Publications by authors named "Diana W Bianchi"

237 Publications

Novel Insights from Fetal and Placental Phenotyping in Three Mouse Models of Down Syndrome.

Am J Obstet Gynecol 2021 Mar 22. Epub 2021 Mar 22.

Center for Precision Health Research ( Section on Prenatal Genomics and Fetal Therapy ), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States of America; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America.

Background: In human fetuses with Down syndrome, placental pathology structural anomalies and growth restriction are present. There is currently a significant lack of information regarding the early lifespan in mouse models of Down syndrome.

Objective: The objective of this study was to examine embryonic (E18.5) and placental genotypes in the three most common mouse models of Down syndrome (Ts65Dn, Dp(16)1/Yey, Ts1Cje). Based on prenatal and placental phenotyping in three mouse models of Down syndrome we hypothesized that one or more of them would have a similar phenotype to human fetuses with trisomy 21, which would make it the most suitable for in utero treatment studies.

Study Design: C57BL6J/6 females were mated to Dp(16)/1Yey and Ts1Cje males and Ts65Dn females to C57BL/B6Eic3Sn.BLiAF1/J males. At E18.5, dams were euthanized. Embryos and placentas were examined blindly for weight and size. Embryos were characterized as euploid or trisomic, male or female by polymerase chain reaction. A subset (34 euploid, 34 trisomic) was examined for malformations.

Results: The Ts65Dn model showed the largest difference in fetal growth, brain development and placental development when comparing euploid and trisomic embryos. For the Dp16(1)/Yey model genotype did not impact fetal growth, but there were differences in brain and placental development. For the Ts1Cje model no significant association was found between genotype and fetal growth, brain development or placental development. Euploid embryos had no congenital anomalies; one was demised. Hepatic necrosis was seen in 6/12 (50%) of Dp(16)1/Yey and 1/12 (8%) Ts1Cje embryos; hepatic congestion/inflammation was observed in 3/10 (30%) Ts65Dn embryos. Renal pelvis dilation was seen in 5/12 (42%) Dp(16)1/Yey, 5/10 (50%) Ts65Dn and 3/12 (25%) Ts1Cje embryos. One Ts65Dn and one Dp(16)1/Yey embryo had an aortic outflow abnormality. Two Ts1Cje embryos had ventricular septal defects. Ts65Dn placentas had increased spongiotrophoblast necrosis CONCLUSIONS: Fetal and placental growth showed varying trends across strains. Congenital anomalies were primarily seen in trisomic embryos. The presence of liver abnormalities in all three mouse models of Down syndrome (10/34) is a novel finding. Renal pelvis dilation was also common (13/34). Future research will examine human autopsy material to determine if these findings are relevant to infants with Down syndrome. Differences in placental histology were also observed between strains.
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http://dx.doi.org/10.1016/j.ajog.2021.03.019DOI Listing
March 2021

Involving Pregnant Individuals in Clinical Research on COVID-19 Vaccines.

JAMA 2021 Mar;325(11):1041-1042

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jama.2021.1865DOI Listing
March 2021

Conversations With the Editors: The Past, Present, and Future of Placental Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Clin Ther 2021 Feb 30;43(2):211-217. Epub 2021 Jan 30.

Mother Infant Research Institute at Tufts Medical Center, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.clinthera.2020.12.020DOI Listing
February 2021

A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials.

Am J Bioeth 2021 Jan 16:1-25. Epub 2021 Jan 16.

National Institutes of Health.

New fetal therapies offer important prospects for improving health. However, having to consider both the fetus and the pregnant woman makes the risk-benefit analysis of fetal therapy trials challenging. Regulatory guidance is limited, and proposed ethical frameworks are overly restrictive or permissive. We propose a new ethical framework for fetal therapy research. First, we argue that considering only biomedical benefits fails to capture all relevant interests. Thus, we endorse expanding the considered benefits to include evidence-based psychosocial effects of fetal therapies. Second, we reject the commonly proposed categorical risk and/or benefit thresholds for assessing fetal therapy research (e.g., only for life-threatening conditions). Instead, we propose that the individual risks for the pregnant woman the fetus should be justified by the benefits for them and the study's social value. Studies that meet this overall proportionality criterion but have mildly unfavorable risk-benefit ratios for pregnant women and/or fetuses may be acceptable.
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http://dx.doi.org/10.1080/15265161.2020.1867932DOI Listing
January 2021

Forever Connected: The Lifelong Biological Consequences of Fetomaternal and Maternofetal Microchimerism.

