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The use of immunosuppressive drugs guarantees the vitality of the graft and allows gestation in spite of intercurrences such as prematurity and intrauterine growth restriction. However, little is known about the direct effects of immunosuppressive drugs on placental cells. We investigated the effects of immunosuppressive drugs in the chorionic villous explants from human term placentas of healthy gestations. Human placental explants from term gestations (37-39 week gestational age, n = 12) were exposed to cyclosporine A (CSA, 0, 62.5, 125, 1250 ng/mL) or azathioprine (AZA, 0, 5, 10, 100 ng/mL) separately or, in combination for up to 48 hours. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed a significant decrease in the explant metabolic activity between AZA and the control group (24 hours, 100 ng/mL, 48 hours, all concentrations, P < .005). Cyclosporin A (CsA) reduced cell activity when associated with AZA (48 hours, P < .005). Fibrinoid deposits increased in AZA-treated explants alone (5 ng/mL, 48 hours; 10 ng/mL, 24-48 hours; P < .005) or when associated with CsA (10 AZA/125 CsA, P < .05), whereas in CsA treatment alone, there was an augment in syncytial knots (24-48 hours, P < .005). The sFLT1 gene (24 hours, P < .05) and protein ( P < .005) expression increased in AZA and CsA-treatments separately or in combination ( P < .05). Placental growth factor increased in AZA (24 hours, 10 ng/mL) and CsA (125 ng/mL; P < .05). In conclusion, our data indicate that AZA primarily acts on the villous metabolism, perturbing placental homeostasis. Since these drugs may alter the balance of angiogenic factors in its selection for clinical application, their impact on the behavior of placental villous should be considered.

Objective:: The aim of the present study was to compare the placental weight and birth weight/placental weight ratio for intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins., Methods:: This was a retrospective analysis of placentas from twin pregnancies. Placental weight and the birth weight/placental weight ratio were compared in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins. The association between cord insertion type and placental lesions in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins was also investigated., Results:: A total of 105 monochorionic (intrauterine growth restriction=40; non-intrauterine growth restriction=65) and 219 dichorionic (intrauterine growth restriction=57; non-intrauterine growth restriction=162) placentas were analyzed. A significantly lower placental weight was observed in intrauterine growth-restricted monochorionic (p=0.022) and dichorionic (p<0.001) twins compared to non-intrauterine growth-restricted twins. There was no difference in the birth weight/placental weight ratio between the intrauterine growth restriction and non-intrauterine growth restriction groups for either monochorionic (p=0.36) or dichorionic (p=0.68) twins. Placental weight and the birth weight/placental weight ratio were not associated with cord insertion type or with placental lesions., Conclusion:: Low placental weight, and consequently reduced functional mass, appears to be involved in fetal growth restriction in monochorionic and dichorionic twins. The mechanism by which low placental weight influences the birth weight/placental weight ratio in intrauterine growth-restricted monochorionic and dichorionic twins needs to be determined in larger prospective studies.

Problem: In twin pregnancies, factors that influence total umbilical cord IgG concentration and IgG transfer ratio are not well known., Method: Blood samples were prospectively collected from 57 twin pregnancies. Stepwise multivariate regression analysis was used to evaluate the association between total IgG levels in the umbilical cord blood and IgG transfer ratio according to serum IgG concentration, pregnancy chorionicity, the presence of abnormal umbilical artery pulsatility index, intrauterine growth restriction, gestational age at delivery (GAD), birthweight, and placental weight., Results: Umbilical cord IgG concentration showed a positive correlation with serum IgG concentration and GAD; levels were significantly lower in monochorionic compared with dichorionic pregnancies. IgG transfer ratio also increased with GAD but was inversely correlated with serum IgG concentration levels., Conclusion: In twin pregnancies, besides serum IgG concentration and GAD, chorionicity also influences umbilical cord IgG concentration. Monochorionic twins have lower IgG cord concentration than dichorionic twins., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The serum amyloid A (SAA) protein is known to function in the acute phase response and immunoregulation. Recently, SAA has been shown to be involved in cell proliferation, differentiation and migratory behavior in different cell types. Here, we evaluated whether exogenous SAA could influence trophoblast invasion and differentiation using both the trophoblast-like BeWo cell line and fully differentiated human extravillous trophoblast cells (EVT) isolated from term placentae. SAA stimulated BeWo cell invasion, as measured in Matrigel invasion assays, and induced metalloprotease mRNA expression and activity. Given that BeWo cells express Toll-like receptor 4 (TLR4), a known receptor for SAA, we examined the role of TLR4 in SAA-induced invasion using a TLR4 neutralizing antibody. We also tested whether SAA could affect markers of trophoblast syncytialization in BeWo cells. We observed that SAA decreased βhCG secretion and did not influence trophoblast syncytialization. Using EVT cells isolated from human term basal plates, we confirmed that SAA at 1 and 10 µg/mL doubled EVT invasion in a TLR4-dependent manner, but at 20 µg/mL inhibited EVT cells invasiveness. In addition, we observed that SAA was expressed in both BeWo cells and human term placentae, specifically in the syncytiotrophoblast, decidual cells and EVT. In conclusion, SAA was identified as a molecule that functions in the placental microenvironment to regulate metalloprotease activity and trophoblast invasion, which are key processes in placentation and placental homeostasis.

