Case finding of early pregnancies at risk of preeclampsia using maternal blood leptin/ceramide ratio: multi-omics discovery and validation from a longitudinal study

Objective To evaluate whether longitudinal measurements of serological adipokines and sphingolipids can predict preeclampsia early in gestation. Design Retrospective multi-omics discovery and longitudinal validation. Setting Maternity units in two US hospitals. Methods A multi-omics approach integrating genomic and lipidomic discoveries was employed to identify leptin (Lep) and ceramide (Cer) as novel PE early gestational biomarkers. The levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1), Lep, and Cer in maternal sera were then determined by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays. Main outcome measures Interval from positive prediction to confirmative diagnosis. Results Genomic meta-analysis compiled six PE placental cohorts with 78 PE and 95 non-PE control placentas. The Testing Cohort included sera from 7 non-PE and 8 PE women collected at confirmatory diagnosis. The Validation Cohort included sera from 20 non-PE and 20 PE women collected longitudinally through gestation. Our findings revealed a marked elevation of maternal serum Leptin/Ceramide (d18:1/25:0) ratio from early gestation (a median of 23 weeks) when comparing later PE-complicated with uncomplicated pregnancies. The maternal Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting PE for sensitivity (85% vs. 40%), positive predictive value (89% vs. 42%), and AUC (0.92 vs. 0.52) from 5 to 25 weeks of gestation. Conclusions Non-invasive longitudinal assessment by serological evaluation of Lep/Cer (d18:1/25:0) ratio can case find early pregnancies at risk of preeclampsia, outperforming sFlt-1/PlGF ratio test. Tweetable abstract Non-invasive longitudinal assessment by serological evaluation of Lep and Cer ratio can predict preeclampsia early in gestation.

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Case finding of early pregnancies at risk of preeclampsia using maternal blood leptin/ceramide ratio: multi-omics discovery and validation from a longitudinal study

10.1101/2020.12.17.20248418 ◽

2020 ◽

Author(s):

Qianyang Huang ◽

Shiying Hao ◽

Jin You ◽

Xiaoming Yao ◽

Zhen Li ◽

...

Keyword(s):

At Risk ◽

Meta Analysis ◽

Maternal Blood ◽

Maternal Serum ◽

Ratio Test ◽

Longitudinal Assessment ◽

Longitudinal Measurements ◽

Tandem Mass Spectrometric ◽

Plgf Ratio ◽

Risk Of Preeclampsia

Objective To evaluate whether longitudinal measurements of serological adipokines and sphingolipids can predict preeclampsia early in gestation. Design Retrospective multi-omics discovery and longitudinal validation. Setting Maternity units in two US hospitals. Methods A multi-omics approach integrating genomic and lipidomic discoveries was employed to identify leptin (Lep) and ceramide (Cer) as novel PE early gestational biomarkers. The levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1), Lep, and Cer in maternal sera were then determined by enzyme-linked immunosorbent (ELISA) and liquid chromatography-tandem mass spectrometric (LC/MS/MS) assays. Main outcome measures Interval from positive prediction to confirmative diagnosis. Results Genomic meta-analysis compiled six PE placental cohorts with 78 PE and 95 non-PE control placentas. The Testing Cohort included sera from 7 non-PE and 8 PE women collected at confirmatory diagnosis. The Validation Cohort included sera from 20 non-PE and 20 PE women collected longitudinally through gestation. Our findings revealed a marked elevation of maternal serum Leptin/Ceramide (d18:1/25:0) ratio from early gestation (a median of 23 weeks) when comparing later PE-complicated with uncomplicated pregnancies. The maternal Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting PE for sensitivity (85% vs. 40%), positive predictive value (89% vs. 42%), and AUC (0.92 vs. 0.52) from 5 to 25 weeks of gestation. Conclusions Non-invasive longitudinal assessment by serological evaluation of Lep/Cer (d18:1/25:0) ratio can case find early pregnancies at risk of preeclampsia, outperforming sFlt-1/PlGF ratio test.

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Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation

BMJ Open ◽

10.1136/bmjopen-2021-050963 ◽

2021 ◽

Vol 11 (11) ◽

pp. e050963

Author(s):

Qianyang Huang ◽

Shiying Hao ◽

Jin You ◽

Xiaoming Yao ◽

Zhen Li ◽

...

Keyword(s):

Placental Tissue ◽

Maternal Blood ◽

Maternal Serum ◽

Ratio Test ◽

Uncomplicated Pregnancy ◽

Longitudinal Measurement ◽

Longitudinal Measurements ◽

Longitudinal Observation ◽

Tandem Mass Spectrometric ◽

Plgf Ratio

ObjectiveThis study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.Study designRetrospective discovery and longitudinal confirmation.SettingMaternity units from two US hospitals.ParticipantsSix previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.Outcome measuresBiomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.ResultsOur discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks’ gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.ConclusionsOur study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

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Abstract 15048: Ischaemic Pre-conditioning: A Non-invasive Intervention That Improves Maternal Endothelial Function in Women With Preeclampsia And at Risk of Preeclampsia

Circulation ◽

10.1161/circ.142.suppl_3.15048 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Tamara Kubba ◽

Sean M Davidson ◽

David Williams

Keyword(s):

