Abstract
Introduction:
Chronic placental inflammation is a routinely diagnosed group of placental lesions that reflect immunologic dysfunction of the mother, fetus, or both.
Methods:
Complete placental pathology examinations were performed for all term births at New York Presbyterian-Brooklyn Methodist Hospital from January 2010- August 2016. Diagnoses were blinded except to gestational age. CPI lesions were marked as chronic choriodeciduitis, decidual plasma cells, chronic inflammation of basal plate with anchoring villitis, and chronic villitis.
Results:
In this cohort of term pregnancies, 257 (11.6%) males and 218 (9.8%) females had ≥1 CPI lesions. Chronic villitis was the most common (319 or 14%), with chronic choriodeciduitis, decidual plasma cells, and chronic inflammation of basal plate with anchoring villitis in 94 (4%), 69 (3%) and 170 (8%), respectively. In males, chronic villitis was associated with lower gestational adjusted birthweight and had no association with placental weight. In females, chronic villitis was associated with lower gestational adjusted birthweight, but the effect became nonsignificant after adjustment for placental weight.
Discussion:
In summary, CPI lesions’ incidence and association with birth weight vary by sex. Chronic villitis is associated with lower birthweight in females; this effect is completely mediated by placental weight. Chronic villitis showed a weak direct association of chronic villitis in males, but no association with lower placental weight in males. We suggest that differences between our results and previous publications reflect effects of sampling bias.
Keywords: placenta, chronic inflammation, chronic villitis, fetal growth
1. Introduction
From the earliest days of pregnancy, the placenta is the fetal organ that forms the interface between the semi-allogeneic conceptus and the mother. Throughout the development of the placenta (and embryo/fetus), carefully synchronized maternal-placental immunologic communication allows repression of immune attack, and activation of immune tolerance[1]. Failure to suppress such expression was believed to be a cause of fetal compromise. Beer and Billingham immunized mother mice to produce impaired fetal growth or “runt disease”, which they aptly attributed to placental impairment. By 1990, the view of the placenta had become more complex [2] as the extent and complexity of the immunologic cross-talk with the mother became clearer even in clinically uncomplicated pregnancies [3,4].
The National Collaborative Perinatal Project published the first codification of placental gross examination and microscopic diagnoses, which listed ”lymphocytic infiltration of decidua, none, slight or marked at margin, in capsularis (membranes), and basalis (basal plate)”[5]. However, the rubella epidemic of the 1960’s led to the appreciation of the role of viral infections, including the ToRCH entities, in congenital anomalies or neurodevelopmental impairment [6,7] and ultimately, to the recognition of a specific pattern of placental chronic inflammation, chronic villitis, by the mid 1970’s [8]. Initially, congenital viral infections associated with chronic villitis were considered to be defined by lymphoplasmacytic infiltrates but by 1974, chronic villitis “indistinguishable from those found in rubella” was found to have lymphocytic and plasma cell infiltrates in the basal plate decidua[9].
Appreciation of that complexity helped to spawn a number of observational studies that linked chronic inflammatory placental disorders to a range of pregnancy outcomes, from preterm birth [10,11], fetal growth restriction in preterm and term births [12–14], in singleton and in multifetal pregnancy [15], and with recurrent adverse pregnancy outcome [16–18]. Published rates of chronic non-specific villitis vary widely, with rates from 7% to as high as 33% [19]. As studies reporting on placentas necessarily rely on those placentas available to pathologists via referral at birth, the wide range of reported prevalence is likely a function of the degree of selection bias produced by variation in referral criteria. The great majority of placentas are discarded, sometimes before the mother and her newborn exit the delivery room. Without universal collection of placentas, studies of placentas suffer from selection bias and cannot inform us about true population prevalence. Furthermore, bias can also distort estimation of effects of chronic inflammatory placental lesions.
Our study addresses that knowledge gap, as our Brooklyn cohort is derived from a rare sample of consecutive placentas examined based on a mandate for universal placental diagnostic examination at a single, high-volume community-based hospital over a more than 6 year period. This unique and valuable cohort of placentas linked with postnatal child follow-up to 2 years of age enables the study of a wide range of perinatal exposures and maternal and child health outcomes. We here present a study of maternal placental and newborn characteristics in 2,000 term singleton liveborn infants with the full range of chronic placental inflammation, including chronic non-specific villitis, but also chronic choriodeciduitis in the membranes, chronic basal deciduitis and anchoring villitis in the basal plate, and the identification of decidual plasma cells.