Clin Chem 2021 Jan;67(2):351-362

Irish Centre for Maternal and Child Health (INFANT), University College Cork, Cork, Ireland.

Background: Originally studied as a mechanism to understand eclampsia-related deaths during pregnancy, fetal cells in maternal blood have more recently garnered attention as a noninvasive source of fetal material for prenatal testing. In the 21st century, however, intact fetal cells have been largely supplanted by circulating cell-free placental DNA for aneuploidy screening. Instead, interest has pivoted to the ways in which fetal cells influence maternal biology. In parallel, an increasing appreciation of the consequences of maternal cells in the developing fetus has occurred.

Content: In this review, we highlight the potential clinical applications and functional consequences of the bidirectional trafficking of intact cells between a pregnant woman and her fetus. Fetal cells play a potential role in the pathogenesis of maternal disease and tissue repair. Maternal cells play an essential role in educating the fetal immune system and as a factor in transplant acceptance. Naturally occurring maternal microchimerism is also being explored as a source of hematopoietic stem cells for transplant in fetal hematopoietic disorders.

Summary: Future investigations in humans need to include complete pregnancy histories to understand maternal health and transplant success or failure. Animal models are useful to understand the mechanisms underlying fetal wound healing and/or repair associated with maternal injury and inflammation. The lifelong consequences of the exchange of cells between a mother and her child are profound and have many applications in development, health, and disease. This intricate exchange of genetically foreign cells creates a permanent connection that contributes to the survival of both individuals.
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http://dx.doi.org/10.1093/clinchem/hvaa304DOI Listing
January 2021

Right or wrong? Looking through the retrospectoscope to analyse predictions made a decade ago in prenatal diagnosis and fetal surgery.

Prenat Diagn 2020 12;40(13):1627-1635

Division of Prenatal Genomics and Fetal Therapy, Medical Genomics and Metabolic Genetics Branch, National Human Genome Institute, National Human Genome Institute, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1002/pd.5870DOI Listing
December 2020

Maternal Morbidity and Mortality.

J Womens Health (Larchmt) 2021 Feb 23;30(2):145-146. Epub 2020 Nov 23.

Office on Women's Health, U.S. Department of Health and Human Services, Washington, District of Columbia, USA.

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http://dx.doi.org/10.1089/jwh.2020.8851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020514PMC
February 2021

Trends in prenatal diagnosis: An analysis of 40 years of Medical Subject Heading (MeSH) terms in publications.

Prenat Diagn 2020 12;40(13):1636-1640

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Objective: To understand the evolution of the field of prenatal diagnosis over the past four decades.

Method: We analyzed the publications in the journal Prenatal Diagnosis from its inception in 1980 to 2019 using Medical Subject Headings (MeSH) to examine the major research topics and trends. The results were analyzed by 10-year intervals.

Results: Publications on prenatal cytogenetics, congenital anomalies and fetal imaging predominated during the first three decades, with a steady increase in molecular genetics over time. Publications on NIPT did not appear until the most recent decade and are likely under-counted because there was no MeSH term for NIPT until 2020.

Conclusion: The topics covered in Prenatal Diagnosis articles have evolved considerably over the past four decades and reflect a response to advances in technology and widespread incorporation of prenatal screening and diagnosis into standard obstetric care. The strengths of this analysis are its objective nature, its use of the standard MeSH terms used for coding, and application of a novel cluster analysis to visualize trends. The analysis also pointed out the fact that MeSH terms in this sub-specialty area are often inconsistent due to manually coding based on individual subject matter expertise.
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http://dx.doi.org/10.1002/pd.5871DOI Listing
December 2020

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model.

Am J Hum Genet 2020 11 23;107(5):911-931. Epub 2020 Oct 23.

Prenatal Genomics and Therapy Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Mother Infant Research Institute, Tufts Medical Center and Tufts Children's Hospital, Boston, MA 02111, USA. Electronic address:

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.
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http://dx.doi.org/10.1016/j.ajhg.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675036PMC
November 2020

Regional Alterations in Cortical Sulcal Depth in Living Fetuses with Down Syndrome.

