Analytical theory of oxygen transport in the human placenta.

We propose an analytical approach to solving the diffusion-convection equations governing oxygen transport in the human placenta. We show that only two geometrical characteristics of a placental cross-section, villi density and the effective villi radius, are needed to predict fetal oxygen uptake. We also identify two combinations of physiological parameters that determine oxygen uptake in a given placenta: (i) the maximal oxygen inflow of a placentone if there were no tissue blocking the flow and (ii) the ratio of transit time of maternal blood through the intervillous space to oxygen extraction time. We derive analytical formulas for fast and simple calculation of oxygen uptake and provide two diagrams of efficiency of oxygen transport in an arbitrary placental cross-section. We finally show that artificial perfusion experiments with no-hemoglobin blood tend to give a two-orders-of-magnitude underestimation of the in vivo oxygen uptake and that the optimal geometry for such setup alters significantly. The theory allows one to adjust the results of artificial placenta perfusion experiments to account for oxygen-hemoglobin dissociation. Combined with image analysis techniques, the presented model can give an easy-to-use tool for prediction of the human placenta efficiency.

Optimal villi density for maximal oxygen uptake in the human placenta.

We present a stream-tube model of oxygen exchange inside a human placenta functional unit (a placentone). The effect of villi density on oxygen transfer efficiency is assessed by numerically solving the diffusion-convection equation in a 2D+1D geometry for a wide range of villi densities. For each set of physiological parameters, we observe the existence of an optimal villi density providing a maximal oxygen uptake as a trade-off between the incoming oxygen flow and the absorbing villus surface. The predicted optimal villi density 0.47±0.06 is compatible to previous experimental measurements. Several other ways to experimentally validate the model are also proposed. The proposed stream-tube model can serve as a basis for analyzing the efficiency of human placentas, detecting possible pathologies and diagnosing placental health risks for newborns by using routine histology sections collected after birth.

Modeling oxygen transport in human placental terminal villi.

Oxygen transport from maternal blood to fetal blood is a primary function of the placenta. Quantifying the effectiveness of this exchange remains key in identifying healthy placentas because of the great variability in capillary number, caliber and position within the villus-even in placentas deemed clinically "normal". By considering villous membrane to capillary membrane transport, stationary oxygen diffusion can be numerically solved in terminal villi represented by digital photomicrographs. We aim to provide a method to determine whether and if so to what extent diffusional screening may operate in placental villi. Segmented digital photomicrographs of terminal villi from the Pregnancy, Infection and Nutrition study in North Carolina 2002 are used as a geometric basis for solving the stationary diffusion equation. Constant maternal villous oxygen concentration and perfect fetal capillary membrane absorption are assumed. System efficiency is defined as the ratio of oxygen flux into a villus and the sum of the capillary areas contained within. Diffusion screening is quantified by comparing numerical and theoretical maximum oxygen fluxes. A strong link between various measures of villous oxygen transport efficiency and the number of capillaries within a villus is established. The strength of diffusional screening is also related to the number of capillaries within a villus. Our measures of diffusional efficiency are shown to decrease as a function of the number of capillaries per villus. This low efficiency, high capillary number relationship supports our hypothesis that diffusional screening is present in this system. Oxygen transport per capillary is reduced when multiple capillaries compete for diffusing oxygen. A complete picture of oxygen fluxes, capillary and villus areas is obtainable and presents an opportunity for future work.

Allometric metabolic scaling and fetal and placental weight.

