Insights into the role of placenta thickness as a predictive marker of perinatal outcome

The placenta is a transitory organ indispensable for normal fetal maturation and growth. Recognition of abnormal placental variants is important in clinical practice, and a broader understanding of the significance of placental variants would help clinicians better manage affected pregnancies. Increased thickness of the placenta is reported to be a nonspecific finding but it is associated with many maternal and fetal abnormalities, including preeclampsia and abnormal fetal growth. In this review, we address the questions regarding the characteristics of placenta thickness and the relationship between thickened placenta and poor pregnancy outcomes.     

Targeting the Dysfunctional Placenta to Improve Pregnancy Outcomes Based on Lessons Learned in Cancer

In recent decades, our understanding of the disrupted mechanisms that contribute to major obstetrical diseases, including preeclampsia, fetal growth restriction, preterm birth, and gestational diabetes, has increased exponentially. Common to many of these obstetric diseases is placental maldevelopment and dysfunction; the placenta is a significant component of the maternal–fetal interface involved in coordinating, facilitating, and regulating maternal and fetal nutrient, oxygen and waste exchange, and hormone and cytokine production. Despite the advances in our understanding of placental development and function, there are currently no treatments for placental maldevelopment and dysfunction. However, given the transient nature and accessibility from the maternal circulation, the placenta offers a unique opportunity to develop targeted therapeutics for routine obstetric practices. Furthermore, given the similar developmental paradigms between the placenta and cancer, there is an opportunity to appropriate current knowledge from advances in targeted therapeutics in cancer treatments. In this review, we highlight the similarities between early placental development and cancer and introduce a number of targeted therapies currently being explored in cancer and pregnancy. We also propose a number of new effectors currently being targeted in cancer research that have the potential to be targeted in the development of treatments for pregnancy complications. Finally, we describe a method for targeting the placenta using nonviral polymers that are capable of delivering plasmids, small interfering RNA, and other effector nucleic acids, which could ultimately improve fetal and maternal outcomes from complicated pregnancies.     

Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches

Adverse influences during fetal life alter the structure and function of distinct cells, organ systems or homoeostatic pathways, thereby 'programming' the individual for an increased risk of developing cardiovascular disease and diabetes in adult life. Fetal programming can be caused by a number of different perturbations in the maternal compartment, such as altered maternal nutrition and reduced utero-placental blood flow; however, the underlying mechanisms remain to be fully established. Perturbations in the maternal environment must be transmitted across the placenta in order to affect the fetus. Here, we review recent insights into how the placenta responds to changes in the maternal environment and discuss possible mechanisms by which the placenta mediates fetal programming. In IUGR (intrauterine growth restriction) pregnancies, the increased placental vascular resistance subjects the fetal heart to increased work load, representing a possible direct link between altered placental structure and fetal programming of cardiovascular disease. A decreased activity of placental 11beta-HSD-2 (type 2 isoform of 11beta-hydroxysteroid dehydrogenase) activity can increase fetal exposure to maternal cortisol, which programmes the fetus for later hypertension and metabolic disease. The placenta appears to function as a nutrient sensor regulating nutrient transport according to the ability of the maternal supply line to deliver nutrients. By directly regulating fetal nutrient supply and fetal growth, the placenta plays a central role in fetal programming. Furthermore, perturbations in the maternal compartment may affect the methylation status of placental genes and increase placental oxidative/nitrative stress, resulting in changes in placental function. Intervention strategies targeting the placenta in order to prevent or alleviate altered fetal growth and/or fetal programming include altering placental growth and nutrient transport by maternally administered IGFs (insulin-like growth factors) and altering maternal levels of methyl donors.     

