SMI for imaging of placental infarction

Since superb Micro-vascular Imaging (SMI) is a new blood flow imaging technique that employs a unique algorithm to minimize motion artifacts, it can visualize low-velocity blood flow in small vessels. We demonstrate SMI imaging of the placental infarction in a case with fetal growth restriction, comparing a normal placenta on the same gestation. While SMI image in normal placenta clearly shows structures from the branching vessels to the peripheral villous trees in the cotyledons, they could not be seen in the case of fetal growth restriction. We think that the clinical value and future potential of SMI in placental evaluation have been clearly demonstrated.     

Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction

IntroductionDiscriminating between placentally-mediated fetal growth restriction and constitutionally-small fetuses is a challenge in obstetric practice. Placental growth factor (PlGF), measurable in the maternal circulation, may have this discriminatory capacity.MethodsPlasma PlGF was measured in women presenting with suspected fetal growth restriction (FGR; ultrasound fetal abdominal circumference <10th percentile for gestational age) at sites in Canada, New Zealand and the United Kingdom. When available, placenta tissue underwent histopathological examination for lesions indicating placental dysfunction, blinded to PlGF and clinical outcome. Lesions were evaluated according to pre-specified severity criteria and an overall severity grade was assigned (0–3, absent to severe). Low PlGF (concentration <5th percentile for gestational age) to identify placental FGR (severity grade ≥ 2) was assessed and compared with routine parameters for fetal assessment. For all cases, the relationship between PlGF and the sampling-to-delivery interval was determined.ResultsLow PlGF identified placental FGR with an area under the receiver-operator characteristic curve of 0.96 [95% CI 0.93–0.98], 98.2% [95% CI 90.5–99.9] sensitivity and 75.1% [95% CI 67.6–81.7] specificity. Negative and positive predictive values were 99.2% [95% CI 95.4–99.9] and 58.5% [95% CI 47.9–68.6], respectively. Low PlGF outperformed gestational age, abdominal circumference and umbilical artery resistance index in predicting placental FGR. Very low PlGF (<12 pg/mL) was associated with shorter sampling-to-delivery intervals than normal PlGF (13 vs. 29.5 days, P < 0.0001).DiscussionLow PlGF identifies small fetuses with significant underlying placental pathology and is a promising tool for antenatal discrimination of FGR from fetuses who are constitutionally-small.     

Restriction of placental vasculature in a non-human primate: a unique model to study placental plasticity

The limits of placental plasticity, i.e., the ability of the placenta to adapt and alter its growth trajectory in response to altered fetal requirements, are not known. We report fetal and placental hemodynamic adaptations in a novel non-human primate model in which the fetal inter-placental bridging vessels were surgically ligated. Doppler ultrasound studies showed that the rhesus placenta compensates for an approximate 40% reduction in functional capacity by increased growth and maintenance of umbilical volume blood flow. This unique experimental animal model has applications for mechanistic studies of placental plasticity and the impact on fetal development.     

Angiogenic factors at diagnosis of late-onset small-for-gestational age and histological placental underperfusion

Objective

This study was designed to explore the association between angiogenic factors levels at diagnosis of small-for-gestational age (SGA) and placental underperfusion (PUP).

Methods

In a cohort of SGA singleton pregnancies, each delivered at >34 weeks, uterine (UtA), umbilical (UA), and middle cerebral (MCA) arteries were evaluated by Doppler upon diagnosis of SGA status. In addition, maternal circulating concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were assayed by ELISA, and each placenta was evaluated for histologic signs of PUP using a hierarchical and standardized classification system. Logistic regression was applied to analyze independent relationships (at diagnosis) between angiogenic factors and Doppler parameters.

Results

A total of 122 suspected SGA pregnancies were studied, 70 (57.4%) of which ultimately met PUP criteria. In this group, 85 placental findings qualified as PUP. Both mean UtA pulsatility index z-values (1.26 vs. 0.84; p = 0.038) and PlGF multiples of normal median (0.21 vs. 0.55; p = 0.002) differed significantly in pregnancies with and without PUP, respectively. By logistic regression, PlGF alone was independently predictive of PUP (OR = 0.11 [95% CI 0.025–0.57]; p = 0.008).

