WO2011067597A1 - Biomarqueurs de l'avortement spontané précoce - Google Patents

Biomarqueurs de l'avortement spontané précoce Download PDF

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Publication number
WO2011067597A1
WO2011067597A1 PCT/GB2010/052005 GB2010052005W WO2011067597A1 WO 2011067597 A1 WO2011067597 A1 WO 2011067597A1 GB 2010052005 W GB2010052005 W GB 2010052005W WO 2011067597 A1 WO2011067597 A1 WO 2011067597A1
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miscarriage
sflt
placental
women
pregnancy
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PCT/GB2010/052005
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English (en)
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Shanthi Muttukrishna
Eric Jauniaux
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Ucl Business Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4737—C-reactive protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • the invention relates to biomarkers of early miscarriage.
  • the biomarkers are useful for identifying women with an increased likelihood of early miscarriage.
  • Placental-related disorders of pregnancy are almost unique to the human species. These disorders, which affect around a third of human pregnancies, primarily include miscarriage and pre-eclampsia 1 . In other mammalian species, the incidence of both disorders is extremely low. Although epidemiological data on animals living in the wild, such as monkeys, are limited, laboratory rodents are known to have post-implantation pregnancy loss rates of less than 10% 1. By contrast in humans, it has been estimated that approximately 50 to 70 percent of spontaneous conceptions are lost prior to completion of the first trimester, most of them during the first month after the last menstrual period 2 . Unlike other species, human placentation is also associated with a 30% incidence of bleeding during the first trimester.
  • the oxidative stress and rise in oxygenation may also stimulate the synthesis of various trophoblastic proteins such as human chorionic gonadotropin (hCG) and oestrogens.
  • hCG human chorionic gonadotropin
  • Maternal serum concentrations of hCG peak towards the end of the first trimester, and oxidising conditions promote assembly of the sub-units in vitro 8 .
  • Our recent data showing a direct relationship between intrauterine PaO 2 in vivo and inhibin A and sFLT-1 concentrations in early pregnancy confirm our hypothesis that specific placental proteins can be regulated by intrauterine O 2 tension 9 .
  • Angiogenesis is characterised by increased vascular permeability and endothelial cell proliferation and migration. It is regulated by various pro- and anti-angiogenic factors, angiopoietins and matrix metalloproteinases. Anti-angiogenic and pro-angiogenic factors are known to play an important role in the pathophysiology of pre-eclampsia 12 . Studies of maternal serum levels of these factors have shown that soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt-1) are elevated in women presenting with PE whereas vascular endothelial growth factor (VEGF) and placental growth factor (P1GF) are decreased. Some of these changes can be detected several weeks before the appearance of clinical symptoms of PE 13 ' 14 .
  • sEng soluble endoglin
  • sFlt-1 soluble fms-like tyrosine kinase 1
  • VEGF vascular endotheli
  • Angiogenic factors and inflammatory have not been previously evaluated in early pregnancy.
  • the inventors aim to determine whether threatened miscarriage which is associated with a focal oxidative stress in the definitive placenta is also associated with changes in angiogenic factors and to investigate if these levels can predict a subsequent full miscarriage or other major perinatal complications such as preterm rupture of the placental membranes and preterm labour Summary of the Invention
  • a method for identifying whether a pregnant subject has an increased risk of miscarriage comprising measuring the concentration of at least one of soluble vascular endothelial growth factor receptor (sFlt-1), Placental growth factor (PIGF) and C reactive proteins in a biological sample obtained from the subject.
  • sFlt-1 soluble vascular endothelial growth factor receptor
  • PIGF Placental growth factor
  • the inventors have identified changes in sFLT-1, PIGF or c reactive protein concentration which are indicative of an increased risk of miscarriage and perinatal complications such as preterm rupture of the placental membranes and preterm labour in women presenting with bleeding in the first trimester.
  • the subject is preferable a mammal, especially a primate.
  • the animal is a human.
  • the sample may be a biological fluid such as blood, saliva or urine obtainable from the subject, but is preferably a serum or plasma sample.
  • the concentration of sFLT-1, PIGF or C reactive protein in the sample may be measured by any known means. Preferable the concentration is measured by an Enzyme immunoassay (ELISA) or an automated immunoassay on a robotic platform.
  • ELISA Enzyme immunoassay
  • change in concentration preferably means that the concentration in the sample is increased or reduced, particularly reduced in comparison with a comparable sample obtained from the same subject earlier in pregnancy or in comparison with average concentrations in comparable samples obtained from other subjects at the same stage of gestation.
  • a change preferably a reduction in sFLT-1, PIGF or C reactive protein is identified as being indicative of an increased likelihood of miscarriage. It is preferred that the method includes the step of assaying the concentration of at least two, more preferably all of sFLT-1, PIGF and C reactive protein and that a reduction in both is particularly indicative of an increased likelihood of miscarriage.
  • Comparable samples are the same type of sample as each other. For example, comparable samples are taken from animals of the same species. Equally, saliva samples should be compared with other saliva samples, urine samples with other urine samples etc. To be considered statistically relevant, the reduction in concentration is preferably a reduction of at least 10%, more preferably at least 15%, more preferably at least 20%, even more preferably at least 30%.
  • the method of diagnosis may comprise comparing the sample with a sample from another animal or human at the same gestational age. More preferably, though, it comprises comparing the sample with samples previously obtained from the subject. Samples may be obtained daily, every two or three days or weekly, for example. Where a subject is considered to be at risk of miscarriage, due to, for example, miscarriage in a previous pregnancy, increased blood pressure etc., samples may be obtained every two or three days or weekly and compared with normal range of gestation matched controls. It is preferred that samples are obtained early in pregnancy, for example before 10 weeks gestation, more preferably before 8 weeks gestation, even more preferably at between 5 and 8 weeks gestation.