The combined effect of ultrasonic exposure and protein restriction on maternal and fetal mice

This investigation was undertaken to assess the combined effects of protein restriction and ultrasonic energy exposure during pregnancy on the maternal and fetal mouse. Pregnant female mice were fed diets containing either 18% casein (control diet) or 6% casein (restricted protein diet) during gestation. All animals were subjected to the ultrasonic exposure procedure (actual: 2.5 W/cm² spatial peak; sham: 0 W/cm²; continuous wave for 20 sec at a frequency of 1 MHz) on day 8 of gestation. On day 18 of gestation, the animals were sacrificed. Products of conception were examined, and chemical analysis were performed on maternal liver, placenta and fetus.Our results suggest that there are possible influences of ultrasonic energy exposure to the mouse fetus and placenta, as indicated by the tendency toward decreases of fetal weight, placental weight, and DNA and RNA contents of both fetus and placenta, especially with restricted protein in the maternal diet during gestation.Protein restriction during pregnancy had an adverse influence on both the maternal organism and her products of conception. The nutritional needs for the fetus were not met at the expense of the maternal organism. Parameters of fetal cellular growth were reduced by gestational protein restriction indicating that there is competition for available nutrients between the fetus under time of stress. Results also show that the trends of fetal and placental growth are in the same general direction suggesting the possible usefulness of human placental tissue as a maker for fetal growth in subsequent population studies.     

声触诊弹性成像技术量化评估孕晚期妊娠糖尿病患者胎盘弹性

目的 评价声触诊弹性成像(STE)技术量化评估孕晚期妊娠糖尿病(GDM)患者胎盘弹性的价值。方法 前瞻性纳入51例确诊的孕晚期GDM患者,由2名医师分别以STE技术测量胎盘母体面及胎儿面弹性模量,其中1名医师测量2次;以组内相关系数(ICC)及Bland-Altman图评价观察者内及观察者间测量结果的一致性,比较胎盘母体面及胎儿面平均弹性模量(E_mean)差异。结果 观察者内及观察者间测量GDM患者胎盘母体面及胎儿面弹性模量的一致性均好(观察者内:ICC=0.908、0.887;观察者间:ICC=0.827~0.905)。Bland-Altman图示STE量化评估胎盘弹性的一致性良好。胎盘母体面及胎儿面的中位E_mean分别为6.01(5.62,6.51) kPa及5.02(4.46,5.52) kPa,差异有统计学意义(P＜0.001)。结论 STE可稳定地量化评估孕晚期GDM患者胎盘弹性;胎盘母体面及胎儿面弹性存在差异。     

Ethical and Regulatory Considerations of Placental Therapeutics

PurposePlacental therapeutics aim to treat placental disease; however, ethical and regulatory issues should be considered if the drug also potentially affects the fetus. Drugs that might transfer or edit genes carry a specific challenge because currently fetal gene editing and fetal gene therapy are considered unethical.MethodsThis article reviews the literature on ethical and regulatory considerations for placental therapeutics.FindingsProposals for maternal gene therapy, directed to the maternal side of the placenta, have been discussed with patients and stakeholders. No absolute ethical, legal, or regulatory barriers to this potential treatment were identified. Patients who have experienced placental disease, such as fetal growth restriction, are interested in these therapies; some would participate in first-in-human trials. Such trials need careful regulatory considerations, such as the steps required to indicate tolerability and efficacy in preclinical models and the optimal animals for reproductive toxicology studies. Ex vivo dual human placenta perfusion experiments and villous explant in vitro studies allow drugs to be tested in normal and diseased human placenta, providing short-term tolerability and toxicologic assessment. Testing drugs in nonhuman primates is an option but carries ethical and feasibility considerations. Selection of inclusion and exclusion criteria for clinical trial participants is important to ensure that the most suitable patients are exposed to a first-in-human drug. These patients will almost certainly be pregnant women with a high risk of perinatal loss and/or perinatal and maternal morbidity. Criteria should identify sufficient numbers of patients to make a trial feasible as well as a phenotype that will respond to the mechanism of action. How to dose escalate and to capture information on adverse events are also key to optimal clinical trial design.ImplicationsDeveloping placental therapeutics requires input from scientists, practitioners, and regulators and close liaison with patients to ensure that new drugs are tested as carefully as possible.     