Discussion

Histologic placental abnormalities in term SGA neonates reflect latent insufficiency in uteroplacental blood supply. The heightened risk of adverse perinatal outcomes in this context underscores a need for new Doppler or biochemical prenatal markers of placental disease. Angiogenic factors may be pivotal identifying SGA neonates.

Conclusions

Diminished circulating levels of placental growth factor, determined upon discovery of SGA status, are associated with histologic evidence of PUP.     

Recapitulation of characteristics of human placental vascular insufficiency in a novel mouse model

Objective

We tested the effects of selective reduction of placental blood flow by mesenteric uterine artery branch ligation (MUAL) resulting in fetal growth restriction (FGR).

Methods

Timed mated C57BL/6J Day(D) 18 dams were divided into two groups: MUAL (n = 18); and control-sham (n = 18). Pups were delivered on D20, cross-fostered to surrogate CD-1 mothers for 4 weeks, and followed for 8 weeks. Outcome data included birth and placental weight, postnatal growth, placental volume determined by stereology, quantification of placental insulin-like growth factors-1(IGF-1) and IGF-2 and IGF binding proteins(IGFBP 2 and 6) by ELISA and gene expression by qPCR and GeneChip microarray analysis.

Results

Compared with control, MUAL had an 11% reduction in mean birth weight (1.06 ± 0.13 g vs. 0.94 ± 0.13 g, p < 0.001) but no difference in placental weight. At 4 weeks of age, mean body weights of MUAL pups were significantly lower than sham. By 8 weeks, males but not females MUAL mice achieved equivalent mean body weight to control. Placental labyrinth depth, volume, and placental gene expression of IGF-1 and 2 were significantly reduced by MUAL. In contrast, placental protein level of IGFBP-2 and 6 were significantly elevated in the MUAL. Genomic expression analysis demonstrated that MUAL pups significantly up-regulated genes that were associated with apoptosis and growth pathways.

Conclusion

This novel mouse animal model of FGR using selective ligation recapitulates multiple characteristics of placental vascular insufficiency (PI) in humans. This is the first non-genetic mouse model of PI which offers its application in transgenic mice to better study the underlying mechanisms in PI.

Condensation

A new mouse model of placental vascular insufficiency by selective ligation of mesenteric uterine artery branch recapitulates multiple findings observed in human placental vascular insufficiency.     

First trimester prediction of ischemic placental disease

Ischemic placental disease is characterized by one or more of the clinical manifestations of preeclampsia, fetal growth restriction, and/or placental abruption, resulting in indicated preterm delivery. Since over half of the indicated preterm deliveries are due to ischemic placental disease, accurate early prediction of the disease is of paramount importance in developing prevention strategies. This review article focuses on studies that have used the first trimester aneuploidy screening timing window to predict those patients who later develop ischemic placental disease. Emphasis was given to studies originating from the Fetal Medicine Foundation because of their uniformity in definitions and expertise of the personnel who performed the ultrasound screening exams.     

Inflammation-induced fetal growth restriction in rats is associated with altered placental morphometrics

Introduction

Evidence links alterations in placental shape and size to fetal growth restriction (FGR). Here we determined whether alterations in placental morphometrics are linked to FGR induced by abnormal maternal inflammation.

Methods

We used an inflammation-induced model of FGR in which pregnant rats receive lipopolysaccharide (LPS) on gestational days (GD) 13.5–16.5. Fetal weights were matched to various parameters of placental morphometrics including weight, area, minor and major axes lengths and thickness.

Results

Compared with saline administration, LPS administration was associated with altered placental morphometrics, including reduced placental weight, decreased placental area and a trend towards reduced placental thickness. When data were dichotomized as FGR or normal-sized fetuses within treatment groups, a significant increase in the placental-weight-to-fetal-weight ratio and placental thickness was observed only in the saline-associated FGR subgroup. Multivariable linear regression revealed that the lengths of the major and minor placental axes were predictors of fetal weight, regardless of treatment modality. Subgroup regression analysis by treatment revealed that the lengths of the major and minor placental axes were predictors of fetal weight in the saline-treatment group while only the minor placental axis was a predictor of fetal weight in the LPS cohort. Finally, placental area and the length of the minor placental axis were correlated with implantation site location only in the saline-treatment group.

Discussion/conclusion

These findings indicate that inflammation-induced FGR is associated with alterations in placental morphometrics. Our data reveal that the mechanisms leading to inflammation-induced FGR may be different from the mechanisms leading to idiopathic FGR.     

