Placental Maturation Research Articles

Cord blood alpha klotho is decreased in small for gestational age preterm infants with placental lesions of accelerated aging

BackgroundIntrauterine growth restriction is often accompanied by placental vascular disease, of which histologic maternal vascular malperfusion is prominent. Maternal vascular malperfusion is characterized by accelerated villous maturation consistent with placental aging. Alpha klotho is an anti-aging protein produced by the placenta. We hypothesize that cord blood alpha klotho varies with maternal vascular malperfusion and small for gestational age infants through dysregulated angiogenesis. MethodsNested case-control study of 54 preterm infants (N = 22 small for gestational age infants, 32 appropriate for gestational age infants, mean gestational age = 33.7 ± 2.7 weeks) and validation sample (N = 39) from a longitudinal birth cohort at Prentice Women's Hospital, Chicago, IL. Cord blood alpha klotho was measured via enzyme-linked immunoassay; concentrations were linked to multiplex data of cord blood angiogenic growth factors. ResultsMedian cord blood alpha klotho was decreased in small for gestational age infants (1200 [859, 2083] pg/mL) versus controls (3193 [1703, 3963] pg/mL; p < 0.01) and with severe maternal vascular malperfusion (1170 [760, 2645] pg/mL; P < 0.01), consistent with validation sample. Alpha klotho was decreased with maternal vascular malperfusion sublesions signifying accelerated villous maturation, including increased syncytial knots (1230 [805, 3606] pg/mL; p < 0.05) and distal villous hypoplasia (1170 [770, 3390] pg/mL; p < 0.05). Among 15 angiogenic markers, alpha klotho correlated directly with angiopoietin-2 (beta-coefficient = 2.6, p = 0.01). ConclusionsCord blood alpha klotho is decreased with small for gestational infants and maternal vascular malperfusion sublesions of accelerated placental villous maturation, and correlated with angiopoietin-2. Alpha klotho may play a role in vascular-mediated accelerated placental aging leading to intrauterine growth restriction.

Placental Sonic Hedgehog Pathway Regulates Fetal Growth via the IGF Axis in Preeclampsia.

Placental dysfunction is the underlying cause of common major disorders of pregnancy, such as fetal growth restriction and preeclampsia. However, the mechanisms of placental dysfunction are not entirely elucidated. We previously reported 10 reliable preeclampsia pathways based on multiple microarray data sets, among which was the sonic hedgehog (SHH) pathway. In this study, we describe the significant role of SHH signaling involved in placental development and fetal growth. The placental expression levels of surrogate markers of the SHH pathway, patched homolog 1 (PTCH1) and glioma-associated oncogene homolog (GLI) 2, were evaluated using quantitative real-time PCR, western blot analysis, and immunohistochemistry. We investigated the underlying mechanisms of the SHH pathway in trophoblast syncytialization, a critical process for placental development and maturation, using primary cytotrophoblasts. Moreover, the potential roles of placental SHH signaling in the regulation of the IGF axis were explored by pathway analysis of microarray data. Finally, the influence of SHH signaling on fetal growth was examined by placental administration of cyclopamine, an SHH pathway inhibitor, to pregnant mice. The SHH pathway was downregulated in preeclampsia placentas, and its activation was highly correlated with birth weight. Trophoblast syncytialization was modulated by noncanonical SHH-adenylate cyclase (ADCY) signaling rather than canonical SHH-GLI signaling. The IGF1 receptor pathway was regulated by both noncanonical SHH-ADCY signaling and canonical SHH-GLI signaling. Inhibition of placental SHH signaling significantly reduced fetal weight in mice. Placental development and fetal growth were regulated through the SHH pathway via the IGF axis.

More Maternal Vascular Malperfusion and Chorioamnionitis in Placentas After Expectant Management vs. Immediate Delivery in Fetal Growth Restriction at (Near) Term: A Further Analysis of the DIGITAT Trial.