Health during pregnancy and beyond: Fetal trophoblast cells as chief co-ordinators of intrauterine growth and reproductive success

Abstract

Differentiation of extra-embryonic tissues and organs, notably the placenta, is vital for embryonic development and growth throughout gestation, starting from a few days after fertilization when the trophoblast cell lineage arises until parturition. In utero metabolic programming events may even extend the impact of placental function well into adulthood as they may predispose the offspring to common pathologies such as diabetes and cardiovascular disease. This review summarizes key steps that lead up to formation of a functional placenta. It highlights recent insights that have advanced our view of how early trophoblast expansion is achieved and how sufficient maternal blood supply to the developing fetus is secured. Exciting cumulative data have revealed the importance of a close cross-talk between the embryo proper and extra-embryonic trophoblast cells that involves extracellular matrix components in the establishment of a stem cell-like niche and proliferation compartment. Remarkably, placental function also relies on beneficial interactions between trophoblast cells and maternal immune cells at the implantation site. Our growing knowledge of the molecular mechanisms involved in trophoblast differentiation and function will help to devise informed approaches aimed at deciphering how placentation is controlled in humans as an essential process for reproductive success and long-term health.     

Nursing assessment and management of nutrition in older people with cancer: An integrative review

BackgroundThere is a risk of malnutrition when older people are diagnosed with cancer, highlighting the need for nutritional assessments and appropriate management to be undertaken by healthcare professionals including nurses. The absence of a standardised assessment method and management of nutrition in older people creates a gap in clinical practice and warrants further research.AimThe aim of this review was to explore the current nutritional assessment methods and evidence-based interventions for improving nutritional outcomes in older people with cancer.MethodsAn integrative literature review was conducted using electronic databases. Papers were limited to those published in English between 2009 and 2021. Search terms included older adult, elder, geriatric, senior, cancer, nutrition, malnutrition, hospital, and inpatient across four databases: Embase, CINAHL, MEDLINE, and Scopus. Using the inclusion and exclusion criteria, 303 articles were screened. A Mixed Methods Appraisal Tool (MMAT) (2018) was used for quality appraisal. Concept analysis explored themes across the included articles.FindingsThe themes from the analysis of 10 primary research articles, which included 5,327 participants, were (i) types of nutritional assessment and (ii) management of older people with cancer. The main nutritional assessment scales used were the Mini Nutrition Assessment and Patient-Generated Subjective Global Assessment.ConclusionThe completion of a comprehensive nutritional assessment by health professionals, including nurses, could facilitate early dietary intervention in older persons with cancer. This would enable supportive dietary advice and supplementation to improve health outcomes.     

The influence of maternal hematocrit on placental development from the first to the second trimesters of pregnancy.

OBJECTIVES: To study the influence of maternal hematocrit (Ht) and hemoglobin (Hb) levels on placental size and growth in the first and mid-second trimesters of pregnancy. SUBJECTS/METHODS: This was a prospective study performed at the fetal medicine unit of a university hospital. One hundred and eighty-one women with a singleton pregnancy were recruited at 11-14 weeks' gestation. For each case three scans of the placenta were performed, the first at recruitment and the following two at 3-week intervals. The volume of the placenta was measured at each visit using a three-dimensional ultrasound scanner. The maternal Hb and Ht were measured within 2 weeks of the first scan. RESULTS: The placental growth during the second trimester was inversely related to the Ht levels (r = -0.29, P = 0.001). It was also related to the Hb level (r = -0.20, P = 0.021). An increase of 0.1 units of Ht was associated with 38% less growth of the placenta (95% confidence interval: 18-54% less growth). DISCUSSION: This study demonstrates the effects of maternal environment on placental growth. Our data suggest that the levels of Ht appear to affect the placental growth during the second trimester. Further studies on the factors that regulate placental growth are needed to elucidate the pathophysiology of these interactions and their effect on pregnancy outcome.     