Long-term maternal morbidity and mortality associated with ischemic placental disease

Ischemic placental disease can have long-term maternal health implications. In this article, we discuss the three conditions of ischemic placental disease (preeclampsia, fetal growth restriction, and abruption placenta) and its associated long-term maternal morbidity. Retrospective observational studies comparing pregnancies complicated by ischemic placental disease to uncomplicated pregnancies suggest an increased long-term risk of hypertension, cardiovascular death, metabolic syndrome, and cerebrovascular disease. This association is much stronger in women who had an indicated-preterm delivery due to ischemic placental disease. It is important to adequately counsel women who are diagnosed with these conditions about their future health risks. Increased awareness of the potential health risks and multidisciplinary collaboration remains paramount to instituting the appropriate screening and preventative strategies (i.e., behavior modification) for affected women.     

Measurement of placental bed vascularization in the first trimester,using 3D-power-Doppler,for the detection of pregnancies at-risk for fetal and maternal complications

Objective

To evaluate the performance of placental bed vascularization in a low-risk population to predict severe pregnancy risks. Vascularization was measured in the first trimester, using 3D power-Doppler vascularization index.

Methods

All women who registered during a period of 3 years for delivery in our hospital were prospectively screened in the first trimester. Power Doppler vascularization index of the placental bed (PBVI) was measured in 4325 women and correlated to 7 outcome groups: 1) normal, 2) IUGR ≤ 3rd centile, 3) delivery ≤ 34 weeks, 4) pregnancy induced hypertension (PIH), 5) all pre-eclampsia (PE), 6) severe PE, 7) severe pregnancy problems (SPP i.e. PIH or PE plus IUGR ≤ 3rd centile and/or delivery ≤ 34 weeks). In addition, measurements of mean uterine artery Doppler at 12 and 22 weeks, placental volume and PAPP-A were also performed on all women and their predictive strength for pregnancy risks was compared with the PBVI.

Results

Severe PE and SPP occurred in 0.6 vs. 1.5% of all pregnancies. First trimester PBVI below the 10th centile detected 60% of severe PE and 66.2% of SPP, the odds ratio being 4.48 (95th CI 1.98–11.82) for severe PE and 9.92 (95th CI 5.55–17.71) for SPP. Second trimester uterine artery Doppler detected 72% of PE and 50.8% of SPP, the odds ratio being 14.58 (95th CI 5.78–36.79) and 5.46 (95th CI 3.18–9.36) respectively. All other measured parameters performed much worse compared to PBVI and 22 weeks uterine artery Doppler.

Conclusion

Placental bed vascularization index could be used for a quick and reliable first trimester assessment of severe pregnancy risks.     

The lifespan of men and the shape of their placental surface at birth

Background

Tall men generally lead longer lives than short men. Within the Helsinki Birth Cohort, however, there is a group of boys among whom being tall when they entered school was associated with reduced lifespan. These boys had birthweights and maternal heights above the median for the cohort; but they tended to be lighter at birth than their mother’s body mass index (weight/height²) in pregnancy predicted. We suggested that, while they had grown rapidly in utero, their growth had faltered at some point; and their tallness at age seven was the result of a resumption during infancy of their rapid growth trajectory. We here examine the size and shape of their placentas at birth to gain further insight into their path of fetal growth.

Methods

We examined all cause mortality in the 1217 men who had birthweights and maternal heights above the median for the cohort. Their birth measurements included placental weight and the length and breadth of the placental surface.

Results

Shorter length of the placental surface was associated with increased mortality (p = 0.002). There was no similar trend with the breadth. Mortality rose as the difference between the length and breadth decreased, that is as the surface became rounder. The hazard ratio was 1.10 (1.03–1.18, p = 0.007) for every cm decrease in the difference. Among men with a round placental surface (length-breadth difference 2 cm or less) increased mortality was associated with lower birthweight (p = 0.03 or 0.005 allowing for mother’s body mass index) and shorter gestation, but not with lower head circumference or length.

Conclusion

Reduced lifespan among men is associated with a particular path of early growth. After rapid growth in early gestation, associated with tall maternal stature, soft tissue growth falters in mid-gestation. Rapid growth resumes in late gestation and continues through infancy.     