BACKGROUND: We tested the hypothesis that the fetal-placental relationship scales allometrically and identified modifying factors of that relationship. MATERIALS AND METHODS: Among women delivering after 34 weeks but prior to 43 weeks' gestation, 24,601 participants in the Collaborative Perinatal Project (CPP) had complete data for placental gross proportion measures, specifically, placental weight (PW), disk shape, larger and smaller disk diameters and thickness, and umbilical cord length. The allometric metabolic equation was solved for alpha and beta by rewriting PW = alpha(BW)beta as ln(PW) = ln alpha + beta[ln(BW)]. alpha(iota) was then the dependent variable in regressions with p < 0.05 significant. RESULTS: Mean beta was 0.78 + 0.02 (range 0.66, 0.89), which is consistent with the scaling exponent 0.75 predicted by Kleiber's Law. Gestational age, maternal age, maternal BMI, parity, smoking, socioeconomic status, infant sex, and changes in placental proportions each had independent and significant effects on alpha. CONCLUSIONS: We find an allometric scaling relation between the placental weight and the birthweight in the CPP cohort with an exponent approximately equal to 0.75, as predicted by Kleiber's Law. This implies that: (1) placental weight is a justifiable proxy for fetal metabolic rate when other measures of fetal metabolic rate are not available; and (2) the allometric relationship between placental and birthweight is consistent with the hypothesis that the fetal-placental unit functions as a fractal supply limited system. Furthermore, our data suggest that the maternal and fetal variables we examined have at least part of their effects on the normal balance between placental weight and birth weight via effects on gross placental growth dimensions.

Modeling the variability of shapes of a human placenta.

BACKGROUND: Placentas are generally round/oval in shape, but "irregular" shapes are common. In the Collaborative Perinatal Project data, irregular shapes were associated with lower birth weight for placental weight, suggesting variably shaped placentas have altered function. METHODS: (I) Using a 3D one-parameter model of placental vascular growth based on Diffusion Limited Aggregation (an accepted model for generating highly branched fractals), models were run with a branching density growth parameter either fixed or perturbed at either 5-7% or 50% of model growth. (II) In a data set with detailed measures of 1207 placental perimeters, radial standard deviations of placental shapes were calculated from the umbilical cord insertion, and from the centroid of the shape (a biologically arbitrary point). These two were compared to the difference between the observed scaling exponent and the Kleiber scaling exponent (0.75), considered optimal for vascular fractal transport systems. Spearman's rank correlation considered p<0.05 significant. RESULTS: (I) Unperturbed, random values of the growth parameter created round/oval fractal shapes. Perturbation at 5-7% of model growth created multilobate shapes, while perturbation at 50% of model growth created "star-shaped" fractals. (II) The radial standard deviation of the perimeter from the umbilical cord (but not from the centroid) was associated with differences from the Kleiber exponent (p=0.006). CONCLUSIONS: A dynamical DLA model recapitulates multilobate and "star" placental shapes via changing fractal branching density. We suggest that (1) irregular placental outlines reflect deformation of the underlying placental fractal vascular network, (2) such irregularities in placental outline indicate sub-optimal branching structure of the vascular tree, and (3) this accounts for the lower birth weight observed in non-round/oval placentas in the Collaborative Perinatal Project.

Amnioinfusion in preterm PROM: effects on amnion and cord histology.

OBJECTIVE: To investigate the effects of transabdominal amnioinfusion (TA) on the histology of amnion (A) and umbilical cord (UC). STUDY DESIGN: From a cohort of 56 singleton pregnancies with premature rupture of membranes (PROM) at

Fractal dimensions and branching characteristics of placental chorionic surface arteries.

We present a novel approach to characterize and compare the placental chorionic surface arteries (PCSA) of normal, preterm, diabetic and preeclamptic pregnancies using their fractal dimension (FD) and branch point number (BPN). Mean FD of PCSA of normal pregnancies was similar to those of diabetic and preeclamptic pregnancies, but significantly different from those of preterm pregnancies. In contrast, the BPN of PCSA of normal and preterm pregnancies was similar but significantly different from diabetic and preeclamptic pregnancies. The results suggest that branching properties of normal and pathological pregnancies are intrinsically different.

Scaling of the surface vasculature on the human placenta.

The networks of veins and arteries on the chorionic plate of the human placenta are analyzed in terms of Voronoi cells derived from these networks. Two groups of placentas from the United States are studied: a population cohort with no prescreening, and a cohort from newborns with an elevated risk of developing autistic spectrum disorder. Scaled distributions of the Voronoi cell areas in the two cohorts collapse onto a single distribution, indicating common mechanisms for the formation of the complete vasculatures, but which have different levels of activity in the two cohorts.

