Publications by authors named "Virginia D Winn"

52 Publications

Single-Cell Analysis of the Neonatal Immune System Across the Gestational Age Continuum.

Front Immunol 2021 23;12:714090. Epub 2021 Aug 23.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States.

Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8CD161 T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections.
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http://dx.doi.org/10.3389/fimmu.2021.714090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420969PMC
August 2021

Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction.

Eur Heart J 2021 Jul 19. Epub 2021 Jul 19.

Department of Biology, Stanford University, Stanford, CA 94305, USA.

Aims: Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We aimed to identify candidate angiocrines expressed by endocardial and ECs inwildtype and LVNC conditions in Tie2Cre;Ino80fl/fl transgenic embryonic mouse hearts, and test the effect of these candidates on cardiomyocyte proliferation and maturation.

Methods And Results: We used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation.

Conclusions: These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.
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http://dx.doi.org/10.1093/eurheartj/ehab298DOI Listing
July 2021

Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset.

Sci Transl Med 2021 05;13(592)

Department of Surgery, Stanford University School of Medicine, Palo Alto, CA 94305, USA.

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [ = 0.85, 95% confidence interval (CI) [0.79 to 0.89], = 1.2 × 10, = 53, training set; = 0.81, 95% CI [0.61 to 0.91], = 3.9 × 10, = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.
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http://dx.doi.org/10.1126/scitranslmed.abd9898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136601PMC
May 2021

Association of preconception paternal health and adverse maternal outcomes among healthy mothers.

Am J Obstet Gynecol MFM 2021 09 23;3(5):100384. Epub 2021 Apr 23.

Department of Obstetrics and Gynecology, Stanford University, Stanford, CA; Department of Urology, Stanford University, Stanford, CA (Ms Li and Dr Eisenberg).

Background: Maternal morbidity continues to be an issue of national and global concern. Paternal preconception health may play a significant role in pregnancy outcomes and has received less attention than maternal health.

Objective: This study aimed to examine the association between preconception paternal health and the risk for adverse maternal outcomes among healthy mothers.

Study Design: This was a retrospective analysis of live births from 2009 through 2016 to healthy women aged 20 to 45 years recorded in the IBM Marketscan research database. Infants were linked to paired mothers and fathers using family ID. Preconception paternal health was assessed using the number of metabolic syndrome component diagnoses and the most common individual chronic disease diagnoses (hypertension, diabetes mellitus, obesity, hyperlipidemia, chronic obstructive pulmonary disease, cancer, and depression). Women with metabolic syndrome components were excluded to avoid potential confounding of maternal and paternal factors. Adverse maternal outcomes that were assessed included (1) abnormal placentation including placenta accreta spectrum, placenta previa, and placental abruption; (2) preeclampsia with and without severe features including eclampsia; and (3) severe maternal morbidity, identified as any indicator from the Centers for Disease Control and Prevention Index of life-threatening complications at the time of delivery to 6 weeks postpartum. The trend between preconception paternal health and each maternal outcome was determined using the Cochran-Armitage Trend test. The independent association of paternal health with maternal outcomes was also determined using generalized estimating equations models, accounting for some mothers who contributed multiple births during the study period, and by adjusting for maternal age, paternal age, region of birth, year of birth, maternal smoking, and average number of outpatient visits per year.

Results: Among 669,256 births to healthy mothers, there was a significant trend between all adverse maternal outcomes and worsening preconception paternal health defined either as the number of metabolic syndrome diagnoses or number of chronic disease diagnoses (P<.001; Cochran-Armitage Trend test). In the generalized estimating equations model, the odds for preeclampsia without severe features increased in a dose-dependent fashion and were 21% higher (95% confidence interval, 1.17-1.26) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for preeclampsia with severe features and eclampsia increased in a dose-dependent fashion and were 19% higher (95% confidence interval, 1.09-1.30) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for severe maternal morbidity were 9% higher (95% confidence interval, 1.002-1.19) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for abnormal placentation were similar between the groups (adjusted odds ratio, 0.96; 95% confidence interval, 0.89-1.03).

Conclusion: Among healthy mothers, we report that preconception paternal health is significantly associated with increased odds of preeclampsia with and without severe features and weakly associated with increased odds of severe maternal morbidity. These findings suggest that paternally derived factors may play significant roles in the development of adverse maternal outcomes in healthy women with a low a priori risk of obstetrical complications.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100384DOI Listing
September 2021

Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies.

