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.

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.

Probability distributions for measures of placental shape and morphology.

Birthweight at delivery is a standard cumulative measure of placental growth, but is a crude summary of other placental characteristics, such as, e.g., the chorionic plate size, and the shape and position of the umbilical cord insertion. Distributions of such measures across a cohort reveal information about the developmental history of the chorionic plate which is unavailable from an analysis based solely on the mean and standard deviation. Various measures were determined from digitized images of chorionic plates obtained from the pregnancy, infection, and nutrition study, a prospective cohort study of preterm birth in central North Carolina between 2002 and 2004. Centroids (geometric centers) and umbilical cord insertions were taken directly from the images. Chorionic plate outlines were obtained from an interpolation based on a Fourier series, while eccentricity (of the best-fit ellipse), skewness, and kurtosis were determined from the method of moments. Histograms of each variable were compared against the normal, lognormal, and Lévy distributions. Only a single measure (eccentricity) followed a normal distribution. All others followed lognormal or 'heavy-tailed' distributions for moderate to extreme deviations from the mean, where the relative likelihood far exceeded those of a normal distribution.

Metabolic scaling law for mouse fetal and placental weight.

Human birth weight does not scale linearly with the weight of the placenta: placental mass (PM) is proportional to the fetal mass (FM) raised to the scaling exponent of 0.75 (PM ∼ FM(0.75)) [1,2]. The mouse is a common model for studying genetic and physiological backgrounds of placental development, function and pathologies. However, to date it has not been known how placental weight scales relative to embryo weight in mice. We analyzed E12.5 litters of CD1 wild-type mice, and found that the mouse placental weight demonstrates a power-law scaling relationship with fetal weight; the value of the scaling exponent is approximately 0.72.

Probability distributions of placental morphological measurements and origins of variability of placental shapes.

INTRODUCTION: While the mean shape of human placenta is round with centrally inserted umbilical cord, significant deviations from this ideal are fairly common, and may be clinically meaningful. Traditionally, they are explained by trophotropism. We have proposed a hypothesis explaining typical variations in placental shape by randomly determined fluctuations in the growth process of the vascular tree. It has been recently reported that umbilical cord displacement in a birth cohort has a log-normal probability distribution, which indicates that the displacement between an initial point of origin and the centroid of the mature shape is a result of accumulation of random fluctuations of the dynamic growth of the placenta. To confirm this, we investigate statistical distributions of other features of placental morphology. METHODS: In a cohort of 1023 births at term digital photographs of placentas were recorded at delivery. Excluding cases with velamentous cord insertion, or missing clinical data left 1001 (97.8%) for which placental surface morphology features were measured. Best-fit statistical distributions for them were obtained using EasyFit. RESULTS AND DISCUSSION: The best-fit distributions of umbilical cord displacement, placental disk diameter, area, perimeter, and maximal radius calculated from the cord insertion point are of heavy-tailed type, similar in shape to log-normal distributions. This is consistent with a stochastic origin of deviations of placental shape from normal. CONCLUSIONS: Deviations of placental shape descriptors from average have heavy-tailed distributions similar in shape to log-normal. This evidence points away from trophotropism, and towards a spontaneous stochastic evolution of the variants of placental surface shape features.

Is the placental disk really an ellipse?

The mean surface shape of placenta is round and common abnormalities of shape are associated with vascular abnormalities and reduced placental functional efficiency. A long-standing approach is to describe shapes as elliptic, and to quantify them by "length" and "breadth". We test this description in two cohorts: National Collaborative Perinatal Project and Pregnancy, Infection and Nutrition Study. We conclude that quantifying placental shape as elliptic is ambiguous and problematic. The "breadth" of the placenta should be interpreted as a combination of two different measurements: placental size and irregularity of the placental surface. It has no intrinsic functional significance.

Variety in placental shape: when does it originate?