Cereb Cortex 2021 Jan;31(2):757-767

Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Down syndrome (DS) is the most common genetic cause of developmental disabilities. Advanced analysis of brain magnetic resonance imaging (MRI) has been used to find brain abnormalities and their relationship to neurocognitive impairments in children and adolescents with DS. Because genetic factors affect brain development in early fetal life, there is a growing interest in analyzing brains from living fetuses with DS. In this study, we investigated regional sulcal folding depth as well as global cortical gyrification from fetal brain MRIs. Nine fetuses with DS (29.1 ± 4.24 gestational weeks [mean ± standard deviation]) were compared with 17 typically developing [TD] fetuses (28.4 ± 3.44). Fetuses with DS showed lower whole-brain average sulcal depths and gyrification index than TD fetuses. Significant decreases in sulcal depth were found in bilateral Sylvian fissures and right central and parieto-occipital sulci. On the other hand, significantly increased sulcal depth was shown in the left superior temporal sulcus, which is related to atypical hemispheric asymmetry of cortical folding. Moreover, these group differences increased as gestation progressed. This study demonstrates that regional sulcal depth is a sensitive marker for detecting alterations of cortical development in DS during fetal life, which may be associated with later neurocognitive impairment.
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http://dx.doi.org/10.1093/cercor/bhaa255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786357PMC
January 2021

Revisiting menstruation: the misery, mystery, and marvel.

Am J Obstet Gynecol 2020 11 24;223(5):617-618. Epub 2020 Jul 24.

Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

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http://dx.doi.org/10.1016/j.ajog.2020.06.007DOI Listing
November 2020

Maternal mortality in the United States: research gaps, opportunities, and priorities.

Am J Obstet Gynecol 2020 10 17;223(4):486-492.e6. Epub 2020 Jul 17.

Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

Maternal mortality and severe maternal morbidity are urgent issues in the United States. It is important to establish priority areas to address these public health crises. On April 8, 2019, and May 2 to 3, 2019, the Eunice Kennedy Shriver National Institute of Child Health and Human Development organized and invited experts with varied perspectives to 2 meetings, a community engagement forum and a scientific workshop, to discuss underlying themes involved in the rising incidence of maternal mortality in the United States. Experts from diverse disciplines reviewed current data, ongoing activities, and identified research gaps focused on data measurement and reporting, obstetrical and health system factors, social determinants and disparities, and the community perspective and engagement. Key scientific opportunities to reduce maternal mortality and severe maternal morbidity include improved data quality and measurement, understanding the populations affected as well as the numerous etiologies, clinical research to confirm preventive and interventional strategies, and engagement of community participation in research that will lead to the reduction of maternal mortality in the United States. This article provides a summary of the workshop presentations and discussions.
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http://dx.doi.org/10.1016/j.ajog.2020.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564012PMC
October 2020

Down syndrome.

Nat Rev Dis Primers 2020 02 6;6(1). Epub 2020 Feb 6.

Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Trisomy 21, the presence of a supernumerary chromosome 21, results in a collection of clinical features commonly known as Down syndrome (DS). DS is among the most genetically complex of the conditions that are compatible with human survival post-term, and the most frequent survivable autosomal aneuploidy. Mouse models of DS, involving trisomy of all or part of human chromosome 21 or orthologous mouse genomic regions, are providing valuable insights into the contribution of triplicated genes or groups of genes to the many clinical manifestations in DS. This endeavour is challenging, as there are >200 protein-coding genes on chromosome 21 and they can have direct and indirect effects on homeostasis in cells, tissues, organs and systems. Although this complexity poses formidable challenges to understanding the underlying molecular basis for each of the many clinical features of DS, it also provides opportunities for improving understanding of genetic mechanisms underlying the development and function of many cell types, tissues, organs and systems. Since the first description of trisomy 21, we have learned much about intellectual disability and genetic risk factors for congenital heart disease. The lower occurrence of solid tumours in individuals with DS supports the identification of chromosome 21 genes that protect against cancer when overexpressed. The universal occurrence of the histopathology of Alzheimer disease and the high prevalence of dementia in DS are providing insights into the pathology and treatment of Alzheimer disease. Clinical trials to ameliorate intellectual disability in DS signal a new era in which therapeutic interventions based on knowledge of the molecular pathophysiology of DS can now be explored; these efforts provide reasonable hope for the future.
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http://dx.doi.org/10.1038/s41572-019-0143-7DOI Listing
February 2020

An Examination of Child and Adolescent Neurodevelopment Through National Institutes of Health Studies.