J Matern Fetal Neonatal Med 2021 Mar 2:1-8. Epub 2021 Mar 2.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Background: Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care.

Objective: The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes.

Study Design: Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE.

Results: The model derived in the Stanford cohort was highly significant ( = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort ( = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant ( = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort ( = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford ( = 1.1E-454,  = 0.92) and Detroit cohorts ( = 1.1.E-92,  = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences.

Conclusions: Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the "same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power.
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http://dx.doi.org/10.1080/14767058.2021.1888915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410912PMC
March 2021

A Letter to President Biden and Secretary Designate of HHS Xavier Becerra: Remove Barriers to Federal Funding of Human Embryo and Fetal Tissue Research.

Reprod Sci 2021 04 26;28(4):933-935. Epub 2021 Feb 26.

Stanford University School of Medicine, Palo Alto, CA, USA.

Human fetal tissue (HFT) has been used in biomedical research for nearly a century and has led to extraordinarily valuable discoveries that have benefitted humankind. Politicization of the use of HFT over recent years has led to the creation of numerous obstacles to scientific progress in this field. In July 2019, the imposition of redundant ethics policies was supplemented with the creation of the Human Fetal Tissue Ethics Advisory Board, which withheld funding of 13 out of 14 NIH grants that were favorably peer reviewed in the Summer of 2020. We believe that these new sets of restrictions are harmful to the goals of scientific progress and call upon the new administration of our government to allow peer review, not politics, to determine scientific merit and to reinstitute the previously existing ethics policies that were more than adequate to assure the appropriateness of human fetal tissue research.
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http://dx.doi.org/10.1007/s43032-021-00491-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909373PMC
April 2021

Early prediction of preeclampsia via machine learning.

Am J Obstet Gynecol MFM 2020 05 14;2(2):100100. Epub 2020 Mar 14.

Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA.

Background: Early prediction of preeclampsia is challenging because of poorly understood causes, various risk factors, and likely multiple pathogenic phenotypes of preeclampsia. Statistical learning methods are well-equipped to deal with a large number of variables, such as patients' clinical and laboratory data, and to select the most informative features automatically.

Objective: Our objective was to use statistical learning methods to analyze all available clinical and laboratory data that were obtained during routine prenatal visits in early pregnancy and to use them to develop a prediction model for preeclampsia.

Study Design: This was a retrospective cohort study that used data from 16,370 births at Lucile Packard Children Hospital at Stanford, CA, from April 2014 to January 2018. Two statistical learning algorithms were used to build a predictive model: (1) elastic net and (2) gradient boosting algorithm. Models for all preeclampsia and early-onset preeclampsia (<34 weeks gestation) were fitted with the use of patient data that were available at <16 weeks gestational age. The 67 variables that were considered in the models included maternal characteristics, medical history, routine prenatal laboratory results, and medication intake. The area under the receiver operator curve, true-positive rate, and false-positive rate were assessed via cross-validation.

Results: Using the elastic net algorithm, we developed a prediction model that contained a subset of the most informative features from all variables. The obtained prediction model for preeclampsia yielded an area under the curve of 0.79 (95% confidence interval, 0.75-0.83), sensitivity of 45.2%, and false-positive rate of 8.1%. The prediction model for early-onset preeclampsia achieved an area under the curve of 0.89 (95% confidence interval, 0.84-0.95), true-positive rate of 72.3%, and false-positive rate of 8.8%.

Conclusion: Statistical learning methods in a retrospective cohort study automatically identified a set of significant features for prediction and yielded high prediction performance for preeclampsia risk from routine early pregnancy information.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100100DOI Listing
May 2020

Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.

JAMA Netw Open 2020 12 1;3(12):e2029655. Epub 2020 Dec 1.

Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.

Importance: Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.

Objective: To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.

Design, Setting, And Participants: This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.

Exposures: Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.

Main Outcomes And Measures: The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.

Results: Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.

Conclusions And Relevance: This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749442PMC
December 2020

Examining Sex Differences in the Human Placental Transcriptome During the First Fetal Androgen Peak.

Reprod Sci 2021 03 4;28(3):801-818. Epub 2020 Nov 4.

Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Dr. H333, Stanford, CA, 94305-5317, USA.