Villus packing density and lacunarity: Markers of placental efficiency?

We evaluate, in routine H&E histology slides, villus quantity in a given area (villous packing density, VPD) and the pattern or "gappiness" of villous distribution (lacunarity), and test for correlations with a proxy for fetoplacental metabolic rate, ß calculated as (ln (placental weight)/ln (birthweight)) from Kleiber's law [1]. Three ∼4.3 mm2 images each were obtained from 88 term placentas. Ranges of VPD and lacunarity were each correlated with ß (r = 0.31, p = 0.003, r = 0.23, p = 0.03 and respectively). The relationship between ß and within-placenta variation in VPD and lacunarity highlights the need to study not merely the mean but the variance of villous geometries and spatial distributions.

Metabolic scaling and twin placentas.

OBJECTIVE: Do monochorionic (MC) and/or dichorionic (DC) twins show allometric scaling between placental and birth weight (PW, BW)? METHODS: We extracted BW, PW, gestational age (GA) and cord insertion type from 52 MC to 310 DC twins to calculate ß. DC twins were analyzed as summed and as individuals if placentas were separate. RESULTS: Mean ß for MC (0.78 ± 0.02), DC summed (0.78 ± 0.02), and DC with separate placentas (0.77 ± 0.03 and 0.76 ± 0.04) all non-significant. GA, summed BWs, total PW, BW discordance, and cord insertion sites did not differ between twin types or with ß. CONCLUSION: MC and DC twins show allometric scaling similar to singletons.

IFPA meeting 2015 workshop report II: mechanistic role of the placenta in fetal programming; biomarkers of placental function and complications of pregnancy.

Workshops are an integral component of the annual International Federation of Placenta Association (IFPA) meeting, allowing for networking and focused discussion related to specialized topics on the placenta. At the 2015 IFPA meeting (Brisbane, Australia) twelve themed workshops were held, three of which are summarized in this report. These workshops focused on various aspects of placental function, particularly in cases of placenta-mediated disease. Collectively, these inter-connected workshops highlighted the role of the placenta in fetal programming, the use of various biomarkers to monitor placental function across pregnancy, and the clinical impact of novel diagnostic and surveillance modalities in instances of late onset fetal growth restriction (FGR).

Shape matching algorithm to validate the tracing protocol of placental chorionic surface vessel networks.

Variability in placental chorionic surface vessel networks (PCSVNs) may mark developmental and functional changes in fetal health. Here we report a protocol of manually tracing PCSVNs from digital 2D images of post-delivery placentas and its validation by a shape matching method to compare the similarity between paint-injected and unmanipulated (uninjected and deflated vessels) tracings of PCSVNs. We show that tracings of unmanipulated vessels produce networks that are very comparable to the networks obtained by tracing paint-injected PCSVNs. We suggest that manual tracings of unmanipulated PCSVNs can extract features of PCSVN growth and structure that may impact fetal wellbeing.

Immunohistochemical localization of carboxypeptidases E and D in the human placenta and umbilical cord.

Carboxypeptidase E (CPE) is highly concentrated in neuroendocrine tissues and is the only carboxypeptidase detected in mature secretory vesicles. Carboxypeptidase D (CPD), a carboxypeptidase with CPE-like activity, is widely distributed in tissues and is present in the trans-Golgi network. Previous work had shown that both CPE and CPD are expressed in the human placenta and that CPD is expressed at much higher levels than CPE. The present work provides evidence for the co-localization of CPE and CPD to basal plate extravillous trophoblasts and maternal uteroplacental vascular endothelial cells, chorionic villous endothelial cells, amnionic epithelial cells, and umbilical venous and arterial smooth muscle cells. Whereas the intensity of CPD immunostaining is similar in the placenta and umbilical cord, CPE staining in the placenta is much weaker than in the umbilical cord, suggesting that CPD plays a more important role in the processing of placental peptides. Immunoelectron microscopy of umbilical venous smooth muscle cells shows subcellular localization of both enzymes to the rough endoplasmic reticulum. In addition, CPE is present just subjacent to the cell membrane. The difference in cellular and subcellular localization between the two enzymes indicates that they perform distinct functions in the processing of placental peptides and proteins.