IFPA Meeting 2013 Workshop Report I: Diabetes in pregnancy,maternal dyslipidemia in pregnancy,oxygen in placental development,stem cells and pregnancy pathology

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2013 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) diabetes in pregnancy; 2) lipids, fatty acids and the placenta; 3) oxygen in placental development and pathologies; 4) stem cells and pathologies.     

Classifying neonatal growth outcomes: use of birth weight,placental evaluation and individualized growth assessment

Objective: To compare neonatal growth outcomes determined by birth weight (BW), placental assessment (Plac Assess) and individualized growth assessment (IGA).

Methods: This retrospective analysis was carried out in 45 selected pregnancies at risk for fetal growth restriction. Serial fetal biometry was carried out in the 2nd and 3rd trimester. First and second trimester placental biomarkers, 2nd trimester uterine artery (Ut A) velocimetry and postnatal placental pathology were evaluated as indicators of placental insufficiency. At delivery, weight (WT), head circumference (HC) and crown–heel length (CHL) were measured. BWs were categorized as large-for-gestational-age (LGA), appropriate-for-gestational-age (AGA) and small-for-gestational age (SGA) (<10th, 10th–90th and >90th percentiles). In these categories, neonatal growth outcomes were classified as growth restricted (GR), normal (NORMAL) or macrosomic (MACRO) based on BW plus Plac Assess (Ut A velocimetry, biomarkers, pathology) or IGA [growth potential realization index profile (WT, HC and CHL)].

Results: There were 6 LGA, 14 AGA and 25 SGA neonates in this sample. All 14 AGA neonates were considered NORMAL by both IGA and BW?+?Plac Assess. All six LGA neonates were classified as MACRO by BW?+?Plac Assess but only four by IGA (the remaining two were NORMAL and high NORMAL). The 25 SGA cases could be divided into five subgroups based on IGA and BW?+?Plac Assess. The largest subgroup (56%) was GR and the next largest (24%) was NORMAL by both classification methods. In the remaining 20%, there was some evidence of GR but IGA and BW?+?Plac Assess were not in complete agreement.

Conclusions: Agreement was good for all three methods in the LGA and AGA groups. The SGA group was heterogeneous but agreement between IGA and BW?+?Plac Assess was 89%. These results, using more sophisticated growth assessment methods, confirm placental insufficiency as a primary cause of growth restriction. Most normal and GR SGA neonates can be identified with conventional anatomical measurements if IGA is used.     

Role of low placental share in twin-twin transfusion syndrome complicated by intrauterine growth restriction

Objectives

Prior studies have demonstrated that donor twin survival following treatment of twin-twin transfusion syndrome (TTTS) was highly associated with donor intrauterine growth restriction (IUGR). Here, we hypothesized that donor IUGR may be attributed in part to low placental share.

Study design

The study population consisted of all patients who underwent laser treatment for TTTS at a single institution between 2006-2010. Only those pregnancies with dual survival at birth were included so that placental share information could be interpreted. We examined the relationships between Quintero Stage (with separate analysis of Stage III patients with critically abnormal donor Doppler findings) and low placental share (defined as ≤ 30%) with IUGR (<10th percentile) using chi-square analysis and multivariable logistic regression modeling.

Results

Of 210 patients treated, 159 (75.7%) had dual survivors at birth. Of these, placental share was documented in 90 cases (56.6%). Twenty-seven (30.0%) had low placental share, and 37 (41.1%) had IUGR. IUGR was associated with low placental share (63.0% vs. 31.7%, P = 0.0116). IUGR was also associated with Stage III patients (57.4% vs. 23.3%, P = 0.0021), and in particular with Stage III patients with donor involvement (77.8% vs. 25.4%, P < 0.0001). In logistic regression modeling, both low placental share and Stage III with donor involvement were independent risk factors for IUGR (OR = 3.5 [1.2-10.3], P = 0.0206, and OR = 10.1 [3.3-30.6], P < 0.0001, respectively).

Conclusions

Donor IUGR in TTTS pregnancies appears to be associated, in part, with low placental share.     