2. Methods
2.1. Study setting and recruitment
The current study capitalizes on banked placentas collected from deliveries at New York Presbyterian- Brooklyn Methodist Hospital (NYP-BMH) between January 2010 and August 2016. For all births at NYP-BMH during this period, a complete placental pathology examination and archiving of formalin-fixed paraffin-embedded (FFPE) placental tissues was mandated at the request of the Departments of Obstetrics and Gynecology and Pediatrics. The delivery population was broadly distributed across the borough, with hospital-affiliated obstetrics practices located in Brooklyn Heights, Park Slope, Crown Heights, Canarsie, Homecrest, Brighton Beach, Gravesend, Bensonhurst, Dyker Heights, Bay Ridge, Flatbush, Midwood and Mapleton.
Selection of the current cohort from that much larger population was determined by the parameters of the Environmental influence on Placental Origins of Development [20] which was awarded in 2018. Inclusion criteria were that the child be a singleton term (37–41+ weeks gestation) liveborn (89% of the singleton newborn population at NYP-BMH) followed to at least age 2 years through either the NYP-BMH Department of Pediatrics faculty or resident practices, and also have at least 2 measures obtained (in addition to birth weight) in Year 1 of life and at least 2 additional visits with growth measures before 2–3 years of age. The inclusion criteria were therefore broad, providing a sample representative of term singleton liveborns with follow-up criteria as described above. This produced a sample of 2,290 births eligible for inclusion. Twenty-two mother-child dyads were excluded because the family requested the placenta, or the placental tissue blocks could not be retrieved in the NYP-BMH tissue block archive. Ten additional dyads were excluded because newborn dried blood spot (DBS) card collected initially for newborn screening could not be found in the New York State Newborn Screening Program Archive or because the DBS were obtained >72 hours after birth. Ultimately, we identified 2216 women delivering singleton pregnancies at term (37–41 weeks gestation (1133 males, and 1083 females) with placentas and DBS, more than 98 percent of the sample. We present analyses based on extant placental diagnostic and maternal and neonatal medical records data. There is no patient involvement to report.
2.3. Overview of EPOD Brooklyn data collection
The subjects of this study are a subset of the Environmental Influences on Placental Origins of Development (EPOD, ES029281) which assembled more than 2000 term singleton livebirths with follow-up in the pediatric faculty or resident practices to age 2 years. Maternal characteristics obtained from the electronic medical record included maternal pre-pregnancy weight, height, gestational weight gain, maternal age, race and ethnicity, insurance type (public, private, or self-pay), pre-existing or gestational diabetes, smoking, drug use, and reproductive history. Chronic hypertension was defined by pre-pregnancy hypertension or hypertension developed before 20 weeks of pregnancy. Preeclampsia was diagnosed as new onset hypertension and proteinuria presenting after 20 weeks of gestation or postpartum. Estimates of gestational age at delivery were corroborated against last menstrual period, ultrasound-based measures of estimated date of delivery, and clinical estimate of gestational age at birth in this clinical population as described elsewhere [21–24]. Results of routine clinical testing as well as information about any known infections, including fever at the time of delivery were abstracted. Finally, we abstracted mode of delivery as well as pregnancy and obstetric and delivery complications. Infant characteristics were obtained from EMR and included: infant sex, date of birth, birth weight and birth length, whether the newborn was admitted to the NICU.
Placental gross measurements and tissue sampling were performed via a uniform protocol. Three slides were prepared for each case, one containing two umbilical cord cross sections and a roll of the extraplacental membranes, and two samples of the chorionic disk. The presence/absence of placental histopathology types was collected as diagnosed by a single pathologist (CMS) at birth. Histopathology diagnoses were performed on review of routine, hematoxylin and eosin stained slides, blinded except to gestational age and specified chronic placental inflammation (CPI) lesions were marked as chronic marginating choriodeciduitis (CD), decidual plasma cells (PCs), chronic inflammation of basal plate with anchoring villitis (Anch) and chronic villitis (CV) [25–28]. Diagnoses were coded as absent or present (0/1 scale) and extracted from the surgical pathology report created at birth by a single dedicated and specially trained pathologist (CMS).
Diagnoses were made according to published standards as follows:
Chronic marginating choriodeciduitis was defined as decidual lymphocytes migrating into the chorion and amnion [18]. Some authors have termed this “chronic chorioamnionitis” [28,29]; the lymphocytes migrating into the chorion and occasionally the amnion originate from the decidua, hence our preference for the term “choriodeciduitis” to include any lesion of decidual lymphocytes migrating into the fetal chorion and/or amnion.