MR imaging of the placenta: what a radiologist should know

Imaging of the placenta can have a profound impact on patient management, owing to the morbidity and mortality associated with various placental conditions. Placental conditions affecting the mother and fetus include molar pregnancies, placental hematoma, abruption, previa, accreta, vasa previa, chorioangioma, and retained products of conception. Although uncommon, abnormalities of the placenta are important to recognize owing to the potential for maternal and fetal morbidity and mortality. Sonography remains the first imaging modality for evaluation of the placenta. Magnetic resonance (MR) imaging has many unique properties that make it well-suited for imaging of the placenta: the multi-planar capabilities, the improved tissue contrast that can be obtained using a variety of pulse sequences and parameters and the lack of ionizing radiation; MR imaging can be of added diagnostic value when further characterization is required. In this article, we review the appearances and the role of MRI in diagnosis and management of these conditions. We present our clinical perspective on diagnosing these challenging problems with MRI and review the imaging findings that can lead to a correct diagnosis.     

Unusual maternal vasculature in the placental periphery leading to the diagnosis of abdominal pregnancy at 25 weeks' gestation

Abdominal pregnancy is a rare condition in which the fetus and placenta are located within the peritoneal cavity. Sonographic findings include visualization of the fetus separate from the uterus, failure to visualize the uterine wall between the fetus and urinary bladder, close approximation of fetal parts to the maternal abdominal wall, eccentric position or abnormal fetal attitude, and visualization of extrauterine placental tissue. We present an unusual case in which mid-trimester transabdominal color Doppler sonographic findings depicted unusual maternal vasculature in the placental periphery leading to the diagnosis of abdominal pregnancy. Postpartum maternal angiography confirmed these vessels as abnormal maternal arterial perfusion of the extrauterine placenta emanating from the uterine arteries and inferior epigastric arteries. Systematic review of the literature confirms that this is the first report of such sonographic manifestations of an abdominal pregnancy.     

Non-invasive transabdominal measurement of placental oxygenation: a step toward continuous monitoring

This study aimed to assess transabdominal placental oxygenation levels non-invasively. A wearable device was designed and tested in 12 pregnant women with an anterior placenta, 5 of whom had maternal pregnancy complications. Preliminary results revealed that the placental oxygenation level is closely related to pregnancy complications and placental pathology. Women with maternal pregnancy complications were found to have a lower placental oxygenation level (69.4% ± 6.7%) than those with uncomplicated pregnancy (75.0% ± 5.8%). This device is a step in the development of a point-of-care method designed to continuously monitor placental oxygenation and to assess maternal and fetal health.     

Comparative in vivo approaches for selective adenovirus-mediated gene delivery to the placenta

Gene delivery to the placenta is one potential way of specifically modifying placental biological processes and fetal development. The aim of this study was to determine the most efficient and least invasive route of placental adenovirus delivery. The feasibility of adenovirus-mediated gene transfer to the rat placenta was addressed by maternal intravenous or direct intraplacental injection of adenoviral vectors expressing the glucose transporter GLUT3, a noncirculating integral membrane protein. Both routes led to transgene expression in the placenta. However, direct intraplacental delivery on day 14 of gestation yielded a higher transduction efficiency than maternal intravenous administration, and markedly reduced transgene expression in maternal liver. Most importantly, the amount of the GLUT3 transgene and the adenovirus itself in fetal tissues was only 1 to 3% of that found in the placenta. These results indicate that the nature of the transgene and the route of adenovirus administration are key parameters in selective placental somatic gene transfer. This novel strategy may prove useful for modifying a placental function without altering the fetal genome.     

