chorioamnionitis at term was 34% (67/195). However, in 96% (64/67) of the cases, microorganisms could not be identified by either cultivation or molecular techniques [177]. Indeed, using cultures and molecular techniques for the identification of viruses and bacteria, our group has shown that most women with clinical or mild histologic chorioamnionitis at term do not have an intra-amniotic infection [169], [174]. Collectively, these findings suggest that mild histologic acute placental inflammation represents the inflammatory process related to parturition or senescence of a placenta [178], [179], [180] rather than to an acute infection.
Chronic placental inflammatory lesions in normal term gestation: evidence of maternal-fetal cellular immunological interaction
Chronic inflammatory lesions are of maternal origin and are either caused by viruses [181], [182], [183], [184], [185], bacteria [185], [186] and/or parasites [183] or are a reaction to the foreign antigens of the fetus [19]. Such lesions can also be of fetal origin, e.g. eosinophilic T-cell vasculitis [20], [187].
The rate of chronic placental inflammatory lesions in our study population was 29.9%, and the most frequent lesion was chronic deciduitis (19.3%), followed by chronic villitis of unknown etiology (18.6%) and chronic chorioamnionitis (12.7%).
There are few reports on the frequency of chronic placental inflammatory lesions in normal term pregnancy, and of these, most have been case-control studies that reported solely on individual lesions and in which normal pregnancies served as the control [18], [24], [131]. The frequency of chronic villitis of unknown etiology ranged between 5% and 33.8% [5], [12], [14], [19], [129], [188], [189], [190], [191], [192] and that of chronic chorioamnionitis between 10% and 19% [18], [19], which agree with our findings, but the current study is the first report on the entire spectrum of chronic placental inflammatory lesions in normal pregnancy.
We doubt that nearly 30% of women with a normal pregnancy would have an infectious agent as an explanation for chronic placental inflammatory lesions and, therefore, favor an immunological mechanism to explain these findings. It is very likely that an immunological stand-off between the mother and fetus occurs at the maternal-fetal interface throughout normal pregnancy, but if maternal lymphocyte infiltration of the fetal tissues is not associated with substantial damage of the chorioamniotic membranes, villous tree or decidua basalis, a pregnancy without clinical complications is possible. Then, the presence of maternal lymphocytes infiltrating the chorioamniotic membranes would represent evidence of maternal-fetal cellular interaction without necessarily indicating a pathologic process.
Maternal and fetal placental vascular lesions in normal pregnancy at term
The frequency of placental lesions consistent with maternal vascular malperfusion and fetal vascular malperfusion in the current study was 35.7% and 19.7%, respectively. Bar et al. [24] reported that the frequency of placental lesions consistent with maternal and fetal vascular malperfusion in an Israeli population was 24.5% and 7.9%, respectively. By contrast, Lee et al. [18] reported that the frequency of placental lesions with maternal and fetal vascular malperfusion were 1.3% and 2.7%, respectively, in an Asian population. The high frequency of placental lesions of maternal vascular malperfusion found in the current study may be attributed to our patient population. For example, our patient population may have a higher prevalence of vascular lesions. The current study shows that obesity was independently associated with placental lesions consistent with maternal vascular malperfusion. This finding is consistent with previous reports that have shown that obese women had an increased risk of placental lesions consistent with maternal vascular malperfusion as compared to women with normal weight [193], [194]. Other explanations for the high frequency of placental lesions of maternal or fetal vascular malperfusion include the following: a larger number of placentas with normal pregnancy outcomes; the use of systematic random sampling and targeted sampling, leading to a higher number of sections evaluated; and meticulous adherence to the placental sampling protocol.
It has been proposed that some lesions consistent with fetal vascular malperfusion may be related to vascular stasis and tissue damage that may occur in the placenta at the end of gestation [195]. Alternatively, these lesions may reflect placental senescence as gestational age advances toward term [178], [179], [180].
Co-occurrence of placental lesions
We did not find a significant correlation among the placental histological lesions with the exception of the co-occurrence patterns between chronic inflammatory lesions (i.e. villitis of unknown etiology) and fetal vascular malperfusion lesions of the villous type. This finding is consistent with previous reports indicating that avascular villi may be part of the spectrum of villitis of unknown etiology [5], [7], [181]. The association of villitis of unknown etiology with villous lesions of fetal vascular malperfusion is most likely a reflection of villous injury caused by inflammation that can lead to luminal obliteration and result in downstream regions of avascular villi [5], [7]. In general, if villitis of unknown etiology is present in the proximal villi, distal avascular villi are not to be considered as lesions of fetal vascular malperfusion [5]. Current terminology for occasional avascular villi seen in a placenta with villitis should be reported as “chronic villitis with associated avascular villi” [21].