At Risk ◽

Endothelial Function ◽

Pregnant Women ◽

Brachial Artery ◽

Invasive Technique ◽

Baseline Measure ◽

Ischaemic Injury ◽

Non Invasive ◽

Flow Mediated Dilatation ◽

Risk Of Preeclampsia

Introduction: Preeclampsia is a pregnancy syndrome defined by the gestational onset of hypertension and proteinuria and characterised by maternal endothelial dysfunction with placental ischaemia. Preeclampsia affects approximately 4% of first-time pregnant mothers, but approximately 20% of women with pre-existing hypertension. Ischaemic pre-conditioning (IPC) is a phenomenon whereby transient episodes of ischaemia protect against future ischaemic injury. IPC has never previously been studied in pregnant women. We investigated whether IPC could improve maternal endothelial function in women at risk of preeclampsia and with preeclampsia. Hypothesis: We hypothesised that IPC would improve maternal endothelial function in women with preeclampsia and at risk of preeclampsia. Methods: We measured brachial artery flow mediated dilatation (FMD), before and after IPC in 3 groups of pregnant women between 24+0 and 36+6 weeks gestation: normotensive pregnancy (n=42), at risk of preeclampsia (n=20) and established preeclampsia (n=11). Following a baseline measure of brachial artery FMD, 3 cycles of 5-minutes of upper arm ischaemia were alternated with 5-minutes of reperfusion. Twenty-four hours later, maternal FMD was re-measured. Results: Women with preeclampsia had the lowest baseline FMD 4.09% +/- 0.73%: mean +/- SEM, which increased to 6.25% +/- 0.83% (p=0.0024) following IPC. Women at risk of pre-eclampsia had baseline FMD 7.57% +/- 0.82%, which increased to 8.93% +/- 0.73% (p=0.025) following IPC. Normotensive pregnant women had the highest baseline FMD (10.32% +/- 0.69%), which did not increase further following IPC (10.52% +/- 0.69%). However, normotensive pregnant women reached peak flow-mediated dilatation more quickly following IPC; 414 s +/- 2.94 s v 425 s +/- 4.22 s (p=0.0302). Conclusions: IPC is a non-invasive technique that we have shown improves local endothelial function in women with preeclampsia and at risk of preeclampsia. IPC merits further study as an intervention to improve systemic endothelial function and pregnancy outcomes for women with hypertensive pregnancies.

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Predictive value of sFlt, PIGF versus sFlt/PIGF ratio test in patients at risk of preeclampsia

Ginecologia ro ◽

10.26416/gine.25.3.2019.2493 ◽

2019 ◽

Vol 3 (25) ◽

pp. 14

Author(s):

Amira-Livia Moldoveanu ◽

D. Oprescu ◽

Liliana Novac

Keyword(s):

At Risk ◽

Predictive Value ◽

Ratio Test ◽

Patients At Risk ◽

Risk Of Preeclampsia

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Association of maternal serum 25-hydroxyvitamin D concentrations with risk of preeclampsia: a nested case-control study and meta-analysis

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2019.1640675 ◽

2019 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Yingdi Yuan ◽

Wen Tai ◽

Pengfei Xu ◽

Ziyi Fu ◽

Xiaolei Wang ◽

...

Keyword(s):

Case Control Study ◽

Meta Analysis ◽

Case Control ◽

Maternal Serum ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Nested Case Control ◽

Control Study ◽

Risk Of Preeclampsia

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Non-Invasive Prenatal Testing: Review of Ethical, Legal and Social Implications

BioéthiqueOnline ◽

10.7202/1044264ar ◽

2018 ◽

Vol 5 ◽

Cited By ~ 3

Author(s):

Hazar Haidar ◽

Charles Dupras ◽

Vardit Ravitsky

Keyword(s):

Large Scale ◽

Empirical Studies ◽

Prenatal Testing ◽

Maternal Blood ◽

Maternal Serum ◽

Social Implications ◽

Maternal Serum Screening ◽

Non Invasive ◽

Fetal Dna ◽

Cell Free Fetal Dna

Non-invasive prenatal testing (NIPT) using cell-free fetal DNA (cffDNA) from maternal blood has recently entered clinical practice in many countries, including Canada. This test can be performed early during pregnancy to detect Down syndrome and other conditions. While NIPT promises numerous benefits, it also has challenging ethical, legal and social implications (ELSI). This paper reviews concerns currently found in the literature on the ELSI of NIPT. We make four observations. First, NIPT seems to exacerbate some of the already existing concerns raised by other prenatal tests (amniocentesis and maternal serum screening) such as threats to women’s reproductive autonomy and the potential for discrimination and stigmatization of disabled individuals and their families. This may be due to the likely upcoming large scale implementation and routinization of NIPT. Second, the distinction between NIPT as a screening test (as it is currently recommended) and as a diagnostic test (potentially in the future), has certain implications for the ELSI discussion. Third, we observed a progressive shift in the literature from initially including mostly conceptual analysis to an increasing number of empirical studies. This demonstrates the contribution of empirical bioethics approaches as the technology is being implemented into clinical use. Finally, we noted an increasing interest in equity and justice concerns regarding access to NIPT as it becomes more widely implemented.

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