Objective: Management of late fetal growth restriction (FGR) is limited to adequate fetal monitoring and optimal timing of delivery. The Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT) trial compared induction of labor with expectant management in pregnancies at (near) term complicated by suspected FGR. Findings of the DIGITAT trial were that expectant monitoring prolonged pregnancy for 10 days and increased birth weight with only 130 grams. This resulted in more infants born below the 2.3rd percentile compared to induction of labor, respectively, 12.5% in induction of labor and 30.6% in expectant monitoring group. The main placental lesions associated with FGR are maternal vascular malperfusion, fetal vascular malperfusion, and villitis of unknown etiology. We investigated whether placentas of pregnancies complicated with FGR in the expectant monitoring group reveal more and more severe pathology due to pregnancy prolongation.Material and methods: The DIGITAT trial was a multicenter, randomized controlled trial with suspected FGR beyond 36 + 0 weeks. We now analyzed all available cases (n = 191) for placental pathology. The macroscopic details were collected and histological slides were recorded and classified by a single perinatal pathologist, blinded for pregnancy details and outcome. The different placental lesions were scored based on the latest international criteria for placental lesions as defined in the Amsterdam Placental Workshop Group Consensus Statement.Results: The presence of maternal vascular malperfusion and chorioamnionitis were higher in the expectant management group (p < 0.05 and p < 0.01, respectively). No differences in placental weight and maturation of the placenta between the induction of labor and the expectant management group were seen. Fetal vascular malperfusion, villitis of unknown etiology and nucleated red blood cell count did not differ between the groups.Conclusion: Expectant management of late FGR is associated with increased maternal vascular malperfusion and chorioamnionitis. This may have implications for fetal and neonatal outcome, such as programming in the developing child influencing health outcomes later in life.

Maternal circulating miRNAs that predict infant FASD outcomes influence placental maturation

Prenatal alcohol exposure (PAE), like other pregnancy complications, can result in placental insufficiency and fetal growth restriction, although the linking causal mechanisms are unclear. We previously identified 11 gestationally elevated maternal circulating miRNAs (HEamiRNAs) that predicted infant growth deficits following PAE. Here, we investigated whether these HEamiRNAs contribute to the pathology of PAE, by inhibiting trophoblast epithelial-mesenchymal transition (EMT), a pathway critical for placental development. We now report for the first time that PAE inhibits expression of placental pro-EMT pathway members in both rodents and primates, and that HEamiRNAs collectively, but not individually, mediate placental EMT inhibition. HEamiRNAs collectively, but not individually, also inhibited cell proliferation and the EMT pathway in cultured trophoblasts, while inducing cell stress, and following trophoblast syncytialization, aberrant endocrine maturation. Moreover, a single intravascular administration of the pooled murine-expressed HEamiRNAs, to pregnant mice, decreased placental and fetal growth and inhibited the expression of pro-EMT transcripts in the placenta. Our data suggest that HEamiRNAs collectively interfere with placental development, contributing to the pathology of PAE, and perhaps also, to other causes of fetal growth restriction.

Changes in Placental Morphology and their Association with Embryonic Skin Development

Abstract Histogenesis and organogenesis in mammals normally transpires in a hypoxic environment. Oxygen diffusing capacity is dependent on diffusion distance, which may vary with the thickness of placental barrier and with the level of tissue vascularity. Since the epidermis is avascular, its development fully depends on dermal blood vessels. Despite the large number of studies focusing on uteroplacental circulation and embryogenesis, it is clear that the current knowledge of how placental changes in pregnancy contribute to skin development is incomplete. The aim of this study was to evaluate the association between structural changes in the placental barrier and development of the integumentary system, with special reference to dermal angiogenesis. The study included specimens of six embryos and ten foetuses from 5 to 24 developmental weeks, and 21 specimens of placental tissue 6–40 weeks gestational age. The panel of antibodies used was S- 100, SMA, CD31, CD34, AE1/AE3 (PCKT), CKRT7, CD 56 and hCG. During the first trimester, maternal blood flow to the placenta appears to be initially restricted by trophoblast plugs. Natural killer cells appear in great abundance in subendothelium of decidual blood vessels, potentially stimulating extensive angiogenesis. By the end of the first trimester, new capillary beds organise to supply the developing epidermal derivatives. During the second trimester, the placental barrier becomes progressively thinner, and uteroplacental circulation is established due to dissolution of endovascular trophoblast plugs. Progression of the formation of skin appendages, hypodermal adipose tissue, demarcation of papillary and reticular dermis, and keratinisation of interfollicular epidermis in the second trimester strongly accompanies the dermal angiogenesis and placental maturation.