The placenta has a large functional reserve
Severe compromise of placental anatomy and function must occur before clinical disease becomes evident. There is a substantial body of clinical and experimental evidence in support of this view [89], [196], [197], [198], [199], [200], [201].
Embolization of the umbilical artery in pregnant sheep can result in a decrease in blood flow, an increase in umbilical artery resistance and the systolic/diastolic ratio, a progression of the diastolic waveform from normal to absent and, subsequently, the reversal of end-diastolic velocity [202], [203]. Substantial embolization of the placental cotyledons must occur before Doppler abnormalities of the umbilical artery are observed. Giles et al. [204] reported that placental microvascular anatomy was dramatically changed in patients with abnormal Doppler velocimetry findings. Specifically, the modal small-artery count in tertiary stem villi was significantly lower in patients with abnormal umbilical artery Doppler velocimetry than in those with normal Doppler indices [204]. Such findings have been confirmed by the observation that absent end-diastolic flow in the umbilical artery of growth-restricted fetuses is demonstrated after there is an approximate 50% reduction of the vessel area in the placental terminal villi [205]. Moreover, mathematical modeling of the placental circulation has shown that obliteration of 80% of the vascular tree is required before dramatic changes occur in the pulsatility index [206]. Similarly, a substantial proportion of the placenta affected by perivillous fibrinoid deposition is required before an adverse pregnancy event will occur, such as severe fetal growth restriction or fetal death [207].
The effect of sampling (frequency and methods) on the prevalence of placental lesions
Placentas were sampled using two different methods (systematic random sampling and targeted sampling). By design, systematic random sampling had a median of two sections while targeted sampling had a median of four sections from the placental disc. We compared the data obtained by the two different methods, stratified by the number of sections, and observed that when the number of placental sections was equal to or less than two in the targeted and random sampling methods, the lesion frequency did not show substantial variation. However, when the number of placental sections in the random and targeted samplings was increased to four or more, targeted sampling yielded a higher frequency of acute placental lesions and lesions of maternal and fetal vascular perfusion.
Many placental lesions are focal and, if not recognized macroscopically, may be missed by the standard sampling method. This is an inherent limitation of systematic random sampling. Targeted sampling, on the other hand, may be associated with selection bias by oversampling grossly visible placental abnormalities [208]. Finally, as already known, overall variation within a study depends upon biologic variability (heterogeneity of placental lesions) and introduces errors (such as sampling/selections bias). Therefore, in order to minimize biologic variation, as well as random errors and/or bias that may inadvertently be introduced by the sampling protocol, the two methods were combined to interpret the data.
At present, no study has compared systematic random sampling to targeted sampling, nor is there a study that has established the minimum number of placental sections for optimal representation of frequency of all placental lesions. Currently, there is only expert opinion stating that at least four samples per placenta are required to generate representative data [208].
Given that there was a different number of placental sections between the two methods of sampling, we cannot determine which method is better to assess the frequency of placental lesions; this should be the subject of future studies.
Strengths and limitations
The strengths of this study include the following: (1) a large number of term placentas from women without any obstetrical complications were studied; (2) an extensive examination of the placental sections was undertaken; (3) a comprehensive description of placental histological lesions and its correlation to demographic and clinical parameters was possible; and (4) the use of standardized protocols for histopathologic examination of the placenta was followed. The limitations of the study include: (1) the non-consecutive enrollment of patients over an extended time period and (2) the lack of follow-up beyond the neonatal period.
Conclusion
We report the frequency and type of histopathological lesions from a large series of placentas of women with a normal pregnancy outcome. Most placentas had some type of lesion (either inflammatory or vascular), but most were mild. The results of this study can be used as a reference when interpreting the results of placental pathology in patients with perinatal complications. Placental histopathological lesions and the extent to which they can cause obstetrical complications need to be rigorously evaluated and quantified.
Current histopathologic assessment of the placenta relies on limited sampling of a large organ, and the taxonomy is based on morphologic criteria that are largely qualitative. The application of advances in molecular pathology that address sampling [208], [209], [210], [211], [212], [213], [214], [215], identification of cellular markers of pathological processes, and computational methods to summarize and analyze data can be utilized in placental pathology to improve the characterization of this important organ.
Acknowledgment
This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services Contract No. HHSN275201300006C (Funder ID: 10.13039/100009633). We would like to acknowledge the assistance of all the laboratory research staff, especially Stella DeWar, for their continuous support during the production of this manuscript.
Author’s statement
Conflict of interest: Authors state no conflict of interest.
Material and methods: Informed consent: Informed consent has been obtained from all individuals included in this study.
Ethical approval: The research related to human subject use has complied with all the relevant national regulations, and institutional policies, and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.
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The online version of this article offers supplementary material (https://doi.org/10.1515/jpm-2018-0055).
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