Effects of oral nutrition supplements in persons with dementia: A systematic review

ObjectivePersons with dementia are at risk of malnutrition, evidenced by low dietary intake, which has consequences for nutritional status, activity of daily living and disease progression. The effects of oral nutrition supplements (ONS) on nutritional intake, nutritional status, and cognitive and physical outcomes in older persons with dementia were evaluated.MethodsPubMed, Medline, Embase, CINAHL and the Cochrane Central Register of Controlled Trials were searched in December 2017, and this was repeated in May 2019. The Preferred Reporting Items for Systematic Reviews and Analysis (PRISMA) checklist was used. Papers were considered if they presented experimental clinical trials using oral nutritional supplements to persons diagnosed with dementia, including Alzheimer's disease and mild cognitive impairment, and conducted in hospitals, nursing homes or homes.ResultsWe included ten articles reporting nine clinical trials. A total of 407 persons with dementia were included, of whom 228 used ONS for 7 to 180 days. Nutritional intake improved by 201 to 600 kcal/day. Energy intake from ordinary foods was not affected, thus ONS improved the persons daily intake of energy and protein. Body weight, muscle mass, and nutritional biomarkers in blood improved in the intervention groups compared with the control groups. No effects on cognition or physical outcomes were observed.ConclusionONS increases the intake of energy and protein and improves nutritional status in persons with dementia; however, RCTs with longer intervention periods are needed to investigate the impact on cognitive and functional outcomes.     

Transplacental transfer and metabolism of buprenorphine.

Information on the direct and indirect effects of buprenorphine (BUP) on the fetus is essential for determining its potential for treatment of the pregnant opiate addict. The goal of this investigation is to determine the transplacental transfer of BUP to the fetal circulation, its metabolism, and effects on the tissue. The technique of dual perfusion of placental lobule is used. The range of BUP concentrations investigated included its peak plasma levels (10 ng/ml) in patients under treatment. A biphasic decline in concentration of the drug in the maternal circulation was observed, initially rapid then slow. During the initial (60 min), the tissue sequestered most of BUP resulting in a low (<10%) transplacental transfer of the drug to the fetal circulation. The concentration ratios of the drug in tissue/maternal and tissue/fetal were 13 +/- 6.5 and 27.4 +/- 0.4. The drug sequestered did not have any adverse effects on placental tissue viability and functional parameters. Less than 5% of the perfused BUP was metabolized to norbuprenorphine during the 4 h of perfusion and the metabolite was distributed between the tissue, maternal, and fetal circulations. Taken together, these data suggest that the therapeutic levels of BUP in the maternal circulation may have no indirect effects (via the placenta) on the fetus. The observed low transplacental transfer of BUP to the fetal circuit may explain the moderate/absence of neonatal withdrawal in the limited number of reports on mothers treated with the drug during pregnancy.     

胎盘异常的产前超声诊断及母婴结局

目的分析胎盘异常的产前超声诊断及母婴结局。方法选择我院收治的300例胎盘异常产妇作为胎盘异常组,另选择同期入院的120例胎盘正常产妇作为对照组。两组均进行产前超声检查,分析产前超声对胎盘异常的诊断结果及母婴结局。结果以病理诊断结果为金标准,产前超声对胎盘异常的检出率为94.33%。与其他类型胎盘异常相比,胎盘植入的漏/误诊占比最高(25.53%)。母婴结局中,胎盘前置和胎盘早剥患者主要为剖宫产和早产,胎盘植入患者主要为剖宫产和产后出血。胎盘异常组的剖宫产、产后出血、低体质量儿和早产发生率高于对照组(P<0.05)。结论产前超声对胎盘异常的诊断准确率高,有助于对胎盘位置、结构等的准确判断。在进行产前超声筛查时,应进行全面扫查,以降低漏/误诊率,减少不良母婴结局的发生。     

