Director of Perinatal Biology, Stanford University School of Medicine
Practices at Stanford Hospital & Clinics, Lucile Packard Children’s Hospital Stanford
- Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development ELIFE 2021; 10 Hide More
Examining Sex Differences in the Human Placental Transcriptome During the First Fetal Androgen Peak.
Reproductive sciences (Thousand Oaks, Calif.)
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 16weeks, 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 placentaand lay the groundwork to understand the mechanistic origins of sex differencesin prenataldevelopment.
View details for DOI 10.1007/s43032-020-00355-8
View details for PubMedID 33150487
Early prediction of preeclampsia via machine learning.
American journal of obstetrics & gynecology MFM
2020; 2 (2): 100100
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 netalgorithm, 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.
View details for DOI 10.1016/j.ajogmf.2020.100100
View details for PubMedID 33345966
Uteroplacental Ischemia Is Associated with Increased PAPP-A2.
Reproductive sciences (Thousand Oaks, Calif.)
Residence at high altitude (>2500m) 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.
View details for DOI 10.1007/s43032-019-00050-3
View details for PubMedID 31994005
- Maternal Height and Risk of Preeclampsia among Race/Ethnic Groups AMERICAN JOURNAL OF PERINATOLOGY 2019; 36 (8): 864–71 Hide More
Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia.
Frontiers in immunology
2019; 10: 1305
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 CD4+T cell subsets (AUC 0.92, p = 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.
View details for DOI 10.3389/fimmu.2019.01305
View details for PubMedID 31263463
View details for PubMedCentralID PMC6584811
- Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia FRONTIERS IN IMMUNOLOGY 2019; 10 Hide More
- Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy HYPERTENSION 2019; 73 (3): 680–90 Hide More
- Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum HYPERTENSION 2019; 73 (3): 640–49 Hide More
- Murine trophoblast-derived and pregnancy-associated exosome-enriched extracellular vesicle microRNAs: Implications for placenta driven effects on maternal physiology PLOS ONE 2019; 14 (2) Hide More