Relation between pregestational obesity and characteristics of the placenta

Objective: To evaluate the morphology of the placenta in patients with pregestational overweight (OW), pregestational obesity (PGOB), or normal weight.Methods: A cross-sectional study including women (n = 114) ≥20 years of age with a singleton pregnancy was carried out. The groups were integrated according to pregestational body mass index (BMI): 51 patients had a normal BMI (18.5–24.99 kg/m2), 30 were overweight (25–29.99 kg/m2), and 33 women were obese (≥30.0 kg/m2). A morphometric study of the placenta was performed and the placental maturity index (PMI) was calculated according to the formula: PMI = number of vasculo-syncytial membranes (VSM) in 1 mm2/VSM thickness. In the histopathological study, the presence of infarcts, calcifications, hemorrhage, thrombosis, fibrosis, cysts, and edema was determined.Results: The weight and length of newborns at birth were greater in the group with PGOB (p < .01). We observed a lower number of VSM (29 ± 9 versus 39 ± 13 and 34 ± 11) and a greater thickness (1.05 ± 0.24 versus 0.95 ± 0.08 and 0.89 ± 0.09) and, therefore, a lower PMI (29.75 ± 12.63 versus 40.88 ± 15.25 and 39.28 ± 14.4) in the group of women with PGOB compared with the group of women with OW or normal weight (p < .01). The histopathological analyses showed a greater frequency of edema and cysts in the PGOB group.Conclusion: PGOB is associated with a higher placental weight and newborn weight, a lower PMI, and the presence of histopathological alterations. The preceding points highlight the importance of promoting an appropriate pregestational weight in women of reproductive age.

Placental villous hypermaturation is associated with improved neonatal outcomes

IntroductionAccelerated placental maturation is considered a sign of maternal vascular malperfusion, and is often interpreted as an adaptive, compensatory response by the placenta. We tested this interpretation by comparing outcomes in pregnancies with and without accelerated maturation. MethodsUsing data from the National Collaborative Perinatal Project, we categorized preterm placentas (24–34 weeks, inclusive; 2525 births) by whether they showed placental villous hypermaturation (PVH), i.e., had the appearance of a placenta of 37 weeks or over upon microscopic examination. We assessed whether PVH was associated with maternal race, maternal BMI, fetal sex, type of preterm birth, preeclampsia, signs of infection or inflammation or placental abruption. We also assessed whether placentas showing PVH were associated with improved outcomes in terms of survival, Apgar score, or oxygen use. ResultsPVH was more common in preeclamptic pregnancies and less common in pregnancies complicated by placental abruption or showing signs of placental infection or inflammation. Adjusting for potentially confounding factors, PVH was associated with reduced odds of fetal death, death between birth and 120 days of age, low Apgar scores and oxygen use. PVH was also associated with higher birthweights for gestational age. When correcting for the effect of birthweight, the association between PVH and reduced fetal and neonatal death remained significant. DiscussionAccelerated placental maturation, as manifested by PVH, is associated with improved outcomes. Our work therefore supports the hypothesis that accelerated maturation is a compensatory response by the placenta to improve its transport capacity in specific pregnancy complications.

Correlating Placental ADC Values with Gestational Age and Grannum Class in Normal Placentas