Objectives: The purpose of this study was to evaluate the association between placental volumes, placental vascularity, and hypertensive disorders in pregnancy., Methods: A prospective case-control study was conducted between April 2011 and July 2012. Placental volumes and vascularity were evaluated by 3-dimensional sonographic, 3-dimensional power Doppler histographic, and 2-dimensional color Doppler studies. Pregnant women were classified as normotensive or hypertensive and stratified by the nature of their hypertensive disorders. The following variables were evaluated: observed-to-expected placental volume ratio, placental volume-to-estimated fetal weight ratio, placental vascular indices, and pulsatility indices of the right and left uterine and umbilical arteries., Results: Sixty-six healthy pregnant women and 62 pregnant women with hypertensive disorders were evaluated (matched by maternal age, gestational age at sonography, and parity). Placental volumes were not reduced in pregnancy in women with hypertensive disorders (P > .05). Conversely, reduced placental vascularization indices (vascularization index and vascularization-flow index) were observed in pregnancies complicated by hypertensive disorders (P < .01; P < .01), especially in patients with superimposed preeclampsia (P = .04; P = .02). A weak correlation was observed between placental volumes, placental vascular indices, and Doppler studies of the uterine and umbilical arteries., Conclusions: Pregnancies complicated by hypertensive disorders are associated with reduced placental vascularity but not with reduced placental volumes. These findings are independent of changes in uterine artery Doppler studies. Future studies of the prediction of preeclampsia may focus on placental vascularity in combination with results of Doppler studies of the uterine arteries.

The aim of the present study was to analyse the influence of stress on pregnant rats, particularly in terms of maternal, placental and fetal weight, placental morphology and placental gene expression of the angiogenic factors Vegfa and Pgf and their receptors. The parameters were evaluated on gestation Day 20. Maternal, fetal and placental weights were statistically lower in stressed animals than controls, suggesting abnormalities in gestational physiology. Morphologically the placentas of rats subjected to stress were reduced in size and weight, with few glycogen cells and a significant increase in the number of apoptotic cells. Stress caused an increase in placental gene expression of Vegfa (P<0.05) and a reduction in Pgf, Flt1 and Kdr expression (P<0.05). It has been suggested that increased VEGF is associated with vasodilatation and hypotension, but in this model persistent hypertension was present. This study suggests that the limited hypotensive Vegfa response to stress-induced hypertension could result from reduced expression of Flt1/Kdr disrupting specific VEGF pathways. These findings may elucidate one of the multiple possible factors underlying how stress modulates placental physiology, and could aid the understanding of stress-induced gestational disorders.

Evaluate the distribution and variation of placental vascular indices according to gestational age and placental volume. From March to November 2007, three-dimensional (3D)-power Doppler ultrasound was performed in 295 normal pregnancies from 12 to 40 weeks of gestation. Using the same preestablished settings for all patients, power Doppler was applied to the placenta and placental volume was obtained by the rotational technique (VOCAL). The 3D-power histogram was used to determine the placental vascular indices: vascularization index (VI), flow index (FI) and vascularization-flow index (VFI). The placental vascular indices were then plotted against gestational age and placental volume. All placental vascular indices showed constant distribution throughout gestation. A tendency for a reduction in placental vascular indices with increased placental volume was observed, but was only statistically significant when placental FI was considered (p<0.05). All placental vascular indices estimated by 3D-power Doppler ultrasonography presented constant distribution throughout gestation, despite the increase in placental volume according to gestational age.