Low clearance of cimetidine across the human placenta

The transfer of cimetidine across the isolated perfused human placenta was examined. Placentas obtained at cesarean section were perfused for 2 hr from both maternal and fetal sides in constant flow recycling systems. Cimetidine was administered as a bolus dose to either the maternal circuit alone (n = 4) or to both maternal and fetal circuits simultaneously (n = 3), to achieve initial concentrations of 4 micrograms/ml. Antipyrine (20 micrograms/ml) and l-leucine (0.25 mM) were administered in like fashion as reference compounds. Two hours after maternal dosage there was equilibration of antipyrine across the placenta, but equilibration of cimetidine was incomplete (fetal/maternal ratio = 0.46 +/- 0.07). The fetal/maternal ratio of l-leucine was greater than unity; consistent with active maternal to fetal transport. Maternal to fetal cimetidine transplacental clearance (0.50 +/- 0.05 ml/min) was 23% of antipyrine clearance. After simultaneous dosage to both maternal and fetal circuits, the l-leucine fetal/maternal ratio was 1.37 +/- 0.08 at 2 hr and maternal and fetal levels of cimetidine and antipyrine were at equilibrium for the duration of the experiment (fetal/maternal ratio of cimetidine = 1.01 +/- 0.02). This study shows that cimetidine is transferred across the human placenta by passive diffusion. In contrast to the rapid placental transfer demonstrated by the majority of drugs studied previously, the placental transfer of cimetidine is slow. We conclude that the human placenta may therefore provide significant protection of the fetus from a single maternally administered dose of cimetidine.     

In vitro analysis of human transplacental transport of desmopressin

OBJECTIVE: Desmopressin (DDAVP) therapy may be required during pregnancy, but there are limited data about its safety. We wished to verify whether DDAVP is transported across the human placenta. METHODS: Using the in vitro human placental cotyledon perfusion model, we performed serial measurements of maternal and fetal DDAVP concentrations. After introducing the drug into the maternal circulation at estimated baseline therapeutic (30 pg/ml) and supratherapeutic (16,000 and 60,000 pg/ml) concentrations, we measured the rate of transplacental drug transfer up to 2 h. RESULTS: There was no detectable transport of DDAVP at a 30 pg/ml concentration, and the maternal drug concentration remained stable over time. At a much higher maternal concentration of 60,000 pg/ml, the mean peak fetal DDAVP concentration was 2990 pg/ml, equivalent to 4.8% of the baseline maternal concentration. CONCLUSION: At a therapeutic maternal drug concentration, DDAVP does not appear to cross the placenta within detectable limits. At much higher drug concentrations, DDAVP may cross the placenta in a small amount. Future in vitro clinical studies should attempt to reproduce these findings.     

大鼠胎盘超声造影灌注特征和生物效应的初步研究

目的 本试验采用妊娠晚期大鼠为模式动物探讨超声造影在胎盘的应用价值和初步研究超声造影对大鼠胎盘组织产生的生物效应,为超声造影应用于产科提供指导意义.方法 随机选择妊娠晚期(第18～21天)的Wistar大鼠30只,体重为(300±50)g,共分三组进行,A组对照组,注射生理盐水2.0 ml/kg;B组高剂量造影剂组,注射剂量为23.6 mg/kg(2.0 ml/kg,11.8 mg/ml);C组低剂量造影组,注射剂量为0.236 mg/kg (2.0 ml/kg,0.118 mg/ml).在ACUSON Sequoia 512超声诊断仪CPS成像系统下选择每只孕鼠腹中的一只胎鼠的胎盘行超声造影检查.造影完毕后取胎盘组织固定、切片、染色观察三组胎盘显微结构的变化.结果 超声造影清晰地显示出了大鼠胎盘绒毛间血流的灌注特点;造影剂不能通过胎血屏障到达胎盘胎儿面及胎鼠;三组胎盘组织切片检查均未见明显母体面毛细血管损伤、红细胞外溢、滋养细胞坏死和空泡形成.结论 超声造影清晰地显示出了大鼠胎盘母体面的血管结构;在此次仪器设置条件下,超声造影未对胎盘组织产生明显的生物效应.     

Free cholesterol levels in plasma from the maternal, placental and fetal circulations during human pregnancy

A sensitive, precise assay for free plasma cholesterol has been developed and used to measure the levels of free cholesterol in plasma samples from sites in the maternal, placental and fetal circulations during human pregnancy. These results demonstrate the removal, during passage through the placenta, of sufficient free cholesterol from the maternal circulation for use as the biosynthetic precursor of placental neutral steroid hormones. There is a suggestion from preliminary data on the arterio-venous differences in the umbilical circulation that a de novo fetal synthesis of cholesterol occurs.