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.

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.

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.

Transanal haemorrhoidal artery echodoppler ligation and anopexy (THD) is effective for II and III degree haemorrhoids: a prospective multicentric study.

AIM: We report a multicentric prospective study which aimed to evaluate Doppler-assisted ligation of the terminal haemorrhoidal arteries (THD) for II and III degree haemorrhoids. METHOD: A total of 112 patients from five colorectal units, including 81 men, mean age 48 +/- 13 years, with II degree (39) and III degree (73) haemorrhoids were treated by Doppler-guided transanal de-arterialization and anopexy using a new device (THD). RESULTS: The mean operative time was 33.9 +/- 8.8 minutes, and the mean number of ligatures applied was 7.2 +/- 1.5. Postoperatively, 72% of patients did not need analgesics and the other 28% used nonsteroidal antiinflammatory drugs 1-3 times/day for less than 2 days. All the patients were operated as a day case. Early postoperative complications included haemorrhoidal thrombosis (2 patients), bleeding (1) treated by haemostatic suture, dysuria (6) and acute urinary retention (1). After a mean follow-up of 15.6 +/- 6.5 months (range 6-32), 2/105 (20.9%) patients complained of minor bleeding, while mild pain was still present in 4/51 patients (7.8%). There were no statistically significant differences in the sample population regarding the gender or stage of the disease. Tenesmus was cured in 15/17 patients, dyschaezia in 20/22 patients and mucous soiling in 10/10 patients. No new cases of altered defaecation or faecal incontinence were recorded. Overall, 85.7% of patients were cured and 7.1% improved. Residual haemorrhoids were treated by elastic band ligation in nine (8%) patients and by surgical excision in further five patients (4.5%). CONCLUSION: Doppler-assisted ligation of the terminal branches of the haemorrhoidal arteries for II and III degree haemorrhoids is highly effective and painless. Complications are few and the technique can be performed as a day case.

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.

Ligasure Precise vs. conventional diathermy for Milligan-Morgan hemorrhoidectomy: a prospective, randomized, multicenter trial.

PURPOSE: Milligan-Morgan hemorrhoidectomy using radiofrequency dissection (Ligasure) has been proposed instead of conventional diathermy in view of its potential benefits in terms of postoperative anal pain and better hemostatic control, but the medical literature is still controversial. This multicenter, randomized, controlled trial was designed to compare the outcomes between Ligasure and conventional diathermy hemorrhoidectomy in the Milligan-Morgan procedures in a sufficient number of patients. METHODS: Patients with Grades III and IV hemorrhoids were randomized to two groups: Ligasure hemorrhoidectomy and conventional diathermy. Postoperative anal pain was measured by the Visual Analog Scale (VAS) and the analgesia required. Postoperative complications, wound healing, and return to working activities also were evaluated as secondary outcomes. RESULTS: A total of 273 patients, well matched for age, gender, working activity and grade of hemorrhoids, were randomized to two groups: Ligasure 146, and diathermy 127. The severity of postoperative anal pain was significantly less in the Ligasure group when measured at least 12 hours after defecation (P < 0.01), whereas it was similar at the time of defecation. The Ligasure group had significantly lower requirements for painkiller pills. There were no significant differences in early and late complications. Return to work and normal activities was significantly faster in the Ligasure group. CONCLUSION: Ligasure hemorrhoidectomy is an effective procedure for Grades III and IV hemorrhoids and facilitates a faster return to work and normal activities by reducing postoperative pain.

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.

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.

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.

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.

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.

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.

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.

Cigarette smoking and pregnancy II: vascular effects.

The act of smoking introduces a complex set of chemicals that have a broad range of effects, both complementary and antagonistic, at various levels within the vascular tree. A general review of these systemic effects is followed by a summary of documented effects of smoking on the uterine vasculature and of relationships of smoking to pregnancy outcomes known to be associated with vascular pathology. Last, we offer a potential resolution for the apparent paradox of the seemingly 'protective' effect of smoking to reduce the incidence of pre-eclampsia, one of the most serious vascular complications of pregnancy.

Cigarette smoking and pregnancy I: ovarian, uterine and placental effects.

This review examines the major observations and principal controversies relating to the effects of smoking and the constituents of tobacco on ovarian, uterine and placental tissues. Maternal exposure is assessed relative to specific tobacco-related chemicals and the feto-placental impact of mutagenic products, in addition to nicotine replacement as a pharmacological intervention for smoking cessation. Important new information is being learned from clinical in vitro fertilization and assisted reproduction technologies regarding the effects of smoking on fertility. Present evidence supports an adverse effect of smoking on ovarian function which is prolonged and dose-dependent, whereas there appear to be more reversible effects on implantation and ongoing pregnancy. The anti-oestrogenic effect of smoking is reviewed in terms of direct effects of nicotine, cadmium and polyaromatic hydrocarbons on oestrogen synthesis and metabolism, oocytes and granulosa-luteal function. Innovative new models provide evidence that smoking may alter fertility through effects on uterine-fallopian tube functions which mediate gamete and conceptus transport. It is of interest that smoking is associated with a decreased incidence of uterine fibroids, endometriosis and uterine cancer, which may reflect inhibitory effects of smoke constituents on uterine cell proliferation and extracellular matrix interactions. The increased miscarriage rate among mothers who smoke may be related to direct adverse effects of nicotine, cadmium and polyaromatic hydrocarbons on trophoblast invasion and proliferation. In this respect, alterations in trophoblast differentiation along invasive or proliferative pathways may explain the changes in endocrine function and vascular morphology that are observed in smokers. In summary, significant advances are being made in the understanding of cellular and molecular mechanisms which underlie the differential effects of cigarette smoking on reproductive tissues.