Public Health Rep 2020 Mar/Apr;135(2):169-172. Epub 2020 Jan 22.

Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

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http://dx.doi.org/10.1177/0033354919900889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036611PMC
May 2020

Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior.

Front Neurosci 2019 17;13:1335. Epub 2019 Dec 17.

Mother Infant Research Institute, Tufts Medical Center, Boston, MA, United States.

Background: Maternal over- and undernutrition in pregnancy plays a critical role in fetal brain development and function. The effects of different maternal diet compositions on intrauterine programing of the fetal brain is a lesser-explored area. The goal of this study was to investigate the impact of two chowmaternal diets on fetal brain gene expression signatures, fetal/neonatal growth, and neonatal and adult behavior in a mouse model.

Methods: Throughout pregnancy and lactation, female C57Bl/6J mice were fed one of two standard, commercially available chow diets (pellet versus powder). The powdered chow diet was relatively deficient in micronutrients and enriched for carbohydrates and n-3 long-chain polyunsaturated fatty acids compared to the pelleted chow. RNA was extracted from embryonic day 15.5 forebrains and hybridized to whole genome expression microarrays ( = 5/maternal diet group). Functional analyses of significantly differentially expressed fetal brain genes were performed using Ingenuity Pathways Analysis and Gene Set Enrichment Analysis. Neonatal behavior was assessed using a validated scale ( = 62 pellet-exposed and 31 powder-exposed). Hippocampal learning, locomotor behavior, and motor coordination were assessed in a subset of adults using fear conditioning, open field testing, and Rotarod tests ( = 16 pellet-exposed, 14 powder-exposed).

Results: Comparing powdered to pelleted chow diets, neither maternal weight trajectory in pregnancy nor embryo size differed. Maternal powdered chow diet was associated with 1647 differentially expressed fetal brain genes. Functional analyses identified significant upregulation of canonical pathways and upstream regulators involved in cell cycle regulation, synaptic plasticity, and sensory nervous system development in the fetal brain, and significant downregulation of pathways related to cell and embryo death. Pathways related to DNA damage response, brain immune response, amino acid and fatty acid transport, and dopaminergic signaling were significantly dysregulated. Powdered chow-exposed neonates were significantly longer but not heavier than pelleted chow-exposed counterparts. On neonatal behavioral testing, powdered chow-exposed neonates achieved coordination- and strength-related milestones significantly earlier, but sensory maturation reflexes significantly later. On adult behavioral testing, powdered chow-exposed offspring exhibited hyperactivity and hippocampal learning deficits.

Conclusion: In wild-type offspring, two diets that differed primarily with respect to micronutrient composition had significant effects on the fetal brain transcriptome, neonatal and adult behavior. These effects did not appear to be mediated by alterations in gross maternal nutritional status nor fetal/neonatal weight. Maternal dietary content is an important variable to consider for investigators evaluating fetal brain development and offspring behavior.
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http://dx.doi.org/10.3389/fnins.2019.01335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928003PMC
December 2019

Fetal fraction and noninvasive prenatal testing: What clinicians need to know.

Prenat Diagn 2020 01 10;40(2):155-163. Epub 2019 Dec 10.

Prenatal Genomics and Therapy Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

The fetal fraction (FF) is a function of both biological factors and bioinformatics algorithms used to interpret DNA sequencing results. It is an essential quality control component of noninvasive prenatal testing (NIPT) results. Clinicians need to understand the biological influences on FF to be able to provide optimal post-test counseling and clinical management. There are many different technologies available for the measurement of FF. Clinicians do not need to know the details behind the bioinformatics algorithms of FF measurements, but they do need to appreciate the significant variations between the different sequencing technologies used by different laboratories. There is no universal FF threshold that is applicable across all platforms and there have not been any differences demonstrated in NIPT performance by sequencing platform or method of FF calculation. Importantly, while FF should be routinely measured, there is not yet a consensus as to whether it should be routinely reported to the clinician. The clinician should know what to expect from a standard test report and whether reasons for failed NIPT results are revealed. Emerging solutions to the challenges of samples with low FF should reduce rates of failed NIPT in the future. In the meantime, having a "plan B" prepared for those patients for whom NIPT is unsuccessful is essential in today's clinical practice.
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http://dx.doi.org/10.1002/pd.5620DOI Listing
January 2020

Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome.