Antenatal corticosteroids and placental histology in preterm birth.

To assess the effects of antenatal corticosteroid use on placental histopathology, we have reviewed a database of 463 consecutive non-anomalous singleton liveborns delivered at less than 32 weeks between April 1988 and December 1994, of which 280 received one or more doses of corticosteroids for promotion of fetal lung maturation. Patients were grouped by the number of corticosteroid doses received (analyzed as none, 1, 2 and 3 or more doses). Clinical and demographic factors were recorded prospectively. Placental histopathology was reviewed blinded to clinical factors except gestational age, and 42 distinct placental lesions were examined and scored for severity. Data were analyzed by contingency tables, one-way analysis of variance, and linear regression analysis. Among clinical variables, univariate analysis showed that the number of corticosteroid doses was significantly related to presence of labour prior to delivery, pre-eclampsia, premature rupture of membranes and clinical suspicion or diagnosis of chorioamnionitis. Using linear regression analysis with these clinical variables as confounders, increased number of doses of antenatal corticosteroids was related to increased severity of villous fibrosis and stromal mineralization, and fewer villous infarcts.

Clinical correlations of patterns of placental pathology in preterm pre-eclampsia.

The objective of this study was to determine if placental histopathology patterns are associated with clinical features of preterm pre-eclampsia. A 1989-1993 database of consecutive non-anomalous singleton livebirths delivered at 22-32 weeks gestation excluding cases of maternal diabetes mellitus and chronic hypertension included 74 cases of pre-eclampsia. Placentae were scored for uteroplacental vascular lesions and lesions of chronic inflammation and coagulation. Thirteen lesion patterns identified by factor analysis were studied in relation to the clinical features. Severe maternal proteinuria was related to placental chronic inflammation, while lower maternal antepartum platelet counts were related to placental abruption and infarct. Lower birthweight percentile and lighter placentae were related directly to uteroplacental vascular lesions. Diagnosis of HELLP and coagulopathy were less common when chronic inflammation scores were high. Serologic studies related to autoimmunity and maternal blood pressures were unrelated to placental histopathology factors. It is concluded that features of maternal and fetal compromise in preterm pre-eclampsia are related to placental histopathology patterns.

Incontinentia pigmenti in a newborn male infant with DNA confirmation.

We report on a woman with incontinentia pigmenti (IP), who had two successive term pregnancies. The first pregnancy ended in the birth of a male infant, who is alive and well at 2 years. A second liveborn male had early postnatal distress and died after 1 day of life, after a fulminating clinical course. Polymorphic microsatellite markers, closely linked to the IP gene on the X chromosome, showed that each son inherited a different X chromosome from his mother. Although in most instances IP appears to be prenatally lethal for the male, the phenotype is not completely known. We propose that the neonatal phenotype may be characterized by lethal disturbances in the hematopoietic and immunologic systems.

Quantitative differences in arterial morphometry define the placental bed in preeclampsia.

The purpose of this study was to quantitatively analyze normal and preeclamptic uteroplacental vasculature. Myometrial arteries from eight placental bed biopsies from uncomplicated term deliveries and 12 from proteinuric preeclampsia were characterized as uteroplacental, spiral, or basal arteries. Basal lumens within 0.2 mm radius and spiral/uteroplacental lumens within 0.4 mm radius were considered as the same artery. The biopsy area, lumen density, and arterial density (after correction for multiple lumens), lumen area, lumen perimeter, mean wall thickness, inflated diameter, and a slant factor, measuring the obliqueness of arterial transection, and ratios of lumen characteristics to mean wall thickness were analyzed. In preeclamptic cases, there were more basal lumens/mm2 and basal arteries/mm2 (P=.003, P=.03), and more spiral lumens/mm2 and spiral arteries/mm2 (P = .01, P = .03). Basal lumen area (P = .0003) and wall thickness (P = .007), and basal and spiral artery lumen perimeters and inflated diameters (for each, P = .0001, P = .048, respectively) and inflated diameter/wall ratios (P = .04, P = .05) were reduced compared with normal cases. Preeclamptic spiral and basal arteries are more tortuous or densely distributed than normal placental bed arteries, with smaller-caliber lumens and thicker walls. Failure of proper placentation may result in abnormal spatial anatomy in the placental bed. Alternatively, an anatomic variant of spiral and basal arteries may be more susceptible to hemodynamic stresses and endothelial damage and may predispose to preeclampsia.