Plasma cells were diagnosed as the presence of round-to-ovoid cells containing abundant deep blue cytoplasm with a pale perinuclear (Golgi) area with a round, eccentrically placed nucleus with coarse chromatin arranged in a clock face pattern [30].
Chronic inflammation of the basal plate anchoring villi marked cases with decidual lymphocytes infiltrating into the bases of anchoring villi embedded in the basal plate, as described by Redline [31].
Chronic villitis (CV) was characterized by focal areas of inflammation with mononuclear cells and areas of fibrinoid necrosis in chorionic villi [19].
The prevalence of the 4 types of CPI lesions in the EPOD data set were determined. The remainder of the analyses were drawn from a nested case-control design comparing newborns with placentas with CPI lesions and placentas with no histopathologic lesions (e.g., no lesions of acute inflammation, nor of maternal and/or fetal vascular malperfusion)[32–34].
Analyses considered categorical values by chi-square test of independence, or Fisher’s exact test when greater than 20% of expected values were less than five. Continuous variables were examined for normality of distribution and analyzed using analysis of variance, Mann-Whitney U-test, or t-test. Categorical variables were compared using chi-square, Fisher’s exact test, or contingency tables.
3. Results
Chronic villitis was the most common lesion, present in 319 (14%) of this population-based cohort, with chronic choriodeciduitis, decidual plasma cells, and chronic inflammation of basal plate with anchoring villitis present in 94 (4%), 69 (3%) and 170 (8%), of placentas, respectively (Table 1). Of the 475 total with any CPI lesions, 343 (72%) had only one type of CPI lesion; the remaining 132 (28%) had 2 or more CPI lesions. 257 (11.6%) males and 218 (9.8%) females had one or more CPI lesion (Table 1).
Table 1.
Prevalence of chronic placental inflammation pathologies in EPOD, stratified by infant sex.
| All N=2216 | Males N= 1133 | Females N= 1083 | |
|---|---|---|---|
|
| |||
| N (%) | N (%) | N (%) | |
| Chronic choriodeciduitis | 94 (4) | 55 (5) | 39 (4) |
| Chronic villitis | 319 (14) | 158 (14) | 161 (15) |
| Decidual plasma cells | 69 (3) | 42 (4) | 27 (2) |
| Chronic inflammation of basal plate with anchoring villitis | 170 (8) | 105 (9) | 65 (6) |
| 1 CPI type present | 343 (15) | 181 (16) | 162 (15) |
| 2+ CPI types present | 132 (6) | 76 (7) | 56 (5) |
| No CPI present* | 1741 (79) | 876 (77) | 865 (80) |
| No histopathology present** | 542 (24) | 255 (23) | 287 (27) |
Absence of CD, CV, PCs, and Anch
Absence of all placental histopathology types: acute inflammation in maternal or fetal tissues, chronic placental inflammation, fetal vascular pathology or malperfusion, maternal uteroplacental vascular malperfusion, and villous dysmaturity.
Basic demographics and comorbidities of this nested study sample stratified by infant sex are presented in Tables 2a and 2b. Comparing all newborn males with CPI lesions to 255 (11.5%) males with no histopathology lesions, male infants showed few associations, confined to p<0.05 only (Table 2a). In females (Table 2b), all 4 CPI lesions were associated with higher gravidity, with only chronic choriodeciduitis associated with more than 3 miscarriages. We next considered maternal age, placental weight (PW), birthweight (BW), and gestational age as both continuous and as categorical variables. In males, CPI lesions as a group were associated with lower birthweight, with 63% of birth weights found in the lower 50 centiles (p=0.035, Table 3). In female infants, CPI lesions as a group were associated with reduced placental weight (p=0.008) and birthweight (p=0.032, Table 3).
Table 2a.