Sex differences in human placenta exist from early pregnancy to term, however, it is unclear whether these differences are driven solely by sex chromosome complement or are subject to differential sex hormonal regulation. Here, we survey the human chorionic villus (CV) transcriptome for sex-linked signatures from 11 to 16 gestational weeks, corresponding to the first window of increasing testis-derived androgen production in male fetuses. Illumina HiSeq RNA sequencing was performed on Lexogen Quantseq 3' libraries derived from CV biopsies (n = 11 females, n = 12 males). Differential expression (DE) was performed to identify sex-linked transcriptional signatures, followed by chromosome mapping, pathway analysis, predicted protein interaction, and post-hoc linear regressions to identify transcripts that trend over time. We observe 322 transcripts DE between male and female CV from 11 to 16 weeks, with 22 transcripts logFC > 1. Contrary to our predictions, the difference between male and female expression of DE autosomal genes was more pronounced at the earlier gestational ages. In females, we found selective upregulation of extracellular matrix components, along with a number of X-linked genes. In males, DE transcripts centered on chromosome 19, with mitochondrial, immune, and pregnancy maintenance-related transcripts upregulated. Among the highest differentially expressed autosomal genes were CCRL2, LGALS13, and LGALS14, which are known to regulate immune cell interactions. Our results provide insight into sex-linked gene expression in late first and early second trimester developing human placenta and lay the groundwork to understand the mechanistic origins of sex differences in prenatal development.
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http://dx.doi.org/10.1007/s43032-020-00355-8DOI Listing
March 2021

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia.

PLoS One 2020 3;15(3):e0230000. Epub 2020 Mar 3.

Clinical and Translational Research Program, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Palo Alto, CA, United States of America.

Background: Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.

Methods: Serum levels of placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice.

Results: An elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs.

Conclusions: Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230000PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053753PMC
June 2020

Multiomic immune clockworks of pregnancy.

Semin Immunopathol 2020 08 4;42(4):397-412. Epub 2020 Feb 4.

Department of Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Preterm birth is the leading cause of mortality in children under the age of five worldwide. Despite major efforts, we still lack the ability to accurately predict and effectively prevent preterm birth. While multiple factors contribute to preterm labor, dysregulations of immunological adaptations required for the maintenance of a healthy pregnancy is at its pathophysiological core. Consequently, a precise understanding of these chronologically paced immune adaptations and of the biological pacemakers that synchronize the pregnancy "immune clock" is a critical first step towards identifying deviations that are hallmarks of peterm birth. Here, we will review key elements of the fetal, placental, and maternal pacemakers that program the immune clock of pregnancy. We will then emphasize multiomic studies that enable a more integrated view of pregnancy-related immune adaptations. Such multiomic assessments can strengthen the biological plausibility of immunological findings and increase the power of biological signatures predictive of preterm birth.
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http://dx.doi.org/10.1007/s00281-019-00772-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508753PMC
August 2020

Uteroplacental Ischemia Is Associated with Increased PAPP-A2.

Reprod Sci 2020 02 28;27(2):529-536. Epub 2020 Jan 28.

Department of Obstetrics and Gynecology, University of Colorado Denver, Aurora, CO, USA.

Residence at high altitude (> 2500 m) has been associated with an increased frequency of preeclampsia. Pappalysin-2 (PAPP-A2) is an insulin-like growth factor binding protein-5 (IGFBP-5) protease that is elevated in preeclampsia, and up-regulated by hypoxia in placental explants. The relationships between PAPP-A2, altitude, and indices of uteroplacental ischemia are unknown. We aimed to evaluate the association of altitude, preeclampsia, and uterine artery flow or vascular resistance with PAPP-A2 levels. PAPP-A2, uterine artery diameter, volumetric blood flow, and pulsatility indices were measured longitudinally in normotensive Andean women residing at low or high altitudes in Bolivia and in a separate Andean high-altitude cohort with or without preeclampsia. PAPP-A2 levels increased with advancing gestation, with the rise tending to be greater at high compared to low altitude, and higher in early-onset preeclamptic compared to normotensive women at high altitude. Uterine artery blood flow was markedly lower and pulsatility index higher in early-onset preeclamptic normotensive women compared to normotensive women. PAPP-A2 was unrelated to uterine artery pulsatility index in normotensive women but positively correlated in the early-onset preeclampsia cases. We concluded that PAPP-A2 is elevated at high altitude and especially in cases of early-onset preeclampsia with Doppler indices of uteroplacental ischemia.
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http://dx.doi.org/10.1007/s43032-019-00050-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539799PMC
February 2020

Maternal Vascular Health in Pregnancy and Postpartum After Assisted Reproduction.