Objective: The purpose of this study was to construct nomograms of placental volumes according to gestational age and estimated fetal weight., Methods: From March to November 2007, placental volumes were prospectively measured by ultrasonography in 295 normal pregnancies from 12 to 40 weeks' gestation and correlated with gestational age and estimated fetal weight. Inclusion criteria were healthy women, singleton pregnancies with normal fetal morphologic characteristics on ultrasonography, and confirmed gestational age by first-trimester ultrasonography., Results: The mean placental volume ranged from 83 cm(3) at 12 weeks to 427.7 cm(3) at 40 weeks. Linear regression yielded the following formula for the expected placental volumes (ePV) according to gestational age (GA): ePV (cm(3)) = -64.68 + 12.31 x GA (r = 0.572; P < .001). Placental volumes also varied according to estimated fetal weight (EFW), and the following mathematical equation was also obtained by linear regression: ePV = 94.19 + 0.09 x EFW (r = 0.505; P < 0.001)., Conclusions: Nomograms of placental volumes according to gestational age and estimated fetal weight were constructed, generating reference values.

Purpose: The aim of this study was to compare pregnancy outcome and pathologic findings in cases of placental lake visualized on sonography in pregnancies without concurrent fetal or maternal disease., Methods: Placental aspect was evaluated sonographically in 4,106 singleton pregnancies without maternal or fetal disease at between 15 and 34 weeks3 gestation. Fifty-nine cases presenting with placental lakes were followed through the end of pregnancy. Obstetric outcome was compared with that of cases with sonographically normal placental aspects (n=37). Macroscopic and microscopic examinations for pathology were also performed in a few cases in both groups., Results: Placental lakes were present in 2.2% (92/4,106) of the cases. No statistically significant difference was observed in birth weight, gestational age at delivery, adverse obstetric outcome, and macroscopic or microscopic results between the control and study groups., Conclusion: Our findings do not seem to indicate an increase in the risk for an adverse pregnancy outcome in cases presenting with placental lakes.

The various neurohumoral and intrinsic factors that control the uteroplacental hemodynamics in health and disease and in responses to physiologic and pharmacologic stimuli have been reviewed. The following conclusions may be derived: We still need improvement in our methodology of monitoring uterine blood flow. The present methods, which have some reliability, are not easily applicable to human subjects and even in animals their use presents problems of accuracy and sensitivity with which the investigator must become familiar. The marked and progressive increase in uterine blood flow that occurs during pregnancy is caused by complex factors, some of which are hormonal and hemodynamic in nature. The increased vascularity of the pregnant uterus and the opening of the arterioles during the process of formation of the intervillous space are important factors that facilitate the increase in uterine blood flow. The increment seems to be totally derived from the increment in the cardiac output that occurs during pregnancy. There seems to be no redistribution among the regional blood flows of the body. In the anesthetized condition the blood flow to the uterus depends largely on the perfusing pressure; the critical closing pressure seems to be around the 40 mm Hg level. This linear flow-pressure relationship does not, however, apply to the unanesthetized condition. A rise or fall in the perfusing pressure in the conscious state may be accompanied by an increase or decrease in the uterine blood flow, depending on the underlying mechanisms. Factors that lead to alpha-adrenergic stimulation produce an increase in uterine vascular resistance and a decrease in flow, irrespective of the status of the perfusing pressure. beta-adrenergic stimulation may increase uterine blood flow either through their vasodilating action or through their myometrial relaxing effects. Hypertensive diseases are most often accompanied by a decrease in uterine blood flow, whereas hypoxic states may decrease the flow even though the arterial pressure may not change significantly. It is extremely risky to extrapolate from information obtained in the anesthetized animal to the unanesthetized, conscious animal. Likewise, data obtained from normotensive conditions may not hold true for the hypertensive or hypotensive states. This is of particular relevance when one is dealing with the effects of pharmacologic agents that act on the cardiovascular system. Uterine contractions, whether induced through spontaneous or oxytocin-induced labor, produce a decrease in uterine blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

An abstract of the research paper "Computerized fetal heart rate analysis in the prediction of myocardial damage in pregnancies with placental insufficiency," by M.Y. Maeda and colleagues is presented.

An abstract of the conference paper "Fetal venosus Doppler velocimetry in twin pregnancies with placental insufficiency," by R. Nomura and colleagues, is presented.