Covariates and their association with chronic placental inflammation types among males.
| No Pathology (ref) N= 255 N (%) | Chronic choriodeciduitis N= 55 N (%) | Chronic villitis N=158 N (%) | Decidual plasma cells N=42 N (%) | Chronic inflammation of basal plate with anchoring villitis N=105 N (%) | |
|---|---|---|---|---|---|
|
| |||||
| Covariates | |||||
| Maternal BMI | |||||
| < 18.5 (underweight) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| 18.5 – 24.99 (healthy) | 28 (11) | 3 (6) | 15 (10) | 4 (10) | 11 (10) |
| 25.0 – 29.99 (overweight) | 89 (35) | 14 (25) | 49 (31) | 14 (33) | 30 (29) |
| 30+ (obese) | 137 (54) | 38 (69) | 94 (59) | 24 (57) | 63 (61) |
| NICU Admission | |||||
| No | 245 (96) | 48 (87) | 145 (92) | 40 (95) | 100 (95) |
| Yes | 10 (4) | 7 (13)* | 13 (8) | 2 (5) | 5 (5) |
| Mode of Delivery | |||||
| NSVD or VAVD | 177 (69) | 34 (62) | 117 (74) | 31 (74) | 71 (68) |
| CS | 78 (31) | 21 (38) | 41 (26) | 11 (26) | 34 (32) |
| Race | |||||
| Unknown | 0 (0) | 0 (0) | 1 (1) | 0 (0) | 0 (0) |
| White/Caucasian | 83 (32) | 14 (25) | 50 (31) | 18 (43) | 38 (36) |
| Black/African American | 158 (62) | 37 (67) | 88 (56) | 20 (47) | 61 (58) |
| Asian | 12 (5) | 3 (6) | 14 (9) | 2 (5) | 5 (5) |
| Native American/ | |||||
| Alaskan/Hawaiian/Pacific Islander | 2 (1) | 1 (2) | 3 (2) | 0 (0) | 0 (0) |
| Other | 0 (0) | 0 (0) | 2 (1) | 2(5)* | 1 (1) |
| Insurance | |||||
| Private | 109 (43) | 24 (44) | 50 (32) | 15 (36) | 33 (31) |
| Medicaid | 129 (50) | 27 (49) | 87 (55) | 24 (57) | 61 (58) |
| Self-pay | 17 (7) | 4 (7) | 21 (13)* | 3 (7) | 11 (10) |
| Previous Preterm Delivery | |||||
| No | 242 (95) | 54 (98) | 149 (94) | 40 (95) | 97 (93) |
| Yes | 13 (5) | 1 (2) | 9 (6) | 2 (5) | 7 (7) |
| Gravida | |||||
| 1–2 | 134 (53) | 26 (47) | 82 (52) | 21 (50) | 59 (56) |
| 3+ | 121 (47) | 29 (53) | 76 (48) | 21 (50) | 46 (44) |
| Para | |||||
| 0 | 109 (43) | 24 (44) | 84 (53) | 20 (48) | 49 (47) |
| 1–2 | 127 (50) | 28 (51) | 65 (41) | 18 (43) | 49 (47) |
| 3+ | 19 (7) | 3 (5) | 9 (6) | 4 (9) | 7 (6) |
| Spontaneous abortions | |||||
| 0 | 175 (69) | 38 (69) | 113 (72) | 32 (76) | 83 (80) |
| 1–2 | 68 (27) | 13 (24) | 35 (22) | 8 (19) | 20 (19) |
| 3+ | 10 (4) | 4 (7) | 9 (6) | 2 (5) | 1 (1) |
| Pregestational diabetes mellitus (DM)/gestational DM | |||||
| No | 229 (90) | 47 (85) | 134 (85) | 38 (90) | 92 (88) |
| Yes | 26 (10) | 8 (15) | 24 (15) | 4 (10) | 12 (12) |
| Preeclampsia | |||||
| No | 229 (90) | 48 (87) | 144 (91) | 40 (95) | 101 (96) |
| Yes | 26 (10) | 7 (13) | 14 (9) | 2 (5) | 4 (4)* |
| Gestational hypertension (GHTN) | |||||
| No | 253 (99) | 54 (98) | 157 (99) | 42 (100) | 102 (97) |
| Yes | 2 (1) | 1 (2) | 1 (1) | 0 (0) | 3 (3) |
| Chronic hypertension (CHTN) | |||||
| No | 244 (96) | 51 (93) | 154 (97) | 42 (100) | 104 (99) |
| Yes | 11 (4) | 4 (7) | 4 (3) | 0 (0) | 1 (1) |
| Superimposed preeclampsia (SIPE) | |||||
| No | 248 (97) | 53 (96) | 156 (99) | 42 (100) | 105 (100) |
| Yes | 7 (3) | 2 (4) | 2 (1) | 0 (0) | 0 (0) |
No Pathology defined as the absence of all placental histopathology types: acute inflammation in maternal or fetal tissues, chronic placental inflammation, fetal vascular pathology or malperfusion, maternal uteroplacental vascular malperfusion, and villous dysmaturity.