Hypertension 2020 02 16;75(2):549-560. Epub 2019 Dec 16.

Department of Obstetrics and Gynecology, Stanford University Medical Center, CA (V.D.W.).

Although most pregnancies after assisted reproduction are associated with a favorable outcome for the mother and infant, reports of abnormal vascular adaptation in early pregnancy and emerging maternal and perinatal pathology warrant further investigations. Herein we extended our previous work and further examined whether perturbations of blood pressure and endothelial function during the first trimester in conceptions with nonphysiological corpus luteum (CL) numbers would persist through the third trimester of pregnancy and into the postpartum period. We investigated both maternal and perinatal outcomes. Participants were grouped according to CL number and method of conception: 0 CL (programmed autologous frozen-thawed embryo transfer, N=10-18); 1 CL (spontaneous conception [N=16] and natural cycle frozen-thawed embryo transfer [N=12]); or >3 CL associated with autologous fresh embryo transfer [N=8-12]. Augmentation index was higher during the third trimester in the absence of a CL compared to 1 CL (=0.03) and in frozen-thawed embryo transfer in a programmed compared to a natural cycle (=0.02). Moreover, baseline pulse-wave amplitude was higher in >3 CL conceptions at all time points (all <0.05). The incidence of preeclampsia and preeclampsia with severe features was significantly higher in the absence of a CL compared to the presence of one or >3 CL (=0.045 and =0.03). Infants from conceptions with >3 CL had lower birth weights (=0.02) and a higher rate of low birth weight offspring (=0.008). Deficient vascular adaptation during early gestation in conceptions with nonphysiological CL numbers might predispose women to adverse pregnancy outcomes, for example, preeclampsia.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491550PMC
February 2020

Data-driven queries between medications and spontaneous preterm birth among 2.5 million pregnancies.

Birth Defects Res 2019 10 21;111(16):1145-1153. Epub 2019 Aug 21.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California.

Background: Our goal was to develop an approach that can systematically identify potential associations between medication prescribed in pregnancy and spontaneous preterm birth (sPTB) by mining large administrative "claims" databases containing hundreds of medications. One such association that we illustrate emerged with antiviral medications used for herpes treatment.

Methods: IBM MarketScan® databases (2007-2016) were used. A pregnancy cohort was established using International Classification of Diseases (ICD-9/10) codes. Multiple hypothesis testing and the Benjamini-Hochberg procedure that limited false discovery rate at 5% revealed, among 863 medications, five that showed odds ratios (ORs) <1. The statistically strongest was an association between antivirals and sPTB that we illustrate as a real example of our approach, specifically for treatment of genital herpes (GH). Three groups of women were identified based on diagnosis of GH and treatment during the first 36 weeks of pregnancy: (a) GH without treatment; (b) GH treated with antivirals; (c) no GH or treatment.

Results: We identified 2,538,255 deliveries. 0.98% women had a diagnosis of GH. Among them, 60.0% received antiviral treatment. Women with treated GH had OR < 1, (OR [95% CI] = 0.91 [0.85, 0.98]). In contrast, women with untreated GH had a small increased risk of sPTB (OR [95% CI] =1.22 [1.14, 1.32]).

Conclusions: Data-driven approaches can effectively generate new hypotheses on associations between medications and sPTB. This analysis led us to examine the association with GH treatment. While unknown confounders may impact these findings, our results indicate that women with untreated GH have a modest increased risk of sPTB.
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http://dx.doi.org/10.1002/bdr2.1580DOI Listing
October 2019

Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia.

Front Immunol 2019 11;10:1305. Epub 2019 Jun 11.

Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Palo Alto, CA, United States.

Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82-0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4T cell subsets (AUC 0.92, = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia.
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http://dx.doi.org/10.3389/fimmu.2019.01305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584811PMC
July 2020

Murine trophoblast-derived and pregnancy-associated exosome-enriched extracellular vesicle microRNAs: Implications for placenta driven effects on maternal physiology.

PLoS One 2019 7;14(2):e0210675. Epub 2019 Feb 7.

Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, United States of America.

