, 15:143 | Cite as

Metabolomic identification of novel diagnostic biomarkers in ectopic pregnancy

  • Onur TurkogluEmail author
  • Ayse Citil
  • Ceren Katar
  • Ismail Mert
  • Praveen Kumar
  • Ali Yilmaz
  • Dilek S. Uygur
  • Salim Erkaya
  • Stewart F. Graham
  • Ray O. Bahado-Singh
Original Article



Ectopic pregnancy (EP) is a potentially life-threatening condition and early diagnosis still remains a challenge, causing a delay in management leading to tubal rupture.


To identify putative plasma biomarkers for the detection of tubal EP and elucidate altered biochemical pathways in EP compared to intrauterine pregnancies.


This case–control study included prospective recruitment of 39 tubal EP cases and 89 early intrauterine pregnancy controls. Plasma samples were biochemically profiled using proton nuclear magnetic resonance spectroscopy (1H NMR). To avoid over-fitting, datasets were randomly divided into a discovery group (26 cases vs 60 controls) and a test group (13 cases and 29 controls). Logistic regression models were developed in the discovery group and validated in the independent test group. Area under the receiver operating characteristics curve (AUC), 95% confidence interval (CI), sensitivity, and specificity values were calculated.


In total 13 of 43 (30.3%) metabolite concentrations were significantly altered in EP plasma (p < 0.05). Metabolomic profiling yielded significant separation between EP and controls (p < 0.05). Independent validation of a two-metabolite model consisting of lactate and acetate, achieved an AUC (95% CI) = 0.935 (0.843–1.000) with a sensitivity of 92.3% and specificity of 96.6%. The second metabolite model (d-glucose, pyruvate, acetoacetate) performed well with an AUC (95% CI) = 0.822 (0.657–0.988) and a sensitivity of 84.6% and specificity of 86.2%.


We report novel metabolomic biomarkers with a high accuracy for the detection of EP. Accurate biomarkers could potentially result in improved early diagnosis of tubal EP cases.


Ectopic pregnancy Metabolomics Nuclear magnetic resonance spectroscopy Biomarker Metabolite 


Author contribution

OT supervised the experiment, manuscript writing and performed statistical data analysis; OT, AC, CK performed specimen collection; SFG supervised all experimental procedures; PK, AY performed the experiments and analyzed the raw data; RBS, SE, DU, IM supervised and designed the experiment and manuscript writing and all authors reviewed the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11306_2019_1607_MOESM1_ESM.pdf (6.5 mb)
Supplementary material 1 (PDF 6656 kb)
11306_2019_1607_MOESM2_ESM.xlsx (69 kb)
Supplementary material 2 (XLSX 68 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Onur Turkoglu
    • 1
    • 4
    Email author
  • Ayse Citil
    • 2
  • Ceren Katar
    • 2
  • Ismail Mert
    • 3
  • Praveen Kumar
    • 1
  • Ali Yilmaz
    • 1
  • Dilek S. Uygur
    • 2
  • Salim Erkaya
    • 2
  • Stewart F. Graham
    • 1
    • 4
  • Ray O. Bahado-Singh
    • 1
    • 4
  1. 1.Department of Obstetrics and GynecologyBeaumont Health SystemRoyal OakUSA
  2. 2.Department of Obstetrics and GynecologyZekai Tahir Burak Women’s Health Education and Research HospitalAnkaraTurkey
  3. 3.Division of Gynecological Oncology, Department of Obstetrics and GynecologyMayo ClinicRochesterUSA
  4. 4.Oakland University-William Beaumont School of MedicineRochesterUSA

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