Background: Recently there have been attempts to link fetal growth retardation to placental morphology as well as apparent-diffusion coefficient (ADC) values. Objectives: The purpose of this study was to investigate the possible correlation of apparent diffusion coefficient (ADC) values of normal placentas with different gestational ages and various Grannum grades (Gg). Patients and Methods: Thirty-eight women were included in this study. All women with singleton pregnancies referred for fetal MRI who were proven normal in pre/postnatal follow-up were included in the study. All placentas were evaluated by ultrasound trans-abdominally. The placenta was assessed for maximal thickness, subjective shape, presence of possible infarcts, sub-placental, and subchorionic hemorrhage. Placentas were also evaluated for G-grading and signal intensities in T2 half-fourier acquisition single-shot turbo spin-echo (HASTE) images. Diffusion weighted imaging (DWI) images were done using two b-value sets (0, 1000 and 50, 400, 800). Largest possible regions of interest (ROI) were drawn over the placenta and ADC values were correlated with gestational-age and Gg using linear regression and Kruskal-Wallis, respectively. Results: There were 11, 18, 9, 0 patients with normal looking placentas with Gg of 0, 1, 2, and 3 respectively. ADC values obtained from b values of 0, and 1000 show a significant correlation with gestational-age (R2 = 0.60, P = 0.000) and Gg (P = 0.004) respectively, while ADC values obtained from b values of 50, 400, and 800 did not show significant correlation with gestational age (R2 = 0.087, P = 0.073) or Gg (P = 0.236). Conclusion: ADC values which were obtained from sets of b values of 0 and 1000 correlated with placental maturity (both gestational age (GA) and Grannum grades). This can be attributed to lower b-values covering the microperfusion in addition to diffusion characteristics of the tissue.

Premature “aging” of placenta: myth or reality?

There was performed a retrospective analysis of pregnancy outcomes in 585 women with different placental maturity. There is given an assessment of premature “aging” of placenta in the prognosis of fetal and newborn development. The third degree of maturity of placenta at 32–34 weeks of gestation was observed more often with normal body weight of children at birth than with slowing fetal growth. In 62.5 % of cases of placental degree registration at 32–34 weeks were born newborns weighing 4000 g. The results suggest that the 3rd degree of placental maturity less than 36 weeks doesn't have a significant impact on the condition and development of the fetus and newborn.

Gimema Registry of Conception/Pregnancy in Adult Italian Patients Diagnosed with Chronic Myeloid Leukemia (CML): Report on 166 Outcomes

Background. The availability of multiple tyrosine kinase inhibitors (TKIs) and precise molecular monitoring has dramatically changed the prognosis in CML patients. With proper medical management, the planning of a pregnancy in both male (M) and female (F) patients is now possible. Towards this goal, the GIMEMA CML working party initiated a retrospective and prospective study to describe all male conceptions/female pregnancy outcomes in the CML Italian population from January 2013.Aims. The specific aims of this study were to analyze conceptions and pregnancies in male and female patients with regard to 3 general issues: 1) Illness issues, including CML treatment prior to conception/during/after pregnancy, transcript kinetics, the recovery of a lost response after therapy cessation, and the effects of treatment modifications (e.g., resistance, switching); 2) Conception/pregnancy issues, including planned, unplanned, spontaneous and medically assisted pregnancies (MAP), spontaneous/elective abortions, pregnancy progression, delivery, and breast feeding; and , 3) Post-natal health issues from birth to walking including speaking and academic performance.Patients and methods. Patients included in the study had to meet the following criteria A) Age >18 yrs; B) Confirmed CML diagnosis; C) Conception or pregnancy; D) TKI treatment before, during and/or after pregnancy; and E) Signed, IRB-approved written informed consent form. Of the 143 enrollees, data were obtained from 135 patients (83M and 52F). A total number of 166 cases were analyzable. Male conceptions were 106, and female pregnancies 60.Results 1) At time of conception 34 patients had no treatment (TF), 8 received interferon-a (IFN), and the remaining were treated with a TKI (Table 1). Considering only female patients, all stopped TKI treatment when pregnancy was discovered at 3-6 weeks (w). After placental maturation (>20w) 13 patients were treated with IFN (10), 2 with Imatinib, and 1 with Nilotinib (N). In this latter patient N concentration was tested in maternal plasma and cord blood at delivery and showed no transfer to the baby. Kinetics of rise was calculated in a subgroup of 17 patients. Doubling time [DT = duration x log(2) /log (final ratio)-log (initial ratio)] exhibits a bimodal trend, very short for some patients (5.8 days mean, range 4.5-8.2) and much longer for others (182 days mean, range 59.2-328.4), This result does not correlate with molecular status pre TF. Furthermore 76.5% of patients will not lose Major Molecular Response during pregnancy, while in TF, that is more than expected when compared to non pregnant controls (TFR). No cases of CML progression or resistance to re-treatment were observed. CML transcript ratios during pregnancy are shown in Fig.1.2) The majority of pregnancies were planned. MAPs were reported in 5M and 3F. Two spontaneous conceptions occurred in 2M after allogeneic transplant. Eleven abortions before 12 w (2 M ,induced; 9F, 5 induced) were reported (not included in the 166 cases). Pregnancies in all cases progressed normally. In F there were 2 pre-eclampsia, 2 oligohydramnios, 1 abruption placenta. In 8M and 8 F babies were born pre term and 1M and 2F were small at birth with no further consequences. Forty-two F (70%) delivered spontaneously. Babies were born at a mean 40 w (34-44) in M, 39 w (33-42) in F. Breast feeding information was collected for 45F of which18 (29%) breast feed for at least one month (range 1-28 mo).3) Post-natal information showed normal child development and growth. One respiratory arrest was noted at birth with rapid recovery and 1 macrocephaly was described with no further consequences. Of the 56 children >3 yrs old attending school (44M,12F), 2M presented with language problems and in one case autism was diagnosed. Other reported outcomes include 1 child diagnosed as having rheumatoid arthritis at 2 yr (F), and 1 diagnosed with celiac disease (M).Conclusions TKI therapy has allowed CML patients to pursue a normal life including planning/managing a family. Males do not need to stop therapy to conceive due to the therapy's non-genotoxic nature, in contrast to females who must cease therapy due to the teratogenic nature of TKIs. Kinetics of regrowth of the CML residual disease during pregnancy in female patients is different than in TFR patients. To our knowledge this is the largest multicentric study regarding CML and reproduction. Results and practical management will be presented. [Display omitted] DisclosuresAbruzzese:Novartis: Research Funding; Pfizer: Consultancy; Ariad: Consultancy; BMS: Consultancy. Castagnetti:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Rambaldi:Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Amgen Inc.: Consultancy. Gaidano:Roche: Consultancy, Honoraria; Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Magnetic resonance imaging of the human placental cotyledon: Proposal of a novel cotyledon appearance score