P-values reported for chi-square test of independence or Fisher's exact test when applicable.
p < 0.05
p < 0.01
p < 0.001
Table 2b.
Covariates and their association with chronic placental inflammation types among females.
| No Pathology (ref) N= 287 N (%) | Chronic choriodeciduitis N= 39 N (%) | Chronic villitis N=161 N (%) | Decidual plasma cells N=27 N (%) | Chronic inflammation of basal plate with anchoring villitis N=65 N (%) | |
|---|---|---|---|---|---|
|
| |||||
| Covariates | |||||
| Maternal BMI | |||||
| < 18.5 (underweight) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| 18.5 – 24.99 (healthy) | 28 (10) | 3 (8) | 15 (9) | 1 (4) | 3 (5) |
| 25.0 – 29.99 (overweight) | 106 (37) | 12 (31) | 63(39) | 8 (30) | 21 (32) |
| 30+ (obese) | 152 (53) | 24 (62) | 83 (52) | 18 (66) | 41 (63) |
| NICU Admission | |||||
| No | 265 (92) | 34 (87) | 153 (95) | 24(89) | 59 (91) |
| Yes | 22 (8) | 5 (13) | 8 (5) | 3 (11) | 6 (9) |
| Mode of Delivery | |||||
| NSVD or VAVD | 173 (60) | 20 (51) | 106 (66) | 18 (67) | 43(66) |
| CS | 114 (40) | 19 (49) | 55 (34) | 9 (33) | 22 (34) |
| Race | |||||
| Unknown | 1 (0) | 1 (2) | 1 (1) | 0 (0) | 0 (0) |
| White/Caucasian | 71 (25) | 7 (18) | 58 (36) | 10 (37) | 26(40) |
| Black/African American | 189 (66) | 26 (67) | 84 (52) | 14 (52) | 32 (49) |
| Asian | 21 (7) | 3 (8) | 12 (7) | 2 (7) | 5 (8) |
| Native American/ | |||||
| Alaskan/Hawaiian/Pacific Islander | 2 (1) | 0 (0) | 4 (3) | 0 (0) | 1 (2) |
| Other | 3 (1) | 2 (5) | 2 (1)* | 1 (4) | 1 (1) |
| Insurance | |||||
| Private | 106 (37) | 15 (39) | 60 (37) | 10 (37) | 24 (37) |
| Medicaid | 143 (50) | 20 (51) | 88 (55) | 15(56) | 38 (58) |
| Self-pay | 38 (13) | 4 (10) | 13 (8) | 2 (7) | 3 (5) |
| Previous Preterm Delivery | |||||
| No | 270 (94) | 37 (95) | 148 (92) | 25 (93) | 59 (91) |
| Yes | 17 (6) | 2 (5) | 13 (8) | 2 (7) | 6 (9) |
| Gravida | |||||
| 1–2 | 159 (55) | 13 (33) | 71 (44) | 7 (26) | 26(40) |
| 3+ | 128 (45) | 26 (67)** | 90(56)* | 20(74)** | 39 (60)* |
| Para | |||||
| 0 | 127 (44) | 15 (38) | 72 (45) | 7 (26) | 20 (31) |
| 1–2 | 136 (48) | 19 (49) | 71 (44) | 15(56) | 37 (57) |
| 3+ | 24 (8) | 5 (13) | 18(11) | 5 (18) | 8 (12) |
| Spontaneous abortions | |||||
| 0 | 211 (74) | 19 (50) | 106 (66) | 19 (70) | 46 (72) |
| 1–2 | 63 (22) | 14 (37) | 46(29) | 6 (22) | 16 (25) |
| 3+ | 10 (4) | 5 (13)** | 9 (5) | 2 (7) | 2 (3) |
| Pregestational diabetes mellitus (DM)/gestational DM | |||||
| No | 258 (90) | 34 (87) | 146 (91) | 25 (93) | 58 (89) |
| Yes | 29(10) | 5 (13) | 15 (9) | 2 (7) | 7 (11) |
| Preeclampsia | |||||
| No | 268 (93) | 35 (90) | 154 (96) | 26 (96) | 63(97) |
| Yes | 19 (7) | 4 (10) | 7 (4) | 1 (4) | 2 (3) |
| Gestational hypertension (GHTN) | |||||
| No | 275 (96) | 35 (90) | 155 (96) | 25 (93) | 61 (94) |
| Yes | 12 (4) | 4 (10) | 6 (4) | 2 (7) | 4 (6) |
| Chronic hypertension (CHTN) | |||||
| No | 283 (99) | 37 (95) | 159 (99) | 26 (96) | 64 (98) |
| Yes | 4 (1) | 2 (5) | 2 (1) | 1 (4) | 1 (2) |
| Superimposed preeclampsia (SIPE) | |||||
| No | 285 (99) | 37 (95) | 160 (99) | 26 (96) | 64 (98) |
| Yes | 2 (1) | 2 (5) | 1 (1) | 1 (4) | 1 (2) |
No Pathology defined as the absence of all placental histopathology types: acute inflammation in maternal or fetal tissues, chronic placental inflammation, fetal vascular pathology or malperfusion, maternal uteroplacental vascular malperfusion, and villous dysmaturity.