The role of extracellular vesicles (EVs), specifically exosomes, in intercellular communication likely plays a key role in placental orchestration of pregnancy and maternal immune sensing of the fetus. While murine models are powerful tools to study pregnancy and maternal-fetal immune interactions, in contrast to human placental exosomes, the content of murine placental and pregnancy exosomes remains largely understudied. Using a recently developed in vitro culture technique, murine trophoblast stem cells derived from B6 mice were differentiated into syncytial-like cells. EVs from the conditioned media, as well as from pregnant and non-pregnant sera, were enriched for exosomes. The RNA composition of these murine trophoblast-derived and pregnancy-associated exosome-enriched-EVs (ExoE-EVs) was determined using RNA-sequencing analysis and expression levels confirmed by qRT-PCR. Differentially abundant miRNAs were detected in syncytial differentiated ExoE-EVs, particularly from the X chromosome cluster (mmu-miR-322-3p, mmu-miR-322-5p, mmu-miR-503-5p, mmu-miR-542-3p, and mmu-miR-450a-5p). These were confirmed to be increased in pregnant mouse sera ExoE-EVs by qRT-PCR analysis. Interestingly, fifteen miRNAs were only present within the pregnancy-derived ExoE-EVs compared to non-pregnant controls. Mmu-miR-292-3p and mmu-miR-183-5p were noted to be some of the most abundant miRNAs in syncytial ExoE-EVs and were also present at higher levels in pregnant versus non-pregnant sera ExoE-EVs. The bioinformatics tool, MultiMir, was employed to query publicly available databases of predicted miRNA-target interactions. This analysis reveals that the X-chromosome miRNAs are predicted to target ubiquitin-mediated proteolysis and intracellular signaling pathways. Knowing the cargo of placental and pregnancy-specific ExoE-EVs as well as the predicted biological targets informs studies using murine models to examine not only maternal-fetal immune interactions but also the physiologic consequences of placental-maternal communication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210675PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366741PMC
October 2019

Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.

Hypertension 2019 03;73(3):640-649

From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology (F.v.V.-H., R.R.F., W.Z., V.L.B.), Stanford University School of Medicine, Sunnyvale, CA.

In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interaction: P=0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation ( P=0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14-6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94-25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P=0.02) and preeclampsia with severe features (9.6% versus 0.8%; P=0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434532PMC
March 2019

Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy.

Hypertension 2019 03;73(3):680-690

Department of Obstetrics and Gynecology, Stanford University Medical Center, CA (P.N., N.M., V.D.W.).

Identifying modifiable factors that contribute to preeclampsia risk associated with assisted reproduction can improve maternal health. Vascular dysfunction predates clinical presentation of preeclampsia. Therefore, we examined if a nonphysiological hormonal milieu, a modifiable state, affects maternal vascular health in early pregnancy. Blood pressure, endothelial function, circulating endothelial progenitor cell numbers, lipid levels, and corpus luteum (CL) hormones were compared in a prospective cohort of women with infertility history based on number of CL: 0 CL (programmed frozen embryo transfer [FET], N=18); 1 CL (spontaneous conception [N=16] and natural cycle FET [N=12]); or >3 CL associated with in vitro fertilization [N=11]. Women with 0 or >3 CL lacked the drop in mean arterial blood pressure compared with those with 1 CL (both P=0.05). Reactive hyperemia index was impaired in women with 0 CL compared with 1 CL ( P=0.04) while baseline pulse wave amplitude was higher with > 3 CL compared with 1 CL ( P=0.01) or 0 CL ( P=0.01). Comparing only FET cycles, a lower reactive hyperemia index and a higher augmentation index is noted in FETs with suppressed CL compared with FETs in a natural cycle (both P=0.03). The number of angiogenic and nonangiogenic circulating endothelial progenitor cell numbers was lower in the absence of a CL in FETs ( P=0.01 and P=0.03). Vascular health in early pregnancy is altered in women with aberrant numbers of CL (0 or >3) and might represent insufficient cardiovascular adaptation contributing to an increased risk of preeclampsia.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378337PMC
March 2019

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

Bioinformatics 2019 01;35(1):95-103

Division of Neonatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

Motivation: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.

Results: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.

Availability And Implementation: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298056PMC
January 2019

Maternal Height and Risk of Preeclampsia among Race/Ethnic Groups.

Am J Perinatol 2019 07 5;36(8):864-871. Epub 2018 Nov 5.

Division of Neonatology and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California.

Objective: Shorter maternal height has been associated with preeclampsia risk in several populations. It has been less evident whether an independent contribution to the risk exists from maternal height consistently across different races/ethnicities. We investigated associations between maternal height and risk of preeclampsia for different races/ethnicities.

