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).

The role of morphology in mathematical models of placental gas exchange.

The performance of the placenta as a gas exchanger has a direct impact on the future health of the newborn. To provide accurate estimates of respiratory gas exchange rates, placenta models need to account for both the physiology of exchange and the organ morphology. While the former has been extensively studied, accounting for the latter is still a challenge. The geometrical complexity of placental structure requires use of carefully crafted approximations. We present here the state of the art of respiratory gas exchange placenta modeling and demonstrate the influence of the morphology description on model predictions. Advantages and shortcomings of various classes of models are discussed, and experimental techniques that may be used for model validation are summarized. Several directions for future development are suggested.

Relationships between misreported energy intake and pregnancy in the pregnancy, infection and nutrition study: new insights from a dynamic energy balance model.

OBJECTIVE: Providing effective dietary counselling so that pregnancy weight gain remains within the 2009 Institute of Medicine (IOM) guidelines requires accurate maternal energy intake measures. Current practice is based on self-reported intake that has been demonstrated unreliable. This study applies an objective calculation of energy intake from a validated mathematical model to identify characteristics of individuals more likely to misreport during pregnancy. METHODS: A validated maternal energy balance equation was used to calculate energy intake from gestational weight gain in 1,368 subjects. The difference between self-reported and model-predicted energy intake was tested for demographics, economic status, education level and maternal health status. RESULTS: A weight gain of 15.2 kg resulted in model-predicted intake during pregnancy of 2,882.97 ± 135.71 kcal day-1, which differed from self-reported intake of 2,180.5 ± 856.0 kcal day-1. The achieved weight gain exceeded the IOM guidelines; however, the model predicted weight gain from self-reported energy intake was below IOM guidelines. Higher income (p = 0.004), education (p = 0.003), birth weight (p = 0.017), gestational diabetes (p = 0.008) and pre-existing diabetes (p < 0.001) were associated with under-reported energy intake. More children living at home (p = 0.001) were associated with more accurate self-reported intake. CONCLUSIONS: When assessing self-reported energy intake in pregnancy studies, birth weight, gestational diabetes status, pre-existing diabetes, higher income and education predict higher under-reporting. Clinicians providing dietary treatment recommendations during pregnancy should be aware that individuals with pre-existing diabetes and gestational diabetes mellitus are more likely to misreport their intake. Additionally, the systems model approach can be applied early in intervention to objectively monitor dietary compliance to treatment recommendations.

Placental 11ß-Hydroxysteroid dehydrogenase type 2 expression: Correlations with birth weight and placental metal concentrations.

INTRODUCTION: Infants born below 2500 g are classified as low birth weight. Excess in utero exposure to cortisol has been linked to restricted fetal growth. Placental production of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) inactivates cortisol before passage into the fetus. The present study tested the hypothesis that placental 11ß-HSD2 expression is positively correlated with an individualized birth weight centile and raw birth weight, and examines the relationship between metal concentrations in placental tissue and 11ß-HSD2 expression. METHODS: Placentae from 191 births were collected and samples preserved to maintain mRNA profile. Placental 11ß-HSD2 expression was measured via qRT-PCR. Addition samples were collected from placental tissues and uniformly dried in order to quantify 18 metals via ICP-MS (n = 160). RESULTS: A significant, positive correlation between 11ß-HSD2 expression and individualized birth weight centile (p = 0.0321) and birth weight (p = 0.0243) was found. Additionally, maternal age and gestational age were positivity correlated with each other (p = 0.0321). Birth weight was significantly different with race, marital status, education and maternal tobacco use. Four metals (Co, Mn, Ni, Zn) demonstrated significant positive correlations (p < 0.05) with 11ß-HSD2 expression. Sex specific differences were found; Co, Cu, Fe, Zn, and Ni were positively correlated with 11ß-HSD2 expression in males only, no significant correlations were found in the female only sample. CONCLUSION: These data indicate that the growth potential of a fetus is related to the 11ß-HSD2 expression in the placenta, and that 11ß-HSD2 expression is related to the trace metals status of the mother.

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.

IFPA Meeting 2013 Workshop Report II: use of 'omics' in understanding placental development, bioinformatics tools for gene expression analysis, planning and coordination of a placenta research network, placental imaging, evolutionary approaches to understanding pre-eclampsia.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At the IFPA meeting 2013 twelve themed workshops were presented, five of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of new technologies for placenta research: 1) use of 'omics' in understanding placental development and pathologies; 2) bioinformatics and use of omics technologies; 3) planning and coordination of a placenta research network; 4) clinical imaging and pathological outcomes; 5) placental evolution.

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.