P-values reported for chi-square test of independence or Fisher's exact test when applicable.
p < 0.05
p < 0.01
p < 0.001
Table 3.
Study population demographics their associations with chronic placental inflammation pathology.
| Males | Females | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| No Pathology (N=255) N (%) | Chronic Placental Inflammation Present(N=257) N (%) | P-value* | No Pathology (N=287) N (%) | Chronic Placental Inflammation Present (N=218) N (%) | P-value* | |
|
| ||||||
| Maternal Age (years) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | ||
| 29.9 (6.1) | 29.9 (6.5) | 29.6 (6.4) | 30.4 (6.3) | |||
| <25 | 58 (23) | 67 (26) | 0.83 | 76 (27) | 46 (21) | 0.47 |
| 25–32 | 109 (43) | 103 (40) | 127 (44) | 100 (46) | ||
| 33–40 | 90 (31) | 78 (30) | 73(25) | 60 (27) | ||
| 41+ | 8 (3) | 9 (4) | 11 (4) | 12 (6) | ||
| Placental weight (g) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | ||
| 492.3 (89.9) | 487.0 (98.6) | 502.6 (93.0) | 472.5 (97.2) | |||
| <25th | 59 (23) | 70 (27) | 0.70 | 57 (20) | 72 (33) | 0.008 |
| 25th - 50th | 80 (31) | 75(29) | 76 (26) | 52 (24) | ||
| 51st - 75 th | 69 (27) | 63 (25) | 92 (32) | 59 (27) | ||
| 76th + | 47 (19) | 49 (19) | 62 (22) | 35 (16) | ||
| Birth weight (g) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | ||
| 3394.2 (420.9) | 3299.5 (469.9) | 3251.7 (432.0) | 3188.2 (469.7) | |||
| <25th | 60 (23) | 79 (31) | 0.035 | 63 (22) | 71 (33) | 0.032 |
| 25th - 50th | 73 (29) | 82 (32) | 96 (33) | 57 (26) | ||
| 51st - 75 th | 62 (24) | 59 (23) | 80 (28) | 50 (23) | ||
| 76th + | 60 (24) | 37 (14) | 48 (17) | 40 (18) | ||
| Gestational age (weeks) | Mean (SD) | Mean (SD) | 0.97 | Mean (SD) | Mean (SD) | 0.63 |
| 38.99 (1.1) | 38.99 (1.1) | 38.96 (1.1) | 39.0 (1.1) | |||
Chronic Placental Inflammation Present defined as the presence of at least one of the following: CD, CV, PCs, or Anch.
No Pathology defined as the absence of all placental histopathology types: acute inflammation in maternal or fetal tissues, chronic placental inflammation, fetal vascular pathology or malperfusion, maternal uteroplacental vascular malperfusion, and villous dysmaturity.
P-values reported for chi-square test of independence or t-test (gestational age)
We conducted regression analyses to test the effects of the four CPI lesion types on BW adjusting for GA (Table 4). In males, Anch was associated with a reduction in birthweight (p=0.04). We then adjusted for PW to determine if some or all of the effect of the CPI lesion was mediated by effects on PW. Anch was no longer associated with lower BW after including PW in the model (p=0.09), indicating that the association of Anch and BW was mediated by effects of Anch on PW. However, CV trended to have lower BW when controlled for GA (p=0.054; after controlling for PW, a weak relationship was identified (p=0.022). This finding is difficult to interpret but suggests CV may have more general effects on placental function than simply affecting PW. We performed the same analyses in females (Table 4). Adjusting for GA, we found that two of the four CPI lesions were significantly associated with reductions in BW (CD, −166.8 g; CV, −95 g). Analyses adjusting for PW in addition to GA showed evidence of mediation of the effects of CPI lesions through impacts on PW. The effect of CV was fully mediated (−2.6 g, p=0.94) while the effect of CD was approximately 50 percent mediated by effects on PW (−77.3 g, p=0.17).