Trends Mol Med 2020 02 7;26(2):150-169. Epub 2019 Nov 7.

Medical Genetics Branch (Prenatal Genomic and Therapy Section), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS. We emphasize the importance of using these cell models to screen for therapeutic molecules, followed by validating them in the most suitable animal models prior to initiating human clinical trials.
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http://dx.doi.org/10.1016/j.molmed.2019.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997046PMC
February 2020

Placental development and function in trisomy 21 and mouse models of Down syndrome: Clues for studying mechanisms underlying atypical development.

Placenta 2020 01 5;89:58-66. Epub 2019 Oct 5.

Medical Genetics Branch (Prenatal Genomics and Therapy Section), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Down syndrome (DS) is the most common genetic disorder leading to developmental disability. The phenotypes associated with DS are complex and vary between affected individuals. Placental abnormalities in DS include differences in cytotrophoblast fusion that affect subsequent conversion to syncytiotrophoblast, atypical oxidative stress/antioxidant balance, and increased expression of genes that are also upregulated in the brains of individuals with Alzheimer's disease. Placentas in DS are prematurely senescent, showing atypical evidence of mineralization. Fetuses with DS are especially susceptible to adverse obstetric outcomes, including early in utero demise, stillbirth and growth restriction, all of which are related to placental function. The placenta, therefore, may provide key insights towards understanding the phenotypic variability observed in individuals with DS and aid in identifying biomarkers that can be used to evaluate phenotypic severity and prenatal treatments in real time. To address these issues, many different mouse models of DS have been generated to identify the mechanisms underlying developmental changes in many organ systems. Little is known, however, regarding placental development in the currently available mouse models of DS. Based upon the relative paucity of data on placental development in preclinical mouse models of DS, we recommend that future evaluation of new and existing models routinely include histologic and functional assessments of the placenta. In this paper we summarize studies performed in the placentas of both humans and mouse models with DS, highlighting gaps in knowledge and suggesting directions for future research.
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http://dx.doi.org/10.1016/j.placenta.2019.10.002DOI Listing
January 2020

Importance of research in reducing maternal morbidity and mortality rates.

Am J Obstet Gynecol 2019 09;221(3):179-182

Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

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http://dx.doi.org/10.1016/j.ajog.2019.05.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586732PMC
September 2019

The 2018 Malcolm Ferguson-Smith Young Investigator Award.

Prenat Diagn 2019 09 15;39(10):835-837. Epub 2019 Aug 15.

John Wiley and Sons, Oxford, UK.

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http://dx.doi.org/10.1002/pd.5533DOI Listing
September 2019

Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome.

Cereb Cortex 2020 01;30(1):382-390

Prenatal Genomics and Fetal Therapy Section, Medical Gen etics Branch, National Human Genome Research Institute, Bethesda, MD, USA.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P < 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.
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http://dx.doi.org/10.1093/cercor/bhz094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029684PMC
January 2020

The Impact of an Institutional Grant Program on the Economic, Social, and Cultural Capital of Women Researchers.

J Womens Health (Larchmt) 2019 12 28;28(12):1698-1704. Epub 2019 Jun 28.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland.

Early funding can have significant impact on a researcher's career. However, funding is not equal for men and women. Not only do female researchers apply for fewer grants than men, but they also experience a lower success rate when they do. The Zucker Grant Program (ZGP) was established in 2000 to promote the early success of women researchers. The purpose of this evaluation is to support other institutions hoping to grow the research careers of women scientists. This program evaluation reviewed the first 16 years of the program's history. Our mixed-methods, outcomes-based evaluation had four phases: (I) interviews with key stakeholders, (II) development and distribution of a survey to ZGP recipients, (III) focus groups and interviews with ZGP recipients, (IV) document analysis from the ZGP Center and the Tufts University School of Medicine (TUSM) Development Office. This article reports on the qualitative data collection and analysis. Between 2000 and 2016, US$377,050 was awarded for 142 recipients. Qualitative data revealed how grant funding was critical to support pilot data in awardees' research to inform extramural grant applications. However, the program evaluation also identified effects on awardees' confidence as researchers and connection to a community. Outcomes are interpreted through the framework of Bourdieu's three forms of capital, including economic, social, and cultural capital. Viewed through this framework, they provide a critical infrastructure to the development and success of early career female investigators. This work offers other institutions a framework to consider when establishing intramural funding and support programs for their early career investigators.
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http://dx.doi.org/10.1089/jwh.2018.7642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998046PMC
December 2019

The power of human touch in the era of artificial intelligence.