OBJECTIVES: Observational and empirical evidence suggest that the average placental shape is round with a centrally inserted umbilical cord. Yet variability of shape is common. When in pregnancy do shape and cord insertion variations originate? MATERIALS AND METHODS: Placental measures from published datasets obtained ultrasonographically at 11-14 weeks and/or at term were correlated. RESULTS: Significant correlations were found between the normalized distance of cord insertion to the margin at 11-14 weeks with the same quantity at delivery (r = 0.509, p < 0.0001). First trimester cord marginality was not correlated with two measures of roundness of the delivered placenta (p = 0.448, and p = 0.812). There was a strong correlation between delivered placental thickness and first trimester cord marginality (r = -0.368, p = 0.009). There was a significant relationship between the cord marginality at 11-14 weeks and the mean chorionic vascular density at delivery (r = -0.287, p = 0.015). Placental position in the uterine cavity influences cord marginality at delivery. Modeling suggests that placental growth in the first trimester is non-round. Placental shape at 11-14 weeks is found to be irregular. This irregularity is not correlated with the roundness of the delivered placenta. Both empirically, and in the context of IVF pregnancies, deformation of the vasculogenic zone yields a bi-lobate placental shape. CONCLUSIONS: Our findings strongly support the hypothesis that abnormal cord insertion and a multi-lobate shape result from early influences on the placental growth, such as the shape of the vasculogenic zone, or placental position in the uterus, rather than trophotropism later in pregnancy.

IFPA Meeting 2011 workshop report II: Angiogenic signaling and regulation of fetal endothelial function; placental and fetal circulation and growth; spiral artery remodeling.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2011 there were twelve themed workshops, three of which are summarized in this report. These workshops related to vascular systems and circulation in the mother, placenta and fetus, and were divided in to 1) angiogenic signaling and regulation of fetal endothelial function; 2) placental and fetal circulation and growth; 3) spiral artery remodeling.

Placental measurements associated with intelligence quotient at age 7 years.

We hypothesized that placental villous branching that is measured by disk chorionic plate expansion and disk thickness is correlated with factors also involved in regulation of branching growth of other fetal viscera (e.g. lung, kidney) including neuronal dendrites, and thus may be associated with variation in childhood intelligence quotient (IQ). IQ at age 7 years was assessed using the Wechsler Intelligence Scale for Children. Placental measures [placental weight (g), thickness (mm), chorionic plate surface diameters (cm), area (cm2), shape, and cord length and cord eccentricity] were independent variables in regression analyses of age 7-year IQ in 12,926 singleton term live born infants with complete placental data. Analyses were stratified on gender with adjustment for socioeconomic status, race, parity, gestational age, exact age at testing and centered parental ages. After adjustment for covariates, placental measurements were independently associated with IQ at age 7 years but results varied by gender. Chorionic plate diameters were only associated with higher IQ in girls. Placental thickness was positively associated with higher IQ for boys and girls. We have previously shown that placental measures affect age 7-year body mass index and diastolic blood pressure. Here we demonstrate that specific measures, placental chorionic plate diameters in girls and disk thickness, independent of gender, are correlated with age 7-year IQ. Further exploration of the possible interaction of these factors on the placental villous arborization reflected by the chorionic plate expansion and placental thickness that correlate with age 7-year IQ, as well as other age 7 somatic features as previously addressed, is indicated.

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.

Variable placental thickness affects placental functional efficiency independent of other placental shape abnormalities.

Our previous work suggests that stressors that impact placental vascular growth result in a deformed chorionic surface shape, which reflects an abnormal placental three-dimensional shape. We propose to use variability of placental disk thickness as a reflector of deviations in placental vascular growth at the finer level of the fetal stems. We hypothesize that increased variability of thickness is associated with abnormal chorionic surface shape, but will be a predictor of reduced placental functional efficiency (smaller baby for a given placental weight) independent of shape. These measures may shed light on the mechanisms linking placental growth to risk of adult disease. The sample was drawn from the Pregnancy, Infection and Nutrition Study. In all, 94.6% of the cohort consented to placental examination. Of the 1023 delivered at term, those previously sectioned by the Pathology Department were excluded, leaving 587 (57%) cases with intact placentas that were sliced and photographed. The chorionic surface shape and the shape of a central randomly oriented placental slice were analyzed and measures were compared using correlation. Lower mean placental disk thickness and more variable disk thickness were each strongly and significantly correlated with deformed chorionic plate shapes. More variable disk thickness was strongly correlated with reduced placental efficiency independent of abnormal chorionic surface shape. Variability of placental disk thickness, simple to measure in a single randomly oriented central slice, may be an easily acquired measure that is an independent indicator of lowered placental efficiency, which may in turn program the infant and result in increased risk for development of adult diseases.

Placental surface shape, function, and effects of maternal and fetal vascular pathology.