ObjectiveTo determine the magnetic resonance imaging (MRI)-detectable morphology of the placental cotyledon, we proposed the first cotyledon appearance scores on MRI. Cotyledon appearance scores consist of two subscores: orthogonal and parallel cotyledon appearance scores. These represent cotyledon appearance orthogonal or parallel to the placental thickness, respectively. Study designThis retrospective study was approved by the institutional review board of our hospital. A total of 51 placentas were studied. Two MRI specialists independently evaluated the two cotyledon appearance subscores at various gestational ages. Scores were related to gestational age. ResultsCotyledons were not evident in the 2nd trimester, but were identified in the 3rd trimester. Cotyledon appearance subscores increased according to gestational age, with subscores showing good inter-observer agreement. ConclusionCotyledon appearance scores determined that placental cotyledons became evident on MRI, suggesting that placental maturity progressed with gestational age. These placental MRI findings may serve as references for placental MRI to detect placental abnormalities.

EP03.14: Shear wave elastography in measurement of placenta in gestational diabetes mellitus

To establish the normal reference range of elasticity in placenta, analysis its relationship with different gestational age and placental mature grading. To compare the difference between gestational diabetes mellitus and normal pregnancy in placental elasticity. Totally 168 normal singleton fetuses between 21and 40 gestational weeks were enrolled in this study, shear wave elastography was used to measure the placental elasticity, the mean, min and max of Young modulus were recorded. The correlation between all measurements and the gestational weeks or placental maturity grading was analysed. 20 fetuses collected randomly was examined by the same/different operator to analysed the repeatability/consistency reliability. 22 placentas of A1 gestational diabetes mellitus and 14 placentas of A2 gestational diabetes mellitus were assessed and compared with the normal. 1. In all healthy controls, placental elasticity had no relationship with gestational age and placental mature grading. 2. The repeatability/consistency reliability of the data obtained by the same /two different operator were good. 3. Young's modulus in normal placenta were 4.04±0.83 kPa (mean), 2.03±0.83 kPa (min) and 6.71±1.44 kPa (max), Young's modulus in A1 gestational diabetes mellitus placenta were 6.39±1.74 kPa (mean), 2.95±1.05 kPa(min) and 10.78±2.94 kPa (max), Young's modulus in A2 gestational diabetes mellitus placenta were 11.96±7.29 kPa (mean), 6.79±4.70 kPa (min) and 18.94±11.61 kPa (max), the interquartile range were 6.54-15.02kPa (mean), 2.58-10.97kPa (min) and 10.43-27.29kPa (max). The measurements of both A1 and A2 were higher than healthy controls (p<0.05) and the measurements of A2 were higher than those of A1 (p<0.05). Placental elasticity had no relationship with gestational age and placental mature grading; Shear wave elastography can be used to measure the elasticity of placenta in normal and gestational diabetes mellitus.

