Novel circulating placental markers prokineticin-1, soluble fms-like tyrosine kinase-1, soluble endoglin and placental growth factor and association with late miscarriage.
Are novel circulating placental markers prokineticin-1 (PK-1), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) associated with late miscarriage in asymptomatic first trimester pregnant women?



Increased serum sFlt-1 or PlGF, but not sEng or PK-1, were significantly associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure.



Abnormal placental development is observed in two-thirds of miscarriages. Identifying women at high risk of late miscarriage could help diagnose potentially treatable causes of miscarriage such as infection, thrombosis or immunological disease. Recently, the circulating placental markers PK-1, sFlt-1, sEng and PlGF have been identified; however, it is not known if circulating levels of these markers are associated with late miscarriage.



A single-centre observational cohort study with prospectively collected data was carried out at a tertiary care centre 2010-2012, in 993 asymptomatic pregnant women. Plasma PK-1, and serum sEng, sFlt-1 and PlGF were measured once in each patient during the antenatal booking visit, and pregnancy outcome was monitored prospectively. Less than 1% of patients were lost to follow-up. Multiples of median (MOM) levels were calculated to adjust for gestational age.



Nine-hundred and ninety-three asymptomatic pregnant women attending antenatal clinic for a routine booking antenatal appointment were recruited to the study, of whom 12 were lost to follow-up and excluded from analysis. Of the cohort, 50 of the remaining 981 women suffered late miscarriage.



Gestation-adjusted sEng, sFlt-1 and PlGF levels were 11% (P < 0.01), 36% (P < 0.001) and 30% (P < 0.001), respectively, lower in women who later suffered miscarriage compared with unaffected pregnancies, while PK-1 did not differ significantly. Logistic regression modelling suggested that increased sFlt-1 (odds ratio (OR) 0.15 95% confidence interval [0.08-0.26], P = 0.0001) and PlGF (OR 0.02 [0.01-0.05], P = 0.0001), but not sEng, were associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure. The combination of sFlt-1 and PlGF did not improve the diagnostic accuracy beyond the use of sFlt-1.



First trimester levels of sFlt-1 and PlGF, but not sEng or PK-1, were associated with late miscarriage risk in asymptomatic women. However, a new prospective study is now required to investigate the utility of these markers to predict early (<10 weeks) and late miscarriage, as well as to predict other complications of pregnancy.



Our data suggest that circulating sFlt-1 and PlGF, but not sEng or PK-1, are independently associated with late miscarriage risk in asymptomatic pregnant women attending their antenatal visit. Therefore, sFlt-1 and PlGF may represent novel markers of placental viability. These data further our understanding of placental function, and have important potential implications for utilizing novel hormonal markers to detect adverse clinical outcomes during pregnancy.



The authors have no competing interests. The Section of Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. This project was funded by an NIHR grant (reference: CDF-2009-02-05). The following authors are also funded as follows: CNJ is supported by an NIHR Clinical Lectureship and AMS/ Wellcome Starter Grant for Clinical Lecturers. AA and ANC are supported by NIHR academic clinical lectureships. CI-E is supported by an Imperial College Healthcare NHS Trust Charity Research Fellowship. WSD is supported by an NIHR Career Development Fellowship.



Q0406/80.
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Jayasena
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Abbara
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Comninos
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Narayanaswamy
Imperial Clinical Trials Unit, Imperial College London, SW7 2AZ, London, UK.
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Gonzalez Maffe
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Izzi-Engbeaya
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Oldham
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Lee
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Sarang
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Malik
Department of Obstetrics & Gynaecology, Queen Charlotte's Hospital, Imperial College NHS Healthcare Trust, W12 0HS, London, UK.
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Dhanjal
Department Obstetrics & Gynaecology, King's College, SE5 9RS, London, UK.
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Williamson
Department of Obstetrics & Gynaecology, St. Mary's Hospital, Imperial College NHS Healthcare Trust, W2 1NY, London, UK.
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Regan
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
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Bloom
Section of Investigative Medicine, Imperial College London, W12 0NN, UK w.dhillo@imperial.ac.uk.
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Dhillo
D000022:Abortion, Spontaneous / Q000097:blood*; D000328:Adult; D015415:Biomarkers / Q000097:blood; D000071063:Endoglin / Q000097:blood*; D005260:Female; D005768:Gastrointestinal Hormones / Q000097:blood*; D006801:Humans; D000072483:Placenta Growth Factor / Q000097:blood*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000097:blood; D011446:Prospective Studies; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000097:blood*
D015415:Biomarkers; D000071063:Endoglin; D005768:Gastrointestinal Hormones; C467610:PROK1 protein, human; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
miscarriage; placental markers; pregnancy; prokineticin-1; soluble endoglin and placental growth factor; soluble fms-like tyrosine kinase-1