Placental pathology in systemic lupus erythematosus and phospholipid antibody syndrome.

Fetal loss is increased in women who meet the Arthritis and Rheumatism Association criteria for systemic lupus erythematosus (SLE) and in women who have phospholipid antibody syndrome (APS). There are multiple causes for this fetal loss, and in patients with SLE, disease activity appears to be an important contributing factor. In APS patients, it appears that some individuals will experience recurrent fetal loss and will continuously fail to complete pregnancy naturally. Placental examination has helped to elucidate some of the pathology that may be contribute to this fetal loss and our studies have shown that the same pathology is repeated in subsequent pregnancies. Placental examination in SLE or APS patients with recurrent fetal loss is vital if we are going to be able to determine appropriate therapy to prevent fetal loss.

The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies.

The clinical relevance of histologic evidence of acute ascending intrauterine infection has been called into question by descriptions of "silent" chorioamnionitis. The described frequencies of silent chorioamnionitis in normal and abnormal pregnancies vary widely because of differences in the definition of a normal pregnancy, methods of placental examination, and pathologic criteria. Therefore, we examined placentas from 161 uncomplicated gestations for the presence and severity of acute inflammation in the amnion, chorion-decidua, chorionic plate, and umbilical cord using strict gross and microscopic protocols. Indicators of amniotic fluid infection, specifically umbilical cord inflammation, amnionitis, and inflammation within the chorionic plate were present in 0, 1.2, and 4% of the cases, respectively. Silent chorioamnionitis was rare. There was a statistical association between the presence of acute inflammation and the occurrence of labor at term. Methods of tissue sampling that included a more extensive examination of the site of membrane rupture resulted in an increased frequency of diagnosis of acute inflammation at the site of rupture in vaginal deliveries at term.

Placental vascular lesions and likelihood of diagnosis of preeclampsia.

OBJECTIVE: To test the hypothesis that a range of severity of placental vascular lesions underlies preeclampsia and that the likelihood of its clinical diagnosis increases with the extent and severity of uteroplacental vascular lesions. METHODS: Four hundred sixty-five consecutive placentas of singleton, nonanomalous, live-born infants born before 32 weeks' gestation were examined prospectively, and uteroplacental vascular and related villous lesions were assigned a semiquantitative lesion score based on severity and extent of lesions. The summed scores of individual lesions yielded a total uteroplacental vascular lesion score, ranging from 0 to 21, that was correlated with the odds of a clinical diagnosis of preeclampsia, as well as with potential confounders, including maternal age, race, gestational age at delivery, and birth weight centile. Statistical analysis was performed using contingency tables, one-way analysis of variance, multiple logistic regression, and receiver operating characteristic curve. P < .05 was considered significant. RESULTS: A clinical diagnosis of preeclampsia was present in 78 of 465 (17%) cases. Logistic regression demonstrated that the total uteroplacental vascular lesion score related significantly to the diagnosis of preeclampsia (odds ratio 1.43, 95% confidence interval 1.31, 1.57) and this association was independent of gestational age at delivery and birth weight centile. Preeclampsia was diagnosed in 12 of 284 (4%) cases with no or minimal histologic evidence of placental vascular injury (total score less than 4). Conversely, the diagnosis was not made in 4% of cases despite the presence of extensive placental vascular injury (total score at least 14). CONCLUSION: The likelihood of clinical diagnosis of preeclampsia before 32 weeks increases with progressive impairment of the uteroplacental circulation. Histopathologic examination of the placenta can be used to confirm the diagnosis of preeclampsia.