Study Design: California singleton live births from 2007 to 2011 were analyzed. Logistic regression was used to estimate adjusted odds ratios for the association between height and preeclampsia after stratification by race/ethnicity. To determine the contribution of height that is as independent of body composition as possible, we performed one analysis adjusted for body mass index (BMI) and the other for weight. Additional analyses were performed stratified by parity, and the presence of preexisting/gestational diabetes and autoimmune conditions.

Results: Among 2,138,012 deliveries, 3.1% preeclampsia/eclampsia cases were observed. The analysis, adjusted for prepregnancy weight, revealed an inverse relation between maternal height and risk of mild and severe preeclampsia/eclampsia. When the analysis was adjusted for BMI, an inverse relation between maternal height was observed for severe preeclampsia/eclampsia. These associations were observed for each race/ethnicity.

Conclusion: Using a large and diverse cohort, we demonstrated that shorter height, irrespective of prepregnancy weight or BMI, is associated with an increased risk of severe preeclampsia/eclampsia across different races/ethnicities.
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http://dx.doi.org/10.1055/s-0038-1675205DOI Listing
July 2019

Placental lipoprotein lipase activity is positively associated with newborn adiposity.

Placenta 2018 04 5;64:53-60. Epub 2018 Mar 5.

Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address:

Introduction: Recent data suggest that in addition to glucose, fetal growth is related to maternal triglycerides (TG). To reach the fetus, TG must be hydrolyzed to free fatty acids (FFA) and transported across the placenta, but regulation is uncertain. Placental lipoprotein lipase (pLPL) hydrolyzes TG, both dietary chylomicron TG (CM-TG) and very-low density lipoprotein TG (VLDL-TG), to FFA. This may promote fetal fat accretion by increasing the available FFA pool for placental uptake. We tested the novel hypothesis that pLPL activity, but not maternal adipose tissue LPL activity, is associated with newborn adiposity and higher maternal TG.

Methods: Twenty mothers (n = 13 normal-weight; n = 7 obese) were prospectively recruited. Maternal glucose, insulin, TG (total, CM-TG, VLDL-TG), and FFA were measured at 14-16, 26-28, and 36-37 weeks, and adipose tissue LPL was measured at 26-28 weeks. At term delivery, placental villous biopsies were immediately analyzed for pLPL enzymatic activity. Newborn percent body fat (newborn %fat) was assessed by skinfolds.

Results: Placental LPL activity was positively correlated with birthweight (r = 0.48;P = 0.03) and newborn %fat (r = 0.59;P = 0.006), further strengthened by correcting for gestational age at delivery (r = 0.75;P = 0.0001), but adipose tissue LPL was not. Maternal TG and BMI were not correlated with pLPL activity. Additionally, pLPL gene expression, while modestly correlated with enzymatic activity (r = 0.53;P < 0.05), was not correlated with newborn adiposity.

Discussion: This is the first study to show a positive correlation between pLPL activity and newborn %fat. Placental lipase regulation and the role of pLPL in pregnancies characterized by nutrient excess and fetal overgrowth warrant further investigation.
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http://dx.doi.org/10.1016/j.placenta.2018.03.001DOI Listing
April 2018

Residential agricultural pesticide exposures and risks of preeclampsia.

Environ Res 2018 07 31;164:546-555. Epub 2018 Mar 31.

California Department of Public Health, Richmond, CA 94804, USA.

We investigated risks of preeclampsia phenotypes from potential residential pesticide exposures, including 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011. The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. The following numbers of women with preeclampsia phenotypes were identified: 1045 with superimposed (pre-existing hypertension with preeclampsia) preeclampsia (265 with gestational weeks 20-31 and 780 with gestational weeks 32-36); 3471 with severe preeclampsia (824 with gestational weeks 20-31 and 2647 with gestational weeks 32-36); and 2780 with mild preeclampsia (207 with gestational weeks 20-31 and 2573 with gestational weeks 32-36). The reference population for these groups was 197,461 women who did not have diabetes (gestational or pre-existing), did not have any hypertensive disorder, and who delivered at 37 weeks or later. The frequency of any exposure was lower or about the same in each preeclampsia case group (further delineated by gestational age), and month time period, relative to the frequency in reference population controls. Nearly all odds ratios were below 1.0 for these any vs no exposure comparisons. This study showed a general lack of increased risks between a range of agriculture pesticide exposures near women's residences and various preeclampsia phenotypes.
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http://dx.doi.org/10.1016/j.envres.2018.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911197PMC
July 2018

A proteomic clock of human pregnancy.