Table 4.
Adjusted effects of chronic placental inflammation on infant birthweight.
| Entire study population | Males | Females | ||||
|---|---|---|---|---|---|---|
|
| ||||||
| Mean difference in birthweight (g) [95% CI] | Mean difference in birthweight (g) [95% CI] | Mean difference in birthweight (g) [95% CI] | ||||
|
| ||||||
| Adjusted for gestational age (weeks) + sex | Adjusted for gestational age (weeks) + sex + placental weight (g) | Adjusted for gestational age (weeks) | Adjusted for gestational age (weeks) + placental weight (g) | Adjusted for gestational age (weeks) | Adjusted for gestational age (weeks) + placental weight (g) | |
|
| ||||||
| All placental histopathology types absenta | 0.0 (reference) | 0.0 (reference) | 0.0 (reference) | 0.0 (reference) | 0.0 (reference) | 0.0 (reference) |
| Chronic choriodeciduitis present | −112.4 [−203.9, −20.9]* | −77.2 [−148.3, −6.2]* | −69.9 [−188.9, 49.2] | −79.0 [−171.5, 13.5] | −166.8 [−309.9, −23.7]* | −77.3 [−189.0, 34.4] |
| Chronic villitis present | −88.3 [−146.0, −30.7]* | −35.9 [−82.1, 10.4] | −81.5 [−164.6, 1.5] | −74.7 [−138.8, −10.6]* | −95.0 [−175.6, −14.5]* | −2.6 [−69.7, 64.6] |
| Decidual plasma cells present | −93.4 [−197.2, 10.4] | −40.0 [−120.9, 42.9] | −94.9 [−227.2, 37.4] | −71.1 [−175.9, 33.6] | −92.0 [−258.6, 74.6] | 10.2 [−121.2, 141.6] |
| Chronic inflammation of basal plate with anchoring villitis present | −90.8 [−164.0, −17.5]* | −33.6 [−90.6, 23.3] | −99.4 [−194.2, −4.5]* | −63.6 [−136.7, 9.5] | −78.2 [−193.8, 37.5] | 11.0 [−79.7, 101.7] |
Defined as the absence of all placental histopathology types: acute inflammation in maternal or fetal tissues, chronic placental inflammation, fetal vascular pathology or malperfusion, maternal uteroplacental vascular malperfusion, and villous dysmaturity.
p < 0.05
To verify the results of the stratified analyses, we next performed regression with infant sex entered as a predictor. In Table 4, adjusted for GA and infant sex, we found CD, CV and Anch were each associated with lower BW. The results of the same analyses adding adjustment for PW, only CD remained significant.
4. Discussion
In summary, the incidence of CPI lesions, and their association with maternal and newborn outcomes including birth weight, varied by sex in our cohort of term births in a population with universal placental assessment. Increased “immunologic discrepancy” of male fetuses has been proposed as an explanation for increased male vulnerability in utero; we find increased CPI lesions in males, which may account for the clinically appreciated increased male vulnerability. However, further examination showed mediation of the birth weight (BW) effects by placental weight (PW). CD and CV are each associated with lower BW in females, but these effects are whole or in part mediated by the effect of CD or CV on PW. Similarly, in males, effects of CPI lesions on BW were lost after adjustment for PW, again consistent with mediation effects. In a regression adjusting for both GA and PW in males, a weak direct association of CV with lowered BW was observed.
Our findings, of minimal direct effects of CPI lesions on BW, contrast with decades of reported immune contribution to fetal growth restriction. We suggest two principal reasons for these differences. First, but potentially least impactful, is the evidence presented here that CPI lesions differ in incidence between male and female infants. The concept that the male fetoplacental unit may cause maternal immune activation that differs in either magnitude, type of response or both, has been demonstrated many times and has been proposed to significantly impact neurodevelopment. Second, and perhaps more germane is that our sample derives from an “all-comers” cohort in which placental examination and histopathology diagnoses were mandated rather than performed after “indications” are met. Reports in the literature are generally derived from hospitals in which placentas are referred for pathological examination based on “indications”, and referrals depend on physician decision-making. These other reports may reflect associations of CV in pregnancies with complications that led to placenta referral. This type of sampling is vulnerable to selection bias that can arise when a study sample is taken not from the general population, but from a subpopulation. Chronic placental inflammation, including chronic villitis, cannot be recognized by specific gross changes; thus, any analysis relying solely on placentas referred for pathology examination, “indicated” examinations, can be biased depending on the reasons for “indicated” examination.