Assessment of Accuracy of Three Ultrasound Methods for Prediction of Intrauterine Growth Restriction

Background: fetal growth restriction (FGR) is one of the most important complications encountered during pregnancy. The growth-restricted fetus is a fetus that fails to reach its growth potential and is at risk for adverse perinatal morbidity and mortality. The American College of Obstetricians and Gynecologists (ACOG) defines an IUGR fetus as a fetus with an estimated weight below the 10th percentile Objective: the study aimed to assess accuracy of transcerebellar diameter (TCD)/ abdominal circumference (AC) ratio, head circumference (HC)/ abdominal circumference (AC) ratio and hepato-cephalic index (HCI) in predicting intrauterine growth restriction (IUGR) after 20 weeks of gestation in pregnant women at risk of developing IUGR. Materials and Methods: a prospective nested cohort study was conducted on 77 pregnant women at risk for IUGR at Ain-Shams University Maternity hospital. all women were examined by abdominal two-dimensional ultrasound after 20 weeks of gestation to assess the sonographic gestational age (BPD, HC, FL, AC, AFI, degree of placental maturation) in fetuses. The Fetal Liver Length (FLL) and Transcelebellar Diameter (TCD) were measured at the time of the scan. Hepato-cephalic index (HCI) was calculated as Fetal Liver Length (FLL)/ Biparital diameter (BPD). TCD/AC ratio was calculated by dividing Transcerebellar diameter (TCD) and abdominal circumference (AC). HC/AC ratio was calculated by dividing Head circumference (HC) and abdominal circumference (AC). All women were followed up and an abdominal ultrasound was done after 3 weeks to confirm diagnosis of IUGR and the same fetal parameters were measured and documented Results: in predicting IUGR; TCD/AC and HC/AC have significant excellent diagnostic performance with 95%CI 0.829–1.000 and 0.851–0.974 respectively. HCI has significant moderate diagnostic performance with 95% CI 0.787–0.956. As regards comparison between the three ratios in prediction of IUGR in our study, we found that: TCD/AC with a cut-off value ≥13.77 has the highest diagnostic performance in prediction of IUGR. HC/AC with a cut-off value ≥1.04 has moderate diagnostic characteristics in prediction of IUGR. HCI with a cut-off value ≤0.55 has the lowest diagnostic characteristics in prediction of IUGR Conclusions: TCD/AC ratio had a better diagnostic validity and accuracy compared to HC/AC and HCI in predicting IUGR.

Maternal and placental responses before preterm birth: adaptations to increase fetal thyroid hormone availability?