Am J Obstet Gynecol 2018 03 24;218(3):347.e1-347.e14. Epub 2017 Dec 24.

Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, CA. Electronic address:

Background: Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable because it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome.

Objective: The recent availability of a highly multiplexed platform affording the simultaneous measurement of 1310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns caused by fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins and link such attributes to relevant immunological changes.

Study Design: Pregnant women participated in this longitudinal study. In 2 subsequent sets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 weeks), second (15-20 weeks), and third (24-32 weeks) trimesters and 6 weeks postpartum for analysis with a highly multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piecewise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term.

Results: An independently validated model consisting of 74 proteins strongly predicted gestational age (P = 3.8 × 10, R = 0.97). The model could be reduced to 8 proteins without losing its predictive power (P = 1.7 × 10, R = 0.91). The 3 top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase and signal transducer and activator of transcription pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top-ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with signal transducer and activator of transcription-5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age.

Conclusion: Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a proteomic clock. Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a clock is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-related pathologies, and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that chrionic somatomammotropin hormone may critically regulate T-cell function during pregnancy.
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http://dx.doi.org/10.1016/j.ajog.2017.12.208DOI Listing
March 2018

Occurrence of Selected Structural Birth Defects Among Women With Preeclampsia and Other Hypertensive Disorders.

Am J Epidemiol 2018 04;187(4):668-676

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California.

To explore a potential association between preeclampsia and selected birth defects, we examined the prevalence of certain birth defects among women with hypertensive disorders including preeclampsia. We analyzed data from 2,499,536 singleton live births in California from 2007 to 2011, including maternal and infant demographics from birth certificates as well as clinical details from delivery hospitalization records. We examined defect groups that were recognizable at birth (e.g., spina bifida and cleft lip). Hypertensive disorders included preexisting hypertension, gestational hypertension, mild preeclampsia, severe preeclampsia/eclampsia, and preeclampsia superimposed on preexisting hypertension. Relative risk values with 95% confidence intervals for each birth defect were calculated by hypertensive group, as well as independent and joint associations of hypertensive and diabetic disorders. Risks of each type of birth defect were higher among offspring of women with hypertensive disorders compared with those without. The risks of birth defects among offspring of women with only a hypertensive disorder were significantly higher than that among women with neither hypertensive nor diabetic disorders (relative risks ranged from 1.37 to 2.77). Risks of birth defects were highest among those born to women with both hypertensive and diabetic disorders compared with those with neither (relative risks ranged from 1.80 to 6.22). These findings support the existence of an association between preeclampsia and certain birth defects and suggest that diabetes may be a contributing factor.
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http://dx.doi.org/10.1093/aje/kwx269DOI Listing
April 2018

An immune clock of human pregnancy.

Sci Immunol 2017 Sep;2(15)

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94121, USA.

The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.
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http://dx.doi.org/10.1126/sciimmunol.aan2946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701281PMC
September 2017

A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus-infected mongolians.

Hepatology 2017 12 30;66(6):1739-1749. Epub 2017 Oct 30.

Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, CA.

Hepatitis delta virus (HDV) causes the most severe form of human viral hepatitis. HDV requires a hepatitis B virus (HBV) coinfection to provide HDV with HBV surface antigen envelope proteins. The net effect of HDV is to make the underlying HBV disease worse, including higher rates of hepatocellular carcinoma. Accurate assessments of current HDV prevalence have been hampered by the lack of readily available and reliable quantitative assays, combined with the absence of a Food and Drug Administration-approved therapy. We sought to develop a convenient assay for accurately screening populations and to use this assay to determine HDV prevalence in a population with abnormally high rates of hepatocellular carcinoma. We developed a high-throughput quantitative microarray antibody capture assay for anti-HDV immunoglobulin G wherein recombinant HDV delta antigen is printed by microarray on slides coated with a noncontinuous, nanostructured plasmonic gold film, enabling quantitative fluorescent detection of anti-HDV antibody in small aliquots of patient serum. This assay was then used to screen all HBV-infected patients identified in a large randomly selected cohort designed to represent the Mongolian population. We identified two quantitative thresholds of captured antibody that were 100% predictive of the sample either being positive on standard western blot or harboring HDV RNA detectable by real-time quantitative PCR. Subsequent screening of the HBV cohort revealed that a remarkable 57% were RNA and an additional 4% were positive on western blot alone.