  • the method of identifying subjects at risk may be used in combination with other methods that identifying subjects at risk. Such methods may include checking other bio markers especially those which have previously been linked with miscarriage, such as inhibin A, activin A, progesterone, oestradiol, and hCG or indicators of oxidative stress such as heat shock proteins and markers of inflammation such as TNF alpha, TNF alpha receptors, Interferon gamma using immunoassays (ELISAs or automated platforms) in biological fluids including blood, saliva and urine.
  • the method of the invention may also be used to identify subjects that may benefit from treatment with an appropriate medicament, such as progesterone.
  • C reactive protein sFLT-1 and/or P1GF for use as a biomarker of early miscarriage.
  • Figure 1 Circulating levels of serum human chorionic gonadotrophs (hCG) in the different groups of women.
  • Figure 2 Circulating levels of serum soluble VEGF receptor 1 (sFLT-1) in the different groups of women.
  • Figure 3 Circulating levels of serum placental growth factor (PIGF) in the different groups of women.
  • Figure 4 Circulating levels of serum soluble Endoglin (sEndog) in the different groups of women.
  • Figure 5 Circulating levels of serum heat shock protein 70 (Hsp 70) in the different groups of women.
  • Figure 6 Levels of c-reactive protein in the different groups of women.
  • Figures 7a to d show the results of example 3, which further analysed the use of soluble FLT- 1 and PIGF as biomarkers of early miscarriage.
  • Quantakine ELISA kits for PIGF and soluble FLT-1 and reagents from a duoset for Soluble Endoglin was used from R&D systems (UK) to measure the respective proteins in serum samples according to the manufacturer's protocol. All samples were assayed in duplicates and the intra and inter assay variations were ⁇ 12% for all assays. The minimum detection limit for the respective assays was PIGF: 3.9pg/ml, sEng: 62.5pg/ml, sFlt-1 31.3pg/ml. Heat shock protein 70 was measured in serum using a highly sensitive assay kit from assays design (Cambridge bioscience, UK). The detection limit of HSP 70 was 0.2ng/ml.
  • the TM group included 26 women who subsequently had a live birth and 19 who subsequently had a miscarriage.
  • the mean MS sFlt-1 level was significantly (P ⁇ 0.001) higher ( ⁇ 20 fold) in the normal pregnancy compared to the non-pregnant group whereas mean MS sFLT-1 levels were significantly (P ⁇ 0.001) lower ( ⁇ 6 fold) in the TM subgroup with a subsequent miscarriage and in the confirmed miscarriage group ( ⁇ 5 fold, P ⁇ 0.001) compared to controls.
  • TM subgroup with a subsequent live birth (figure 2) also had significantly (P ⁇ 0.001) higher ( ⁇ 4 fold) mean MS sFLT-1 compared to TM subgroup with a subsequent miscarriage, and to the miscarriage group (-2.5 fold, P ⁇ 0.05).
  • MS PIGF levels were significantly (P ⁇ 0.001) higher in pregnancy than in nonpregnant controls and significantly (P ⁇ 0.001) higher in TM patients with a subsequent live birth compared to TM patients who subsequently miscarried ( ⁇ 2 fold) Control pregnant women had significantly (P ⁇ 0.001) higher levels of MS PIGF compared to TM patients with subsequent miscarriage (>4 fold) or miscarriage ( ⁇ 5 fold) (figure 3).
  • HSP70 is a sensitive marker of oxidative stress in tissues and we have previously found a peak in the expression of HSP70 in the placental tissue from normal pregnancies at 8-10 when the membranes start to form3. We also found that the immunoreactivity for HSP70 is greater in samples from peripheral than from central regions of normal placentas immunostaining and in the whole placental tissue in missed-miscarriage 3 . Early flow is restricted to the peripheral regions of most normal placentas whereas in missed miscarriages it was most common in central regions or throughout the placenta 3 ' 11 .
  • Soluble fms-like tyrosine kinase 1 (sFLT-1) and Endoglin (sEng) are members of the TGF ⁇ family.
  • Soluble Endoglin is a placenta derived soluble TGF-beta co-receptor.
  • sFLT-1 is soluble vascular endothelial growth factor (VEGF) receptor 1 (sFLT-1) and antagonises the effect of VEGF.
  • Soluble Endoglin inhibits the formation of blood vessels and induces vascular permeability and hypertensionl7.
  • VEGF- A and placental growth factor (P1GF) have been investigated extensively in normal and abnormal placental vascular development 18-20 .
  • sFltl is an endogenous protein that is produced by the placenta. sFltl is able to bind to the angiogenic growth factors vascular endothelial growth factor and placental growth factor, thereby neutralizing their functions.
  • sFLT-1 rose by 20 fold in pregnancy state confirming that the feto-placental unit is a major source for this molecule in early pregnancy.
  • P1GF also increased by around 5 fold in early pregnancy.
  • no difference was found levels in the concentrations of sEng between samples from non-pregnant women, from early pregnancy and from miscarriage suggesting that the source of this protein is extra placental.
  • sFLT-1 may be compensatory as the placenta may be producing more VEGF and the soluble VEGF-R1 that is unbound to VEGF in circulation could be reduced.
  • both VEGF and the receptor production may be lower in patients who subsequently have a miscarriage thus reflecting lower levels of sFLT-1 in maternal circulation in these cases.
  • O 2 free radicals OFR
  • sFLT-1 O 2 free radicals
  • TM there is a focal bleed mainly in the membranes in the periphery of the developing placenta. This common pregnancy complication occurs mainly at the time of the formation of the membranes at 8-12 weeks and can lead to a complete miscarriage if the hematoma extends into the definitive placenta 27 .
  • C-reactive protein is an acute-phase protein secreted by the liver in response to inflammation. It is not specific for infection but is a marker used for the diagnosis of many inflammatory, infective and malignant conditions (Wiwanitkit, 2005).
  • High-sensitivity C- reactive protein (hsCRP) has been gaining recognition as an independent risk factor for cardiovascular disease.
  • increased level of hsCRP have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels (Ridker and Silvertown, 2008).
  • Evidence supporting a link between periodontal disease and cardiovascular disease is accumulating in the literature. Recent studies have also shown that pre-eclamptic women present a high prevalence of periodontitis, suggesting that active periodontal disease may play a role in the pathogenesis of pre-eclampsia (Vergnes, 2008).
  • hsCRP were measured in serum using a highly sensitive assay kit from assays design (Cambridge bioscience, UK). The detection limit of hsCRP was 600mg/ml respectively.
  • the TM group included 26 women who subsequently had a live birth and 19 who subsequently had a miscarriage.
  • MShSCRP levels were significantly (P ⁇ 0.05) lower in TM subgroup with a subsequent miscarriage compared to normal control pregnant women ( ⁇ 4 fold) and TM patients with a subsequent live birth ( ⁇ 3 fold). Significantly (P ⁇ 0.05) lower mean level of MShsCRP were found in the missed-miscarriage group compared to pregnant normal control women ( ⁇ 4 fold) (figure 6).