Authors:
Diana W Bianchi

Pediatr Res 2019 11 25;86(5):670-671. Epub 2019 Jun 25.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41390-019-0484-7DOI Listing
November 2019

Addressing the impact of opioids on women and children.

Am J Obstet Gynecol 2019 08 28;221(2):123.e1-123.e4. Epub 2019 May 28.

Environmental Influences on Child Health Outcomes (ECHO) Program, Office of the Director, National Institutes of Health, Bethesda, Maryland. Electronic address:

Women and children bear a substantial part of the burden of opioid overuse in the United States. Opioid use during pregnancy can lead to neonatal opioid withdrawal syndrome, and both the mothers and babies may be at higher risk of opioid use and its consequences later in the life course, setting up intergenerational cycles of opioid overuse. As part of the HEAL (Helping to End Addiction Long-term) Initiative of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Environmental influences on Child Health Outcomes program are together launching observational and intervention research programs to interrupt these cycles, beginning with opportunities in pregnancy and the newborn period. The Eunice Kennedy Shriver National Institute of Child Health and Human Development has also launched programs to find alternatives to opioids for painful conditions in women of reproductive age, including a range of gynecologic conditions. These coordinated efforts promise to help turn the tide against the opioid crisis by providing the necessary evidence to improve care for women and children affected by these substances.
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http://dx.doi.org/10.1016/j.ajog.2019.02.050DOI Listing
August 2019

Turner syndrome: New insights from prenatal genomics and transcriptomics.

Authors:
Diana W Bianchi

Am J Med Genet C Semin Med Genet 2019 Jan 31. Epub 2019 Jan 31.

Section on Prenatal Genomics and Fetal Therapy, Medical Genetics Branch, National Human Genome Research Institute, and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

In some parts of the world, prenatal screening using analysis of circulating cell-free (cf) DNA in the plasma of pregnant women has become part of routine prenatal care with limited professional guidelines and without significant input from the Turner syndrome community. In contrast to the very high positive predictive values (PPVs) achieved with cfDNA analysis for trisomy 21 (91% for high-risk and 82% for low-risk cases), the PPVs for monosomy X are much lower (~26%). This is because the maternal plasma sample contains both maternal cfDNA and placental DNA, which is a proxy for the fetal genome. Underlying biological mechanisms for false positive monosomy X screening results include confined placental mosaicism, co-twin demise, and maternal mosaicism. Somatic loss of a single X chromosome in the mother is a natural phenomenon that occurs with aging; this could explain many of the false positive cfDNA results. There is also increased awareness of women who have constitutional mosaicism for 45, X who are fertile. It is important to recognize that a positive cfDNA screen for 45, X does not mean that the fetus has Turner syndrome. A follow-up diagnostic test, either amniocentesis or neonatal karyotype/chromosome microarray, is recommended. Research studies on cell-free mRNA in second trimester amniotic fluid, which is almost exclusively fetal, demonstrate consistent dysregulation of genes involved in the hematologic, immune, and neurologic systems. This suggests that some of the pathophysiology of Turner syndrome occurs early in fetal life and presents novel opportunities for consideration of antenatal treatments.
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http://dx.doi.org/10.1002/ajmg.c.31675DOI Listing
January 2019

In case you missed it: The prenatal diagnosis editors bring you the most significant advances of 2018.

Prenat Diagn 2019 01;39(2):61-69

North East Thames Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1002/pd.5407DOI Listing
January 2019

Current Controversies in Prenatal Diagnosis 2: NIPT results suggesting maternal cancer should always be disclosed.

Prenat Diagn 2019 04 10;39(5):339-343. Epub 2018 Dec 10.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1002/pd.5379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714972PMC
April 2019