Background: During pregnancy, maternal thyroid hormone supply is crucial for fetal development. Preterm infants often present with hypothyroxinemia. Preterm birth, either spontaneous or medically indicated, is always the result of a complicated pregnancy. We hypothesized that in preterm birth, the maternal transplacental thyroid hormone supply is influenced by the pregnancy complication and we questioned whether maternal and placental compensatory mechanisms are activated to increase thyroid hormone transfer.Methods: Observational case-control study in mother–infant-dyads with complicated pregnancies ending in spontaneous preterm birth (n = 31) or indicated preterm birth due to vascular complications (n = 45) and normal pregnancies (healthy term controls; n = 41). At delivery, maternal and cord blood and placenta samples were collected. Cord and maternal plasma concentrations of thyroid stimulating hormone (TSH), total T4, fT4/FTI, total T3, and T4 binding globulin (TBG), and maternal serum concentrations of thyroid peroxidase (TPO)-antibodies were measured. Placental maturity was evaluated histologically and mRNA and/or protein levels of thyroid hormone deiodinases (DiO) 1, 2 and 3, and transporters (MCT8, MCT10, and OATP1c1) were quantified.Results: In indicated and spontaneous preterm births, cord plasma T4 concentrations were lower than in healthy term controls (p ≤ .001), whereas T3 was only decreased in spontaneous preterm birth (p ≤ .001). Compared with spontaneous preterm births and healthy term controls, indicated preterm birth was characterized by higher maternal plasma TSH (p ≤ .05), earlier placental maturation, higher placental DiO2 gene and MCT10 protein levels and lower DiO3 gene levels (all p ≤ .01).Conclusions: Low T4 was observed in preterm infants irrespective of the cause of preterm birth, while maternal (TSH) and placental (DiO2, DiO3, and MCT10) compensatory responses were only activated in indicated preterm birth due to vascular complications. This may have mediated the normal fetal T3 availability in preterm infants born after indicated preterm birth but not after spontaneous preterm birth.

Apparent Diffusion Coefficient of the Placenta in Twin versus Singleton Pregnancies

Previous studies in singleton pregnancies reported conflicting trends in apparent diffusion coefficient (ADC) values with gestational age (GA) and stable relative ADC (rADC; ADC placenta divided by ADC globe) throughout pregnancy. The purpose of our study was to compare the ADC and rADC of placentas of twin and singleton pregnancies. Materials and Methods: Fetal MRI of 11 twin and 23 singleton pregnancies were retrospectively analyzed. Each group was further divided by GA (≤24 and >24 weeks). On ADC, 3 regions of interest were selected in the placenta and 1 in the globe. ADC and rADC measurements were compared between different GA and between singleton and twin placentas. Results: No significant difference was shown between ADC and rADC values of singleton and twin placentas as well as between ADC and rADC values of singleton and twin placentas at different GA. No significant difference was shown when accounting for both GA and number of fetuses. Conclusion: The diffusion characteristics of twin placentas are similar to those of singleton placentas. ADC and rADC remain stable throughout pregnancy in twin and singleton placentas, reflecting stable extracellular water diffusion, despite changes associated with placental maturation.

Pregnancy-associated glycoproteins in cows with retained fetal membranes

In cows, retained fetal membranes (RFM) are a major problem in reproduction. The timely detachment of fetal membranes after parturition requires well coordinated maturation processes in the placenta. One feature of placental maturation in cows is a prepartal decline in the number of binucleate trophoblast giant cells (BNC) in the fetal chorion. Pregnancy associated glycoproteins (PAGs) are a group of proteins, produced by trophoblast cells in artiodactyls. We studied aspects of PAG expression in cows with and without RFM. The numerical density of PAG-positive immunostained BNC in placentomal samples, collected from cows with normal expulsion of fetal membranes (n = 20) and cows with RFM (n = 20) was determined. The number of PAG-positive BNCs was significantly higher in cows with RFM, compared to controls. The concentration of PAGs in maternal serum in prepartum, intrapartum, and postpartum cows was measured (RFM n = 20; controls n = 68). No significant differences between RFM and controls were detected. Microarray analysis of placental PAG mRNA expression was done with two types of microarrays: Affymetrix (RFM n = 20; controls n = 20) and Agilent (RFM n = 8; controls n = 8). Both microarrays showed a significantly higher expression of modern PAGs in RFM cases.Our results show that the expression of modern PAGs, which are produced by BNCs and are secreted into the maternal organism, are differentially expressed in RFM. Although the concentration in peripheral maternal blood did not differ between RFM and controls, the local concentration in the placenta is likely to be higher in RFM cases. This suggests the possibility of local regulatory roles of PAG in the release of bovine fetal membranes.