The Expression of Connective Tissue Growth Factor in Pregnancies Complicated by Severe Preeclampsia or Fetal Growth Restriction

We tested the hypothesis that the expression of placental connective tissue growth factor (CTGF) is enhanced in pregnancies complicated by severe preeclampsia (PE) or fetal growth restriction (FGR). CTGF expression was analyzed using immunostaining, western blot and real-time quantitative PCR in placental samples obtained after third trimester cesarean deliveries without labor from women with severe PE (n = 11), idiopathic FGR (n = 14), or healthy controls (n = 14). Serum CTGF concentrations were analyzed using ELISA. We found that CTGF was stably expressed in villous trophoblasts throughout pregnancy. The expression of CTGF mRNA in placentas from severe PE or FGR was higher than placentas from controls. Whereas the levels of placental CTGF protein were similar between normal and severe PE, maternal and fetal serum CTGF levels were elevated in severe PE. Maternal CTGF levels were also distinctively elevated in women with PE or FGR with histological evidence of placental injury. The enhancement of CTGF expression as well as serum CTGF levels in clinical conditions attributed to placental dysfunction suggests a role for this secretary protein in the pathophysiology of placental injury or its sequelae.     

Pregnancy outcome and placental pathology in small for gestational age neonates in relation to the severity of their growth restriction

Purpose: To investigate neonatal outcome and placental pathology in pregnancies complicated with small for gestational age neonates (SGA), in relation to the severity of growth restriction.

Methods: The medical records and placental histology reports of all neonates with a birth-weight (BW) ≤10th percentile, born between 24–42 weeks, during 2010–2015, were reviewed. Placental lesions were classified into maternal and fetal vascular malperfusion (MVM and FVM) lesions. Results were compared between neonates with BW <5th percentile (severe SGA group), neonates with BW between 5th–10th percentile (mild SGA group) and a control group of appropriate for gestational age (AGA) neonates. Composite neonatal outcome was defined as one or more of early complications.

Results: Overall, 753 neonates were included, 238 in the severe SGA group, 266 in the mild SGA group, and 249 in the control group. The severe SGA group had higher rates of composite adverse neonatal outcome as compared with the mild SGA and control groups (37.2 versus 17.6%, versus 24.5%, respectively, p?p?Conclusions: Worse neonatal outcome and more placental MVM and FVM lesions correlate with the severity of neonatal growth restriction in a “dose-dependent” manner.     

A new biological and clinical resource for research into pregnancy complications: The Baby Bio Bank

About 20% of pregnancies are affected by some form of complication. Research has shown that anomalies in implantation, development, and growth of the fetus; ineffective nutrient exchange between mother and fetus due to placental dysfunction; and maternal problems such as hypertension or infection during pregnancy can all lead to adverse pregnancy outcomes. However, the molecular aetiology of such events remains poorly understood. Fetal growth restriction (FGR), recurrent miscarriage (RM), preterm birth (PTB), and pre-eclampsia (PE) are the most common pregnancy complications encountered in the UK and these outcomes can result in an array of morbidities in both mother and baby, and in the most severe cases in mortality. We need to know more about normal pregnancy and where the important triggers are for failure. This prompted us to collect a large set of biological samples with matching clinical data from over 2500 normal and abnormal pregnancies, for use in research into these conditions. This paper outlines the nature of these sample sets and their availability to academia and industry, with the intention that their widespread use in research will make significant contributions to the improvement of maternal and fetal health worldwide (http://www.ucl.ac.uk/tapb/sample-and-data-collections-at-ucl/biobanks-ucl/baby-biobank).     

胎盘生长因子在高危妊娠中的研究进展

妊娠是复杂的生理过程,胎盘通过营养、代谢、交换、内分泌等作用调节母儿循环,是母儿联系的桥梁,对胎儿的生长发育及母体生理机能改变起着重要的作用。胎盘的正常发育及良好的生理功能是维持妊娠及胎儿生长发育的先决条件。胎盘形成及功能异常与妊娠期高血压疾病(hypertensive disorders of pregnancy,HDP)、胎儿生长受限(fetal growth restriction,FGR)、流产和唐氏综合征(Down′s syndrome,DS)等的发生密切相关。胎盘生长因子(placenta growth factor,PlGF)是丰富表达于胎盘的一种重要的生长因子,与血管内皮生长因子(vascular endothelial growth factors,VEGF)具有高度同源性,主要由滋养细胞和绒毛间质内皮细胞分泌,对滋养细胞增殖、活化及胎儿胎盘血管网形成起重要作用,故对PlGF进行深入研究对胎盘形成异常相关疾病的病因学研究及临床监测均具有重要意义。