Conclusion: The quantitative microarray antibody capture assay's unique performance characteristics make it ideal for population screening; its application to the Mongolian HBV surface antigen-positive population reveals an apparent ∼60% prevalence of HDV coinfection among these HBV-infected Mongolian subjects, which may help explain the extraordinarily high rate of hepatocellular carcinoma in Mongolia. (Hepatology 2017;66:1739-1749).
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http://dx.doi.org/10.1002/hep.28957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441964PMC
December 2017

Umbilical Cord Blood Circulating Progenitor Cells and Endothelial Colony-Forming Cells Are Decreased in Preeclampsia.

Reprod Sci 2017 07 23;24(7):1088-1096. Epub 2016 Nov 23.

2 Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO, USA.

Preeclampsia (PE) is a pregnancy-specific disease characterized by the new onset of hypertension and proteinuria. Mothers with PE are known to develop endothelial dysfunction, but its effect on infants has been understudied, as newborns are often asymptomatic. Recent studies indicate that infants born from preeclamptic pregnancies develop endothelial dysfunction including higher blood pressure during childhood and an increased risk of stroke later in life. We hypothesize that PE reduces the number and function of fetal angiogenic progenitor cells and may contribute to this increased risk. We quantified 2 distinct types of angiogenic progenitors, pro-angiogenic circulating progenitor cells (CPCs) and endothelial colony-forming cells (ECFCs), from the umbilical cord blood of preeclamptic pregnancies and normotensive controls. Pro-angiogenic and nonangiogenic CPCs were enumerated via flow cytometry and ECFCs by cell culture. Additionally, we studied the growth, migration, and tube formation of ECFCs from PE and gestational age-matched normotensive control pregnancies. We found that PE resulted in decreased cord blood pro-angiogenic CPCs and ECFCs. Nonangiogenic CPCs were also decreased. Preeclamptic ECFCs demonstrated decreased growth and migration but formed tube-like structures in vitro similar to controls. Our results suggest that the preeclamptic environment alters the number and function of angiogenic progenitor cells and may increase the risk of later vascular disease.
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http://dx.doi.org/10.1177/1933719116678692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344827PMC
July 2017

Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy.

J Immunol 2016 12 28;197(11):4482-4492. Epub 2016 Oct 28.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305;

Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4 and CD8 T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal TbetCD4 T cells, CD8 T cells, B cells, and CD56CD16 NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.
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http://dx.doi.org/10.4049/jimmunol.1601195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125527PMC
December 2016

Differential expression of human placental PAPP-A2 over gestation and in preeclampsia.

Placenta 2016 Jan 23;37:19-25. Epub 2015 Nov 23.

University of Colorado School of Medicine, Department of Obstetrics and Gynecology, 12631 E. 17th Avenue, Aurora, CO, USA. Electronic address:

Introduction: Pregnancy Associated Plasma Protein A2 (PAPP-A2) is a pregnancy related insulin-like growth factor binding protein-5 (IGFBP-5) protease, known to be elevated in preeclampsia. As the insulin-like growth factors are important in human implantation and placentation, we sought to determine the expression pattern of PAPP-A2 over human gestation in normal and preeclamptic pregnancies to evaluate its role in placental development and the pathogenesis of preeclampsia.

Methods: Placental basal plate and chorionic villi samples, maternal and fetal cord blood sera were obtained from preeclamptic and control pregnancies. Formalin-fixed tissue sections from across gestation were stained for cytokeratin-7, HLA-G, and PAPP-A2. PAPP-A2 immunoblot analysis was also performed on protein lysates and sera.

Results: PAPP-A2 expression is predominately expressed by differentiated trophoblasts and fetal endothelium. Chorionic villi show strong expression in the first trimester, followed by a progressive decrease in the second trimester, which returns in the third trimester. PAPP-A2 expression is not impacted by labor. PAPP-A2 is increased in the basal plate, chorionic villi and maternal sera in preeclampsia compared to controls, but is not detectable in cord blood.

Discussion: PAPP-A2 is differentially expressed in different trophoblast populations and shows strong down regulation in the mid second trimester in chorionic villous samples. Both maternal sera and placental tissue from pregnancies complicated by preeclampsia show increased levels of PAPP-A2. PAPP-A2 levels are not altered by labor. Additionally, PAPP-A2 cannot be detected in cord blood demonstrating that the alterations in maternal and placental PAPP-A2 are not recapitulated in the fetal circulation.
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http://dx.doi.org/10.1016/j.placenta.2015.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848394PMC
January 2016
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