Bovine placentomal heparanase and syndecan expression is related to placental maturation

IntroductionImpaired placental maturation has been associated with retention of fetal membranes, which is a major reproductive disease in cattle. This maturation includes alterations in all tissue compartments of the placenta, specifically of epithelial and stroma cells and extracellular matrix. It is believed to be controlled by hormones, adhesion molecules and proteolytic enzymes. To investigate if the proteolytic enzyme heparanase and its substrates, the syndecans (SDCs) could be involved in the release of fetal membranes, their expression in bovine placentomes was analyzed. MethodsPlacentomes were taken from gestational day 35 until term, directly after spontaneous parturition, after preterm caesarean section, and after chemically induced parturition. Heparanase and SDCs were localized by immunohistochemistry and the respective mRNAs were quantified by qRT-PCR. Heparanase expression was additionally quantified by Western blot. ResultsHeparanase, SDC1 and SDC4 displayed significant changes in expression and localization depending on gestational progress and mode of parturition. All three proteins showed an expression at the end of gestation, together with an altered, predominant localization in fetal and maternal epithelia. After physiological parturition, the placentomal tissue stained weaker for all syndecans. This change in staining pattern could not be observed after induced preterm parturition. SDC2 expression did not change during the course of gestation. DiscussionThe changing placental expression patterns of heparanase, SDC1 and SDC4 indicate that these molecules might be involved in fetomaternal communication and placental maturation in cattle. The matrix degrading properties of heparanase could assist in a timely reduction of fetomaternal adhesion and thus promote separation of the membranes after parturition.

Is preterm placental calcification related to adverse maternal and foetal outcome?

This prospective cohort study aimed to evaluate the role of premature placental calcification in adverse pregnancy outcomes and identify its associated potential risk factors. We consecutively enrolled 293 women who presented to three academic medical centres from September 2011 to March 2013. Participants underwent transabdominal sonographies between 28–36 weeks of gestation in an attempt to determine placental maturity. We compared maternal and foetal outcomes between two groups of women, those with grade III placenta (n = 69) and those without grade III placenta (n = 224). Passive smoking was the only predictor of early placental calcification. There were more abnormal Doppler, low birth weight (LBW) and caesarean section (CS) deliveries observed in the preterm calcification group. No definite relationship existed between maternal hypertension (HTN), diabetes and other medical diseases with placental calcification. In conclusion, umbilical artery (UA) resistance index (RI) and absent or reversed end-diastolic velocity (AREDV) were observed more often in preterm placental calcification. Serious antepartum follow-up should be advised for these mothers.Impact Statement • Placental calcification is a physiological phenomenon but normally, a grade III placenta is not frequently found until 36 weeks of gestation (so is called preterm placental calcification – PPC). There is currently a lack of consistent evidence on the clinical significance of PPC and pregnancy outcome. The present study was designed to evaluate the role of PPC in adverse pregnancy outcomes. • In our study, although none of the pregnant women were smokers, we found that passive smoking was the only predictor of PPC. Abnormal umbilical artery Doppler waveforms considerably and absent end diastolic velocity pattern significantly were observed more often in the PPC group. • We observed that PPC can be a landmark for high-risk pregnancy and an alarm sign for placental dysfunction. So, close antepartum follow up should be advised for these mothers. Regular and frequent foetal wellbeing tests should be done to prevent pregnancy complications. Certainly larger and more extensive study can provide more valid results.

Correlation between Ultrasonographic Placental Maturation Study and Pregnancy Outcome

Correlation between Ultrasonographic Placental Maturation Study and Pregnancy Outcome

G9a controls placental vascular maturation by activating the Notch Pathway.

Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation, during which blood vessels elongate. However, the cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase G9a, also known as Ehmt2, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand owing to decreased endothelial cell proliferation and increased trophoblast proliferation. Moreover, G9a deficiency altered the transcriptional switch initiating placental maturation and caused downregulation of Notch pathway effectors including Rbpj Importantly, Notch pathway activation in G9a-deficient endothelial progenitors extended embryonic life and rescued placental vascular expansion. Thus, G9a activates the Notch pathway to balance endothelial cell and trophoblast proliferation and coordinates the transcriptional switch controlling placental vascular maturation. Accordingly, G9A and RBPJ were downregulated in human placentae from IUGR-affected pregnancies, suggesting that G9a is an important regulator in placental diseases caused by defective vascular maturation.