GOAL: In clinical practice, variability of placental surface shape is common. We measure the average placental shape in a birth cohort and the effect deviations from the average have on placental functional efficiency. We test whether altered placental shape improves the specificity of histopathology diagnoses of maternal uteroplacental and fetoplacental vascular pathology for clinical outcomes. MATERIALS AND METHODS: 1225 Placentas from a prospective cohort had chorionic plate digital photographs with perimeters marked at 1-2 cm intervals. After exclusions of pre-term (n = 202) and velamentous cord insertion (n = 44), 979 (95.7%) placentas were analyzed. Median shape and mean perimeter were estimated. The relationship of fetal and placental weight was used as an index of placental efficiency termed "ß". The principal placental histopathology diagnoses of maternal uteroplacental and fetoplacental vascular pathologies were coded by review of individual lesion scores. Acute fetal inflammation was scored as a "negative control" pathology not expected to affect shape. ANOVA with Bonferroni tests for subgroup comparisons were used. RESULTS: The mean placental chorionic shape at term was round with a radius estimated at 9.1 cm. Increased variability of the placental shape was associated with lower placental functional efficiency. After stratifying on placental shape, the presence of either maternal uteroplacental or fetoplacental vascular pathology was significantly associated with lower placental efficiency only when shape was abnormal. CONCLUSIONS: Quantifying abnormality of placental shape is a meaningful clinical tool. Abnormal shapes are associated with reduced placental efficiency. We hypothesize that such shapes reflect deformations of placental vascular architecture, and that an abnormal placental shape serves as a marker of maternal uteroplacental and/or fetoplacental vascular pathology of sufficiently long standing to impact placental (and by extension, potentially fetal) development.

Birth weights smaller or larger than the placenta predict BMI and blood pressure at age 7 years.

We hypothesized that the altered placental proportions that influence birth weight affect childhood body proportions, and that these effects would be independent of birth weight. We also hypothesized that altered placental proportions might affect the fetal cardiovascular system, and may be reflected in variation in childhood blood pressure. By using linear regression with birth weight as the dependent variable, placental variables were entered as predictors. The predicted birth weights based on placental factors were then obtained. The ratio of the actual birth weight to that predicted by placental parameters (observed/expected ratio, OER) was used as the independent variable in analyses of age 7 year body mass index (BMI) and diastolic blood pressure (DBP) in the 15,902 singleton liveborns delivered between 34 and 43 weeks. The standardized residual birth weight was also used as a variable to examine the effects of birth weight that is not consistent with placental parameters. For each unit increase in the OER, BMI at 7 years increased 1 kg/m2 (P < 0.0001). The OER also had a significant effect on DBP (ß = 4.52, P < 0.001) at 7 years of age but only among African-American children. Results for the standardized residual birth weight variable were consistent with the OER. All results were adjusted for gestational age, sex, socioeconomic status, African-American race and maternal pre-pregnancy BMI. Being larger or smaller than predicted by one's placenta affects childhood body composition and blood pressure. The placental measurements provide insight into pathophysiological mechanisms of the developmental origins of adult disease.

Non-linear and gender-specific relationships among placental growth measures and the fetoplacental weight ratio.

GOALS: Fetal growth depends on placental growth; the fetoplacental weight ratio (FPR) is a common proxy for the balance between fetal and placental growth. Male and female infants are known to have differing vulnerabilities in fetal life, during parturition and in infancy. We hypothesized that these differences may be paralleled by differences in how birth weight (BW) and the fetoplacental weight ratio (FPR) are affected by changes in placental proportions. MATERIALS AND METHODS: Placental proportion measures (disk shape, larger and smaller chorionic diameters, chorionic plate area calculated as the area of an ellipse with the 2 given diameters, disk thickness, cord eccentricity and cord length) were available for 24,601 participants in the Collaborative Perinatal Project delivered between >34 and <43 completed weeks. The variables were standardized and entered into multiple automated regression splines (MARS 2.0, Salford Systems, Vista CA) to identify nonlinearities in the relationships of placental growth measures to BW and FPR with results compared for male and female infants. RESULTS: Changes in chorionic plate growth in female compared to male infants resulted in a greater change in BW and FPR. The positive effects of umbilical cord length on BW reversed at the mean umbilical cord length in females and at +0.08 SD in male infants. CONCLUSIONS: Female infants' BW and FPR are each more responsive to changes in placental chorionic plate growth dimensions than males; this may account for greater female resilience (and greater male vulnerability) to gestational stressors. The effect of umbilical cord length on FPR may be due to longer cords carrying greater fetal vascular resistance. Again male fetuses show a higher "threshold" to the negative effects of longer cords on FPR.