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Abstract

Cette invention concerne une méthode permettant de déterminer si une femme enceinte présente un risque accru d'avortement spontané, ladite méthode consistant à mesurer la concentration d'un récepteur soluble du facteur de croissance endothéliale vasculaire (sFlt-1), d'un facteur de croissance placentaire (PlGF) ou de protéines réactives C dans un échantillon biologique prélevé chez le sujet.
PCT/GB2010/052005 2009-12-02 2010-12-01 Biomarqueurs de l'avortement spontané précoce WO2011067597A1 (fr)

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GB0921156A GB0921156D0 (en) 2009-12-02 2009-12-02 Biomarkers of early miscarriage
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013068475A1 (fr) * 2011-11-09 2013-05-16 Roche Diagnostics Gmbh Dynamique du rapport sflt-1 ou endogline/pigf comme indicateur d'une prééclampsie imminente et/ou d'un syndrome hellp
CN109073654A (zh) * 2016-04-20 2018-12-21 苏州爱尔迪思生物科技有限公司 用于预测早产的方法和组合物
CN111257569A (zh) * 2020-02-26 2020-06-09 首都医科大学附属北京妇产医院 一组诊断复发性流产的标志物及其应用
CN111257570A (zh) * 2020-02-26 2020-06-09 首都医科大学附属北京妇产医院 一组血栓前状态引起流产早期诊断用标志物及其应用
RU2731800C1 (ru) * 2019-03-12 2020-09-08 Федеральное государственное бюджетное научное учреждение "Дальневосточный научный центр физиологии и патологии дыхания" Способ прогнозирования риска развития внутриутробных инфекций новорожденного по морфометрическим параметрам терминальных ворсин плаценты
CN115323050A (zh) * 2022-08-26 2022-11-11 天津大学 预测复发性流产人群孕期胎盘功能异常的标志物和方法
RU2797679C1 (ru) * 2022-12-28 2023-06-07 Федеральное государственное бюджетное образовательное учреждение высшего образования "Астраханский государственный медицинский университет" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Астраханский ГМУ Минздрава России) Способ диагностики оксидативного стресса при невынашивании беременности

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2009071950A1 (fr) * 2007-12-07 2009-06-11 University Of Leicester Procédés de détection d'un risque de fausse couche

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