Our data is drawn from a multiethnic hospital population with a unique mandate for universal placental examination, a population of “all-comers”, with CPI lesions diagnosed in placentas that in other US hospitals would have been discarded at birth. As such it provides the denominator that has been missing from other attempts to quantify CPI lesions and their impacts on pregnancy. Outside of a few large epidemiologic studies, the placenta is, with rare exceptions, sent for pathology study only if there is a clinical basis to conclude that the pregnancy is abnormal. Even in large clinical trials, placental pathology may not be included due to issues both regulatory and ethical, as well as funding constraints.[35]. This is a glaring gap in knowledge despite the increasing attention paid to the effects of pathologic immune responses on the placenta and fetus. In the last 5 years alone a NLM PubMed search of “chronic villitis” yields 87 results; no study reflects the rates of CV and other forms of CPI in other than restrictive subgroups such as monozygotic and dizygotic twinning [36], term newborns with stroke [37] or recurrent preterm birth [38]. Studies that seem to offer more, such as “Chronic villitis of unknown etiology: an Australian institution’s 5-year experience”, do not offer the critical “denominator”, even in the abstract [39]. However, over this 5 year period, review of those placentas from pregnancies deemed sufficiently pathologic to be sent for formal examination yielded 714 cases of chronic nonspecific villitis, while approximately 50,000 infants were delivered at Mater Mother’s Hospital [40]. In the same vein, research that purports to estimate the recurrence risk for chronic villitis yielded, at an institution that delivers over 12,000 babies per annum [41] 883(4%) had placental pathology reports available for two pregnancies between January 2009 and March 2018. Whether the risk of recurrence (2.76 (2.25, 3.37) unadjusted; 2.59 (2.12–3.15) adjusted) is inflated or deflated by the highly selected nature of the study sample is unknowable. In other research, the same authors describe 79,825 deliveries in the study period with pathology review performed in only 12,074 (15%) with 2873 cases of chronic nonspecific villitis which would lead to a population rate estimate of 3.5% [42]. This would require the assumption that every case of chronic villitis resulted in a clinical indication for placental examination, which our experience suggests is not likely.
4.1. Strengths and Limitations
This report is confined to a term subset of the total delivery population at New York Presbyterian-Brooklyn Methodist Hospital that was assembled to fulfill the Aims and Methods of the NIEHS grant “Human Placental Morphology, Function, and Pathology: Relationship to Environmental Exposures and Newborn and Child Health”. The mandated placental examination was in effect from 2010–2016, during which time ~36,000 births were delivered. We are currently reviewing all pregnancies born to the mothers with CPI in this cohort, before or following the date of birth of the child in this cohort, including miscarriages and stillbirths. A limitation of this study is the provision of 3 blocks of representative tissue, one containing two umbilical cord cross sections and a membrane roll plus 2 random central section of placental disk; a recent recommendation suggested that 3 placental tissue sections should be collected [43]. The data we present may reflect an underestimation of the incidence of CPI lesions, and may be skewed toward more severe lesions.
In 1990, “Why all placentas should be examined by a pathologist in 1990” suggested that, while placental pathology is rarely a part of the training for either obstetrician or pathologist, benefits of routine placental examination could include clarification of the causes of many adverse pregnancy outcomes, improvement of the risk assessment for future pregnancies, and ascertainment of newborn risk for long-term neurodevelopment sequelae [44]. Information on placental abnormalities could reveal the presence of chronic fetal insults and allow their differentiation from acute (peripartum) stresses. What was true in 1990 remains true today: “Current methods of risk assessment fail to identify the majority of pregnancies that end in prematurity, stillbirth, growth retardation, or fetal distress”[44]. Incomplete ascertainment of placental gross and histopathology will assure that any progress in these regards will be slow.
Highlights:
Chronic placental inflammation is common in low-risk term pregnancies.
Chronic placental inflammation has sex-specific associations with fetal growth restriction.
Chronic villitis is the most common type of chronic placental inflammation in term pregnancies.
Footnotes
Declaration of interests
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Carolyn Salafia reports financial support was provided by National Institute of Environmental Health Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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